The Sage Handbook of

Cognitive and
Systems Neuroscience

Neuroscientific Principles, Systems and Methods

This page intentionally left blank
 The Sage Handbook of
Cognitive and
Systems Neuroscience

Neuroscientific Principles, Systems and Methods

Edited by
Gregory J. Boyle
with
Georg Northoff
Aron K. Barbey
Felipe Fregni
Marjan Jahanshahi
Alvaro Pascual-Leone and
Barbara J. Sahakian

Associate Editors
Nadia Bolognini and
Anja Soldan
1 Oliver’s Yard
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Editor: Janka Romero
Editorial Assistant: Benedict Hegarty
Production Editor: Neelu Sahu
Copyeditor: Martin Noble
Proofreader: Lawrence Baker
Indexer: KnowledgeWorks Global Ltd
Marketing Manager: Camille Richmond
Cover Design: Ginkhan Siam
Typeset by KnowledgeWorks Global Ltd
Printed in the UK
Editorial Arrangement © Gregory J. Boyle, Georg Northoff, Aron K. Barbey, Felipe
Fregni, Marjan Jahanshahi, Álvaro Pascual-Leone, and Barbara J. Sahakian, 2024
Chapter 1 © Gregory J. Boyle,
Georg Northoff, Nadia Bolognini,
Aron K. Barbey, Marjan Jahanshahi,
Álvaro Pascual-Leone, and
Barbara J. Sahakian, 2024
Chapter 2 © Georg Northoff, Philipp
Klar, 2024
Chapter 3 © Lídia Vaqué-Alcázar,
Anja Soldan, David Bartrés-Faz,
2024
Chapter 4 © Tiago Lazzaretti, Paulo
Ricardo de Melo, Anna Marduy,
Rafaella Rogatto de Faria, 2024
Chapter 5 © Joan Y. Chiao, 2024
Chapter 6 © Alexei Verkhratsky, Alexey
Semyanov, Arthur Butt,
Olga Garaschuk, 2024
Chapter 7 © Jack van Honk, Zhang Li,
Norihiro Sadato, Joan Y. Chiao, 2024
Chapter 8 © Saana M. Korkki, Goran
Papenberg, Marc Guitart-Masip, Alireza
Salami, Nina Karalija, Lars Nyberg,
Lars Bäckman, 2024
Chapter 9 © Daniel Osorio-Gómez,
María-Isabel Miranda, Federico
Bermúdez-Rattoni, Kioko Guzmán-
Ramos, 2024
Chapter 10 © María-Isabel Miranda,
Kioko Guzmán-Ramos,
Daniel Osorio-Gómez,
Federico Bermúdez-Rattoni, 2024
Chapter 11 © Jiang-Fan Chen, Yan
Li, 2024
Chapter 12 © Linda Becker, Nicolas
Rohleder, 2024
Chapter 13 © Anneke Alkemade,
Bernadette C. M. van Wijk, Birte U.
Forstmann, 2024
Chapter 14 © Mario Manto, 2024
Chapter 15 © Hans Joachim
Markowitsch, Jens Borgelt, Angelica
Staniloiu, 2024
Chapter 16 © Rosanna Olsen,
Mrinmayi Kulkarni, 2024
Chapter 17 © Luis M. García Marín,
Zuriel Ceja, Miguel E. Rentería,
Albert Galaburda, 2024
Chapter 18 © Giacomo Rizzolatti,
Leonardo Fogassi, 2024
Chapter 19 © Martin Seeber, Thomas
Koenig, Christoph M. Michel, 2024
Chapter 20 © Arcady A. Putilov, 2024
Chapter 21 © Erich Schröger,
Alexandra Bendixen, 2024
Chapter 22 © Paul C. J. Taylor, 2024
Chapter 23 © Jon H. Kaas, Leah A.
Krubitzer, Hui-Xin Qi, Jamie L. Reed,
2024
Chapter 24 © Vishal Rawji, John
Rothwell, Marjan Jahanshahi, 2024
Chapter 25 © Anna Kristina
Hernandez, Laiquan Zou, Thomas
Hummel, 2024
Chapter 26 © Hugo Critchley, Yoko
Nagai, Lisa Quadt, 2024
Chapter 27 © Claudio Brozzoli,
Nadia Bolognini, Alessandro Zanini,
Alessandro Farnè, 2024
Chapter 28 © Randolph F. Helfrich,
Robert T. Knight, 2024
Chapter 29 © Irina G. Skotnikova,
Alexei N. Gusev, Alexandr M.
Chernorizov, 2024
Chapter 30 © John Bickle, David J.
Parker, 2024
Chapter 31 © Jorge F. Mejías, Katrin
Amunts, Jan G. Bjaalie, Sander M.
Bohté, Alain Destexhe, Lars Muckli,
Pier S. Paolucci, Martin J. Pearson,
Cyriel M. A. Pennartz, 2024
Chapter 32 © Sicong Tu, William
Huynh, Matthew Kiernan, 2024
Chapter 33 © Matt Tharp, Shannon
L. Risacher, Paula Bice, Paul M.
Thompson, Andrew J. Saykin,
Meichen Yu, 2024
Chapter 34 © Rotem Botvinik-Nezer,
Tor D. Wager, 2024

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In loving memory of my dear wife Dolores
– GJB
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 Contents

The Editors and Contributors x

1 Cognitive Neuroscience: Basic Principles, Systems, and Methods 1

Gregory J. Boyle, Georg Northoff, Nadia Bolognini, Aron K. Barbey,
Marjan Jahanshahi, Álvaro Pascual-Leone, and Barbara J. Sahakian

PART I BACKGROUND CONSIDERATIONS

2 Historical, Empirical, and Philosophical Perspectives on

Cognitive Neuroscience 17
Georg Northoff and Philipp Klar

3 Aging Brain Changes across the Lifespan 30

Lídia Vaqué-Alcázar, Anja Soldan, and David Bartrés-Faz

4 Innovation Pathways, Real-life Neuroscience Startups, and

Applications 48
Tiago Lazzaretti, Paulo S. de Melo, Anna Marduy, Rafaella Rogatto de Faria,
Marcel Simis, and Felipe Fregni

PART II NEUROSCIENTIFIC SUBSTRATES AND PRINCIPLES

5 Neural Processes and Activity: Cultural Neuroscience 65

Joan Y. Chiao

6 Role of Neuroglia in Cognition 79

Alexei Verkhratsky, Alexey Semyanov, Arthur Butt, and Olga Garaschuk

7 Cognitive Neurogenetics 102

Jack van Honk, Zhang Li, Norihiro Sadato, and Joan Y. Chiao

8 Dopamine System and Cognitive Function across the Adult Life Span 114
Saana M. Korkki, Goran Papenberg, Marc Guitart-Masip,
Alireza Salami, Nina Karalija, Lars Nyberg, and Lars Bäckman

9 Neurotransmission and Neuromodulation of Recognition Memory:

Novelty vs. Familiarity 133
Daniel Osorio-Gómez, María-Isabel Miranda, Federico Bermúdez-Rattoni,
and Kioko Guzmán-Ramos
viii THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

10 Neurotransmission and Neuromodulation of Memory: Intensity and Valence 151

María-Isabel Miranda, Kioko Guzmán-Ramos, Daniel Osorio-Gómez,
and Federico Bermúdez-Rattoni

11 Neuromodulator Adenosine A2A Receptor Control of Cognition 171

Jiang-Fan Chen and Yan Li

12 Hormonal Influences on Cognition 185

Linda Becker and Nicolas Rohleder

PART III NEUROANATOMICAL BRAIN SYSTEMS

13 Modeling of Basal Ganglia Structure and Function 197

Anneke Alkemade, Bernadette C. M. van Wijk, and Birte U. Forstmann

14 Cerebellum: Advances in Understanding of Cerebellar Functions 212

Mario Manto

15 Amygdaloid Complex 227

Hans J. Markowitsch, Jens Borgelt, and Angelica Staniloiu

16 Hippocampal Formation 242

Rosanna K. Olsen and Mrinmayi Kulkarni

17 Cerebral Lateralization and Hemispheric Specialization 259

Luis M. García-Marín, Zuriel Ceja, Miguel E. Rentería, and
Albert M. Galaburda

PART IV NEURAL DYNAMICS AND PROCESSES

18 Mirror Mechanism in Cognition 279

Giacomo Rizzolatti and Leonardo Fogassi

19 Spatio-temporal Dynamics of Brain Rhythms 305

Martin Seeber, Thomas Koenig, and Christoph M. Michel

20 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness 318

Arcady A. Putilov

PART V SENSORY-PERCEPTUAL SYSTEMS AND COGNITION

21 Auditory Processing 337

Erich Schröger and Alexandra Bendixen

22 Vestibular Processing in Cognition 351

Paul C. J. Taylor
 Contents ix

23 Somatosensory Processing 365

Jon H. Kaas, Leah A. Krubitzer, Hui-Xin Qi, and Jamie L. Reed

24 Motor Control: Response Preparation, Initiation, and Inhibition 379

Vishal Rawji, John C. Rothwell, and Marjan Jahanshahi

25 Olfactory and Gustatory Sensation-Perception 398

Anna Kristina Hernandez, Laiquan Zou, and Thomas Hummel

26 Interoception and Thermoreception 414

Hugo D. Critchley, Yoko Nagai, and Lisa Quadt

27 Peripersonal Space Representation: Neural Bases, Properties,

and Functional Significance 435
Claudio Brozzoli, Nadia Bolognini, Alessandro Zanini, and
Alessandro Farnè

PART VI METHODOLOGICAL ADVANCES

28 Neural Recordings and Time Series Analyses 453

Randolph F. Helfrich and Robert T. Knight

29 Advances in Psychophysical Techniques 472

Irina G. Skotnikova, Alexei N. Gusev, and Alexandr M. Chernorizov

30 Revolutions in “Wet” Neurobiology 495

John Bickle and David J. Parker

31 Human Brain Project and Beyond 511

Jorge F. Mejías, Katrin Amunts, Jan G. Bjaalie, Sander M. Bohté,
Alain Destexhe, Lars Muckli, Pier S. Paolucci, Martin J. Pearson,
and Cyriel M. A. Pennartz

32 Advances in Brain Imaging 533

Sicong Tu, William Huynh, and Matthew C. Kiernan

33 Novel Approaches to Large-scale Data in Neuroimaging 553

Matthew Tharp, Shannon L. Risacher, Paula Bice,
Paul M. Thompson, Andrew J. Saykin, and Meichen Yu

34 Advancing Cognitive Neuroscience 569

Rotem Botvinik-Nezer and Tor D. Wager

Index 590
 The Editors and Contributors

EDITOR-IN-CHIEF

Gregory J. Boyle is an Hon. Professorial Fellow at the University of Melbourne. He earned separate
PhDs from both the University of Delaware, and the University of Melbourne. Also, he earned a DSc from
the University of Queensland, for his sustained contributions to psychological science. He is a Fellow of
both the Association for Psychological Science, and the Australian Psychological Society, and recipient
of the Buros Institute of Mental Measurements Distinguished Reviewer Award. Dr. Boyle has produced
some 300 scholarly publications and has served as lead editor of several international handbooks includ-
ing: The SAGE Handbook of Personality Theory and Assessment (2 Vols.); Measures of Personality and
Social Psychological Constructs (Academic Press); as well as the SAGE Benchmarks in Psychology
Series: Work and Organisational Psychology (5 Vols.); Psychological Assessment (4 Vols.); and
Psychology of Individual Differences (4 Vols.). He is also Editor-in-Chief of the current volumes.

EDITORS

Aron K. Barbey is Professor of Psychology, Neuroscience, and Bioengineering at the University of

Illinois at Urbana-Champaign. He is chair of the Intelligent Systems Research Theme, leader of the
Intelligence, Learning, and Plasticity Initiative, and director of the Decision Neuroscience Laboratory at
the Beckman Institute for Advanced Science and Technology. Dr. Barbey’s research investigates the
neural mechanisms of human intelligence and decision making, with particular emphasis on enhancing
these functions through cognitive neuroscience, physical fitness, and nutritional intervention. His research
has been supported by the Office of the Director of National Intelligence, the Department of Defense, the
White House BRAIN Initiative, the National Institutes of Health, the National Science Foundation, and
private industry (Abbott Nutrition, Google Brain, and PepsiCo). Dr. Barbey has received multiple
research awards and is editor of The Cambridge Handbook of Intelligence and Cognitive Neuroscience
and the forthcoming Oxford Handbook of Cognitive Enhancement and Brain Plasticity. He earned his
doctorate in Psychology from Emory University and completed a research fellowship in Cognitive
Neuroscience at the National Institutes of Health.

Felipe Fregni is Professor of Physical Medicine and Rehabilitation, Harvard Medical School, Professor
of Epidemiology, Harvard School of Public Health, and Director of the Spaulding Neuromodulation
Center. He is also the course director for the HMS continuing medical education course, Principles and
Practice of Clinical Research, a six-month distance learning course. Currently, his research is focused on
understanding neuroplastic changes associated with conditions such as chronic pain, Parkinson’s disease,
and stroke, using non-invasive brain stimulation as an investigative tool for such aims. In addition, his
laboratory comprises about 15 research fellows and staff and is a training center for clinical research and
neuromodulation methodology. Dr. Fregni’s laboratory is funded by several sponsors including NIH, the
Christopher and Dana Reeve Foundation, CIMIT, and the RJG Foundation.

Marjan Jahanshahi is Professor Emeritus of Clinical Neuropsychology at the UCL Queen Square
Institute of Neurology. She is a Fellow of the British Psychological Society. She trained as a clinical
psychologist and neuropsychologist. She was a principal investigator at the Sobell Department of Motor
Neuroscience & Movement Disorders, UCL Queen Square Institute of Neurology; where she led the
 The Editors and Contributors xi

Cognitive-Motor Neuroscience Group. She was also a founding member and the honorary consultant
neuropsychologist at the Functional Neurosurgery Unit, the National Hospital for Neurology &
Neurosurgery for 15 years. Her research focuses on movement disorders such as Parkinson’s disease and
dystonia, including assessment of the impact of surgical treatments such as deep brain stimulation for
these disorders on cognition and movement and investigation of the psychosocial impact of these chronic
disorders on the quality of life of the patients and their families. She has published 350 papers in peer-
reviewed journals with an h-index of 90 and also 2 books.

Georg Northoff is Professor of Neurosciences and Mental Health and holds a Canada Research Chair for
Mind, Brain Imaging and Neuroethics at the University of Ottawa/Canada. Dr. Northoff has made major
contributions in neuroscience regarding the neural correlates of mental features such as consciousness,
self, mind wandering and mental disorders, having discovered their spatiotemporal mechanisms bridging
the gap of neural and mental activity. This led him to develop an integrated brain-mind model for which
Spatiotemporal Neuroscience is the key discipline (www.georgnorthoff.com).

Álvaro Pascual-Leone is Professor of Neurology and Director of the Berenson-Allen Center for
Noninvasive Brain Stimulation at Beth Israel Deaconess Medical Center and Harvard Medical School,
where he also serves as Program Director of the Harvard-Thorndike Clinical Research Center. His
research aims at understanding the mechanisms that control brain plasticity across the lifespan to be able
to modify them for the subject’s optimal behavioral outcome. Pascual-Leone combines various brain
imaging and brain stimulation methodologies to establish a causal relationship and a precise chronometry
between regional brain activation and behavior, and uses noninvasive brain stimulation techniques to
modulate brain plasticity, suppressing some changes and enhancing others, to gain a clinical benefit and
behavioral advantage for a given individual. Such non-invasive approaches can lead to clinically relevant
therapeutic effects in neuropsychiatry and neurorehabilitation, and serve as proof-of-principle prior to
more invasive neuromodulatory interventions. A major interest of current work aims at translating
insights from cognitive neuroscience into clinical interventions (h-index 192).

Barbara J Sahakian is Professor of Clinical Neuropsychology in the Department of Psychiatry at the

University of Cambridge. She is a Fellow of the British Academy and a Fellow of the Academy of
Medical Sciences. She is also a Fellow of Clare Hall. She is a past president of the International
Neuroethics Society and of the British Association for Psychopharmacology. According to Research.com
she is among the very top researchers worldwide in the fields of neuroscience and psychology. Dr.
Sahakian has contributed over 550 publications (h-index 162) in scientific journals, including Science,
Nature and The Lancet. She has also been a leader in Government Policy on neuroscience and mental
health, including the UK Government Foresight Project. She is co-Inventor of the Cambridge Cognition
CANTAB computerized cognitive tests used worldwide, the PEAK Wizard Memory Game, and the
Decoder Attention and Concentration Game. Cambridge Cognition is a prominent neuroscience technol-
ogy organization that seeks to optimize cognitive assessment. Dr. Sahakian is also co-inventor of the
EMOTICOM computerized tests of social and emotional cognition. She is co-author of two popular sci-
ence books, entitled Bad Moves and Sex, Lies and Brain Scans.

ASSOCIATE EDITORS

Nadia Bolognini is Professor of Psychobiology and Physiological Psychology at the University of

Milano Bicocca and Director of the Laboratory of Neuropsychology at the I.R.C.C.S. Istituto
Auxologico Italiano (Milan, Italy). She is also currently coordinator of the Bachelor of Science in
Psychological Science and Techniques at the University of Milano Bicocca. She received her PhD in
Clinical and Experimental Psychology from the University of Bologna (Italy). Dr. Bolognini has been a
visiting researcher at the Department of Neurobiology and Anatomy of Wake Forest University, North
Carolina, at Spaulding Rehabilitation Hospital, and at Beth Israel Deaconess Medical Center, Harvard
Medical School. She has published more than 120 peer-reviewed scientific papers specifically within
the field of cognitive neuroscience, has edited two books, and has contributed 16 national and interna-
tional book chapters.
xii THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Anja Soldan is an Associate Professor of Neurology at Johns Hopkins University School of Medicine.
She holds PhD in Cognitive Neuroscience from New York’s Columbia University. She completed a post-
doctoral fellowship in Neuropsychology and Cognition in Aging at Columbia University Medical Center
and was an Assistant Professor of Psychology at the University of Massachusetts – Dartmouth, prior to
joining the faculty at Johns Hopkins University in 2011. Dr. Soldan’s research focuses on the cognitive
changes that occur with age and Alzheimer’s disease and their relationship to brain structure and function.
Her research has focused on characterizing the earliest cognitive and brain changes associated with
Alzheimer’s disease to identify early markers for cognitive decline. Additionally, she is investigating
individual differences in modifiable risk and protective factors for cognitive decline (such as cognitive
reserve and vascular risk) and their relationship to genetic factors.

CONTRIBUTORS

Anneke Alkemade is an expert in human neuroanatomy and Assistant Professor working at the Brain and
Cognition, Psychology Department, at the University of Amsterdam. In her work she aims to uncover the
functional neuroanatomy in health and disease, and to translate post-mortem histological findings into
information relevant for clinicians as well as other fields of neuroscience. Her work contributes to
increase the understanding of the pathogenesis underlying neurological disease and is focused on increas-
ing insight in the human subthalamic nucleus, which is targeted by deep brain stimulation in patients with
Parkinson’s disease. Dr. Alkemade’s work is published in journals from the fields of neuroscience, neu-
roanatomy, psychiatry, biochemistry, and endocrinology.

Katrin Amunts is Neuroscience Professor at the Cécile and Oskar Vogt Institute for Brain Research at
the University Hospital of Düsseldorf, and is also Director of the Institute of Neuroscience and Medicine
in INM-1 in Forschungszentrum Jülich and the Scientific Research Director of the Human Brain Project.
Her research focus is on brain mapping, particularly on creating a three-dimensional multi-level brain
atlas (including the cytoarchitectonic Julich-Brain atlas and the “Big Brain”) to allow the complex con-
figuration of brain regions and functions to be imaged and understood microscopically. This would
advance current abilities to combat diseases or disorders such as depression, addiction, dementia, and
Parkinson’s disease.

Lars Bäckman has been a Professor in the Cognitive Neuroscience of Aging since 2002 at the Aging
Research Center at Karolinska Institute, Sweden. He has previously held professorships at Gothenburg
University (1993–1998) and Uppsala University (1998–2002), Sweden. He is a cognitive psychologist by
training and received his PhD from Umeå University, Sweden, in 1984. He is a member of the Royal
Swedish Academy of Sciences and the European Academy of Sciences. Lars Bäckman’s primary research
area is cognition in normal and pathological aging, with special focus on memory. His research activities
range from large-scale epidemiological studies to experimental brain-imaging work.

David Bartrés-Faz is Professor of Medical Psychology at the University of Barcelona. He received train-
ing in neuropsychology, brain imaging and non-invasive brain stimulation and performed postdoctoral
stages at the INSERM (France) and at Harvard Medical School (USA). His research focus on modifiable
factors and neural mechanisms that explain maintenance of brain and mental health in advanced age. PI
of consecutive Spanish National grants since 2004 and PI of the University of Barcelona Center for
European Programs FP7 and Horizon 2020. PI of the prospective study Barcelona Brain Health initiative
(BBH), Honorary member of the Department of Clinical Educational and Health Psychology, University
College London (2022-2027) and chair (2001-2003) of the “Reserve, Resilience and Protective Factors”
Professional Interest Area of the Alzheimer International Association (ISTAART). He sits on the
Director’s board of the Institute of Neuroscience at the University of Barcelona and has been awarded
with a Ramon y Cajal and an ICREA Academia fellowships by the Spanish and Catalan Governments.

Linda Becker received her diploma degrees (equivalent to Master of Science) in physics and in psychol-
ogy in 2007 from the University of Bremen (Germany). In 2016, she received her PhD in psychology from
the Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany. Her research focusses on the
relationships between peripheral physiological and cognitive processes. Her main research interests are
 The Editors and Contributors xiii

the associations between biological stress responses and cognitive functions. In her research, she is using
a variety of bio-psychological and neuroscientific methods such as electroencephalography (EEG), mag-
netencephalography (MEG), as well as the measurement of stress hormones and inflammatory markers.

Alexandra Bendixen is a professor of Structure and Function of Cognitive Systems at the Institute of
Physics at Chemnitz University of Technology. Her main scientific contributions are in the field of audi-
tory perception and cognition, auditory scene analysis, sensory ambiguity, and multistability, as well as
resource allocation and interference.

Federico Bermúdez-Rattoni obtained his M.D. from UNAM and a Ph.D. from the University of
California, Los Angeles. He is a Guggenheim Fellow and External Fellow of the Center for the
Neurobiology of Learning and Memory, University of California, Irvine. He obtained the Mexican National
Science Prize, UNAM prize and Syntex Prize. Currently, he is an Emeritus Professor and Head of the
Cognitive Neuroscience Department of the Cellular Physiology Institute, UNAM, Mexico City Campus.

Paula J. Bice has a broad background in Neuroscience, with specific training and expertise in neurobiol-
ogy of addiction. Her earlier research in the Alcohol Research Center in the Indiana University School of
Medicine (IUSM) focused on identifying and characterizing genes underlying addiction. Additionally,
she has taught Neuroscience and other related courses, such as Neurobiology of Addiction and Drugs in
the Nervous System. Currently, as a faculty member in the Indiana Alzheimer’s Disease Research Center
in the IUSM, she utilizes her background in neuroscience to assist faculty and trainees with scientific
writing, research project development, grant development, statistics, graphics, media, and metrics.

John Bickle is Professor of Philosophy and Shackouls Honors College Faculty at Mississippi State
University, and Scientist Educator in the Department of Advanced Biomedical Education at the University
of Mississippi Medical Center. His research areas are the philosophy of neuroscience and the philosophy
of science-in-practice. He is the author of four academic books, Psychoneural Reduction: The New Wave
(MIT Press, 1998), Philosophy and Neuroscience: A Ruthlessly Reductive Account (Kluwer, now
Springer, 2003), Understanding Scientific Reasoning, 5th Ed. (co-authors Ronald Giere and Robert
Mauldin, Cengate, 2005), and Engineering the New Revolution in Neuroscience (co-authors Alcino J.
Silva and Anthony Landreth, Oxford University Press, 2014), and around 100 papers and chapters in
philosophy of science and neuroscience journals and book volumes. He has edited two collections of
essays, including The Oxford Handbook of Philosophy and Neuroscience (2009), and most recently The
Tools of Neuroscience Research: Philosophical and Scientific Perspectives (co-editors Carl F. Craver and
Ann-Sophie Barwich, Routledge, 2021).

Jan Bjaalie is Professor at the Institute of Basic Medical Sciences, University of Oslo, Norway,
Infrastructure Director of the EU Human Brain Project, leader of the EBRAINS Data services, and Head
of the Norwegian Neuroinformatics Node. His research group joined the Centre for Molecular Biology
and Neuroscience, a Norwegian Centre of Excellence appointed by The Research Council of Norway, in
2002. His laboratory has discovered fundamental principles of sensory map transformations in large
projection systems of the brain and has performed novel regional and whole brain atlasing and histologi-
cal mapping. Professor Bjaalie has served as co-Chair of the International Brain Initiative since 2019,
Head of the Institute of Basic Medical Sciences at the University of Oslo, Chair of the Governing Board
and founding Executive Director of the International Neuroinformatics Coordinating Facility (INCF), and
member of the Neuroinformatics Committee of the Society for Neuroscience.

Sander M. Bohté is Principal Investigator in the CWI Machine Learning group and also a part-time
Professor of Cognitive Computational Neuroscience at the University of Amsterdam. He received his PhD
in 2003 at CWI on the topic of “Spiking Neural Networks.” He then did a postdoc with Michael Mozer
at the University of Colorado in Boulder. In 2004, he rejoined CWI as junior permanent staff to work on
distributed spiking neural network models and multi-agent systems. In 2016, he co-founded the CWI
Machine Learning group, where his research bridges the field of neuroscience with applications thereof
as advanced neural networks. His work has been pioneering in the development of advanced and efficient
spiking neural networks, including seminal work on supervised learning with spike-time coded networks.
Recent work has focused on large-scale and effective spiking neural networks next to biologically plau-
sible deep learning and deep reinforcement learning models for cognition.
xiv THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Jens Borgelt completed his doctoral studies at the University of Konstanz, Germany, in the field of func-
tional brain imaging and clinical psychophysiology, investigating neural correlates of altered information
processing in PTSD via MEG (magnetoencephalography). Dr. Borgelt has also studied and worked in the
Department of Psychiatry, Oxford University, and in the Department of Psychiatry and Behavioral
Sciences, Stanford University. Later he became a licensed psychotherapist in cognitive behavior therapy
and has worked in several clinical fields including neurorehabilitation and the treatment of severe psychi-
atric disorders and is now chief psychologist at the private Oberberg Clinic, Black Forest, Germany.

Rotem Botvinik-Nezer is a postdoctoral researcher in Psychological and Brain Sciences at Dartmouth

College and incoming faculty at the Psychology Department at the Hebrew University of Jerusalem. With
background in decision-making, behavioral change, and neuroplasticity, Dr. Botvinik-Nezer’s current
research focuses on beliefs and expectations, in the context of the placebo effect and beyond. Dr.
Botvinik-Nezer studies how beliefs and expectations are formed and updated given new information, and
how they affect mental, physiological, and social processes, with diverse tools from behavioral experi-
mental manipulations to computational modeling to neuroimaging. Dr. Botvinik-Nezer is also proactively
conducting and promoting open and reproducible scientific research, with a particular emphasis on repro-
ducibility, transparency, robustness to analytical decisions, and inclusion.

Claudio Brozzoli is an INSERM senior researcher at the IMPACT team of the Centre de Recherche en
Neuroscience de Lyon (CRNL). He received his master degree in Psychology at the University of
Bologna (Italy) and his PhD in Cognitive Neuroscience from the Neuroscience and Cognition doctoral
school of the University Claude Bernard of Lyon. He is currently leading several research programs
focusing on the multisensory representation of the body and the space near the body (peripersonal space),
their role in action planning and execution and how these multisensory and motor processes support
human cognition for language and social interactions.

Arthur Butt is a Professor of Biology and has been a glial cell biologist for over 25 years. He received
his PhD from King’s College London in 1986, working with Joan Abbott, a leader in blood-brain barrier
research. After a postdoctoral position in North Carolina with Ed Lieberman, he was awarded a Grass
Fellowship to work at the world-famous Wood’s Hole Marine Biology Laboratories. Next, he moved to
Yale University to work with Bruce Ransom, where he began his work on optic nerve glia, a line of
research he has pursued ever since. On return to King’s College in the UK, he received a Royal Society
Fellowship to work at the Marine Laboratories in Plymouth, UK, before obtaining his first independent
position at Guy’s and St Thomas’ Hospitals in 1990. After gaining a personal Chair at King’s College in
2000, he moved to the University of Portsmouth in 2005, where he was Director of the Institute of
Biomedical and Biomolecular Sciences. Much of his work has focused on oligodendrocyte cell biology
and the factors that regulate their regeneration.

Zuriel Ceja is a PhD student at The University of Queensland and QIMR Berghofer Medical Research
Institute in Brisbane. He holds a degree in Psychology from the University of Guanajuato in Mexico. His
research interests focus on behavioral science and psychiatric genetics. He has previously held a research
internship at the Instituto de Neurobiología of the Universidad Nacional Autónoma de México in
Juriquilla, Mexico. He was a Summer Research Intern sponsored by the Mexican Academy of Sciences,
was a Mitacs Globalink research intern in Toronto, Canada, and served as a Delegate at the Canada-
Mexico Youth Lab.

Jiang-Fan Chen at Wenzhou Medical University, China undertakes research into the neuromodulator
adenosine A2A receptor control of cognition within the Molecular Neuropharmacology Lab, School of
Optometry and Ophthalmology, Wenzhou, China. Dr. Chen also undertakes research into cognition within
the State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, China.

Joan Y. Chiao is the Director of the International Cultural Neuroscience Consortium. She earned her PhD
from Harvard University in Psychology and B.S. with Honors from Stanford University in Symbolic
Systems. She is the Director of the Laboratory for Social and Affective Neuroscience. She is a Fellow of
the American Psychological Society, Society for Personality and Social Psychology, and the Society for
Experimental Social Psychology. She is an editor of peer-reviewed journals and book series such as The
Oxford Handbook of Cultural Neuroscience. She is a recipient of the Distinguished Scientist Award and
Fields Prize from the International Cultural Neuroscience Society.
 The Editors and Contributors xv

Hugo Critchley is Professor of Psychiatry at Brighton and Sussex Medical School. Hugo’s research
focuses on brain mechanisms supporting normal and abnormal emotion, with particular emphasis on
bidirectional brain–body interactions. This work encompasses basic and clinical investigation of emo-
tions, autonomic control, interoception and their disorders. Hugo studied Physiology and Medicine in the
University of Liverpool before completing a Doctorate in Psychological Studies at the University of
Oxford. He trained in Psychiatry and clinical neuroscience at the Kings College London Institute of
Psychiatry and University College London (UCL) Institute of Neurology, developing his own research
programme through research fellowships. Hugo moved to Sussex from UCL as foundation Professor of
Psychiatry in 2006. He was also a founding co-director of the Centre for Consciousness Science at the
University of Sussex in 2010. Hugo works clinically as a neuropsychiatrist at the Neurodevelopmental
Services at Sussex Partnership NHS Foundation Trust.

Alain Destexhe is Director of Research at CNRS, Vice Director of NeuroPSI and Director of the
European Institute for Theoretical Neuroscience in Paris, France. His research activity in computational
neuroscience is at the interface between physics (dynamic systems) and neuroscience (electrophysiol-
ogy). His current research projects include the study of collective dynamics of neural networks, the
genesis of brain states and sensory responses, as well as sensory perception.

Alessandro Farnè is Inserm Research Director, Head of the Impact team of the Lyon Neuroscience
Research Center (CRNL) and of the Neuro-immersion CRNL facility. He is currently member of the
Direction Committee of the CRNL. After obtaining his PhD degree (1999) at the University of Bologna,
a Post-Doc (2000) at Rice University in Houston, and Assistant Professorship (2001) at the faculty of
Psychology in Cesena, he got an INSERM research position (2005) in Lyon. His research interests con-
cern the multisensory integration processes for perception and action in the peripersonal space, the sen-
sorimotor control of hands and hand-held tools, body representation and somatosensory plasticity,
combining methods from experimental psychology and cognitive neuroscience.

Birte U. Forstmann is a Professor for Cognitive Neurosciences and Director of the Amsterdam Brain and
Cognition Center at the University of Amsterdam. She earned her PhD in 2006 at the Max Planck Institute
for Human Cognitive and Brain Sciences in Leipzig, Germany. After completing her postdoc in 2008 at
the University of Amsterdam, she became a tenured Research Fellow at the Cognitive Science Center
Amsterdam with the focus of model-based cognitive neurosciences. Since then she has contributed to a
range of topics in cognitive neuroscience, experimental psychology, mathematical psychology, and lately
also in quantitative neuroanatomy. Despite its diversity, her work is motivated by a single strong convic-
tion, namely that behavioral data and brain measurements need to make contact with psychological theory
via concrete mathematical models of latent cognitive processes. A recurrent theme in her work is the
development and testing of quantitative models of cognition.

Leonardo Fogassi has a master’s degree in biology and a PhD in Neuroscience. He was trained in
Neurophysiology at the University of Parma in the lab of Professor Rizzolatti. He also spent one year in
the Richard Andersen’s neurophysiology lab at the Department of Brain and Cognitive Sciences of MIT
(Cambridge, MA). He is now Professor of Physiology in the Department of Medicine and Surgery. His
research focused on the investigation of high order sensory-motor properties of fronto-parietal areas of
non-human primates and humans. In particular, he studied, by using electrophysiological, behavioral and
neuroimaging technique, the processes of visuomotor transformations and the cognitive functions of the
motor system, among which the properties of the mirror neuron system, of which he is co-discoverer. His
research is testified by numerous publications on prestigious international journals. He received, together
with Giacomo Rizzolatti and Vittorio Gallese, the Grawemeyer Award for Psychology (2007).

Albert M. Galaburda is a renowned neuroscientist and Emeritus Professor of Neurology at Harvard

Medical School. He has served as Co-Director of the Mind, Brain, and Behavior Interfaculty Initiative at
Harvard University and as Chief of the Division of Cognitive Neurology at the Beth Israel Deaconess
Medical Center (BIDMC) in Boston. Originally from Chile, he received his medical degree from Boston
University’s School of Medicine. Throughout his career, he has directed the Laboratory for the
Neuroscience of Cerebral Lateralization and Dyslexia at BIDMC and has published extensively in his
field, with over 230 original articles, reviews, book chapters, and books to his credit. He has received
numerous awards and honors, including the Pattison Prize in Neuroscience, the IPSEN Prize in Neural
xvi THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Plasticity, the American Academy of Neurology Decade of the Brain keynote speaker award, the
Behavioral Neurology Society of the American Academy of Neurology’s Lifetime Achievement Award,
and the International Dyslexia Association’s Samuel T. Orton Award. He currently lives in Cambridge,
Massachusetts with his wife, Susana.

Olga Garaschuk is an internationally recognized scholar in the field of neuronal and microglial physiol-
ogy/neuroscience, best known for establishing the techniques for in vivo calcium imaging of neuro-glial
networks at single-cell resolution and the discovery of neuronal as well as microglial hyperactivity during
ageing and in mouse models of Alzheimer’s disease. Garaschuk’s laboratory was the first to study in vivo
calcium signaling of microglia and to reveal that midlife represents the first turning point in microglial
homeostasis. Moreover, she has significantly contributed to understanding the mechanisms of rhythmo-
genesis of the developing cortical and hippocampal networks and the role of sleep-associated rhythmic
activity in this process.

Luis M. García-Marín is a doctoral candidate at The University of Queensland and QIMR Berghofer
Medical Research Institute in Brisbane, Australia. He holds a B.Sc. in Biotechnology Engineering from
the Instituto Tecnológico y de Estudios Superiores de Monterrey (ITESM) in Guadalajara, Mexico. His
research focuses on identifying genetic biomarkers for complex neurological and psychiatric disorders.
He has been recognized for his work with the Lindon Eaves Award from the Institute of Behavioral
Genetics at the University of Colorado Boulder, and the Enrico Greppi Award from the Italian Society for
the Study of Headaches and the European Headache Federation.

Erhan Genç obtained his diploma in psychology at the University of Mannheim and completed after-
wards his PhD at the Max Planck Institute for Brain Research in Frankfurt am Main. Subsequently, he
was a postdoc and principal investigator at the Ruhr University Bochum. Currently, he is a group leader
at the Department of Psychology and Neurosciences at the Leibniz Research Centre for Working
Environment and Human Factors at Technical University of Dortmund (IfADo). He is highly interested
in the neural basis of intelligence and personality. In his research he uses a multimodal approach to link
behavior to brain structure and function. His research has been supported by the German Research
Foundation (DFG). He is a member of the editorial board of the journal Intelligence.

Marc Guitart-Masip is an Associate Professor at the Aging Research Center at Karolinska Institute,
Sweden. In parallel, he works as a consultant psychiatrist at the Affective disorder unit at Psykiatri
Nordväst, Stockholm, Sweden. He has a degree in Medicine (2002) and a PhD in Neuroscience (2006)
from Universitat Autònoma de Barcelona, Spain. During his PhD, he performed experiments in the field
of Behavioral and Molecular Pharmacology using animal models of vulnerability to addiction. After his
PhD, his interests expanded to Cognitive Neuroscience and between 2008 and 2012 he was a post-doc-
toral fellow first at the Institute of Cognitive Neuroscience, and thereafter at the Wellcome Trust Centre
for Neuroimaging, at University College London (UCL), UK.

Alexei N. Gusev is Professor of Faculty of Psychology of Lomonosov Moscow State University. In 1981,
he graduated from the Faculty of Psychology of Lomonosov Moscow State University and specialized in
the fields of psychophysics and cognitive psychophysiology. The main areas of scientific interests are
psychophysics, cognitive psychology, computer psychodiagnostics. The research results are presented in
more than 180 articles, 21 handbooks, monographs and collective monographs (Psychophysics of sensory
tasks, 2002, Sensation and Perception, 2007, 2009, Psychological Measurements: Theory and Methods,
2011, Measurement in psychology, 1997-2005). Alexei N. Gusev - Laureate of the Lomonosov Prize for
Pedagogical Activity, (1998), Awardee of the Russian Government Prize in Education (2010), Winner of
the Moscow Innovator competition (2022).

Kioko Guzmán-Ramos (Universidad Autónoma Metropolitana) completed her PhD at Department of

Neuroscience at the Instituto de Fisiología Celular at the Universidad Nacional Autónoma de México
(UNAM) focusing her research on molecular processes of learning and memory and the dopaminergic
influence on the cognitive impairment developed in Alzheimer’s Disease models. She is currently
Principal Investigator at Universidad Autónoma Metropolitana and Head of Health Sciences Department
investigating the effect of obesogenic environments on cognitive performance.
 The Editors and Contributors xvii

Randolph F. Helfrich is a clinician-scientist at the Center for Neurology and the Hertie-Institute for
Clinical Brain Research at the University of Tübingen, Germany. His lab studies large-scale network
mechanisms underlying human cognition and sleep physiology using intracranial electrophysiology. He
is the recipient of an Emmy Noether Award of the German Research Foundation and the Career
Development Award of the Ernst Jung Foundation.

Anna Kristina Hernandez is a researcher at the Smell and Taste Clinic in the Department of
Otorhinolaryngology, Technische Universität Dresden, Dresden, Germany and an Otorhinolaryngologist –
Head and Neck Surgeon at the Philippine General Hospital and Asian Hospital and Medical Center in the
Philippines. Dr. Hernandez graduated with a degree in Psychology from the University of the Philippines –
Diliman and subsequently completed her medical education at the College of Medicine, University of the
Philippines - Manila. She finished her residency training in Otorhinolaryngology at the University of the
Philippines – Philippine General Hospital, with subsequent completion of fellowships for Olfaction and
Gustation at the Technische Universität Dresden and Head and Neck Oncologic Surgery at Erasmus MC
in Rotterdam, Netherlands. Her research interests include olfactory and trigeminal dysfunction, as well as
psychophysical testing.

Thomas Hummel received his medical education at the University of Erlangen-Nürnberg, Germany.
There, he also went through a special program in Pharmacology and Toxicology (“Habilitation”) which
was guided by Dr. Gerd Kobal. As a post-doc, in 1994, he stayed at the Department of Pharmacology at
the University of Iowa, Iowa City, USA. From 1997 to 1998, Dr. Hummel was an Assistant Professor at
the Department of Otorhinolaryngology of the University of Pennsylvania, Philadelphia, USA where he
worked at the Smell and Taste Center under the guidance of Dr. Richard L. Doty. In 1998, Dr. Hummel
started a Smell and Taste Clinic at the Department of Otorhinolaryngology, Technische Universität
Dresden, where he sees approximately 1000 patients per year. He is the author/co-author of more than
700 peer-reviewed, original publications, more than 80 reviews in the chemosensory area, over 50 book
chapters and is the editor of three books about the chemical senses.

William Huynh is a clinical academic and translational researcher dividing his time between clinical
neurology and neurophysiology, and research, as well as teaching. He holds appointments as a Consultant
Neurologist and Clinical Neurophysiologist at the Prince of Wales Tertiary Teaching Hospital in Sydney,
Australia; Associate Professor with the Faculty of Health and Medicine at University of Sydney. His
research has been focused on multiple areas along the spectrum of neurodegenerative disorders.

Jon H. Kaas is a Distinguished Centennial Professor of Psychology at Vanderbilt University, Nashville,

TN, USA. He received his Ph.D. training in comparative studies of forebrain organization in mammals in
the laboratory of Dr. I. T. Diamond at Duke University and studied cortical organization during his post-
doctoral training in the comparative neurophysiology laboratory of Dr. C. N. Woolsey at the University
of Wisconsin. He is an elected member of the National Academy of Sciences and the American Academy
of Arts and Sciences. Dr. Kaas is a recipient of the Javits Neuroscience Investigator Award from the
National Institute of Neurological Disorders and Stroke, the Karl Spencer Lashley Award from the
American Philosophical Society, the Krieg Cortical Discoverer Award from the Cajal Club, and the Ralph
W. Gerard Prize in Neuroscience, the highest honor from the Society for Neuroscience.

Nina Karalija is an Associate Professor at the Department of Integrative Medical Biology at Umeå
University, and a researcher at Umeå Center for Functional Brain Imaging (UFBI), Sweden. She has an
MSc in Chemical Engineering (2008), and a Ph.D.in Medical Science (2013) with orientation towards
histology and cell biology. Her past and present research has focused on the dopamine system, with the
aim to understand how dopamine decline in disease and healthy aging affects motor and cognitive func-
tions. She also studies how other brain changes, e.g., cerebrovascular dysfunction and neuroinflammation,
affect dopamine decline and cognition in aging. These research questions have been studied via experi-
mental neuroscience methods and brain imaging (PET and MRI).

Matthew Kiernan is the Bushell Chair of Neurology at the University of Sydney, Consultant Neurologist
at Royal Prince Alfred Hospital and Co-Director of the Brain and Mind Centre. He is Chair of the World
Federation of Neurology ALS/MND Specialty Group and established the Pan-Asian Consortium for
Treatment and Research in ALS (PACTALS). He is President of the Brain Foundation and currently
serves as Editor-in-Chief of the Journal of Neurology, Neurosurgery & Psychiatry.
xviii THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Philipp Klar is graduate student for Ph.D. in neuroscience at the University of Duesseldorf/Germany. His
main interest is neurophilosophy and especially consciousness with its neural mechanisms and correlates.

Robert T. Knight is a neurologist and professor of Neuroscience and Psychology at UC Berkeley. He has
received the Jacob-Javits-Award from the National Institute of Neurological Disorders and Stroke, the
Distinguished Career Contribution Award from the Cognitive Neuroscience Society and the Howard-
Crosby-Warren-Medal for Distinguished Career Contributions to Psychological research. He is a member
of the American Association for the Advancement of Science and a Fellow of the American Academy of
Science. His laboratory records intracranial EEG to understand the role of prefrontal cortex in goal-
directed behavior.

Thomas Koenig is a professor of psychiatric neurophysiology and head of the EEG research laboratories
of the University Hospital of Psychiatry of the University of Bern. His research has been focused on link-
ing mental processes and experiences to EEG data, including the development of theoretical models and
the corresponding analysis tools, as well as empirical studies in healthy and mentally ill subjects. Methods
and theory-wise, He has been one of the key promotors of the EEG microstate methodology that is receiv-
ing increasing attention in the EEG community, and where he contributed a series of software tools to
conduct such analyses. He also developed novel statistical procedures for the analysis of ERPs and makes
a continuously evolving open-source toolbox implementing those tools openly available. Regarding
empirical studies, he has a steady track of contributions to the psychological correlates of EEG micro-
states during resting and to the neurophysiology of auditory verbal hallucinations and experience (or lack
thereof) of agency in the context of psychosis.

Saana M. Korkki is a post-doctoral researcher at the Aging Research Center at Karolinska Institute,
Sweden. Prior to joining Karolinska Institute, she completed a PhD in Psychology (2020) and held a post-
doctoral position at the University of Cambridge, UK. Her research interests concern the cognitive and neural
mechanisms underpinning episodic memory decline in aging. To address these questions, she uses a range
of methods including functional, structural, and molecular neuroimaging and behavioral experiments.

Leah A. Krubitzer is an American neuroscientist, Professor of Psychology, and head of the Laboratory
of Evolutionary Neurobiology in the Center for Neuroscience at the University of California, Davis, USA.
She earned her Ph.D in Psychology at the laboratory of Dr. Jon H. Kaas at Vanderbilt University,
Nashville, TN, USA. She continued her training in the laboratory of Dr. M.B. Calford at the University
of Queensland, Brisbane, Australia. Her research interests center on how complex brains in mammals
evolve from simpler forms, as well as the roles of environment and sensory experience on the functional
organization of the cortex. Among her awards is the MacArthur “genius grant” Fellowship from the John
D. and Catherine T. MacArthur Foundation.

Mrinmayi Kulkarni is a post-doctoral researcher in the labs of Dr. Rosanna Olsen and Dr. Bradley
Buchsbaum, at the Rotman Research Institute, Baycrest Health Sciences. She completed her Master’s
degree in Neuroscience at the University of York, UK, and received her Ph.D. from the University of
Wisconsin Milwaukee. Mrinmayi is interested in studying the brain networks underlying learning and
memory. She uses multimodal techniques such as structural and functional neuroimaging, and eye-
tracking to examine how long-term memory interacts with other systems such as the attention and cogni-
tive control system to support behaviour. She aims to examine how these processes change with age and
disease, with an emphasis on identifying factors that may alleviate age-related cognitive decline.

Tiago Lazzaretti is a Collaborative Professor, Researcher and Advisor of the Post Graduate Program of
Science in Musculoskeletal System from the Faculty of Medicine, University of São Paulo. Founder and
Director of the program Scholars in Medical Innovation since 2020. Founder and CEO of SPERO Science
Innovation company. Member of INOVAHC, Center of Innovation and Entrepreneurship of Hospital das
Clínicas, University of São Paulo. Post doctorate program (2017-2019) related to Tissue Engineering &
Cartilage Regeneration - University of São Paulo, Medical School with research fellow at Harvard
Medical School (CAPES 88881.171651/2018-01). International Society of Knee Surgery and Sports
Medicine (ISAKOS) Osteoarthritis Award - 2017. Doctorate Sandwich Program at Harvard Medical
School (CAPES, 2014). Scientific Coordinator of Tissue Engineering of Bone and Cartilage, Sports
Medicine Division and Site Director of PPCR (Principles and Practice on Clinical Research Harvard
 The Editors and Contributors xix

Medical School / Harvard T.H. Chan) at Sírio-Libanês Hospital. Physician assistant of Sports Medicine
Division at University of São Paulo Medical School and collaborator of FIFA Medical Center of
Excellence (IOT-FMUSP).

Yan Li is an associate Professor of Neurology at the 2nd Affiliated Hospital of Wenzhou Medical
University, Wenzhou, China. He received his PhD from Wenzhou Medical University in 2015, following
Jiang-fan Chen, a leading researcher in adenosine neurobiology and received further education as Visiting
Professor from 2019-2020 at the Beth Israel Deaconess Medical Center (BIDMC) of Harvard Medical
School, Boston, USA. Currently, his research focuses on executive dysfunctions of Parkinson’s Disease
and the role of adenosine neuromodulator in cognition.

Zhang Li is a professor who is conducting research into cognitive neurogenetics within the Department
of Psychology at Capitol Normal University, Beijing, China.

Anna Marduy is a medical student and completed a Research Fellowship at the Spaulding
Neuromodulation Center, Boston-MA. She started medical school in 2017 at the University União
Metropolitana de Educação e Cultura, UNIME, Lauro De Freitas, Brazil; where she had positions as
Teaching assistant on Anatomy and Histology, and Medical Semiology. She completed a research intern-
ship at Neuromodulation Research Center – Spaulding Rehabilitation Hospital/Harvard Medical School –
in 2021 and was certified by the Principles and Practice in Clinical Research course – Harvard T.H. Chan
School of Public Health, USA in 2020, a course that he worked after as Boston Local Site Monitor in
2021 and a Teacher Assistant I in 2022. Her interest are focus on neuromodulation, chronic pain in post-
surgical settings, and surgical interventions for cardiovascular disease.

Mario Manto is Professor of Neuroanatomy at the University of Mons (Mons, Belgium). He also teaches
pathophysiology of the nervous system. He is Head of the Department of Neurology at the CHU-
Charleroi (Charleroi, Belgium). He is Editor of The Cerebellum (Springer Nature).

Hans J. Markowitsch was Professor of Physiological Psychology at the University of Bielefeld. He

studied psychology and biology at the University of Konstanz, was studying and working in the Medical
Faculty of the University of Copenhagen and in the Faculty of PPP of Oxford University and had profes-
sorships for biopsychology and physiological psychology at the Universities of Konstanz, Bochum, and
Bielefeld and was offered chairs of psychology and neuroscience at Australian and Canadian Universities.
His research centers on the neural and psychic bases of memory disorders and on interactions between
memory and emotion. He is author, co-author or editor of about 30 books and has written about
700 scientific articles and book chapters.

Jorge Mejias is Assistant Professor of computational neuroscience at the University of Amsterdam in the
Netherlands. He also serves as external faculty at the Carlos I Institute of Theoretical Physics in Spain and
at the European Institute for Theoretical Neuroscience in Paris, France. His team in Amsterdam conducts
theoretical and computational research into the mechanistical principles of perception and memory, with a
particular focus on modeling brain networks as a multiscale system and using such models to understand the
emergence of cognitive functions such as working memory, multisensory integration, and predictive coding.

Paulo S. de Melo began medical school in 2017. He is currently in the sixth year of his graduate course
at Escola Bahiana de Medicina e Saúde Pública (EBMSP), where he had experience as a biomorphology
monitor in 2017 and neuroanatomy monitor in 2018/2019. He completed a research internship at
Neuromodulation Research Center, Spaulding Rehabilitation Hospital/Harvard Medical School, in 2021
and was certified by the Principles and Practice in Clinical Research program, Harvard T.H. Chan School
of Public Health, USA in 2020, working after as the Boston Local Site Monitor in 2021 and as Teacher
Assistant I in 2022. He had experience as a junior scientific consultant at Neurive Inc in 2022.

Christoph Michel has studied Behavioral Biology at the Swiss Federal Institute of Technology (ETH)
in Zurich. He is now Full Professor at the Neuroscience Department of the Medical Faculty of the
University Geneva and Head of the HUG/UNIGE-EEG core of the Biomedical Imaging Center
Lausanne-Geneva. He is the Past-President of the Swiss Society for Neuroscience. He has authored over
260 articles and book chapters and is first author of the book “Electrical Neuroimaging” published by
xx THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Cambridge University Press in 2009. He is Editor-in-Chief of the journal Brain Topography, Associate
Editor of the European Journal of Neuroscience, and Associate Editor of Frontiers in Behavioral
Neuroscience. His group is applying electrical neuroimaging tools to cognitive as well as clinical studies
with the aim to unravel the spatio-temporal properties of large-scale brain network communication in
health and disease.

Alexandr M. Chernorizov – is Professor and Head of the Psychophysiology Department Faculty of

Psychology, Lomonosov Moscow State University (MSU), Russia. Dr. Chernorizov’s main research inter-
est is undertaking fundamental research in comparative psychophysiology of color perception in humans
and animals. The main provisions of “vector psychophysiology” are verifying experimentally, describing
information processing in neural networks. In neurophysiological experiments a generalized spherical
model of light and color perception mechanisms was substantiated in humans and animals. This model
allows combining of psychophysical (behavioral) and neurophysiological results of color perception
study, within a single metric system. Dr. Chernorizov’s research results are presented in more than 150
peer-reviewed articles and summarized in the 2019 monograph, “Vector psychophysiology: From behav-
ior to neuron”.

María-Isabel Miranda earned her PhD in Neuroscience at the Instituto de Fisiología Celular of the
Universidad Nacional Autónoma de México (UNAM), where she focused on cortical cholinergic system
function during memory formation. Dr. Miranda completed a postdoctoral fellowship at at the Center for
Neurobiology of Learning and Memory in Dr. James McGaugh´s laboratory at the University of
California, Irvine,. In 2004, she joined the Instituto de Neurobiología, UNAM as a Principal Investigator,
where she is currently working on several projects related to neurochemical and anatomical interactions
during learning and memory.

Lars Muckli is Professor of Visual and Cognitive Neurosciences, Director of fMRI at the Centre for
Cognitive Neuroimaging (CCNI) in Glasgow, and Co-chair of 7T-Imaging Center of Excellence (ICE)
MRI. He has worked for 24 years in the field of fMRI and multi-modal brain imaging. His work focuses
on brain imaging of cortical feedback, investigation of layer specific fMRI, and multi-level cross –species
computational neuroscience. The Muckli-lab was previously funded by ERC consolidator grant on “Brain
reading of contextual feedback and predictions.” Since 2016, Lars is member of the Human Brain Project
(HBP), leading a work package on rodent and human neuroscience on “Context-sensitive multisensory
object recognition a deep network model constrained by multi-level, multi-species data.”

Yoko Nagai is a Senior Lecturer at Brighton and Sussex Medical School. She is a translational neurosci-
entist with interest in mind-body interaction and autonomic function. Her research over the last 20 years
has centred on investigating and developing a non-pharmacological treatment for epilepsy. This pioneer-
ing work attracted funding for clinical trials from various grant bodies. Two clinical trials involving
patients with drug resistant epilepsy demonstrated successful outcome and this non-drug therapy is
undergoing translation for clinical dissemination. More recently, her research interests expanded from
human wellbeing to social wellbeing, integrating her educations in science, business and law.

Lars Nyberg serves as Professor of Psychology and Neurosciences at Umeå University, Sweden. He has
been active in the field of functional neuroimaging of memory since 1994. He is the director of Umeå
Center for Functional Brain Imaging (UFBI), and a principal investigator of the Betula longitudinal pro-
ject on aging, memory, and dementia. Since 2008, he is a member of the Royal Swedish Academy of
Sciences. Lars Nyberg’s research is focused on the identification of genetic, brain, and life-style predic-
tors of heterogeneity in cognitive-aging profiles.

Rosanna K. Olsen is a Senior Scientist at the Rotman Research Institute, Baycrest Health Sciences and
an assistant professor in the Department of Psychology at the University of Toronto. She completed her
undergraduate degree at the University of California, San Diego and her Ph.D. at Stanford University.
Dr. Olsen studies how the brain supports human memory and how these memory-related brain regions
change as we age. She uses neuroimaging as well as eye-tracking to better understand how memories are
formed and later recalled. She also leads an international working group on the standardization of neuro-
imaging methods.
 The Editors and Contributors xxi

Daniel Osorio-Gómez received his BS in Psychology, a MS, and PhD in Biochemistry from the
Universidad Nacional Autónoma de México (UNAM). In 2018, He was incorporated as an Associated
Researcher at Instituto de Fisiología Celular, UNAM. His research focuses on the involvement of the
brain circuits associated with emotional learning and memory with a special interest in appetitive and
aversive gustatory memories. He is a member of the National System of Investigators under the National
Council of Science and Technology of Mexico (CONACyT).

Kevin Pacheco-Barrios holds a medical degree, a master’s degree in neuroscience, and a master’s
degree in public health with a concentration in quantitative methods and artificial intelligence from the
Harvard T.H. Chan School of Public Health. Currently, he is a senior research associate in the
Neuromodulation Center & Center for clinical research learning, at Spaulding Rehabilitation Hospital
and Massachusetts General Hospital, Harvard Medical School. He also is an active member in the
COCHRANE and GRADE methodological working groups. He has published over 100 papers in
indexed journals and presented in several international conferences. His main research interests are pain
medicine, neuromodulation, e­ vidence-based neurology, global neurology, patient-empowerment
­methods, and adaptive neurotechnology.

David J. Parker is a lecturer at the Department of Physiology, Development and Neuroscience,

University of Cambridge. His research interests are in nervous system plasticity and neural circuits. This
work started during his PhD and continued in his postdoctoral work on the lamprey locomotor network.
Has has examined the synaptic organization of the locomotor network, and more recently changes in
spinal cord function after injury.

Goran Papenberg is a Principal Researcher at the Aging Research Center at Karolinska Institute,
Sweden. He conducted his PhD in Psychology at the Max Planck Institute for Human Development
(Berlin, Germany), awarded in 2012 by the Free University in Berlin. His main field of research is the
molecular contributions to cognitive aging, with a special focus on dopamine and neuroinflammation. He
uses genetic, epigenetic, lifestyle, and neuroimaging techniques (MRI and PET) to understand the hetero-
geneity in brain and cognitive aging.

Martin J. Pearson is a Senior Lecturer at the University of the West of England, Bristol and theme leader
for Neurorobotic and Biomimetic research at the Bristol Robotics Laboratory. He holds a BEng. In
Electronic and Electrical Engineering from the University of Manchester and MSc. and PhD. from
University of the West of England, Bristol. His research interest lies at the intersection of robotics, animal
behaviour, neuroscience, and AI and has published this work in over 50 peer reviewed articles.

Cyriel Pennartz is Professor of Cognitive and Systems Neuroscience at the Swammerdam Institute for
Life Sciences and the University of Amsterdam, the Netherlands. His current research is focused on
neural mechanisms of memory, perception, sleep, and consciousness. His group uses a multidisciplinary
combination of techniques to understand the relationships between distributed neural activity and cogni-
tion, including in vivo electrophysiology and in vivo two-photon imaging, animal behavior, and compu-
tational modeling. A specialty of this group is to perform high-density parallel recordings from neuronal
ensembles in task-performing animals and analyze population codes, rhythmicity and coherence of neural
activity, and correlate neuronal firing patterns to behavioral and cognitive events. In the field of con-
sciousness research, he developed a theory called Neurorepresentationalism, which uses predictive coding
circuits as building blocks for multi-level perceptual representations.

Arcady A. Putilov is an expert on scientific study of rhythmic phenomena in living nature and individual
variation in the fields of chronophysiology, psychology, and psychiatry. Dr. Putilov is the head of inde-
pendent research group for Mathematical Modeling of Biomedical Systems (the Research Institute for
Molecular Biology and Biophysics of the Federal Research Centre for Fundamental and Translational
Medicine, Novosibirsk). He is the first and/or corresponding author of 95% of more than a hundred
research papers on chronobiology, somnology, personality, biological psychiatry, etc. published in peer
reviewed international journals.

Hui-Xin Qi is a Research Associate Professor of Psychology at Vanderbilt University, Nashville, TN,

USA. She received her Ph.D. in Neurophysiology from the laboratory of Dr. Marie-Claude
xxii THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Hepp-Reymond in the Brain Research Institute, University of Zurich (Zurich, Switzerland). Her current
research interest is on understanding the mechanisms of recovery in the somatosensory and motor systems
of primates after sensory loss by using of anatomical, behavioral, and functional approaches. With long-
standing collaboration with Dr. J. H. Kaas, they continue to make contributions toward fundamental and
translational neuroscience.

Lisa Quadt is a neurodivergent researcher at the Department of Clinical Neuroscience, Brighton and
Sussex Medical School. She applies her research interest in the central and autonomic nervous system
to the understanding of the unique strengths and challenges of neurodivergent populations. She attained
her PhD in Philosophy, taking an interdisciplinary approach to characterizing social cognition before
transitioning into neuroscience. She has led the implementation and testing of a large randomized clini-
cal trial using interoceptive training to decrease anxiety in autistic adults, which was subsequently pub-
lished in EClinicalMedicine.

Vishal Rawji completed his medical training and MBPhD at University College London with Professor
John C. Rothwell, Professor Marjan Jahanshahi and Professor Tom Foltynie. He used non-invasive brain
stimulation techniques and reaction time paradigms to study motor physiology and movement in healthy
individuals and patients with neurological disorders such as Tourette syndrome and Parkinson’s disease.
His research interests include human motor control, motor neuroscience in neurological disorders and
brain stimulation techniques. He is currently a post-doctoral research fellow working with Professor
Dario Farina at Imperial College London and is also working as a medical doctor at St Thomas’
Hospital, London.

Jamie L. Reed is a Research Assistant Professor of Psychology at Vanderbilt University, Nashville, TN,
USA. She was trained in the laboratory of Dr. J. H. Kaas at Vanderbilt, whose work in comparative neu-
roanatomy and neurophysiology has been foundational in understanding the evolution and functional
organization of sensory and motor systems. There she has continued her long-time research collaborations
to characterize contributions to the receptive field properties of neurons in primary somatosensory cortex
and the effects of sensory loss and therapeutic interventions.

Miguel E. Rentería leads the Computational Neurogenomics Laboratory at the QIMR Berghofer
Medical Research Institute in Brisbane, Australia. He has received recognition for his work, including the
2023 Rosenstrauss Fellowship from the Rebecca L. Cooper Medical Research Foundation in Sydney,
Australia. With a background in human genetics, Miguel holds a PhD from the University of Queensland,
Australia, a Master of Public Policy from Oxford University, and a BSc in Genomic Sciences from the
Universidad Nacional Autónoma de México. He has further advanced his expertise through postdoctoral
research at the Brigham and Women’s Hospital and Harvard Medical School in Boston, USA, supported
by an early career fellowship from Australia’s National Health and Medical Research Council. His
research focuses on using clinical, genetic, and neuroimaging data from global cohorts to understand and
identify biomarkers for complex psychiatric and neurological disorders, including depression, self-harm,
chronic pain, migraine, Parkinson’s disease, and sleep apnea. Additionally, he is an Atlantic Global
Fellow of the Global Brain Health Institute, an initiative from the University of California, San Francisco,
and Trinity College Dublin.

Shannon L. Risacher is trained in medical neuroscience with a focus on neuroimaging of Alzheimer’s

disease and related dementias (ADRD), as well as other neurodegenerative diseases. Her publications
focus on imaging and other biomarkers of ADRD, primarily structural and functional magnetic resonance
imaging (MRI) and positron emission tomography (PET). She has evaluated structural and functional
MRI scans with automated and semi-automated programs, as well as PET scans with multiple tracers (i.e.,
amyloid, tau, etc) from local cohorts (i.e., Indiana Memory and Aging Study (IMAS), Indiana Alzheimer’s
Disease Research Center (IADRC)) and national initiatives (i.e., Alzheimer’s Disease Neuroimaging
Initiative (ADNI)). She also works collaboratively to integrate neuroimaging measures with genetics,
cognitive and clinical variables, medical history, and environmental factors. Dr. Risacher also investigates
novel sensory biomarkers of ADRD, including vision, olfaction, and auditory function in older adults at
risk for ADRD. Finally, she focuses on the impact of lifestyle and co-morbid medical conditions, as well
as medication use, on neuroimaging biomarkers of ADRD.
 The Editors and Contributors xxiii

Giacomo Rizzolatti graduated in Medicine and Neurology in Padua. He has been Professor of Human
Physiology in Parma since 1975. He is member of Accademia Nazionale dei Lincei, Academia Europaea,
Académie Francaise des Sciences, American Academy of Arts and Sciences, National Academy of
Science, Royal Society and Istituto Lombardo. He received the Prize Feltrinelli for Medicine, Grawmeyer
Prize for Psychology, the Prize Prince of Asturias and the Brain Prize for Neuroscience from Lundbeck
Foundation. He has been awarded with Honorary Degrees from Universities of Claude Bernard Lion,
St. Petersburg, K U of Leuven, Sassari, San Martin of Buenos Aires and Universidad de Montevideo.

Rafaella Rogatto de Faria is a Biomedical Engineer graduated from PUC-SP and a Doctoral student in
sciences of the musculoskeletal system at the Faculty of Medicine, University of São Paulo. She works
as a researcher at Cultivare and with projects in the field of tissue engineering and healthcare innovation
at the startup Spero Science Innovation. She won 1st place in the Cândido de Pinto Melo Award, granted
by SBEB at the Brazilian Congress of Biomedical Engineering.

Nicolas Rohleder graduated from University of Trier in Germany, in 2003. He is a psychologist with a
focus on biological and health psychology. His main research interest is on the pathways between Central
Nervous System (CNS) states such as stress, depression, and trauma and pathophysiological changes in
the organism. He currently directs the chair of Health Psychology at Friedrich-Alexander University
Erlangen-Nürnberg.

John C. Rothwell is currently Emeritus Professor of Human Neurophysiology at UCL Queen Square
Institute of Neurology and Fellow of the Academy of Medical Sciences. His work has provided the theo-
retical rationale and methodological developments underpinning the use of transcranial magnetic stimula-
tion (TMS) as a novel therapy in stroke and depression. He has been a primary contributor to our
understanding of how TMS interacts with ongoing brain activity, and has devised techniques to probe
synaptic connections between brain areas that are now used as biomarkers in neurological disease and
movement disorders. He has pioneered methods of repetitive stimulation that modulate synaptic plasticity,
the basis of behavioural learning. This provides a unique opportunity to influence activity in human cer-
ebral cortex and has opened up new therapeutic opportunities in neurology and psychiatry. He is an author
on over 700 publications with an h-index of 159.

Norihiro Sadato is Professor at the National Institute for Physiological Sciences (since 1999) in Japan.
Following completion of his MD, he subsequently earned a PhD at Kyoto University. Dr Sadato’s
research interests include understanding the human brain’s plastic change mechanisms, accompanied by
learning, sensory deprivation, and development of social cognition and its neural correlates (explored via
functional MRI). Other multimodal measures employed by Dr Sadato include the Electroencephalogram
(EEG), Magnetoencephalography (MEG), and Near-infrared spectroscopy (NIRS), as appropriate. In
addition, he utilizes hyper-scanning fMRI (with two MRI scanners) in exploring the neural substrates of
interpersonal cognitive interactions (e.g., during joint attention and eye contact).

Alireza Salami is an Associate Professor and a group leader at the Wallenberg Centre for Molecular
Medicine at Umeå University, Sweden, and a Principal Investigator at the Aging Research Center at
Karolinska Institute, Sweden. He received his PhD in Physiology (Neuroscience) in 2012 from Umeå
University. The main aim of his research is to better understand molecular and functional basis of cogni-
tive decline in normal and pathological aging, using advanced functional magnetic resonance imaging
(fMRI) and positron emission tomography (PET) techniques.

Andrew J. Saykin is the Raymond C. Beeler Professor of Radiology and Imaging Sciences, and
Professor of Medical and Molecular Genetics, Neurology and Psychiatry, at Indiana University School of
Medicine. He serves as director of the IU Center for Neuroimaging as director of the NIA-designated
Indiana Alzheimer’s Disease Research Center. Dr. Saykin leads the Genetics Core of the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) and co-leads several other research consortia including
CLEAR-AD, AI4AD and KBASE. Dr. Saykin’s research program focuses on precision medicine for early
detection of AD and related dementias and identification of disease mechanisms and potential diagnostic
and therapeutic targets. He co-leads a collaborative group of investigators and trainees using integrative
analysis strategies to study the relationship among clinical phenotypes, genetic susceptibility, and
xxiv THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

molecular signatures of Alzheimer’s and other complex diseases. Computational approaches to address
key questions include artificial intelligence (deep learning, machine learning) and network science (brain
connectomics, systems biology and social network analysis). Dr. Saykin participates in multiple pre- and
post-doctoral training programs, is an author or co-author of over 550 publications, and is the founding
Editor-in-Chief of Brain Imaging and Behavior, a Springer-Nature journal.

Martin Seeber obtained his Ph.D. at Graz University of Technology, studying neural correlates of move-
ment including gait. Afterward, he joined the basic neuroscience department at Campus Biotech in
Geneva, Switzerland, to investigate intrinsic, spontaneous brain dynamics by combining intracranial and
scalp electroencephalography. Currently, he is an Assistant Researcher at UCLA, where he aims to better
understand neural oscillations related to movement trajectories and the formation of episodic knowledge
with intracranial EEG and full-body motion capture.

Erich Schröger is a Professor of Cognitive and Biological Psychology at the Wilhelm Wundt Institute of
Psychology at Leipzig University. His fields of research include perception, voluntary and involuntary
attention, memory, and the perception-action cycle, all of which he mainly studies in the auditory domain.

Alexey Semyanov is a Professor of Neurophysiology known for his pioneering work in the field of extra-
synaptic signaling in the brain. He also described local synaptic and perisynaptic signaling mediated by
potassium. His most recent work is related to astrocytic physiology. Semyanov revealed spatiotemporal
properties of calcium activity in single astrocytes and astrocytic networks. In the serious of recent papers,
he described spatiotemporal remodeling of astrocytes in neurodegenerative diseases and ageing.

Marcel Simis is a Neurologist, Neurophysiologist and Physiatrist. He is a Collaborative Professor at

Faculty of Medicine, University of São Paulo (USP). He is the head of the Neuromodulation Laboratory
at Institute of Physical Medicine and Rehabilitation at USP.

Irina G. Skotnikova has a PhD in Psychological Science and is Leading Researcher at the Institute of
Psychology Russian Academy of Sciences, laboratory of Cognitive Processes and Mathematical
Psychology. In 1972 she graduated from the Faculty of Psychology of Lomonosov Moscow State
University, where she specialized in the fields of Psychology of Cognitive and Emotional Processes. The
main fields of research are: psychophysics, visual discrimination, time and face perception, decision
making, individual differences in humans and animals, cognitive styles, confidence, mathematical mod-
eling, subject-oriented psychophysics, animal psychophysics and cognitions. The role of a subject’s activ-
ity structure (of his/her tasks goals and conditions, individual differences and mental states) was revealed
while performing sensory and cognitive tasks in uncertain situations. Thus, a subject-oriented approach
in psychophysics was justified. The research results are presented in more than 140 articles, and results
in the field of psychophysics in 11 handbooks, monographs, and collective monographs.

Angelica Staniloiu is a senior lecturer at the Universities of Bielefeld (Germany) and Bucharest
(Romania). She studied medicine and psychology at Universities in Bucharest, Boston, and Bielefeld and
has certificates and licenses for practicing medicine and psychiatry from the Massachusetts Board of
Registration in Medicine, the Royal College of Physicians and Surgeons (Ontario, Canada), the Medical
Council of Canada, the American Board of Psychiatry and Neurology, and the Government of North-
Rhine Westphalia and the Ärztekammer Münster (for Germany and the European Union). She is staff
psychiatrist at Oberberg Clinic in the Black Forest. She has a number of publications on memory and
memory disorders, consciousness, and emotion, including articles in Lancet on “Amnesic disorders” and
in Lancet Psychiatry on “Dissociative amnesia.”

Pier S. Paolucci is Researcher at INFN (Istituto Nazionale di Fisica Nucleare) in Rome, Italy. His
­interests are the modeling of the beneficial cognitive and energetic effects of sleep during incremental
learning and the development of tools for the characterization and comparison of the spatio-temporal
features of cortical waves expressed by actual brains and brain models. Between 1998 and 2009, he served
as CTO of the design center of a leading semiconductor manufacturer, directing the design of the Diopsis
family of Multi-Processor Systems-on-Chip. Since 1984, he has been a member of the INFN APE
parallel/­distributed computing laboratory, where he has contributed to the application-hardware-software
 The Editors and Contributors xxv

co-design essential for several generations of APE parallel and distributed systems. He is inventor and
co-inventor of several international patents, numerical algorithms, and hardware-software co-design
solutions.

Francesca Starita is a Junior Assistant Professor at the Department of Psychology of the University of
Bologna and researcher at Center of Studies and Research in Cognitive Neuroscience and the Motivation,
Decision and Learning Group. Her research concerns the psychophysiological, cognitive, and neural
bases of human reinforcement learning, decision making and affective processing, with a particular focus
on aversive motivation and fear. She uses a multimodal approach, combining behavioral methods, psy-
chophysiological (e.g. skin conductance, electromyography, eye tracking) and electrophysiological
(EEG) techniques, and non-invasive brain stimulation (e.g. TMS), both in healthy participants and in
patients with brain injury.

Paul C. J. Taylor is a cognitive neuroscientist. After initial graduate and postgraduate work at Oxford
and London he has held positions at LMU Munich in the medicine, philosophy, and psychology faculties.
Paul and his group research into attention, vestibular cognition, and perception during movement. They
often use transcranial magnetic stimulation (TMS) in order to investigate the causal roles of cortical areas
in perceptual cognition. They also contribute to the development of new approaches, such as combining
EEG online with TMS, tACS, eye movements and locomotion, looking for new ways to find out what our
attentional systems do as we explore the world around us.

Matthew Tharp received their B.S. in biomedical engineering from Purdue University where they devel-
oped an interest in data methods in neuroscience while assisting in the development of mathematical
models to study central auditory processing under Dr. Edward Bartlett. They since joined the Center for
Neuroimaging (CfN) and Indiana Alzheimer’s Disease Research Center (IADRC) to provide support for
data projects with a focus in preprocessing methods for neuroimaging and novel analytical approaches in
statistics, dimensionality reduction, and machine learning in addition to developing web applications to
streamline large-scale neuroimaging data management.

Paul M. Thompson is a Professor of Neurology, Psychiatry, Radiology, Pediatrics, and Engineering,

at the University of Southern California (USC) where he directs the Imaging Genetics Center, and is
Associate Director for the Stevens Neuroimaging & Informatics Institute. Professor Thompson is
also PI and Co-founder of the ENIGMA Consortium (http://enigma.ini.usc.edu). ENIGMA has coop-
eratively analyzed data from over 45 countries to publish the largest worldwide neuroimaging studies
of over 15 brain diseases and conditions, including Parkinson’s disease, epilepsy, ataxia and brain
injury, PTSD, substance use disorder, bipolar disorder, and major depression, and neurodevelopmen-
tal conditions including OCD, ADHD and ASD. In parallel, the ENIGMA Consortium has led world-
wide imaging genetics studies that discovered over 500 common and rare genomic variants that
affect brain structure, disease risk, and brain connectivity (Grasby et al., Science, 2020). Recent
efforts have discovered major factors influencing brain development and disease worldwide, in popu-
lations of diverse ancestry. Dr Thompson also co-leads AI4AD - an $18M NIH Initiative developing
AI methods for automatic disease subtyping, genetic target discovery and drug discovery in
Alzheimer’s disease.

Sicong Tu is a cognitive neuroscientist and Lenity Fellow for neurodegenerative disorders at the Brain
and Mind Centre, University of Sydney. He was awarded his PhD from the University of New South
Wales, examining the neural bases of episodic memory in young-onset dementia using multi-modal mag-
netic resonance imaging (MRI). Findings were translated as novel clinical screening assessments now
implemented across multi-national research programs and clinical trials in Alzheimer’s disease. He com-
pleted his post-doctoral studies at the Wellcome Centre for Integrative Neuroscience, University of
Oxford, performing advanced clinical MRI at 3T and ultra-high 7T magnetic field strength to capture
neurodegenerative change. Dr Tu’s research currently specializes in characterizing neural substrates of
cognitive dysfunction across neurodegenerative conditions for the development of novel longitudinal
imaging biomarkers of disease.

Jack van Honk is Professor of Social Neuroscience at Utrecht University as well as at the Neuroscience
Institute, University of Cape Town. He has investigated causal research methodologies in social, affective,
xxvi THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

cultural and clinical neuroscience, using techniques such as EEG, ECG, eye-tracking, fMRI, rTMS, as
well as manipulation of steroid and peptide hormones. He leads the combined University of Cape Town/
University of Stellenbosch research program into the South African variant of Urbach-Wiethe disease
(UWD), a rare genetic disorder resulting in selective calcification of the basolateral amygdala, the social-
emotional center of the brain.

Bernadette C.M. van Wijk earned her PhD in human movement sciences at the Vrije Universiteit
Amsterdam. She focused beta oscillations in the sensorimotor system of healthy individuals using elec-
troencephalography (EEG), magnetoencephalography (MEG), and electromyography (EMG). Since
2013, she has held postdoctoral positions at University College London and the Charité – University
Medicine Berlin, where she investigated LFP recordings from deep brain stimulation electrodes in
patients with movement disorders. Using advanced signal processing techniques (such as cross-frequency
coupling and dynamic causal modeling), she has investigated physiological and pathological neural oscil-
lations within the cortico-basal ganglia network with the aim of improving deep brain stimulation treat-
ment for Parkinson’s disease patients.

Lídia Vaqué-Alcázar obtained her Biomedical Sciences degree from the University of Barcelona. In
2020, she acquired the PhD in Medicine and Translational Research from the University of Barcelona.
As a predoctoral researcher, her main scientific interest has been the study of brain mechanisms that
support preserved cognition in aging. Specifically, she has used multimodal magnetic resonance imag-
ing and non-invasive brain stimulation tools to better understand the structural and functional brain
changes related to the aging processes, the associations of these neural substrates with cognition, and
how cognitive reserve acts as a modulator of these factors and their associations. In 2022, she joined the
Sant Pau Memory Unit as a postdoctoral researcher, where she develops research on reserve and resil-
ience mechanisms in Alzheimer’s disease in adults with Down’s syndrome applying multimodal neuro-
imaging approaches.

Alexei Verkhratsky is an internationally recognized scholar in the field of cellular neurophysiology, best
known for his contributions to our knowledge of the physiology and pathophysiology of neuroglia.
Dr. Verkhratsky also pioneered the emerging field of neurogliopathology, having characterized astroglial
asthenia and paralysis as key pathogenetic steps in age-dependent neurodegenerative diseases. In a series
of conceptual papers and monographs he has outlined basic principles of glial physiology and pathophysi-
ology, which have greatly influenced this rapidly developing area of neuroscience.

Tor Wager is the Diana L. Taylor Distinguished Professor in Neuroscience at Dartmouth College, and
the Director of Dartmouth’s Cognitive and Affective Neuroscience laboratory, the Dartmouth Brain
Imaging Center, and the Dartmouth Center for Cognitive Neuroscience. Professor Wager’s research cent-
ers on the neurophysiology of affective processes – pain, emotion, stress, and empathy – and how they
are shaped by cognitive and social influences. One focus area is the impact of thoughts and beliefs on
learning, brain function, and brain–body communication. Another focus is the development of brain bio-
markers that track and predict affective experience, including pain and other clinical symptoms. A third
focus is on statistical, machine learning, and computational techniques that provide a foundation for new
models of the affective brain. Professor Wager’s laboratory conducts basic research in these focus areas
and applies the resulting techniques and models to collaborative, translational research on clinical disor-
ders and interventions. In support of these goals, Professor Wager and his group have developed several
publicly available software toolboxes (see http://canlab.github.io). He also teaches courses and workshops
on fMRI analysis and has co-authored a book, Principles of fMRI. More information about Dr. Wager and
his lab’s activities, publications, and software can be found at http://canlab.science.

Meghan Whalen is currently a PhD student at Tufts University studying Psychology. Her research
focus is fear learning and affect labeling as a potential treatment for post-traumatic stress disorder
(PTSD), anxiety, and other emotional disorders. Prior to her doctoral studies, Meghan worked in clinical
trials for neuromodulation of chronic pain conditions at Spaulding Rehabilitation Hospital’s
Neuromodulation Center.
 The Editors and Contributors xxvii

Meichen Yu is an Assistant Professor at the Department of Radiology and Imaging Sciences at Indiana
University School of Medicine. Dr. Yu’s research expertise is in the areas of multimodal neuroimaging
(MRI and EEG/MEG) and human connectome analyses in dementia and mood disorders. He worked as
a Postdoc Fellow in Computational Neuroscience at the Department of Psychiatry at the University of
Pennsylvania, Philadelphia. He obtained a Ph.D. in Computational Neuroscience from the Amsterdam
University Medical Center (location VUmc), The Netherlands. He earned his master’s degree in
Theoretical Physics from Lanzhou University in China. Dr. Yu has been serving on the editorial boards of
several peer-reviewed journals, including Brain Imaging and Behavior, Frontiers in Psychiatry, and
Frontiers in Psychology. Dr. Yu’s research has been supported by several grants from the Alzheimer’s
Association and National Institute on Aging. Since 2013, Dr. Yu has published several research articles in
top-tier peer-reviewed journals, such as Nature Reviews Neurology, PNAS, Brain, Trends in Cognitive
Sciences, Neuroimage, Neuroimage: Clinical, Human Brain Mapping, Molecular Psychiatry, Lancet
Psychiatry, Chaos, and Neurobiology of Aging.

Alessandro Zanini completed his undergraduate degree in Clinical Psychology and Neuropsychology at
the University of Milano-Bicocca (Italy), with a master thesis focused on the effects of tDCS on motor
planning in both healthy-brain participants and apraxic patients. He subsequently received his PhD at the
Claude Bernard University of Lyon (France) in 2021, where he studied the behavioral effects and fMRI
responses induced by the presentation of multisensory stimuli within the peripersonal space in humans.
His current research as postdoctoral associate at the Centre for Functional and Metabolic Mapping
(Western University, London, Ontario) focuses on the behavioral, cognitive, and MRI repercussions of
alpha-synuclein propagation in marmosets’ brain.

Laiquan Zou completed his Ph.D. in the Institute of Psychology, Chinese Academy of Sciences,
Beijing, China. He was also a visiting scholar at the Interdisciplinary Center for Olfaction and Gustation,
Technische Universität Dresden, Germany. Currently, Dr. Zou is an Associate Professor in the
Department of Psychology, Southern Medical University, Guangzhou, China. His research is focused on
multimodal brain imaging technology, neurophysiological and psychophysical methods in relation to the
processing mechanism of olfaction in neuropsychiatric diseases such as Anorexia Nervosa, Parkinson’s
Disease, and Schizophrenia.
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 1
Cognitive Neuroscience: Basic
Principles, Systems, and Methods
Gregory J. Boyle, Georg Northoff,
Nadia Bolognini, Aron K. Barbey,
Marjan Jahanshahi, Álvaro Pascual-Leone,
and Barbara J. Sahakian

INTRODUCTION processes can offer not only relevant fundamental

Cognitive neuroscience is the interdisciplinary
study of how cognitive/intellectual functions are
processed and represented within the brain (e.g.,
Braun et al., 2015; Buzsáki, 2019, 2020; Carrion-
Castillo et al., 2020; Chen et al., 2019; Costanzo
et al., 2015; Donoso et al., 2014; Douw et al.,
2016; Gazzaniga, 2018; Gotts et al., 2013; Gross,
1995; McAvoy et al., 2016; Northoff, 2018, 2022;
Picchioni et al., 2007; Poeppel et al., 2020;
Sahakian, 2014; Sahakian and Gottwald, 2016;
Tandon, 2000; Wang et al., 2014; Winters et al.,
2004; Wu et al., 2021, 2022a; Zhang et al., 2022).
Cognitive neuroscience is the result of merging
psychology (i.e., the scientific exploration of
human cognitive mental processes), and neurosci-
ence (i.e., the scientific study of the central
nervous system or CNS), in order to study how the
human brain processes and supports cognitive
functions using rather sophisticated technologies
(e.g., fMRI; fNIRS; MEG – see below). Since its
inception in the early 1990s, cognitive neurosci-
ence has shed substantial light on many such
important questions despite the emergence of
some critiques (e.g., Uttal, 2011). Essentially, the
core belief underlying cognitive neuroscience is
that understanding the neurobiological underpin-
nings of psychological, cognitive, and behavioral
insights into brain–behavioral relations, but pos-
sibly also lead to actionable knowledge that can
lead to impactful translational clinical applica-
tions and novel therapeutic approaches to patients
with various brain-related disabilities.
HISTORICAL TRACES OF COGNITIVE
NEUROSCIENCE
Cognitive neuroscience can be traced historically
to behavioural neurology and clinical neuropsy-
chology during the nineteenth century wherein
patients with brain lesions were investigated
(cf. Boyle et al., 2012b, 2023a,b). The study of
brain-injured patients has revealed how cognitive
functions, such as attention (e.g., visual attention;
Kastner and Ungerleider, 2000), perception
(Pomerantz, 2003), working memory (Baddeley,
2007; Redondo-Camós et al., 2022; Schacter and
Addis, 2007), awareness, and learning (Terry,
2006) are affected by lesions within particular
anatomical areas of the brain. Historically, the
investigation of brain lesions led French neurolo-
gist Paul Broca to discover a distinct brain region
in the left inferior frontal cortex that is primarily
2 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
dedicated to speech production – designated as the
speech motor articulation center (Broca’s area; cf.
Hagoort, 2014). Likewise, Carl Wernicke discov-
ered the predominant sensory speech reception
center (Wernicke’s area) in the left temporo-parietal
cortex, necessary for speech reception and com-
prehension (cf. DeWitt and Rauschecker, 2013).
The application of lesion methods to the study of
large-scale brain networks further enabled the
characterization of cognitive control networks for
adaptive behavior and decision making
(Barbey et al., 2012, 2013; Hsu et al., 2022;
Ji et al., 2019; Shine et al., 2016), along with
neural networks that underlie specific facets of
intelligence (cf. Barbey et al., 2014a, 2021; cf.
Boyle, 1988; Boyle et al., 2012a; Brody, 1992;
Carroll, 1993; Cattell, 1982, 1987; Horn, 1988;
Neisser et al., 1996; Sternberg and Kaufman,
1998; Varshney and Barbey, 2021), including the
ability factors included in the comprehensive
Cattell-Horn-Carroll (CHC) theory of cognitive
abilities (Schneider and McGrew, 2018).
In this context of lesion-studies and brain–
behavior relations, it is important to recall the semi-
nal contributions of Constantin von Monakov who
emphasized the crucial role of the time domain or
“chronometry” in understanding the neural sub-
strate on the basis of brain lesions and argued that
knowing the location and characteristics of a lesion
is necessary but not sufficient in understanding its
impact on behavior (von Monakow and Harris,
1969). Instead, von Monakov pioneered the idea
that lesions impact activity across distributed net-
works of the brain (‘functional localization’) and
the brain in turn adapts to such functional impact
given rise to signs and symptoms (‘symptom
localization’). Informed by such notions and lev-
eraging the capabilities of modern brain imaging,
resting-state functional magnetic resonance imag-
ing, large data-sets, and sophisticated analytic
methodologies, “lesion network mapping” offers
a transformative method to relate patterns of brain
activity and the functional impact of brain lesions
to cognitive processes, behaviors, and symptoms
of disease (Boes et al., 2015; Fischer et al., 2016;
Joutsa et al., 2022; Kim et al., 2021).
In the development of cognitive neurosci-
ence, the early neuroanatomical discoveries by
Broca and Wernicke (cf. Raichle, 2009) and the
theoretical elaborations by von Monakov served
as paradigmatic examples that have extended
into the contemporary connectome mapping
of cognitive, affective, and social functions in
relation to specific anatomical brain regions/
networks (cf. Bassett et al., 2020; Bolognini et al.,
2013; Glasser et al., 2013; Neumann et al., 2015,
2016; Toga et al., 2012; Van Essen et al., 2013).
Localization of cognitive functions to specific
brain regions and networks is distinguished from
a more holistic view that assumes global brain
activity to be central for cognition (equipotential-
ism; cf. Halstead, 1947; Hugdahl, 2000). Initially,
equipotentiality had been defined by Karl Lashley
in the 1950s as the capacity of an intact section
of the brain to carry out functions lost by damage
incurred in other areas of the brain (cf. Fancher
and Rutherford, 2012).
Another historical origin of cognitive neuro-
science was behaviorism at the beginning of the
twentieth century wherein psychological func-
tions were explained in terms of their behavior
as input–output relations (extended into the mod-
ern cognitive science era wherein such functions
are accounted for largely in terms of cognitive
input–output relations). Behavioral scientists rec-
ognized the importance of investigating actual
observable behaviors (e.g., Skinner, 1976; Watson,
2017; cf. Carpintero, 2004; Malone, 2014; Rilling,
2000). Behaviorism did not deny the existence
of subjective experiences but viewed any con-
scious or cognitive phenomena (Gage and Baars,
2018; Kosslyn and Andersen, 1995) as depending
on the behavior of the organism. As subjective
experience (e.g., cognition) was defined as inac-
cessible for scientific inquiry, this shifted the focus
onto behavioristic stimulus–response relation-
ships. Such stimulus–response relationships have
been studied with different types of tasks such as
simple choice, and go- versus no-go reaction times
that have measured and compared response times
to a wide range of incoming stimuli (Jahanshahi,
2003). In conjunction with the go- no-go reac-
tion time tasks that allow investigation of action
restraint, subsequent development of a stop sig-
nal reaction task (Logan and Cowan, 1984) and
variants of this have facilitated the study of behav-
ioural inhibition, which is an important compo-
nent of cognitive control (Jahanshahi et al., 2015).
In recent decades, there has been extensive
examination of the brain regions and neural
networks involved in the stop signal reaction time
task. Aron et al. (2003) discovered that a neural cir-
cuit including the right inferior frontal gyrus was
responsible for response inhibition. A subsequent
study demonstrated a reduction in impulsivity by
drugs that enhance both dopamine and noradren-
aline activity in the brain, such as methylpheni-
date, but also drugs which were more selective for
noradrenaline, such as atomoxetine (Chamberlain
et al., 2006). In a functional magnetic resonance
imaging (fMRI) study, Chamberlain et al. (2009)
showed that atomoxetine modulated right infe-
rior frontal activation during inhibitory control,
thus demonstrating that noradrenaline modulates
response inhibition by its actions on the right
inferior frontal gyrus.
 Cognitive Neuroscience: Basic Principles, Systems, and Methods
Current Status of Cognitive
Neuroscience
Cognitive psychology merged with neuroscience,
leading to the development of cognitive neurosci-
ence as an autonomous discipline in the late
1980s, with many researchers who had been car-
rying out psychological and behavioral studies
now looking for neuroscientific explanations of
their findings. During the twentieth century, cog-
nitive psychology emerged as a separate field of
study, which together with the development of
computational models (Churchland and
Sejnowski, 1988, 2017; Dayan and Abbott, 2001)
served as a basis for the subsequent emergence of
cognitive neuroscience (the so-called “cognitive
revolution” – Boone and Piccinini, 2016;
Gazzaniga et al., 2018; Mandler, 2002; Miller,
2003; Poeppel et al., 2020). Now cognition was
seen as mediating the behavioral response to sen-
sory input and therefore central to understanding
the nature of human behavior (cf. Cuzzolin et al.,
2020; Laird et al., 2017; Langley et al., 2022).
Other key ideas from the “cognitive revolution”
included that while the mind is modular, with
distinct neural systems dedicated to specific func-
tions, orchestrated in the service of complex, goal-
directed behavior (Pinker, 2002).
Emergence of the “cognitive revolution”
opened the door for investigating the multifaceted
neural underpinnings of cognitive functions such
as attention, working memory, and executive func-
tions, as well as of higher-order processes includ-
ing conceptualization of the self and consciousness
(Chan et al., 2008; Chiao et al., 2009a,b; Chiao and
Blizinsky, 2016; Fregni et al., 2005; Gazzaniga,
2018; Northoff, 2014a,b; Northoff et al., 2006;
Poeppel et al., 2020; Schaefer and Northoff,
2017), paving the way for the future dialogue with
other disciplines such as social cognition and the
psychological study of personality (cf. Boyle,
2019; Boyle and Saklofske, 2004a,b; Boyle et al.,
2008a,b; 2015; Neumann et al., 2016).
CAMBRIDGE NEUROPSYCHOLOGICAL
TEST AUTOMATED BATTERY
In response to gaining a better understanding of
attention, working memory and executive function
processes, a computerized battery incorporating a
wide variety of objective neuropsychological
tests – the Cambridge Neuropsychological Test
Automated Battery or CANTAB (camcog.com) –
was constructed (Robbins et al., 1994, 1997,
2012). Many CANTAB subtests have since been
3
adapted for neuroimaging (cf. Langley et al.,
2023). For example, during the CANTAB paired
associates learning task (PAL), at lower levels of
difficulty, the hippocampi of MCI patients were
activated significantly more than in controls, and
significantly less at higher levels of difficulty.
Thereby, providing neural validation for the
CANTAB PAL test in the early detection of
Alzheimer’s disease (De Rover et al., 2011).
Using the CANTAB intra extra dimensional set
shifting task (IED), Langley et al. (2021) showed
that the frontal striatal circuits involved in
cognitive flexibility were altered in premanifest
Huntington’s disease. Moreover, development of
objective standardized neurocognitive psychomet-
ric testing has also aided in the understanding of
neuromodulation by neurotransmitters (cf.
Pama et al., 2013; Sahakian and Owen, 1992).
Mehta et al. (2000) using the CANTAB spatial
working memory task (SWM) showed that meth-
ylphenidate induced improvements in working
memory performance, which was associated with
task-related reductions in regional cerebral blood
flow in the dorsolateral prefrontal cortex and pos-
terior parietal cortex. This demonstrated that
methylphenidate improved performance through
greater efficiency of the neural network underly-
ing working memory. In addition, they found that
the beneficial effects of methylphenidate on work-
ing memory were greatest in the subjects with
lower baseline working memory capacity (e.g.,
episodic autobiographical memory recall;
Roehri et al., 2022).
Role of Emotions and Nonconscious
Processes
However, until 1990s, the role of emotions and
nonconscious processes remained largely
neglected by cognitive neuroscientists. At that
time, researchers prioritized the analysis of
mental states that could be translated in terms of
computational operations, namely perception,
learning, and memory, excluding the study of
emotions, affects, and nonconscious processes
among the research interests of the cognitive
neurosciences (Barbey et al., 2014b, 2014c;
Damasio, 2000; LeDoux, 2000). Recently, com-
puterized batteries for assessing social and emo-
tional cognition have also been developed. For
example, the EMOTICOM battery has not only
been used in healthy volunteers (Bland et al.,
2016), including with tryptophan depletion
(Kanen et al., 2021), but also in patients with
depression (Dam et al., 2019) and Huntington’s
disease (Scahill et al., 2020).
4 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
METHODOLOGIES AND TECHNIQUES IN
COGNITIVE NEUROSCIENCE
In more recent years, leveraging further techno-
logical developments, new tools have emerged
that capture behavior and cognitive processes with
exquisite sensitivity leveraging mobile sensors
and multimodal signal acquisition (Gomes-Osman
et al., 2021; Libon et al., 2022; Souillard-Mandar
et al., 2021). Digital technologies can offer time-
efficient brain assessments that uncover issues not
otherwise detectable using standard tests. First,
they can capture metrics with a much higher sam-
pling rate than a human observer (e.g., eye move-
ments, postural and facial expressions, drawing,
writing, and spoken output). Second, they enable
the analysis of process by quantifying neurocogni-
tive operations in real time as individuals try to
solve a given task (e.g., Boston Process Approach),
thus quantifying with great accuracy highly
nuanced and subtle behaviors previously unob-
tainable. Third, data-driven AI-supported analytic
approaches can detect subtle signs of brain decline
and illness with greater sensitivity and specificity
so they can be better managed before they become
clinically evident and disabling for the patient.
Importantly, such approaches can be deployed in
real-life settings, avoiding the need for the stress-
ful and artificial constraints of formal testing
conditions.
Cognitive neuroscience has been greatly facili-
tated by the emergence of cutting-edge brain
imaging technologies over recent decades, making
it possible to investigate the neural correlates of
various cognitive functions including identifica-
tion of which regions/networks and frequencies in
the brain’s neural activity are recruited in response
to specific cognitive tasks (Bassett and Sporns,
2017). Both single photon emission computed
tomography (SPECT), and positron emission
tomography (PET) emerged in the 1970s (Portnow
et al., 2013). For example, a relatively early study
combined the spatial resolution of PET with the
temporal resolution of movement-related poten-
tials, to compare the neural substrates of temporal
decision-making by comparing self-initiated and
externally triggered movements. This compari-
son revealed that the dorsolateral prefrontal cor-
tex mediated volitional decisions about timing of
movements; whereas the activation of the supple-
mentary motor area (SMA) related to preparation
(Jahanshahi et al., 1995), and as confirmed in a
subsequent PET study of stimulus predictability,
the activation of the rostral SMA relates to prepa-
ration whereas the caudal SMA is a motor execu-
tion area (Jenkins et al., 2000). Subsequently,
nuclear magnetic resonance (NMR) became
possible – later termed magnetic resonance imag-
ing or MRI (see NMR Progress Report, 1984).
Using fMRI, the experimenter can administer a
cognitive task that manipulates an independent
variable (e.g., the number of items to be main-
tained in working memory) and measure the
Blood-Oxygen-Level-Dependent (BOLD) signal
(dependent variable), while simultaneously moni-
toring brain activity (Ogawa et al., 1992) in spe-
cific neuroanatomical regions or networks. While
early work using neuroimaging focused on finding
“brain lesions” or other biomarkers of pathology,
contemporary research is focused on detecting
disruptions in the of neurocircuitry connectiv-
ity including subtle “brain signatures” associated
with certain brain disorders. In addition, high-
resolution, high-density electroencephalographic
(EEG) methods along with computational analysis
of the recorded signals, enables the identification
of spatio-temporal patterns of brain activity linked
to specific cognitive processes, disease symptoms,
and behaviors (Michel and Pascual-Leone, 2020).
Non-Invasive Brain Stimulation
(Neuromodulation) Techniques
More recently, non-invasive neuromodulation
techniques including transcranial electrical stimu-
lation (tES; Brunoni et al., 2022; Fregni et al.,
2005; Woods et al., 2016), and transcranial mag-
netic stimulation (TMS; Caballero-Villarraso
et al., 2022; Jannati et al., 2023; Pascual-Leone
et al., 1991, 1999, 2000, 2005, 2011; Redondo-
Camós et al., 2022), have expanded our knowledge
of brain plasticity (Pascual-Leone et al., 2005) by
probing the causal contribution of brain areas to
behaviour, moving beyond the correlational meth-
ods of fMRI (Boes et al., 2018; Frohlich, 2016)
and enabling the dissection of chronometric pro-
cesses of cognition and the mind (Pascual-Leone
et al., 2000; Walsh et al., 2006; Walsh and Pascual-
Leone, 2003). Both tES and TMS can be combined
with high spatial and temporal resolution tech-
niques (MEG1-EEG; EEG-fMRI; EEG-fNIRS2),
linking structural and neurochemical data (PET-
CT; PET-MRI), or using one modality to alter
neurocircuitry, and another to establish in vivo the
disruptive impact (e.g., fMRI-TMS or tES; TMS-
EEG; TMS-fNIRS; EEG-tES; cf. Bolognini and
Diana, 2021; Bolognini and Ro, 2010; Farzan
et al., 2016; Shafi et al., 2012; Wagner et al., 2007).
Such multi-modal association approaches further
helped to elucidate human brain networks and the
mechanisms by which they process cognition,
behavior, and emotion. In an early review of appli-
cations of TMS for the study of cognition, the
 Cognitive Neuroscience: Basic Principles, Systems, and Methods
range of questions that could be addressed with
TMS included a temporary “lesion” effect to deter-
mine whether the contribution of a target area to
task performance is essential, identifying the time
course of cognitive processes (i.e., time window
during which the contribution of a brain area is
essential or the relative timing of the contribution
of two or more brain areas to task performance),
what changes in excitability occur in target brain
areas with learning, and investigation of intracorti-
cal and transcallosal connectivity (Jahanshahi and
Rothwell, 2000). TMS can be reliably and safely
applied to disrupt the activity of a given brain
region transiently and thus provide insights about
the causality of brain activity in behavior. As an
early application, Pascual-Leone et al. (1991)
showed that repetitive TMS can be used to induce
speech arrests and study language networks in
health and disease – the Neuronix eXimia System
is now cleared by the Food and Drug Administration
in the United States for this application. Similar
application of “temporary lesion approaches”
using the controlled perturbation induced by TMS
and guided by brain imaging, has served to clarify,
for example, the causal role of primary visual
cortex (Kosslyn et al., 1999), and the dynamics of
interhemispheric compensatory processes (Sack
et al., 2005), during mental imagery; or the need
for fast back-projections in visual awareness
(Pascual-Leone and Walsh, 2001).
Subsequent electrophysiological research has
employed TMS not only for establishing functional
specialization, but also for examining functional
connectivity, afunctional interaction, and integra-
tion within the cognitive domain (Jahanshahi,
2005). Other applications of TMS to the investi-
gation of cognition have included the pharmacol-
ogy of cognition through the study of the effects
of medication, the impact of surgical or rehabili-
tative interventions, as well as brain damage, and/
or neurological or psychiatric disorders on cogni-
tion (Jahanshahi, 2005; Jahanshahi and Rothwell,
2000). Subsequent applications of TMS as a thera-
peutic tool have included increasing processing
speed, improving selective attention or naming,
improving accessibility to memory, or enhancing
implicit learning (Bolognini and Miniussi, 2018;
Jahanshahi, 2005; Vallar and Bolognini, 2011). In
addition, in treatment resistant patients with obses-
sive-compulsive disorder, deep brain stimulation
(DBS) has been shown to improve cognitive flex-
ibility (Tyagi et al., 2019). The past 25 years has
brought substantial advances in knowledge about
the mechanisms of action of non-invasive brain
stimulation; novel and more precise technologies;
safety, training, regulatory and ethical guidelines
along with research applications and their clinical
translation. New non-invasive brain stimulation
5
methods and techniques, such as Temporal
Interference Stimulation (TIS) enable more precise
and even selective non-invasive stimulation of deep
brain structures (Grossman et al., 2017).
DECADE OF THE BRAIN:
COMPUTATIONAL APPROACHES AND
COGNITIVE NEUROSCIENCE STUDIES
The decade of the brain (Jones and Mendell,
1999) has inspired extensive brain mapping efforts
worldwide, including the Human Brain Project in
Europe (HBP; Markram et al., 2011; Sahakian
et al., 2021), the ENIGMA Consortium (Kong
et al., 2018), the Human Connectome Project
(HCP; Toga et al., 2012; cf. Glasser et al., 2013;
Van Essen et al., 2013), the China Brain Project
(CBP; Poo et al., 2016), and the BRAIN Initiative
(BI; Litvina et al., 2019). Some of the highlights
of the HBP include the development of the
Julich-Brain Atlas (JBA; Amunts et al., 2020) and
the Virtual Epileptic Patient (VEP; Jirsa et al.,
2017). The European-funded HBP has also cre-
ated EBRAINS, an open research infrastructure
built on the scientific advances and tools devel-
oped by the project’s research teams, and making
them available to the scientific community via a
shared digital platform (https://ebrains.eu/).
Computational tools have been developed and
Big Data has been compiled (Fox and Lancaster,
2002; Yarkoni et al., 2011), as well as the recent
standardization Neuroimaging Meta-Analysis
Research Environment (NiMARE)3 endeavor.
The aim has been (1) to link functional and struc-
tural brain maps to cognitive tasks from previous
studies and (2) to amass and share large data sets.
These large-scale collaborations have enabled
application of artificial intelligence techniques
using machine learning to predict behavior from
measures of brain activity (Li et al., 2019). The
combination of Big Data from neuroimaging with
the human genome project and genetic neuroimag-
ing provide remarkable opportunities for the next
decade of research and discovery in cognitive neu-
roscience. Even more powerful is when these Big
Data cohorts include neuroimaging, cognitive and
behavioural measures, such as in the IMAGEN,
ABCD, and UK Biobank research projects.
Recent publications from these large cohorts have
investigated many aspects of brain and behavioral
function, including sleep (Li et al., 2022), social
isolation (Shen et al., 2022), attention deficit
hyperactivity disorder (Shen et al., 2020a,b), OCD
(Wu et al., 2022b), and the androgynous brain
(Zhang et al., 2021).
6 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Comparative Cognitive Neuroscience
Including Studies Into Infra-Human
Species
The study of non-human primates is also an area
of interest in cognitive neuroscience that examines
our similarities with respect to cognitive capabili-
ties, physiology, neuroanatomy, social complex-
ity, reproduction, and development. Recent
developments in magnetic resonance imaging, for
instance, have the potential for extracting neuro-
biological measures that can be compared between
species within a phylogenetic framework.
Comparative cognitive neuroscience enriches the
understanding of how the human brain works and
the appreciation of its uniqueness by looking to
problems the brain evolved to solve and how these
relate to its organization (Mars et al., 2014). Both
historical lines of development involving the neu-
roscientific study of the human brain and of the
brains of non-human primates allows comparative
cognitive neuroscience to share certain empirical
features and philosophical assumptions.
Spatiotemporal Cognitive
Neuroscience
However, both the human and non-human primate
models of cognitive neuroscience have certain
limitations with respect to mental features like self
and consciousness (e.g., Chiao et al., 2009a,b)
making necessary its extension into what has been
termed “spatiotemporal cognitive neuroscience.”
Most cognitive neuroscientists agree that we need
to link mental operations to brain functions and to
do so within an interdisciplinary framework that
appreciates the importance of both experimental
cognitive psychology and neuroscience. We
emphasize the need for approaches that seek to
integrate experimental psychology with cognitive
neuroscience, such as spatiotemporal cognitive
neuroscience (Northoff and Hirjak, 2022; Northoff
and Huang, 2017; Northoff et al., 2020a,b), as
well as cognitive computational neuroscience
(Kriegeskorte and Douglas, 2018).
SUMMARY AND CONCLUSIONS
Over recent years, cognitive neuroscience has
been greatly facilitated by development of cut-
ting-edge brain imaging technologies, enabling
investigation of the neural correlates of various
cognitive functions and the identification of
which regions/networks in the brain’s neural
activity are recruited in response to specific cog-
nitive tasks (Bassett and Sporns, 2017). The
decade of the brain (Jones and Mendell, 1999)
has inspired extensive brain mapping efforts
worldwide, including the Human Brain Project
in Europe (HBP; Sahakian et al., 2021), the
ENIGMA Consortium (Kong et al., 2018), the
Human Connectome Project (HCP; Toga et al.,
2012), the China Brain Project (CBP; Chang
et al., 2021), and the BRAIN Initiative (BI;
Litvina et al., 2019). Some of the highlights of
the HBP include the development of the Julich-
Brain Atlas (JBA; Amunts et al., 2020) and the
Virtual Epileptic Patient (VEP; Jirsa et al.,
2017). It has also created EBRAINS, an open
research infrastructure available to the scientific
community via a shared digital platform (https://
ebrains.eu/). Computational tools have been
developed and Big Data has been compiled
(Yarkoni et al., 2011), as well as the recent
Neuroimaging Meta-Analysis Research
Environment (NiMARE) endeavor.
Combining Big Data from neuroimaging with
the human genome project and genetic neuro-
imaging (e.g., Wu et al., 2022b) has enabled
remarkable opportunities for future research and
discovery within cognitive neuroscience. These
Big Data cohorts include neuroimaging, cogni-
tive and behavioural measures, such as in the
IMAGEN, ABCD, and UK Biobank research
projects. Recent publications from these large
cohorts have investigated many aspects of brain
and behavioral function, including sleep (Li et al.,
2022), social isolation (Shen et al., 2022),
attention-deficit hyperactivity disorder (Shen
et al., 2020a,b), obsessive-compulsive disorder
(Wu et al., 2022b), and the androgynous brain
(Zhang et al., 2021).
One point we wish to emphasize is that even
though the cognitivist paradigm reintroduced the
notion of “mind” into experimental cognitive psy-
chology, it led cognitive neuroscience into mutu-
ally exclusive paradigms, both philosophically
and empirically, which have resurfaced in terms
of the distinction between the brain’s neuronal
activity versus cognition. Recent developments
have expanded the spatiotemporal framework of
cognitive neuroscience by intrinsically integrating
both neuronal activity and cognition, into the cur-
rent approach of “Spatiotemporal Neuroscience.”
Clearly though, we consider that there is need for
approaches that seek to integrate, for example,
cognitive neuroscience with spatiotemporal neu-
roscience, along with cognitive computational
neuroscience.
 Cognitive Neuroscience: Basic Principles, Systems, and Methods
Notes
1  MEG: Magnetoencephalography (a non-invasive
functional neuroimaging technique) measures
magnetic fields at the scalp resulting from electri-
cal brain activity.
2  fNIRS: functional Near-Infrared Spectroscopy (a
non-invasive optical imaging technique) mea-
sures brain changes in hemoglobin concentra-
tions upon light being shone through the skull
and refracted back to a specialized detector
(optode).
3  NiMARE provides workflows as command-line
interfaces, including ALE meta-analysis, meta-
analytic coactivation modeling (MACM) analysis,
peaks2maps image reconstruction, and contrast
map meta-analysis. Each workflow generates a
boilerplate paragraph with workflow details and
relevant citations.
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hbm.26024
 PART I
Background Considerations
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Historical, Empirical, and
Philosophical Perspectives on
Cognitive Neuroscience
Georg Northoff and Philipp Klar
INTRODUCTION
The development of neuroimaging in the last
three decades, especially since the dawn of func-
tional magnetic resonance imaging (fMRI) from
1990 to 1992 (Bandettini et al., 1992; Kwong
et al., 1992; Ogawa et al., 1992), led to an emerg-
ing novel domain in brain research. This novel
domain allows merging cognitive psychology
with neuroscience, namely, cognitive neurosci-
ence (Gazzaniga et al., 2018; Passingham, 2016).
The convergence between both scientific disci-
plines allowed to introduce cognitive concepts
from psychology into neuroscience. The opera-
tionalization of cognitive concepts enabled their
utilization for neuroimaging. Cognitive neurosci-
ence was consequently able to map cognitive
functions onto both brain areas and networks,
reflecting localizationism.
To link the mind with the brain, traditionally,
task-based research designs are utilized in fMRI.
While lying in the scanner, the subject has to per-
form a task during which the brain’s higher blood-
oxygenation-level-dependent contrast (BOLD)
relative to another task and/or baseline level is
measured in distinct areas of the brain. Such
research paradigm is a partial reminiscence of
behaviorism in a more cognitive way: the measured
2
brain’s neuronal activity is conceived to be a pas-
sive response to exteroceptive input provided by
the environment, e.g., to visual or auditory stimuli
by the respective task. The brain is consequently
treated as a passive or reflexive organ in relation to
the environment (Northoff, 2018a; Raichle, 2015).
Notably, the discovery of the default-mode-
network (DMN) of the brain’s intrinsic sponta-
neous activity in 2001 (Raichle et al., 2001) led
to additional and intensive resting-state research
designs. Contrary to task-based research designs,
where task-evoked or stimulus-induced activity of
the brain in response to extrinsic stimuli is inves-
tigated, resting-state designs (Northoff, 2014a;
Raichle, 2015) aim to understand the brain’s con-
stantly ongoing intrinsic spontaneous activity, that
is, spontaneous activity (BOLD fluctuations) that
correlate across brain areas independent of a task.
Here, in addition to the passive-reflexive side of
the brain, an additional active side of the brain’s
intrinsic functional architecture and organization
comes into play (Northoff, 2018a). What is ulti-
mately measured even in task-based designs, pre-
cisely stimulus-induced/task-evoked activity, is
the result and hybrid mixture of a dynamic inter-
action between the intrinsic spontaneous activity
and extrinsic stimuli (Boly et al., 2007; Braun
et al., 2021; Deco et al., 2013; Fox et al., 2007;
18 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
He, 2013; Huang et al., 2017; Raichle, 2015;
Wainio-Thberge et al., 2021; Wolff et al., 2021).
Subjects are usually instructed to lie in the scanner
without thinking of anything in particular in one of
three possible conditions: (1) eyes open, (2), eyes
closed, or (3) eyes open focusing a fixation cross.
The brief introduction of resting-state and
task-based paradigms in fMRI research reflects
a central theoretical aspect in cognitive neurosci-
ence: a fluctuation between the inside of the brain
(i.e., the resting-state activity), and the outside
(i.e., cognition and behavior). This inside-outside
dichotomy has recently been thematized in cog-
nitive neuroscience by various authors includ-
ing Buszaki (2019, 2020), Northoff (2012, 2014,
2018b), Poeppel and Adolfi (2020), and Raichle
(2010). We introduce the inside-outside trajecto-
ries over the course of the chapter stemming from
the historical origins of cognitive neuroscience.
FROM LOCALIZATIONISM TO COGNITIVE
NEUROSCIENCE
Brain function is related to specific
regions
One of the main methodological approaches in
neurology at the beginning of the twentieth cen-
tury, when neuroscience as a distinct scientific
discipline did not exist, was the investigation of
patients with brain lesions. These patients revealed
how cognitive functions, paradigmatically aware-
ness, memory, attention, or learning, were affected
by lesions in particular regions. The investigation
of brain lesions led the French neurologist Paul
Broca (1824–1880) to a famous discovery of a
distinct region in the left frontal cortex that cor-
responds to speech production, today called
Broca’s area. Broca observed that patients with a
lesion in the left lateral frontal cortex showed
major deficits in producing words and language,
hence presenting expressive aphasia. These clini-
cal observations led Broca to infer that the regions
BA44 and 45 must be in charge of producing
words, thus localizing speech production in
Broca’s area. Observation of patients with lesions
and their corresponding disturbances has since
been a major tool of insight into brain function.
Besides distinct cognitive functions, conscious-
ness and particularly self-consciousness are cur-
rently investigated in neurological patients who
suffer from various localized lesions in the brain
(Feinberg, 2009; Feinberg and Keenan, 2005). It
can be argued that the recent shift from single and
clusters of areas towards widespread networks
(Menon, 2011) changes the conceptual and empir-
ical approach.
The shift from areas to networks is rather quan-
titative than a qualitative change (i.e., a change in
degrees). One can thus speak of a localization-
based approach to the brain and its constitutive
role for experience and behavior. The localization-
based approach is defined in two principal ways.
First, it implies the neuropsychological assump-
tion that a particular cognitive function identifies
with neural activity in a specific brain region or
network. The methodological localization by
neuropsychology and cognitive neuroscience in
regions and networks has its roots in the meta-
physical domain. The philosophical assumption
is that of identity or emergence between human
experience and the brain’s neuronal activity in
specific regions and networks. Today, localiza-
tionism is one of the guiding theoretical forces of
functional magnetic resonance imaging (fMRI).
For this reason, we will elaborate more on locali-
zationism in the following.
From regions to modules
Localizationism of cognitive functions via lesion
studies and neuroimaging stems from the theory
of modules by cognitive psychology. Cognitive
psychology proposed specific functional modules
in charge of processing sensory input and that
modular-based computational processes would
subsequently lead to phenomenal representations
and their associated behavior.
Historically, the idea of the mind’s rational or
modernly speaking cognitive modules traces back
to the roots of psychology in philosophy. The
German philosopher Immanuel Kant (1724–1804)
developed the idea of a priori categories in one of
his main books, namely the Critique of Pure Reason
(Kant, 1781/1996). A priori categories constitute
even the most basic aspects of human experience,
such as space, time, and causality. Following
Kant’s transcendental philosophy, the experience
of space and time derives from the human mind’s a
priori categories. The latter provide a general point
of view that is subsequently applied to the world
for the very possibility of experience. In Kant’s
transcendental philosophy, the status of a priori
categories is not ontological, i.e., based on the
world independent of human experience, but epis-
temological. The mind’s a priori categories offer
no intuitive information about the thing-in-itself
or the noumenal world. In Kant’s terminology,
these terms describe the world apart from human
experience. Instead, the mind and inherent a pri-
ori categories reflect the insurmountable window
 HISTORICAL, EMPIRICAL, AND PHILOSOPHICAL PERSPECTIVES
through which we perceive ourselves in relation to
the world, hence categories are a priori – prior to
and shaping experience. Consequently, the mind’s
a priori categories concern limitations of principal
human knowledge about the world beyond shap-
ing immediate and pre-reflective phenomenology.
The philosophical-epistemological idea of
categories of human perception and cognition
emerged in the famous psychological school of
Gestalt Psychology (Koffka, 1935; Lersch, 1956;
Wertheimer, 2017). At the beginning of the twenti-
eth century, Gestalt psychology schools appeared
in central Europe, mainly from the Austrian and
German universities (in Graz, Leipzig, and Berlin).
The German word “Gestalt” means form or pat-
tern. The Gestalt psychologists proposed gestalt
principles of human perception such as proxim-
ity, similarity, closure, continuity, or common
fate (Köhler, 1920, 1935). The Gestalt psycholo-
gists chose this term to refer to their idea that the
perception of the whole is more or different from
the sum of its single constituents. Concerning the
formation of human experience, the mind contrib-
utes intrinsic ingredients to sensory input from the
environment. The philosophical reminiscence is
obvious: the principal idea of Kantian categories
reappeared in scientific psychology. Kant was
probably among the first philosophers who, in
modern terms, introduced the notion of cogni-
tive functions as distinct from sensory inputs. The
philosophical idea of categories and their trans-
lation into psychology as modules is one of the
factors that laid the theoretical background for
the so-called “cognitive revolution” which started
in the second half of the twentieth century. The
cognitive revolution represents a paradigm shift in
psychology from behaviorism to cognitivism and
cognitive science. At the same time, the develop-
ment of modern computer systems provided terms
such as “modules” and “information processing”
to cognitive psychology. In analogy to computer
systems, modules represent solid and geneti-
cally determined neuronal substrates underlying
human perception and cognition (Fodor, 1983,
1985, 1998). The abstract and formerly genuine
philosophical idea of the mind’s categories found
application on the empirical level of neuropsy-
chology. When cognitive psychology fused with
neuroscience, the concept of psychological mod-
ules could perfectly converge with the former neu-
rological theory of localizationism (van Eijsden
et al., 2009). Localizationism holds in cognitive
neuroscience: “I take the modular organization of
many brain systems as a well-established fact, and
discuss only how far fMRI can go in revealing the
neuronal mechanisms of behavior by mapping dif-
ferent systems modules and their dynamic inter-
relationships” (Logothetis, 2008).
19
However, recent findings in brain imaging put
such modular organization into a wider context
of a hierarchical whole-brain organization (i.e.,
topography). For instance, there is a topographic
distinction of core and periphery: core regions
(like default-mode network regions) are strongly
connected among each other while peripheral
regions (like sensory regions) are less connected
with each other and the core regions (Golesorkhi
et al., 2021; Margulies et al., 2016, Smallwood
et al., 2021). Hence, single modules such as par-
ticular sensory systems (e.g., auditory or visual)
are integrated within a hierarhical-topographic
organization of the whole brain.
Cognitive ontology
Localizationism converges with the more recent
idea of “cognitive ontology” from cognitive neu-
roscience (Bilder et al., 2009, 2013; Poldrack
et al., 2011). Cognitive ontology holds a broad
definition of cognition. In cognitive ontology,
cognition refers to all psychological contents and
processes. While the term “cognition” appears
harmless, it lacks a profound conceptual defini-
tion. What is missing is a unified theoretical
framework about cognition that could converge
the epistemological dualism between the psychol-
ogy of human experience and physiological pro-
cesses in the nervous system. In cognitive
psychology and neuroscience, the term cognition
is broadly equated with mental, rational, complex
phenomena, or, broadly speaking, consciousness.
Cognitive ontology reaches even beyond brain
function, as it assumes that not only cognitive
phenomena can be mapped onto specific brain
regions and networks, but even on genes (Poldrack
et al., 2011). The modular theory of the mind thus
perfectly matches cognitive ontology. Cognitive
neuroscience proposes the disassembly of the
mind into various constituents that would allow
human brain mapping. Processes of the brain and
its functions are consequently considered primar-
ily in cognitive terms and models.
One ultimate goal of cognitive ontology is the
development of a “cognitive atlas” in human brain
mapping (Poldrack et al., 2011). Inferences of the
functional topography in the brain rest on correla-
tions between cognitive-behavioral tasks and neu-
ronal activation patterns. Best possibly, specific
task performances supposedly represent isolated
cognitive functions. Respective concepts describ-
ing cognitive entities or functions are related to
each other. For that reason, cognitive ontology
distinguishes between different kinds of relations
between concepts that stem from cognitivism. For
20 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
instance, concept A is identical with concept B, or
A could be part of B, hence presenting a mereolog-
ical relation. B could result from a transformation
of A, and A could cause B (Poldrack et al., 2011).
These connections are logical-conceptual relation-
ships between different cognitive concepts. It is
questionable to what extend logical relationships
correspond to neurobiological processes in the
brain. Logico-conceptual relationships can demar-
cate the boundary of unambiguous localizationism
in cognitive neuroscience between cognition and
correlated statistical parametric maps in fMRI.
However, several criticisms of the use of neuro-
imaging techniques in the field of cognitive neu-
roscience are evident. Methodological concerns
especially about the use of fMRI arise in relation
to the particular statistical and data analytic opera-
tions carried out (Sucz and Ionnaides, 2017), as
well as concerns in relation to physiology (e.g., the
neuro-vascular BOLD effect; Logothetis, 2008).
In order to reconstruct what happens in the brain
based on how blood is distributed it is necessary to
adopt many intermediate operations to move from
the distribution of blood to the distribution of acti-
vations in the various brain areas. These interme-
diate operations are, in most cases, unknown to the
researcher who relies on the expertise of physicists
and computer scientists for their execution which
almost always involves “packages” of statistical
operations applied, more or less blindly. These
operations are prone to errors (on the incorrect use
of statistical inference in the field of neuroscience;
Button et al., 2013; Eklund et al., 2016; Szucs and
Ioannidis, 2017).
In addition, epistemological issues including
the distinction of instruments (e.g., thermometer)
versus apparatus (e.g., fMRI) need to be consid-
ered when interpreting fMRI data (Metraux and
Frisch, 2020). The process of measuring brain
activation via fMRI differs greatly from measur-
ing temperature using quicksilver thermometers,
or from measuring atmospheric pressure through
barographs. The difference is not linguistic, but
rather ontological and epistemological in nature.
Epistemological issues also arise in the case of
cognitive ontology. Since cognitive ontology
defines human experience in sole cognitive terms,
both on the empirical level of conceptualiza-
tion and operationalization, the epistemological
gap and the language barrier between cognition
and brain is re-confirmed rather than bridged.
Cognitive ontology itself seems to acknowledge
implicitly such a gap when speaking about a
“latent unobservable construct” (Poldrack et al.,
2011) and the observables of the brain’s physi-
ological processes. Missing in the current frame-
work of cognitive neuroscience and its ontology
is what we label the “common currency” between
consciousness and corresponding physiological
processes of the nervous system (Northoff et al.,
2020). How seemingly two epistemological and
natural levels of reality, namely the philosophi-
cal assumption of an inside level (cognition and
consciousness) as opposed to another outside level
(biological and physiological processes of the
brain), can be overcome remains inconceivable.
Note that the notions of inside and outside take
in a more epistemological than empirical mean-
ing. Empirically, we can observe that the inside
is associated with the brain and the outside with
cognition (Buszaki, 2019, 2020). Taken in a more
epistemological context, the inside is associated
with cognition or consciousness (i.e., from first-
person perspective). Whereas the brain’s neuronal
activity is considered as outside (i.e., from third-
person perspective). The conclusion is that major
traces of empirical and epistemological dualism
resurface in cognitive neuroscience. We discuss
this topic below.
FROM BEHAVIORISM TO COGNITIVE
NEUROSCIENCE
Input–output relation vs. cognitive
function
How can we investigate human experience and
behavior? The answer to this question has been
oscillating between inside and outside approaches.
An early striking example of the outside approach,
from the beginning to the middle of the twentieth
century, was the US paradigm of behaviorism.
Behaviorism heavily dominated psychology as
well as theories about the functionality of the
nervous system. After WW2, behaviorism spread
from the United States to Europe and heavily
influenced continental psychology. The American
psychologists John B. Watson (1878–1958) and
Burrhus F. Skinner (1904–1990) were two of the
most prominent behaviorists. Behaviorism stated
that the principal aim of psychology was the
investigation of behavior.
According to behaviorism, to achieve the sta-
tus of a respected science, psychology must focus
solely on the investigation of observable and exper-
imentally influenced behaviors from the objective
“third-person” perspective. The aforementioned
extreme physicalist stance was paradigmatic for
the title of the famous book Psychology of the
Other-One from the year 1922 by behaviorist
psychologist Max F. Meyer (1873–1967) (Meyer,
1922). Behaviorism did not deny the exist-
ence of subjective experience in the first-person
 HISTORICAL, EMPIRICAL, AND PHILOSOPHICAL PERSPECTIVES
perspective but regarded any conscious or cog-
nitive phenomena as superfluous regarding the
behavior of organisms. More importantly, subjec-
tive experience, i.e., cognition, was defined to be
inaccessible for scientific inquiry. From the per-
spective of the philosophy of science, behaviorism
can thus be defined to take a rather implicit instru-
mentalist stance towards experience. Cognition
was considered to be merely epiphenomenal.
Behaviorism consequently defined both human
and animal organisms as “black boxes” or “empty-
organisms” that lack intentionality and are fully
determined by the environment via input–output
(stimuli–response) associations. These associa-
tions stem entirely from the organism’s interaction
with the environment and are learned by linking
specific stimuli with immediate responses via
classical and operant conditioning. In reference to
these ideas, B. F. Skinner labeled one of his main
works, Beyond Freedom and Dignity (Skinner,
1971), whereby the notion of negated free will
(Skinner, 1971) was based on the behaviorist idea
that behavior is determined solely by external
environmental stimuli. Previously, Skinner had
speculated on the creation of an optimal society,
arising through use of societally induced operant
conditioning (Skinner, 1948/2005).
Early empirical findings that revealed evidence
against the behaviorist paradigm emerged in the
first half of the twentieth century. One historic
critique by German physiologist Erich von Holst
(1908–1962) was entitled Vom Wesen der Ordnung
im Zentralnervensystem [On the essence of order
in the central nervous system] (von Holst, 1937).
This critique challenged the behaviorist notion of
locomotion, the idea that the motor output of an
organism is solely determined by a sequence of
interconnected stimulus–response (S–R) reflexes.
These muscle contractions are in turn themselves
initially caused by environmental stimuli. Von
Holst severed the corresponding nerve connec-
tions of an earthworm to show that the motor out-
put remained at a constant up to increased speed.
The conclusion was that the nervous system
exhibits intrinsic spontaneous activity that does
not require peripheral input from environmen-
tal stimuli; hence, the nervous system can also
be characterized by endogenous activity against
the radical paradigm of a simplified input–output
determination of organisms by the environment. A
later and even more famous article was named Das
Reafferenzprinzip: Wechselwirkungen zwischen
Zentralnervensystem und Peripherie [The reaffer-
ence principle: Interactions between the central
nervous system and the periphery] (von Holst and
Mittelstaedt, 1950). Erich von Holst and his student
Mittelstaedt argued that physiology previously only
asked about the afferent and efferent relationship
21
(i.e., the input–output relationship in the nervous
system). The authors explicitly favored a paradigm
shift from external and passive views on the brain
to an inside and active perspective and investiga-
tion of the brain’s ongoing spontaneous activity.
The paradigm of behaviorism was further put
in doubt by both scientists from the west and the
east. Russian successors of the physiologist and
founder of classical conditioning Ivan Pavlov
(1849–1936), paradigmatically neuropsycholo-
gist Alexander Luria (1902–1977), argued against
behaviorism. From the beginning of the 1960s,
even American scientists, notably Edward Tolman,
John Garcia, and Martin Seligman established
significant empirical foundations against the
input–output theory for human and animal behav-
ior. John Garcia (1917–2012) provided evidence
against radical behaviorism in his taste aversion
experiment. The “Garcia effect” was named after
Garcia and Koelling. They experimentally showed
that specific biological predispositions can
increase the likelihood of associative connections
between certain reactions to a priori presented
stimuli. Furthermore, and just as strikingly against
the perspective of behaviorism, some stimulus-
response (S–R) connections could simply not
be established in certain organisms such as rats
(Garcia et al., 1955; Garcia and Koelling, 1966).
This finding later was summarized under the term
“preparedness” (Seligman, 2016; Seligman et al.,
1970). Certain responses, due to protective biolog-
ical predispositions rooted in phylogenesis, allow
no conditioning to occur.
As the cognitive revolution progressed over sev-
eral decades, the powerful behavioristic paradigm
gradually faded. Cognitivism represents the main-
stream today, hence the term cognitive science.
Cognitivism reintroduced the inner perspective of
the organism into psychology and ultimately has
largely replaced behaviorism. While cognitivism
overcame the one-sided outside view of the behav-
ior of organisms, it reverted into a latent form of
behaviorism and Cartesianism. Cognitivism now
repeats the same mistake of behaviorism, albeit
with inverted signs. Instead of completely over-
coming the stimulus-response (S–R) paradigm
of behaviorism, cognitivism introduced a cogni-
tive information processing layer in between the
immediate S–R association. Behaviorist and car-
tesian roots in cognitivism become visible when
cognitive scientists talk about “sensory inputs,”
which are “processed” and subsequently used for
the construction of “cognitive representations” of
the environment within the organism. The results
of internal processing mechanisms in the organ-
ism then affect the final behavioral output.
Eventually, this paradigm remains in nothing
but the S-O-R loop (stimulus–organism–response).
22 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
First, the difference with behaviorism is that the
suggested mediating processes (O) are described
in a cognitive language. Second, cognitive rep-
resentations reintroduce a cartesian notion that
human experience is principally different from
the rest of the body and the world. The cartesian
Res Cogitans now appears covered as an example
of “cognitive representation,” although localized
within in the brain (Bennet and Hacker, 2003;
Fuchs, 2018). Even though today’s cognitive
neuroscience rejects ontological cartesian dual-
ism, it remains in the inside (cognition/mind/
consciousness)-outside (the brain, body, and the
world) distinction where Descartes’ mind resur-
faces labeled “cognitive representations” being an
epistemological dualism between the former and
a so-called “external world.” In post-behaviorist
psychology, the term “cognition” was used as a
stopgap able to fill wide-ranging gaps left behind
by the anti-mental stance of behaviorism against
all experiential intentional terms. In the cogni-
tivist paradigm, the term cognition is nowadays
simply equated to the development of meaning
(i.e., the semantic content of information). The
result is an imprecise concept to the extent that
even unconscious processes can be cognitive since
neuronal processes that do not correspond with
conscious experience can carry semantic content.
Behaviorism was a reaction against introspect
psychology and the assumption of an unobserv-
able level of the “inside” mind. While cognitive
psychology reintroduced the idea of cognition,
computational processes, and the mind, it never
seriously considered human phenomenology for
scientific inquiries.
Spontaneous activity vs. task-related
activity
How can we characterize the brain by itself inde-
pendent of cognition? One empirical characteriza-
tion of the brain is allowed by what is immediately
observable in neuroscience, namely the brain’s
neuronal activity. The brain’s activity allows two-
fold division: first, the brain exhibits intrinsic
spontaneous activity, methodologically called
resting-state or baseline. Second, extrinsic intero-
ceptive and exteroceptive stimuli, respectively
originating from the body and the environment
(Northoff, 2014a; Raichle, 2015). Cognitive neu-
roscience initially focused heavily on the brain’s
extrinsic stimulus-induced activity (task-evoked
activity). The central role of the brain’s intrinsic
ongoing activity (i.e., its spontaneous activity, has
only recently been considered by the mainstream
via the utilization of resting-state paradigms).
Historically, German psychiatrist and devel-
oper of electroencephalography (EEG) Hans
Berger (1873–1941) early on observed spontane-
ous activity in the brain that remained independ-
ent of external tasks or stimuli (Berger, 1929). The
investigation into the brain’s spontaneous activ-
ity was further suggested by Bishop (1933) and
has recently gained more traction in neuroscience
with the observation of spontaneous oscillations
(Buszaki, 2006; Llinas, 1988; Yuste et al., 2005),
spontaneous coherence or connectivity between
different regions’ neuronal activities (Biswal et al.,
1995; Greicius et al., 2003), and the default-mode
network (DMN) (Greicius et al., 2015; Raichle
et al., 2001; Reiss and Menon, 2003). Historical
and modern observations point out the central role
of the brain’s spontaneous activity (Huang et al.,
2015; Northoff, 2014a.b; Northoff et al., 2010,
2012a,b). Research on the brain’s spontaneous
activity has shifted theories and models about the
brain. Instead of considering the brain as extrinsi-
cally driven device, spontaneous activity suggests
what Raichle described as an “intrinsic model of
brain” (Raichle, 2009, 2010). This is reminiscent
of a Kantian model of the mind that, applied to the
brain, suggests the brain’s spontaneous activity to
structure and organize its stimulus-induced activ-
ity of sensory and cognitive functions (Fazelpour
and Thompson, 2015; Northoff, 2012a,b, 2014a,b).
Traditional models of the brain were largely neu-
rosensory and neurocognitive in that they focus
on the brain’s sensory and cognitive functions
as mostly mediated by stimulus-induced activity
(Churchland, 2012; Northoff, 2016a, 2018).
The observation of the spontaneous activity
may put the brain’s neurosensory and neurocog-
nitive function into a larger empirical context.
The kind of brain model required remains unclear
(Klein, 2012; Northoff, 2012, 2018). Concerning
brain function, stimulus-induced activity reflects
the traditional external task-driven view on the
brain, while the brain’s intrinsic spontaneous
activity may account for an inside view. Hence,
what the inside in context of function and behav-
ior (i.e., cognitive function as distinguished from
input–output relations), is the outside in context
of brain activity (i.e., task-evoked activity) The
brain’s spontaneous activity itself provides the
fundamental layer.
Relationship of spontaneous and
task-related activity
How are intrinsic and extrinsic brain activity
related? Traditionally, spontaneous and stimulus-
induced activity were assumed to operate
 HISTORICAL, EMPIRICAL, AND PHILOSOPHICAL PERSPECTIVES
in parallel without interaction. The impact of
external stimuli or tasks was supposed to be pro-
cessed separately from pre-stimulus spontaneous
activity in a purely additive fashion (Arieli et al.,
1996; Fox et al., 2006). The additive model is put
in doubt by recent studies that provide evidence of
how spontaneous activity levels modulate the
degree to which external stimuli can elicit task-
related activity changes (Braun et al., 2021; He,
2013; Huang et al., 2017; Northoff et al., 2010;
Wainio-Theberge et al., 2021; Wolff et al., 2021).
Recent studies suggest non-additive or non-linear
rather than additive and linear interaction between
spontaneous and task-related activity. Non-
additive interactions are not only important in
neuronal terms but influence cognitive function.
Both fMRI and EEG studies show that pre-stimu-
lus resting-state activity levels strongly impact the
contents of consciousness (Hesselmann et al.,
2008; Sadaghiani et al., 2010). Based on various
findings on consciousness, Northoff and Lamme
(2020) recently suggested a nested model of spon-
taneous and task-related activity. Spontaneous
activity shapes pre-stimulus activity, which in turn
nests and contains early task-related activity
changes. Task-induced neuronal states finally nest
and contain late task-related activity.
What can dynamic non-additive interactions
between spontaneous and stimulus-induced activ-
ity imply, especially concerning inside and outside
views on brain activity? Non-additive rest–task
interaction provides a model where the brain’s
ongoing activity strongly shapes task-related
activity. Unlike in the additive model, neuronal
inside and outside are no longer operating in par-
allel but are dynamic changes of the same process.
The brain’s activity is a hybrid mixture of both
intrinsic and extrinsic causes. Wolff et al. (2021)
showed that early stimulus-induced activity
(0–300ms) is strongly impacted by pre-stimulus
activity, whereas only later periods (300–600ms)
are more shaped by external stimuli. These
and other results (Braun et al., 2021; He, 2013;
Huang et al., 2017; Wainio-Theberge et al., 2021)
strongly suggest that inside and outside (i.e., spon-
taneous and task-related activity) are integrated in
the brain’s neuronal activity. Rather than operating
in parallel, the brain seems to constitute an inside-
outside continuum of neuronal activity. A quanti-
tative inside–outside continuum undermines the
qualitative historical inside vs. outside debate. The
inside vs. outside dichotomy stems from observa-
tional and methodological limitations. Both per-
spectives are epistemological but not ontological/
natural (i.e., they are not rooted in the neurobiol-
ogy of the brain itself), that is, the way it operates
and functions independent of our investigation and
methodological approaches.
23
“Inside–out” vs. “outside–in”
approach
The question of the relationship between the
brain’s neuronal activity and consciousness, para-
digmatically conceptualized by the philosophical
mind–body problem of Western philosophy, has
fascinated philosophers over centuries. Roughly
20 years ago, the topic of consciousness also
entered neuroscience where, for instance, Buszaki
(2019, 2020) (abbreviated as GB in the following)
and Poeppel and Adolfi (2020) (abbreviated as
DP/FA in the following) offer contrasting views
how to research brain and mind. GB opts for the
primacy of the brain’s inside over cognition and
behavior at its outside – this is reflected in his shift
from outside–in to an inside–out approach
(Buszaki, 2019, 2020). In contrast, DP/FA suggest
that we need to consider both the brain’s inside
and its outside namely behavior/cognition to
understand the brain–mind relationship. Put in a
nutshell, one emphasizes the priority of the brain’s
inside over the behavior/cognition at its outside
(GB) while the other suggest parallelism of both
inside and outside (DP/FA). Who is right and
which approach shall we follow? Are they mutu-
ally exclusive? We propose that they are not mutu-
ally exclusive but can be reconciled on a deeper
more fundamental level of the brain’s activity.
Cognitivism and cognitive neuroscience take a
cognitive view on the brain (Poeppel et al., 2020)
which also provides the background assumption
for the commentary by DP/FA. Cognitive function
is taken as starting point and independent variable
to search for its neuronal correlates whose meas-
ures serve as a dependent variable – this is what
GB terms “outside–in approach” (Buszaki, 2019,
2020). The cognitive model is contrasted with
what can be described as “neuronal model” of the
brain: here the brain and its inside are no longer
primarily determined by the outside, i.e., cogni-
tive function, but by neuronal activity mostly on
the cellular and regional level – this amounts to
what GB describes as “inside–out” model which
has also been emphasized by others (Northoff,
2014a,b; Northoff et al., 2010a,b; Raichle, 2009).
Rather than opposing the brain’s inside and out-
side, we aim to reconcile GB and DP/FA by point-
ing out their similarities on a fundamental level.
Our guiding question is: what is shared between
the brain’s spontaneous activity on its inside and
cognition/behavior on the outside? The search for
the similarities of inside and outside rather than
for their differences entails the quest to identify
their “common currency,” as we recently put for-
ward (Northoff et al., 2020a,b). Both GB (Buszaki,
2020) and DP/FA (Poeppel and Adolfi, 2020)
hint upon a possible key role of brain dynamics
24 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
without elaborating it in full detail. Brain dynam-
ics may consist of the brain’s inner time and space.
The spontaneous activity’s inner time and space
shape the outside, i.e., task-related activity and
cognition, in a non-additive fashion. Such shaping
of the outside by the inside can be based on the
inside’s temporal and spatial dynamics, which are
thereby linked to spatiotemporal configurations of
the outside. Hence, the brain’s inside and outside
share temporo-spatial dynamics and topography.
This resolves the debate between GB and DP/
FA. Both approaches, inside–out and outside–in,
are feasible as in both instances one searches for
what is shared between them, namely their spatial
topography and temporal dynamics. The brain’s
dynamics are what is shared inside and outside.
Temporo-spatial dynamics can be approached
from either direction, that is, from inside–out and
outside–in.
Brain’s inner time–space shapes the
outer time–space of cognition
DP/FA consider GB’s focus on the brain’s inside
as insufficient. According to them, the real prob-
lem is how to connect neuronal and psychological
concepts. DP/FA are well aware of this – they call
it “alignment or mapping problem” that consists
in, as they describe it, how to connect or align the
elementary units or primitives of psychology to
the ones of the brain. The alignment or mapping
problem (AMP) contains two subproblems, the
granularity mismatch problem (GMP) and the
ontological incommensurability problem (OIP):
the GMP refers to the problem that two disciplines
like psychology and neuroscience may target the
same phenomenon but in different resolutions,
while the OIP brings up the potential incompati-
bility of neural and psychological concepts and,
more generally, of brain and mind.
Hasson’s group conducted a series of fMRI
(and intra-cranial EEG) task studies showing that
different regions are recruited for the information
processing of different temporal duration (Chen
et al., 2015; Hasson et al., 2015; Honey et al.,
2012; Regev et al., 2019). For instance, short fea-
tures like single words or phonemes recruit early
sensory regions in the auditory and/or visual cor-
tex, while longer features like sentences activate
intermediate regions such as the superior temporal
gyrus and inferior frontal gyrus (Stephens et al.,
2013). Finally, even longer information like whole
paragraphs activates regions in the default-mode
network (DMN) (Chen et al., 2015). Departing
from these findings, the concepts of “tempo-
ral receptive fields” (Cavanagh et al., 2016) or
“temporal receptive windows” (Chaudhuri et al.,
2015; Hasson et al., 2012, 2015; Honey et al.,
2012; Huang et al., 2018; Kiebel et al., 2008;
Lerner et al., 2011; Raut et al., 2020; Stephens
et al., 2013; Wasmuht et al., 2018; Watanabe et al.,
2019; Wolff et al., 2019) have been introduced to
describe such temporal structuring of input and
information processing.
How is such temporal (and spatial) structuring
of our perception and cognition during the brain’s
task states related to the spontaneous activity and
its intrinsic neural timescales? A recent study by
Golesorkhi et al. (2021) investigated intrinsic neu-
ral timescales (i.e., the autocorrelation window;
ACW), in rest and task MEG. They observed cor-
relations of rest and task ACW (ranging from 0.7
to 0.9) including the almost complete preservation
of the temporo-spatial core–periphery organiza-
tion during different tasks with only a few regions/
networks showing task-specific changes in ACW.
Albeit tentatively, these findings provide a first
bridge between the brain’s inside (GB) and its out-
side (DP/AF): they show how the brain’s intrinsic
temporo-spatial dynamics (i.e., the brain’s inside
as emphasized by GB) is carried over and con-
nects to the outside, namely the cognitive function
during task states as they are the focus of DP/AF.
Hence the brain’s temporo-spatial dynamics may
provide a bridge, a “common currency” between
GB’s inside approach and DP/AF’s considera-
tion of an outside approach, and thus between
the brain’s inside and outside and thereby also
between brain and world. Temporo-spatial dynam-
ics may thus be conceived to be shared as “com-
mon currency” of inside (i.e., brain), and outside
(i.e., cognition and mind), requiring what recently
has been termed “Spatiotemporal Neuroscience”
(Northoff et al., 2019, 2020).
SUMMARY AND CONCLUSIONS
This chapter has focused on empirical and philo-
sophical presuppositions of cognitive neurosci-
ence and their historical origin. Localizationism
stemmed from neurology, while the input–cogni-
tion–output relationship in cognitive psychology
ultimately derives from behaviorism. The combi-
nation of the scientific disciplines cognitive psy-
chology with neuroscience resulted in a framework
that comprises contradictory theories about the
mind, brain function, and the relation between
human experience and corresponding physiologi-
cal processes in the nervous system. A unified
framework in neuroscience that could contribute
toward the solution of controversy around these
 HISTORICAL, EMPIRICAL, AND PHILOSOPHICAL PERSPECTIVES
themes is lacking. We suggest that neuroscience
and the science of the mind can profit from
Spatiotemporal Neuroscience. This step could
contribute by intrinsically linking human phenom-
enology with the brain’s neuronal activity to
advance our understanding of the seeming opposi-
tion between the discussed topics. Brain and mind
could be integrated via their “common currency”
on a most fundamental level of time and space.
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Aging Brain Changes
across the Lifespan
L í d i a V a q u é - A l c á z a r, A n j a S o l d a n ,
INTRODUCTION
There is probably no time along the life cycle
where the brain remains “static.” Brain changes
occurring during late life were once conceptual-
ized as almost separate in nature, regarding those
during development. However, current mounting
evidence, including data from both structural and
functional neuroimaging favors a non-linear per-
spective of lifespan changes, where modes of vari-
ations or patterns of brain changes observed in
adulthood and aging are already shaped early in
life and are associated with inter-individual differ-
ences in cognitive trajectories. Furthermore, in
combination with one’s genetic background, life-
style factors and environmental influences may
impact aspects of cognitive performance across
the lifespan. Different theoretical models of cog-
nitive and brain aging have been put forward with
a focus on elucidating the factors and neurobio-
logical underpinnings associated with the mainte-
nance of cognitive function as we age. Going
forward, the increased access to massive multi-
center longitudinal databases combined with con-
trolled interventional approaches should propel
our understanding of the determinants and mecha-
nisms that account for the lifespan individual dif-
ferences that influence how our brain ages.
3
and David Bartrés-Faz
Ultimately, such advances shall result in more
individually tailored recommendations to opti-
mize brain and cognitive health across the
lifespan.
This chapter discusses recent scientific evi-
dence aimed at investigating the origins, factors,
and mechanisms that explain how the brain ages
in humans. We focus primarily on findings derived
from human neuroimaging evidence, through
magnetic resonance imaging (MRI), which is a
non-invasive technique that uses a magnetic field
and radiofrequency waves to create detailed pic-
tures of organs and structures inside the body
(Mori and Barker, 1999). In recent decades, the
availability of diverse MRI methods has contrib-
uted significantly to greater knowledge and under-
standing of how the brain experiences age-related
changes at an anatomical and functional level.
Brain MRI can be broadly divided into struc-
tural and functional acquisitions. MRI sequences
that assess aspects of brain structure include
structural T1- and T2-weighted (T1w and T2w)
MRI acquisitions that allow for high-­resolution
imaging of the brain’s tissues, including gray
matter (GM) and white matter (WM), with good
anatomic detail. In addition, diffusion-weighted
imaging (DWI) is increasingly being used to
assess the microstructural properties of the brain,
 Aging Brain Changes across the Lifespan
particularly of WM fiber tracts, by measuring the
diffusion of water molecules. Functional brain
MRI measures include the T2w* images based
on the Blood-Oxygen-Level Dependent (BOLD)
signal, which can inform about the brain areas and
networks that are active during cognitive demands
or can be used to identify resting-state functional
brain networks.
Lifespan Changes in Gray Matter
There is a growing corpus of scientific literature
investigating the changes in GM structures
(volume, surface, and/or thickness) across the
lifespan. Broadly, GM increases during develop-
ment and decreases with aging (Pfefferbaum
et al., 2013; Pomponio et al., 2020). At least some
portion of the lifespan changes in cognitive func-
tion and behavior are caused by lifespan-related
changes in cortical morphology (Fjell et al.,
2014a; Schmitt et al., 2019).
Human volume cortical growth arises through
the complex interplay of several distinct facets of
cortical anatomy, such as changes in cortical thick-
ness (CTh), cortical area and gyrification during
development (Tamnes et al., 2017). Maturation
changes are highly heterogeneous across regions
(Shaw et al., 2008). Furthermore, human brain
development is characterized by a great expan-
sion in the surface area of the cerebral cortex,
exhibiting rapid increases during infancy, further
expansion during childhood, and a peak in late
childhood or adolescence, followed by stability
or subtle decreases in adulthood (Norbom et al.,
2021). The areas that expand the most during
human development correspond to those that dif-
fer most markedly compared to macaque monkey
brains (Rilling, 2014). There has been a debate in
the literature on whether CTh “peaks” are observ-
able in early development, or whether this meas-
ure rather shows monotonic thinning from early
to late childhood, adolescence, and beyond across
most regions over the entire lifespan (Walhovd
et al., 2016). Using a lifespan perspective, a
study including cross-sectional data from 17,075
healthy individuals aged 3–90 years (Frangou
et al., 2022) revealed that the highest CTh values
were observed in childhood (between 3 and 10
years of age). Additionally, there appeared to be
a stronger relationship between increased age and
lower CTh early in life (i.e., up to the second or
third decade) compared to later in life (Frangou
et al., 2022), with the strength of this association
becoming weaker thereafter (Ziegler et al., 2012).
Macroscopic MRI cortical changes observed
during maturational stages can be linked to specific
31
neurobiological processes. For example, cortical
thinning occurring from childhood to adolescence
might correspond to a progressive reduction in
synaptic and neural density, as well as a possible
reduction in the number of cortical glial cells, and
changes in intracortical myelinization, a measure
that can be estimated through MRI (i.e., using
T1w contrast and T1w/T2w ratio). Furthermore,
recently available resources of the RNA transcripts
expressed in the human brain, such as the Allen
Human Brain Atlas (https://portal.brain-map.
org/), or the BrainSpan atlas (www.brainspan.
org/), are providing insight into how maturational
inter-regional patterns of changes seen in MRI
(e.g., cortical thinning) relate to the gradients of
glial or neural-specific cell-type gene expression,
and how they may differ across the lifespan (i.e.,
development vs. adulthood; Vidal-Piñeiro et al.,
2020). This type of knowledge should be critical
to understanding the neurobiological mechanisms
governing interindividual differences in lifespan
trajectories regarding cortical changes and cogni-
tion, including the neurodevelopmental origins of
major neuropsychiatric conditions.
Studies investigating the topographic pat-
tern of GM changes among older adults, have
reported a prominent reduction of the prefrontal
cortex, particularly dorsolateral and dorsomedial
regions, with many also implicating lateral pari-
etal and lateral temporal areas (Fjell et al., 2014a;
Raz et al., 2005; Salat, 2004). Moreover, related
to the negative association between age and
GM values, there appears to be an exponential
increase of ventricular cerebrospinal fluid with
age (Pfefferbaum et al., 2013). The lateral ventri-
cles show a continuous enlargement throughout
the lifespan (Dima et al., 2022), and is detectable
over one-year follow-up even among cognitively
normal older adults at low-risk of AD (Fjell et al.,
2013).
Many earlier studies of GM change did not spe-
cifically screen participants at baseline or follow-
up Mild Cognitive Impairment (MCI), an indicator
of the presence of underlying disease processes,
including Alzheimer’s disease (AD) and cer-
ebrovascular disease. Longitudinal cohort stud-
ies of middle-aged and older adults with normal
cognition at baseline (as determined by extensive
clinical and cognitive evaluations) have shown
that rates of GM decline are lower among those
who remain cognitively normal over the follow-
up period compared to those who develop MCI
or dementia over time (Armstrong et al., 2019;
Soldan et al., 2015). These types of studies have
also shown that rates of GM and ventricular change
among middle-aged and older adults with normal
cognition at baseline are greater in those with car-
diovascular risk factors, such as smoking, high
32 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
blood pressure, obesity, and elevated cholesterol
levels (Armstrong et al., 2019) those at genetic
risk for AD (Mishra et al., 2018; Reiter et al.,
2017) and those with more abnormal baseline lev-
els of amyloid, tau, or neuroinflammation (Halaas
et al., 2020). The greatest and earliest declines in
GM among cognitively normal middle-aged and
older adults are often seen in medial-temporal
lobe regions, including the entorhinal cortex, hip-
pocampus, parahippocampal gyrus (Mishra et al.,
2018; Reiter et al., 2017). Differentiating GM
changes related to pre-clinical disease processes
from those that reflect non-disease related aging
requires extensive follow-up (to determine who
eventually develops cognitive impairment), and
careful cognitive and clinical evaluations of par-
ticipants, as well as the collection of biomarkers
to assess preclinical disease levels.
In contrast to the monotone thinning of the cer-
ebral cortex (Storsve et al., 2014), subcortical GM
structures experience age-dependent changes across
the human lifespan that are more divergent and
complex (Fjell et al., 2021; Narvacan et al., 2017;
Walhovd et al., 2005), and these changes are related
to cognitive performance, behavioral skills, and/or
the pathophysiology of age-related brain diseases
(Narvacan et al., 2017). A recent lifespan study
with structural MRI data from 18,605 individuals
aged 3–90 years demonstrated that the volumes of
subcortical structures were at their maximum value
early in life. Striatal and pallidal volumes peaked
in childhood (i.e., during the first decade of life)
and the volumes of the thalamus, hippocampus,
and amygdala peaked later (i.e., during the 20s–
30s; Dima et al., 2022). The basal ganglia volume
showed a predominant negative association with
age, while GM volumes of the thalamus, amygdala,
and hippocampus showed a prolonged period of
stability (Dima et al., 2022; Pomponio et al., 2020).
However, after the 60s these structures also showed
an abrupt negative association with age, potentially
related, at least in part, to AD pathology, which
tends to have early and pronounced effects on the
hippocampus and amygdala.
As discussed below, the combination of genetic
and environmental determinants contributes to
explaining interindividual differences in GM
changes observed across the lifespan. In any case,
there is still significant uncertainty about the shape
and interindividual variability regarding the asso-
ciation between age and GM in specific areas. Prior
studies have reported linear and nonlinear asso-
ciations (Mills et al., 2016), and there are notable
exceptions to the general pattern described above in
structures such as cingulate and insula (Grieve et al.,
2005), the orbitofrontal cortex (Raz et al., 2005),
and the hippocampus (Grieve et al., 2005; Raz
et al., 2005). The hippocampus seems to suffer a
relatively more pronounced decline, compared
to other subcortical regions (Dima et al., 2022;
Pomponio et al., 2020), potentially related to pre-
clinical and early AD-related pathology.
In this context of high heterogeneity, a recent
study applying a graph theory approach to analyze
over 6,000 longitudinal MRIs of individuals rang-
ing in age from 2 to 89 demonstrated that subcor-
tical GM volumetric changes can be grouped into
clusters of regions that show correlated change
over time. These clusters tended to follow trends
from embryonic brain development, suggesting
continuity from earlier to later stages of the lifes-
pan (Fjell et al., 2021). This consistency in patterns
of change of subcortical structures across the lifes-
pan identified by the authors can be summarized
as three independent trajectories: (1) accelerated
increase for the ventricles; (2) inverted U-shape
progression for structures such as the hippocam-
pus and brain steam (Fjell et al., 2013; Walhovd
et al., 2005); and (3) linear decline through adult-
hood following a peak in childhood (among
caudate, pallidum, putamen, amygdala, nucleus
accumbens, and cortical areas). However, for the
third trajectory, differences in shapes of the slopes
were observed, stressing divergences in the initial
increase in childhood (Fjell et al., 2021).
Therefore, although cross-sectional studies
usually find linear relationships between older age
and smaller regional brain volumes, which sug-
gests that aging affects the cortex diffusely (Salat,
2004), some studies have reported tendencies of
accelerating or decelerating estimated decline with
increasing age during the last decades of life (Fjell
et al., 2014b). For instance, Frangou et al., (2022),
showed how the entorhinal and temporo-polar cor-
tex are largely preserved across the lifespan until
the 70s–80s, whereafter both regions showed an
age-related decrease in CTh (also consistent with
(Sele et al., 2021). In addition, Frangou et al.,
(2022) suggested that the interindividual variabil-
ity seemed to be largest in temporal and frontal
regions across the lifespan. Interestingly, a recent
longitudinal study of older non-demented partici-
pants (mean baseline age = 70 years) found that
cortical surface area showed a clear decline, on
average, over a span of up to seven years that was
greater in magnitude than for CTh (i.e., 1–5% vs.
0–2% annual decline, respectively). However, the
correlation pattern of CTh change between brain
regions was strong and largely homogenous, sug-
gesting that cortical thinning with increasing age
is correlated across regions. For cortical surface
area, the pattern of between-region change was
similar but weaker, suggesting the existence of a
regional heterogeneity (Sele et al., 2021).
Changes in frontostriatal areas supporting
cognitive control and executive functions have
 Aging Brain Changes across the Lifespan
been proposed to be characteristic hallmarks of
aging (Buckner, 2004), emphasizing that late-­
maturing regions are most vulnerable to age-
related changes, often referred to as the “last in,
first out” or “retrogenesis” hypothesis (Fjell et al.,
2014a; Grieve et al., 2005). It seems that areas that
take longer to mature because they follow more
complex developmental trajectories (Shaw et al.,
2008), also are more vulnerable to the negative
effects of aging. Thus, the “last in, first out” model
has many similarities to the traditional “frontal
theory of aging” (West, 1996). In addition, there is
a growing realization that genetically programmed
neurodevelopmental events may have a lifelong
impact on the organization of the cerebral cor-
tex decades later (Fjell et al., 2013). These find-
ings reveal the need for more research focused on
identifying the genetic determinants and environ-
mental aspects that influence age-related cortical
changes. Moreover, the differences in rates of
regional GM change reported above may reca-
pitulate distinct patterns of brain aging and in this
regard, it has been challenging to address whether
there are organizing principles underlying the
relatively greater selective vulnerability of some
regions as opposed to others.
In this regard, Cox et al., (2021) used multivari-
ate longitudinal analyses to investigate clusters of
regions showing shared morphometric cortical
changes amongst individuals aged 70 and older
and with MRI acquisitions at three occasions.
Results revealed that beyond a general factor of
global brain atrophy, two other orthogonal patterns
emerged, one characterized by more marked atro-
phy in fronto-temporal regions and another pre-
dominantly in occipito-parietal areas, with negative
correlations between them (i.e., indicating that the
participants exhibiting higher decline in one, tend
to express less declining in the other). In another
study derived from the European Lifebrain pro-
ject (www.lifebrain.uio.no), Gorbach et al. (2020)
observed a stronger association between hippocam-
pal volume changes and memory changes amongst
Apolipoprotein E (APOE) ε4 carriers compared to
non-carriers (both groups included non-demented
older adults). Altogether, these findings are helping
to elucidate differences in the brain systems and
brain–behavior associations that are more vulner-
able for particular groups of individuals.
White Matter Trajectory Over
Lifespan
Classically, WM changes as seen with MRI have
been assessed by Fluid Attenuation Inversion
Recovery (FLAIR) acquisitions, which is an
MRI structural sequence able to identify areas of
33
abnormally high signal, referred to as WM
hyperintensities (WMH; also known as leu-
karaiosis, or WM lesions, WML). WMH are
presumed to have a vascular origin with advanced
age and hypertension being the major risk factors
(Wardlaw et al., 2013). The main cause of WML
is thought to be chronic ischemia and they may
reflect pathogenic mechanisms, related to demy-
elination, gliosis, edema, apoptosis, and axonal
atrophy in adjacent fiber tracts (Fazekas et al.,
1998; Sasson et al., 2013). The prevalence and
extent of WML increase with age (De Leeuw
et al., 2002), and they represent one of the most
common structural brain changes among older
adults. According to some estimates, they are
present in almost 95% of adults over 45 years of
age (De Leeuw et al., 2002; Habes et al., 2018).
WML have been associated with the cognitive
profile commonly seen among older adults,
being associated with lower executive function-
ing and slower speed of processing. They have
also been associated with cognitive impairment
(Raji et al., 2012), and they predict an increased
risk of developing dementia. Recent evidence
suggests that WML contribute to the neurode-
generation of cholinergic pathways among non-
demented older adults (i.e., above and beyond
AD pathology), likely helping to explain its role
in cognitive function and cognitive deterioration
(Cedres et al., 2022).
Beyond the study of small vessel disease-
related MRI changes reported above, diffusion-
weighted imaging (DWI) has become one of most
popular MRI techniques in brain research (Assaf
and Pasternak, 2008). DWI provides maps of
microscopic structural information of brain tis-
sue (Lamar, 2014) and is most frequently used to
study WM fiber tracts. These images can be used
to study the directionality of axons by measuring
the diffusion of water molecules in the brain. The
most used DWI-derived metrics include fractional
anisotropy (FA), a measure of directional diffu-
sion (Mukherjee et al., 2008), mean diffusivity
(MD), radial diffusivity (RD), and axial diffusiv-
ity (AxD). The MD may help characterizing tis-
sue composition; RD appears has been suggested
to be related to myelin content; and AxD appears
to be more specific to axonal injury (Bennett and
Madden, 2014). Because these diffusion meas-
ures are affected by a variety of factors, including
fiber arrangement, axon density, myelination, and
axonal degeneration, their biological interpret-
ability is limited (Jones et al., 2013). In general,
however, higher FA and lower RD and MD values
tend to represent greater WM “integrity” (Bennett
and Madden, 2014).
Over the lifespan, the WM trajectory follows
an inverted U-shape curve, detectable across
34 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
modalities (i.e., using both volume analyses from
structural images and DWI methods; (Bennett and
Madden, 2014; Salat et al., 2005, 2011; Sexton
et al., 2014; Sullivan and Pfefferbaum, 2006). That
is, global FA values on average, peak around the
30s, followed by a weak yet stable linear decrease
until approximately 65 years, when there is a sub-
sequent accelerating decline (Sexton et al., 2014).
Studies of neurodevelopment overwhelmingly
demonstrate regional differences in the rates of
WM maturation (Lynch et al., 2020), which are
characterized by FA increases and MD decreases
during childhood and adolescence (Lebel et al.,
2019). Several studies have suggested a posterior-­
to-anterior gradient of WM maturation, with
anterior and associative tracts (e.g., the anterior
thalamic radiation) displaying a greater change
during childhood (Krogsrud et al., 2016) than more
posterior tracts. Recent technological advances
have provided new insights into a range of micro-
structural aspects of WM that may be more closely
related to fundamental neurodevelopmental pro-
cesses (Lynch et al., 2020) than more traditional
diffusion measures. For example, neurite orienta-
tion dispersion and density imaging (NODDI) has
been established as a powerful complementary
technique able to quantify other WM microstruc-
tural properties, including the density of neurites
(both axons and dendrites), measured by the neu-
rite density index (NDI), and the variability of
neurite orientation (i.e., all parallel vs. randomly
oriented), measured by the orientation dispersion
index (ODI). NODDI-based studies demonstrate
age-related increases in NDI across tracts in child-
hood and adolescences, while ODI remains rela-
tively stable in this period (Mah et al., 2017).
Current findings suggest that during the last
decades of life, FA decreases, whereas MD and
RD increase, indicative of a decrease of WM
microstructural integrity with age. Additionally,
there appear to be regional differences in the rate
and magnitude of WM changes. Initial studies
reported larger age-related decreases in FA in fron-
tal regions (Kiely et al., 2022; Salat et al., 2005),
though subsequent investigations suggested that
the anterior-posterior gradient may be an over-
simplification. For example, Davis et al. (2009)
found that WM tracts traversing the frontal cortex
exhibited a monotonic age-related decrease in FA
that was stable across the frontal lobe boundary.
Furthermore, some posterior WM regions exhib-
ited larger age-related declines in FA compared to
frontal regions (Salat et al., 2005).
In addition, other researchers have suggested
the existence of a superior-inferior gradient,
in which superior WM is more susceptible to
age-related declines relative to inferior regions
(Zahr et al., 2009). Altogether, the diversity of
patterns identified is consistent with the “last in,
first out” hypothesis (also known as “retrogene-
sis”). This pattern is characterized by greater sus-
ceptibility of the anterior brain that develops late
to degeneration in old age, and the relative spar-
ing of posterior brain regions (i.e., occipital lobe)
that develop late (Bouhrara et al., 2021; Brickman
et al., 2012). This idea (cf. Kiely et al., 2022), is
similar to what has been proposed for GM, pos-
tulating that late-myelinated WM fibers are most
vulnerable to age-related changes (and/or disease-
related degeneration), which in turn, mediate
cognitive decline (Brickman et al., 2012). Indeed,
available DWI-based studies have provided sup-
port for the “gain-predicts-loss hypothesis” of
WM tissue maturation and degeneration (Kiely
et al., 2022; Slater et al., 2019), suggesting that the
rate of tissue loss at older ages is equal to the rate
of tissue gain during maturation at younger ages.
Studies relating DWI measures to cognitive
function have been driven by diverse hypotheses
about the effects of WM maturation and disruption
in cognition. During development, WM maturation
gives rise to greater stability in cognitive function
(Samara et al., 2019), stressing the importance of
considering heterogeneities in the neurobiologi-
cal basis underlying cognitive development (Bells
et al., 2019; Buyanova and Arsalidou, 2021). In
the aging field, alterations in WM integrity have
been linked with cognitive disruption (Sang et al.,
2021). Additionally, some researchers have pro-
posed various forms of “dis-connectivity” hypoth-
eses to explain age-related cognitive and affective
impairments (Filley, 2005). These theoretical
models suggest that disconnection leads to dys-
function, because WM tracts represent structural
connections of the functional networks recruited
during task performance, reductions in their integ-
rity are correlated with declines in cognitive skills
(Salat, 2011; Sullivan and Pfefferbaum, 2006).
It is worth noting that in parallel with these
changes in structural connectivity, functional
network reorganizations also occur (see below).
Although the precise link is not fully understood,
structural and functional connectivity (FC) are
related (Hermundstad et al., 2013), and this rela-
tionship appears to become less cohesive with age
(Betzel et al., 2014). In addition, the development
of structural brain networks has been character-
ized by using different GM-related anatomical
properties such as CTh. The cortical development
of GM structural networks is also strongly corre-
lated with (1) the acquisition of high-level cogni-
tive skills (Nie et al., 2014); (2) changes in cortical
fiber density in early postnatal stages (Li et al.,
2015); and (3) decreased centrality of subcortical
regions during the FC development in adolescence
(Sato et al., 2015).
 Aging Brain Changes across the Lifespan
Lifespan Changes in Functional MRI
Functional MRI (fMRI; Matthews and Jezzard,
2004) is sensitive to dynamic changes in the
blood (i.e., hemodynamics) and can be used to
examine neuronal activity. In its more traditional
application, fMRI has been used to identify areas
of increased or decreased neuronal activity during
the performance of a task (i.e., task-based fMRI;
Logothetis, 2008). Nevertheless, fMRI is increas-
ingly being used to explore how functional brain
networks that can be identified when individuals
are not engaged in a task, the so-called resting-
state networks (RSN), operate and influence
cognition (Bressler and Menon, 2010; Smith
et al., 2009).
Functional Connectivity Changes
Assessed By rs-fMRI
Rs-fMRI is used to identify spontaneous fluctua-
tion in activity among brain regions, which offers
insights into intrinsic brain organization
(Bijsterbosch et al., 2017). In the last decades,
the increasing interest in analyzing neural
dynamics with this technique has given rise to
the understanding that the human brain is com-
posed of a set of complex functional RSNs
(Bressler and Menon, 2010) that are continu-
ously interacting in a dynamic way with each
other to modulate cognitive performance
(Bressler and Menon, 2010; Smith et al., 2009).
Thus, the network-based approach has provided
valuable metrics to understand the functional
brain changes and their cognitive and behavioral
associations during the lifespan.
Diverse methodological approaches to study FC
with rs-fMRI have been proposed. One of the most
widely used techniques is independent component
analysis (ICA), based on a data-driven approach
(i.e., non-required predefined regions) that identi-
fies regions with similar patterns of synchronized
activity (i.e., brain network; Nickerson et al.,
2017). Using the approach, several main RSNs
have been consistently identified across studies
(Moussa et al., 2012), including a visual process-
ing network, the default-mode network (DMN),
and cerebellum, sensorimotor, auditory, executive
control, and frontoparietal networks (Damoiseaux
et al., 2006; Smith et al., 2009). Another increas-
ingly popular approach for the study of brain con-
nectivity is graph theory, a set of mathematical
tools to characterize topology of networks, both
on a global and local level (Sporns, 2018).
Edde et al., (2021) recently proposed that
development of FC changes can be separated into
three main phases after birth according: (1) during
35
the first years of life, there is a strong widespread
organization of networks which starts with segre-
gation processes followed by a continuous increase
in integration (Stevens, 2016); (2) from adoles-
cence to early adulthood, a refinement of exist-
ing networks in the brain occurs (i.e., integration
increases until about the 4th decade); and (3) the
middle age period is associated with an inversion
of the functional brain trajectories and a decrease
in segregation (Betzel et al., 2014), in conjunc-
tion with a large-scale reorganization of between
network connections. Broadly, the rs-fMR stud-
ies about brain maturity have reported consist-
ent changes in the human functional brain over
development (Fransson et al., 2007). Analyzing
data from people aged 7–30 years, Dosenbach
et al., (2010) suggested that the functional matu-
ration growth curve follows a non-linear asymp-
totic shape, characterized by the weakening of
short-range functional connections between the
adult brain’s main functional networks. During
development, connectivity increases and become
more coordinated, particularly along the anterior-
posterior axis (Dosenbach et al., 2010; Grayson
and Fair, 2017). Furthermore, it has been sug-
gested that brain networks tend to exhibit a
positive-to-negative shift when anterior–posterior
and posterior–subcortical nodes are evaluated,
whereas anterior-subcortical associations tend to
involve positive correlations that become less pos-
itive across the lifespan (Rosenberg et al., 2020).
FC changes with advanced age (Ferreira and
Busatto, 2013). Since RSN represent known
functional networks (i.e., regions that are known
to support cognitive functions), the study of the
DMN has attracted much interest, owing to its crit-
ical role in human brain function (Buckner, 2012).
The structural architecture of the DMN includes
core areas such as the precuneus/posterior cingu-
late cortex, the medial frontal cortex, and other
regions, such as the parietal, angular gyri, and the
hippocampus (Buckner et al., 2008). This cohe-
sive brain network (Greicius et al., 2003) shows
decreased activity during the performance of a
wide range of tasks (Alves et al., 2019), while is
typically active during periods of rest or introspec-
tion (Snyder and Raichle, 2012). Convergent find-
ings further demonstrate that the DMN is fairly
established from five years of age (Cao et al., 2014)
and connectivity within DMN regions decreases
with increasing age (Andrews-Hanna et al., 2007),
showing deactivation deficits. The most important
age-related effect seems to entail FC disruption
between the medial frontal and posterior midline
structures (Andrews-Hanna et al., 2007). Further,
FC between cortical and subcortical nodes of the
DMN, such as the hippocampus, also changes
with advanced age (Salami et al., 2014).
36 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
The above-mentioned age-related antero- pos-
terior alterations within the DMN are consistent
with the hypothesis that among older adults, long-
range FC is decreased (Andrews-Hanna et al.,
2007; Cao et al., 2014; Ferreira and Busatto, 2013;
Vidal-Piñeiro et al., 2014), while short-range FC
increases (Cao et al., 2014; Sala-Llonch et al.,
2014). Notably, an adequate balance between
long- and short-distance connectivity is rele-
vant for preserved cognition among older adults
(Andrews-Hanna et al., 2007; Sala-Llonch et al.,
2014; Vidal-Piñeiro et al., 2014), and a loss in this
balance might boost between network connec-
tivity, leading to a less segregated brain (Spreng
et al., 2016). DMN regions are also critically vul-
nerable to aging, with annual rates of decline in
cortical volume in DMN areas being higher than
for most other cortical regions (Fjell et al., 2014a).
This specific vulnerability in the cortical sys-
tems constituting the DMN was hypothesized by
Buckner et al. (2009) to explain the predilection of
these areas to amyloid-β deposition. One specula-
tion is that DMN areas are critically vulnerable to
subtle age-related lesions and pathology accumu-
lating through life because these regions are char-
acterized by a high degree of life-long plasticity
(Rapoport and Nelson, 2011).
Activity Pattern Changes Assessed by
Task-Based fMRI
Moreover, fMRI acquisitions can provide infor-
mation about the spatial patterns of brain regions
that activate and deactivate in synchrony under
different task conditions by subtracting the
BOLD signal between these conditions (Buch­
binder, 2016). Task-based fMRI is acquired
while a subject is inside the scanner and
instructed to perform a goal-directed task, afford-
ing an identification of areas involved in the task
performance and the corresponding scores.
A central question in cognitive neuroscience
is the characterization of putative developmental
changes in brain functioning underlying the acqui-
sition of skills and higher cognitive functions
(Johnson, 2001). Most published studies com-
pare groups of children vs. adults, stressing that
fMRI can be used to distinguish different kinds of
involvement among brain regions that change over
development (Booth et al., 2003; Gaillard et al.,
2003; Luna et al., 2001). Studies using fMRI have
shown that both progressive age-related devel-
opmental changes (i.e., specialization increases)
and regressive changes (i.e., specialization
decreases) occur (Joseph et al., 2011). This idea
concurs with the interactive specialization theory
predicting significant reorganization in multiple
brain regions from childhood to adulthood and
going further to the maturational perspective of
neural development, which would predict a shift
from minimal/no-activation to activation, or pro-
gressive age-related activity increases in adults
compared to children (Joseph et al., 2011). One
of the processes involved in the correct matura-
tion trajectories during childhood and adolescence
is the balance of functional networks integration
and segregation. Importantly, functional networks
interaction throughout development is mediated
by functional (i.e., highly connected brain areas)
which take a prolonged maturation course result-
ing on the regulation of neural activity (Cao et al.,
2014). Findings in this field, combining rs-fMRI
and task-based fMRI data, have pointed out that
centrality (i.e., a measure that reveal internetworks
interactions; Hwang et al., 2013) of cerebellum
and cingulo-opercular components are key factors
for the normal acquisition of executive functions
(Kolskår et al., 2018).
In aging, task-based fMRI studies compar-
ing brain activity patterns of older adults with
those observed among younger counterparts
have revealed differences at the level of intensity
(hypo- or hyper- activation) as well as at the level
of the topographical distribution of the affected
areas (Grady, 2008, 2012). The main functional
changes in aging could be summarized in:
(1) hyperactivation in the frontal and parietal
regions, (2) hyperactivation of the DMN during
task demands, and (3) hypoactivation of the medial
temporal lobe. One the one hand, decreased brain
activity has typically been interpreted as a reflec-
tion of cognitive deficits in older adults and has
been linked to structural changes (Nyberg et al.,
2010). On the other hand, increased brain func-
tional values have been understood as a compen-
satory mechanism (Cabeza, 2002; Reuter-Lorenz
and Park, 2014; see below). Compensation is a
complex phenomenon that states that older adults
show more activity in a brain region than younger
peers whilst they perform a task at the same level
as younger adults (Cabeza, 2002; Cabeza and
Dennis, 2013), or when this increased activity
is positively correlated to performance in older
adults, but not younger adults (Reuter-Lorenz
et al., 2000). Thus, the term compensation is con-
ditioned by the fact that activity increases would
be directly associated with improvements in
task performance, and this is not always accom-
plished. Some investigations have suggested that
these over-recruitments, typically identified as
more activity in frontal regions (Cabeza, 2002;
Park and Reuter-Lorenz, 2009) are not invariably
linked to better cognitive performance (Rypma
et al., 2007). In these cases, increased activations
 Aging Brain Changes across the Lifespan
have been conceived as attempted or unsuc-
cessful compensatory mechanisms (Cabeza and
Dennis, 2013) or dedifferentiation (Carp et al.,
2011). Finally, it should be noted that within the
fMRI framework, as investigated longitudinally,
increases in brain activity instead of reflecting
compensatory mechanisms as described in cross-
sectional approaches (Cabeza, 2002; Reuter-
Lorenz and Park, 2014), might underlie cognitive
decline (Pudas et al., 2017; Vaqué-Alcázar et al.,
2020). Maintaining brain health across the lifes-
pan depends on a variety of factors, including
genetic and lifestyle components, as well as
their interaction, which predicts substantial vari-
ability in developmental and aging trajectories
(Valenzuela and Sachdev, 2006).
Genetic Effects on Brain Change
Trajectories
Genetic factors are important in determining corti-
cal architecture (Lenroot et al., 2009) and there
are common genetic variants that affect age-
related brain changes across the lifespan. Further,
longitudinal cohort studies have indicated that
genetic differences between individuals have a
role in interindividual variability in age-related
cognitive changes, although they may be impor-
tant in establishing performance levels and less in
lifespan trajectories (Nyberg and Pudas, 2019).
Although the study of genetic influences on brain
structure and function supports different methodo-
logical approaches, from classical twin studies to
the assessment of specific variations or polymor-
phisms. Regarding the latest perspective, an
approach that has recently proliferated is the
genome-wide association study (GWAS), which is
based on examining associations between DNA
phenotypes variations (i.e., single-nucleotide pol-
ymorphisms; SNPs) and traits or diseases
(Manolio, 2010). Although not the focus of this
chapter, it seems suitable to highlight a recent
publication (Brouwer et al., 2022) that analyzed
longitudinal data from 15,640 individuals using a
GWAS approach. Broadly, this study showed that
GPR139, DACH1, and APOE genes are associ-
ated with metabolic processes, CDH8 with cogni-
tive function, GPR139, SORCS2, and CDH8 with
psychiatric traits, and NECTIN2 and APOE with
AD (Brouwer et al., 2022). Some of the identified
genetic variants for structural brain changes were
stable throughout life (i.e., independent of age),
suggesting that these genetic variants are equally
crucial for both early brain development and neu-
rodegenerative processes in the rates of brain
changes.
37
Despite the results above including GWAS,
and those using other approaches such as the
epigenome-wide association study (EWAS) based
on characterizing differences in DNA methyla-
tion status (Unnikrishnan et al., 2019), it should
be noted that when considering brain and cogni-
tive changes in advanced age, the most investi-
gated genetic variation has been that of the APOE.
APOE (located on chromosome 19q13.2) is a pol-
ymorphic gene resulting in three different alleles
(ε2, ε3, and ε4). The APOE ε4 isoform is the strong-
est genetic risk factor for sporadic late-onset AD
(Koutsodendris et al., 2021; Serrano-Pozo et al.,
2021). In this regard, it has been shown that car-
rying an APOE ε4 allele impacts non-pathological
brains (Flowers and Rebeck, 2020). From early
studies, it has been proved that APOE ε4 isoform
negatively influences cognitive status (Bartrés-Faz
et al., 2001) and cognitive decline trajectories in
healthy aging (Riaz et al., 2021; Yaffe et al., 2009).
These effects may be derived from the impact of
this genetic isoform on different biological path-
ways and mechanisms (Parhizkar and Holtzman,
2022; Serrano-Pozo et al., 2021), whereas carry-
ing the APOE ε2 isoform (i.e., APOE ε3/ε2 geno-
type) appears to be protective (Serrano-Pozo et al.,
2021). From a neuroimaging point of view, APOE
ε4 isoform is related to multimodal changes
(Cai et al., 2017): reduced glucose metabolism
from midlife in AD-prone areas (Paranjpe et al.,
2019), higher medial temporal lobe atrophy, dif-
ferential brain activity during cognitive demands
(Bartrés-Faz et al., 2008), and GM network abnor-
malities in those APOE ε4/ε4 even in the absence
of amyloid-β deposition (Cacciaglia et al., 2020).
From a lifespan perspective, there has been a
debate as regards the putative antagonistic pleio-
tropic effects of APOE ε4 on brain and cognition,
prompted by some evidence indicating that ε4 car-
riers would have better cognitive status at younger
ages in some cognitive domains (Marioni et al.,
2015). However, recent empirical and metanalytic
evidence assessing cognitive and brain measures
do not support the antagonistic hypothesis (Corder
et al., 2022), and rather subtle abnormalities in
hippocampus and cortical measures have already
been detected in infants and even prenatal MRI
findings (Chang et al., 2016). These results indi-
cating that the effects of APOE on brain and cog-
nition in advanced age are partially rooted during
neurodevelopment do not imply that the poten-
tially deleterious impact of this genetic variant on
brain health amongst older adults is immutable. In
this regard, for example, another series of investi-
gations suggest that APOE ε4 carriers might ben-
efit more from preventive lifestyle exposures such
as higher cognitive (Ma et al., 2022) or physical
(Perez-Lasierra et al., 2021) activities.
38 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Environmental Effects and Models
of Brain Aging
There is ample evidence for the influence of life-
style factors on cognition and brain health, par-
ticularly in advancing age, suggesting that
age-related impact can be viewed in the context of
balance between risk and protective elements
(Mattson and Magnus, 2006). Thus, the different
interactions with the environment have the poten-
tiality to move an individual into a more positive
(or negative) aging trajectory (Lindenberger,
2014). Within this context, a growing amount of
evidence (Mintzer et al., 2019) highlights the
importance of sustaining healthy habits such as
engaging in cognitively stimulating activities,
social interactions, and good dietary patterns such
as the Mediterranean diet (Guasch-Ferré et al.,
2017), adequate and good sleep quality (Leng
et al., 2017), weekly moderate/vigorous exercise,
not smoking (Yaffe et al., 2009), and engaging in
behavior to maintain mental well-being (Marchant
et al., 2020).
Considering this view from a lifespan per-
spective appears to be particularly relevant. For
example, the combination of main modifiable
risk and protective factors for dementia seems to
have a different weight depending on when, dur-
ing the life course, individuals are exposed (i.e.,
early, middle, or advanced age; Livingston et al.,
2020), and they influence markers of biological
brain aging as well (see below). In addition, con-
verging evidence indicates that early factors (i.e.,
birth weight, polygenetic risk scores, early life
sleep patterns; Lokhandwala and Spencer, 2022)
or those already measurable at neurodevelopmen-
tal stages (i.e., general cognitive ability) contribute
significantly to explain subjects brain differences
across the whole life course, including middle and
older ages (Walhovd et al., 2016, 2022).
Nowadays, there are different concepts and
theoretical models that roughly directly incor-
porate the relevance of modifiable factors to
explain interindividual differences in brain and
cognition across the lifespan (Cabeza et al., 2018;
Reuter-Lorenz and Park, 2014; Stern et al., 2020).
Concepts such as “reserve,” “resilience,” “resist-
ance,” “neuroprotection,” or “brain maintenance,”
are often used by researchers working in this field
(Bartrés-Faz et al., 2020) and efforts to develop a
framework of operational definitions as investiga-
tions both in human and non-human species to
understand the underlying biological mechanisms
of the observed effects have been put in place
(Arenaza-Urquijo and Vemuri, 2018; Pascual-
Leone and Bartres-Faz, 2021).
Early influential findings indicated that a por-
tion of individuals with advanced age can sustain
notable brain pathological changes (Stern and
Barulli, 2019). These observations, together with
longitudinal population-based investigations indi-
cating that engaging in complex mental activi-
ties during lifecourse is related to a significant
decrease in the prevalence of dementia (Valenzuela
and Sachdev, 2006), resulted in the foundations of
the cognitive reserve (CR) model, a theoretical
concept proposed to account for the frequent dis-
crepancy between a person’s underlying level of
age-related brain changes (or brain pathology) and
the observed cognitive profile that is expected to
result of that damage (Stern, 2009). It is relevant
to highlight that there are differences across indi-
viduals because CR is dynamic and influenced
by the interaction between innate characteristics
(genome) and lifetime exposures (Barulli and
Stern, 2013; Stern et al., 20). Because there is exten-
sive epidemiological evidence for the independent
association of different lifetime exposures with
more successful aging (Lövdén et al., 2005), CR is
typically measured via a set of potential “proxies”
including educational attainment, life-time occu-
pation or estimated premorbid intelligence among
others. Contrarily, there are factors associated with
an increased vulnerability to developing dementia,
such as elevated levels of anxiety and stress or a
high burden of repetitive negative thinking, a pro-
cess presented across mental diseases that encom-
passes worry and rumination (Schlosser et al.,
2020). There are different potential mechanisms
underlying the positive effects on clinical manifes-
tations and cognition predicted by the CR theory,
mainly functional brain compensatory reorganiza-
tions occurring in the face of pathology to sustain
cognition (Lee et al., 2019; Stern, 2009). However,
recent evidence does not support a consistent asso-
ciation between CR estimates and longitudinal
cognitive changes in healthy aging performance
(Vaqué-Alcázar et al., 2020; Wilson et al., 2019).
Similarly, recent longitudinal findings (based on
4,422 structural MRI observations) suggested that
despite GM displaying marked age-related atrophy
in regions such as the cortex and hippocampus,
years of formal education (i.e., CR) did not influ-
ence rates of change in this brain structure meas-
ures (Nyberg et al., 2021), which are more strongly
precited by estimations of global cognitive ability
(i.e., those with higher general cognitive ability
experiencing less cortical thinning across the lifes-
pan; Walhovd et al., 2022).
The brain maintenance (BM) model highlights
that across the life course, and in particular in
advancing age, interindividual differences in brain
and cognition can be partially accounted for by
the fact that some people show a relative lack of
age-related brain changes in neurochemical, struc-
tural, and functional level, allowing performance
 Aging Brain Changes across the Lifespan 39

stability by the preservation of neural resources in atrophy rates and/or cognitive decline associ-
(Nyberg and Pudas, 2019). BM concept is consist- ated with age due to the capacity of these systems
ent with the notion that during late life, the neu- to identify groups or subtypes.
ral resources can remain preserved through the
action of protective mechanisms of cellular repair
(Cabeza et al., 2018) and may overlap to a large
degree with mechanisms of brain plasticity in SUMMARY AND CONCLUSIONS
adulthood (Lövdén et al., 2010).
Summarizing, the current evidence focused on
determining brain characteristics that change
Future Perspectives throughout life has shown that this organ experi-
ences numerous modifications over time, being
All of this leads to highlight the importance of
both the first and last decades of life those periods
developing new methodologies to apprehend the
with more abrupt transformations. Processes of
plastic changes experienced by our brain along
maturation and degeneration are in line with the
the life cycle become necessary. For example,
development of cognitive and sensory abilities
the combination of MRI and Non-Invasive Brain
throughout life, as well as their deterioration.
Stimulation (NIBS) suppose an innovative meth-
Interestingly, the changes associated with aging
odology, which allows interrogating and charac-
seem to mimic, to a certain extent, symmetric
terizing in a controlled manner the brain function.
development, and growth processes. In other
Specifically, combining NIBS and fMRI results
words, there is an inversion of developmental
in a powerful approach able to provide novel
processes during aging, which is in accordance
experimental data on the putative neurophysio-
with the developmental models defending that the
logical mechanisms underlying inter-individual
latest matured regions are the first to deteriorate.
differences and may help reformulate the theo-
Therefore, the brain undergoes numerous plastic
retical models proposed within this field by
changes throughout life, which are the result of
exploring functional mechanisms sustaining dif-
the complex interaction between environmental
ferent levels of cognition and brain properties,
factors and genetic determinants, giving rise to a
such as plasticity (Abellaneda-Pérez et al., 2019).
great inter-individual heterogeneity especially
Moreover, the combination of cross-sectional
relevant in aging.
and longitudinal designs to investigate the effect
Overall, the available literature provides evi-
of age on brain changes across the lifespan to
dence that the brain experiences several changes at
identify multidimensional systems-vulnerability
distinct levels (i.e., structural, functional, and met-
models (Walhovd et al., 2014) have already gained
abolic) which can be assessed by MRI. However,
importance in recent years as an optimal solution
we must not ignore that these macroscopic meas-
overcoming the limitations of cross-sectional clas-
ures are reflecting microscopic changes in our
sical research comparing younger versus older
brain (such as changes in vesicle trafficking, mem-
adults (Fjell et al., 2014a, 2014b). Thereby, neuro-
brane receptors expression, immune system reac-
science has experienced unprecedented growth in
tions, glial composition, neural death, etc.). In this
the accessibility of large-scale data sets including
regard, future research has the challenge of com-
massive genetic data (Tibon et al., 2022).
bining these techniques with more sophisticated
Thus, the new technological research frame-
biological and genetic markers to unravel those
work is mainly focused on multicentric consor-
specific factors conferring resilience/vulnerability
tia and large-scale multimodal initiatives such as
to brain disorders. In conclusion, studying these
the UK biobank (Sudlow et al., 2015), Lifebrain
elements and their neural underpinnings becomes
(Carver et al., 2022), the ENIGMA Consortium
vital to improve the quality of life of anyone by
combining brain imaging with genetic data
unrevealing the crucial determinants that could
(Thompson et al., 2022), integrating biomedi-
lead us to develop, promote, and maintain brain
cal databases and multilevel research resources.
health throughout the lifespan.
In this light, the use of artificial intelligence and
complex computational models has gained inter-
est in recent years (Pillow and Sahani, 2019). For
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Innovation Pathways, Real-life
Neuroscience Startups,
and Applications
Tiago Lazzaretti, Paulo S. de Melo,
Anna Marduy, Rafaella Rogatto de Faria,
Marcel Simis, and Felipe Fregni
INTRODUCTION
Advances in neuroscience and better knowledge
of the brain have leveraged the development of
neuro-technologies. Important advances are tak-
ing place in treatment, diagnosis, quality of life,
and performance. In addition, the growing preva-
lence of neuropsychiatric disorders related to the
world’s emergent aging population and environ-
mental exposures leads to evident need of innova-
tive neurotechnological. This demand has been
met with global research and development initia-
tives focused on the study of brain physiology and
neurological disorders in countries such as the
United States, Japan, Israel, China, and the
European Union. Nonetheless, the initiatives
encompass a broad range of aims, on the study of
several neurological aspects, which comes with its
set of challenges. These programs face predica-
ments such as the need for investment, concilia-
tion of basic and translational research, and the
acceleration of neurotech device market imple-
mentation (Grillner et al., 2016). The private ini-
tiative is deeply involved in the process of trying
to overcome these obstacles and advance innova-
tion practices.
However, big corporations are not always able
to meet the innovation demand of the neurotech
4
field at its needed speed. Considering the com-
plexity and multilevel management of healthcare
giants, the process of innovation within these
companies undergoes great bureaucratic proce-
dures, which slows down the process. This is when
startups have the potential competitive advantage
to introduce novel devices and industry models at
a faster pace (Freeman and Engel, 2007).
Startups are entrepreneurial business models
engaged with innovation and surrounded by rapid
growth. Since changes in the healthcare system
happen fast, this business model is gaining space
in the sector, as they can rapidly find novel solu-
tions and scale products or services, that already
implement innovation in their foundation as a key
factor of disruption (Spender et al., 2017). This is
especially true in the field of neurotechnology, as
startups have become attractive channels for nov-
elty. To their advantage, their small size allows for
a larger focus on faster and larger-scale production
of innovation (Freeman and Engel, 2007).
Innovative implementations within the neuro-
science field are important measures to improve
people’s lifestyles, lower costs, and increase effi-
ciency. And with the advent of an aging popula-
tion, unhealthy lifestyle tendencies, or even an
unexpected pandemic, there is a requirement
for change in the actual care models, especially
 INNOVATION PATHWAYS AND REAL-LIFE NEUROSCIENCE STARTUPS
considering most of the time, an innovative idea
does not correspond to a successful real-world
opportunity (Chen, 2021; Moroni et al., 2015). In
fact, innovation is not only defined by the creation
of a new idea. It has to be followed by its success-
ful implementation in the market (Freeman and
Engel, 2007).
Risk of failure is even more prominent with
up-and-coming neurotech startups considering
the fast pace at which the field is growing, and
the unpredictable nature of innovation in the area
(Freeman and Engel, 2007; Garden et al., 2019).
Therefore, to advance innovation in this business,
companies need to take advantage of startup strat-
egies including user experience (UX), biodesign,
pivoting, and attracting investments. In this chap-
ter, we discuss these strategies and how they are
being applied by neurotech startups to promote
innovation and provide a comprehensive summary
of the main acting neurotech startups today.
Furthermore, we provide some examples of
innovations related to treatment, diagnosis, quality
of life and performance, including approaches such
as wearable sensors, predictive medicine, preci-
sion medicine, brain computer interface, genetics,
non-invasive stimulation, among others. There is
no conflict of interest between the authors or com-
panies mentioned. Those are examples of potential
paths to the future and are not necessarily endorsed
at this stage due to the need for scientific validation.
STARTUP STRATEGIES TO ADVANCE
INNOVATION
User Experience and Innovation Cycle
Corporations and startups must be able to com-
bine innovation with user experience (UX), a set
of elements that focuses on the user needs, affec-
tive responses, and behaviors. Essentially, UX has
been shown to engage an innovation cycle, in
which the feedback of users instigates novelty,
which in turn makes users expect further innova-
tion to be that incremental to the novel aspect or
completely revolutionary. To be successful, the
incorporation of the user of experience requires a
methodical approach to optimize user feedback in
the development of innovation (Djamasbi and
Strong, 2019).
Thus, an UX method that should be applied in
the initial and final steps of the innovation process
is the well-known Golden Circle created by Sinek
(2009), consisting of three layers: why, how, and
what. The first layer depicts that what first inspires
the community is the reason why the technology
49
is being developed and why the company exists,
the purpose of the business. The second layer rep-
resents the how associated with an action plan on
how to conquer the innovation goals to make the
business succeed. The third and last layer is the
what, which is the final product or service. The
Golden Circle urges the business to think about
the value offered by the new creation. Currently,
companies that most thrive seek to disseminate not
what they do, but why (Sinek, 2009).
This is seen in the healthcare field, as patients
are always seeking new technologies to enhance
the experience and improve quality of life and
well-being, therefore UX must be considered at
all stages of the innovation process in this field
(Djamasbi and Strong, 2019). About innovations
in the neurotech field, the use of UX has been ini-
tially seen in the development of Brain-Computer
Interfaces (BCIs). BCIs are programs that connect
the brain to computerized devices that are widely
used in the recovery of individuals with motor
impairments (Lebedev and Nicolelis, 2017). Inci-
ting the previously mentioned innovation cycle
of this strategy, incremental BCI changes have
been suggested based on UXs of entertainment
technology, which will consecutively bring about
more innovation to this therapeutic model (Bram
et al., 2011). Therefore, UX can serve as a trigger
and instigator for neurotech innovation strategies.
Although UX is a promising cog for the innova-
tion mechanism in neurotechnology startups,
this experience can sometimes be too broad, and
mislead innovative initiatives in the field, wasting
needed resources and capital invested in startups,
which requires more focused strategies for suc-
cessful innovation processes to be implemented.
Stanford Innovation Biodesign Model
Filling entrepreneurial gap of
neurotech startups
With a growing focus on patient-centered innova-
tion practices, strategies to develop new technol-
ogy such as Stanford University’s Biodesign
Model (SBCB, 2022) are a need-based, problem-
solving alternative that consider the patient’s per-
spective and create effective solutions. This tool
combines particularities of Design Thinking and
Design Sprint in the three phases of this approach:
identification, invention, and implementation
(SBCB, 2022).
Succinctly, the identification phase consists
of finding and collecting the health needs of the
patients. Challenges and opportunities are taken
into consideration through the full cycle of care
(diagnosis, treatment, recovery, and billing), but
50 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
mostly it is associated with a key aspect of the
innovative process: the deep empathy with the
end-user. Empathy enables contemplating differ-
ent points of view, needs, and desires into a prod-
uct or service that will impact society (Bazzano
et al., 2017). This observational phase is based on
collect hundreds of needs without judgment, then
we need to implement rigorous filter of this list tak-
ing in consideration the potential that those ideas
must improve healthcare and each need effect on
the stakeholders. Finally, the two or three needs
with the highest potential from those identified
are deeply assessed (SBCB, 2022). Taking these
factors into consideration increases the chances of
successful market implementation of innovative
practice or device.
The invention phase consists of coming up
with ideas and solutions to later filter into a via-
ble technology that improves patient care. After
acknowledging the real problems faced by real
people, the ideation process takes place, consist-
ing of a brainstorming activity to find a creative
and viable solution (Caprari et al., 2018). In this
step, it is important to collect different perspec-
tives from people that somehow are connected to
the project: patient relatives, health professionals,
hospital managers, and executives. Different types
of solution prototypes are built in a fast “think-
build-rethink” way, to identify potential prob-
lems and failures on those solutions. Besides, it
is important to consider the intellectual property,
business model, reimbursement, and regulatory
aspects (Maher et al., 2019). Significantly, start-
ups propitiate an adequate scenario for this phase
to be developed. Creativity and innovation walk
hand in hand with the entrepreneurial model of
startups, leading to the successful accomplishment
of this step (Freeman and Engel, 2007).
The implementation phase occurs when the
prototyping and testing are done, the final step to
translate an idea into a final technology to reach
the market. Prototyping aims to provide a sense
of a real experience to detect possible problems of
the innovation through an iterative improvement.
Practical issues as testing to validate a selected pro-
totype, patenting, regulatory approval, reimburse-
ment, search the market potential, and explore
funding take place. This is where, biodesign incor-
porates, in a more goal-oriented way, the use of
UX to make refinements and improve the final
solution (Zenios and Yock, 2010).
The key aspect of the use of biodesign for inno-
vation is that it is a need-based system. This comes
with several, marketable advantages for start-
ups including more focus on the field’s demand,
being able to stipulate values to the innovative
technology of model one is trying to implement,
which leads to more investments and venture
capital influx, and less spending and wasting of
resources. This is especially important consider-
ing entrepreneurs in the neurotech field are usually
clinical researchers that wants to commercialize
their significant findings. However, they lack the
business knowledge to successfully implement
their devices on the market. Biodesign combines
the individualized input of patient needs – familiar
to the clinical researcher – with the necessities of
an entrepreneurial model – often foreign to them
(Zenios and Yock, 2010).
In the neurotech field, the first biodesign efforts
were instigated by the needs of the world’s large –
soon to become larger – aging population. With the
maturing of the world’s population, the demand
for innovations that target neurocognitive disor-
ders took significant proportions, and thus, the
neurotech field decided to target the development
of innovative devices focusing on the diagnosis or
treatment of disorders under the cognitive impair-
ment umbrella, opting for a need-based approach
in a societal scale (Garden et al., 2019).
Lean Startup Method
A different framework currently used by startups
including those in the neurotech field is the lean
startup method. It is a scientific based approach to
create a startup and the desired product faster and
with less chance of failure (Blank, 2013; Ries,
2022). The key principles of this process involve
the build-measure-learn feedback loop, the mini-
mal viable product (MVB), pivot, among others.
Such principles favor the experimentation, cus-
tomer feedback, integrative design, over an elabo-
rate planning, intuition, or a traditional design
development. The method establishes the transi-
tion to a quicker implementation and exposition of
the business model to learn from the feedback
provided.
The build–measure–learn process consists in
repeated learning cycles, starting with a MVP,
with only critical concepts, receiving feedback
from customers, and then reviewing the MVP.
During the process, lean startups prioritize the
agile development, that optimize time develop-
ing the product and the business model through
interaction and incrementation by the customers
and the market. The MVP is the minimal version
of the product that allows the maximum amount
of learning and information with the least effort.
This concept states that it is more efficient and
faster to expose your product to the market and
customers’ feedback than to wait to build the
perfect product before launching it (Blank, 2013;
Ries, 2022).
 INNOVATION PATHWAYS AND REAL-LIFE NEUROSCIENCE STARTUPS
These methods, similar to Stanford’s Innovation
Biodesign Model (SBCB), are starting to be intro-
duced in different business schools and used by
large companies to induce innovation and as a
replacement to the old regimen (Blank, 2013).
They help the accurate detection of client needs,
being able to change company strategies in order
to better assist the customer and innovate even
more in the process of development, the busi-
ness model, and the final product. Being able to
change company’s strategy based on feedback and
customer’s needs is a key tool in the startup envi-
ronment and has been implemented in different
situations.
Pivoting
Although biodesign focuses on a need-based
approach to construct innovation, the neurotech
field is considerably malleable and susceptible to
fast changes. These changes modify patients’
needs and require startups in the field to adapt to
them and this is when pivoting takes over. Pivoting
is the process of conducting strategic changes and
reorientations that have a direct impact on the suc-
cess rate of a business (Kirtley and O’Mahony,
2020). The term was first introduced with the lean
startup methodology. According to Failory (2021),
startups that pivot once or two times have a better
chance of growth and raise more money than
those pivot zero or more than two times (Kotashev,
2022). Thus, pivoting becomes an intrinsic mech-
anism to keep startups afloat with the constant
demand evolution of the neurotech and medical
industry in general.
Pivoting is known as a strong strategic tactic to
build value and maintain relevance in the business
world. Emphatically, it has become a progres-
sively frequent tactic in the medical industry. The
COVID-19 pandemic conveyed a crucial pivoting
point for several medical industry companies that
tweaked their business models to accommodate
the global demand, or completely changed their
medical product focus (Laur et al., 2021). Thus,
pivoting allows for relocation of resources that
were being used toward an unmarketable innova-
tion, to focus on tangible demands and therefore
successfully complete the innovation process.
Pivoting in the neurotechnology field fre-
quently involves the switch from therapeutic
innovation to diagnostic or detective innovation.
An opposite movement may occur. An example is
transcranial magnetic stimulation (TMS), which
was initially developed by Professor Anthony
Barker as a tool for neurophysiological studies
but is currently more used for different therapeutic
51
purposes. Great strides in neurotechnology are
still overshadowed by the large unknown physi-
ological factors of brain circuitry, being essential
the initiatives for the study of the central nervous
system (CNS), as described below.
WORLD’S BRAIN RESEARCH PROJECTS
Currently, there are several large worldwide initia-
tives that seek to improve the understanding of the
CNS, which will allow the generation of impor-
tant insights for the development of innovations in
neurotechnology. The expectations of these pro-
jects are very high, since they involve high-quality
researchers from different areas of science, in
addition to a massive investment that exceeds
billions of dollars.
Among them stand out the US BRAIN initiative
is a billion-dollar project, “aimed at revolution-
izing our understanding of the human brain. By
accelerating the development and application of
innovative technologies, researchers will be able
to produce a revolutionary new dynamic picture of
the brain that, for the first time, shows how indi-
vidual cells and complex neural circuits interact in
both time and space. Long desired by researchers
seeking new ways to treat, cure, and even prevent
brain disorders, this picture will fill major gaps in
our current knowledge and provide unprecedented
opportunities for exploring exactly how the brain
enables the human body to record, process, utilize,
store, and retrieve vast quantities of information,
all at the speed of thought” (Jorgenson et al., 2015;
NIH Brain Initiative, 2022).
The Human Brain Project (HBP) (Amunts
et al., 2019; HBP, 2022) commenced in 2013,
“aiming to make two major innovations: first,
a new type of science, creating synergy at the
interface of empirical research on the brain with
advanced computing, and second, an eco-system
and new culture of collaboration leading to sub-
stantial progress in our understanding of the brain,
brain medicine, and brain-inspired technologies.”
It is a project co-founded by the European Union
(EU), with participation of several countries, with
an estimated budget of US1.3 billion dollars (HBP,
2022; Reardon, 2014).
Another example is the China Brain Project
(CBP; Normile, 2018; Poo et al., 2016) sup-
port three key research areas. The body of this
research aims to study the neural basis of cog-
nitive functions, improve, and develop diagno-
ses and therapies for major brain disorders, and
develop brain-machine intelligence technologies
(Poo et al., 2016; Reardon, 2014). The project
52 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
estimates an investment US$157 million per year
and states the international cooperation as a prior-
ity. The center is expected to be a national effort
to bring the country to the top of neuroscience
development, being similar to the US and EU in
the field (Normile, 2018).
The International Brain Initiative (IBI) was
established to catalyze and advance ethical
neuroscience through international collaboration
and knowledge sharing, uniting diverse ambi-
tions and disseminating discoveries for the benefit
of humanity (IBI, 2018). It has participation of
some of the world’s major brain research projects,
including the HBP, BRAIN initiative, Australian
Brain Alliance (ABA, 2022), Chinese Institute for
Brain Research (Cyranoski, 2018), Japananese
Brain Mapping by Integrated Neurotechnologies
for Disease Studies (Brain/MINDS, 2021; Okano
et al., 2015), Korean Brain Research Initiative
(KBRI, 2022), and the Canadian Brain Research
Strategy (CBRS, 2022).
Besides the largest initiative, there are many
smaller projects worldwide contributing to the
expansion of this important knowledge. One
example is the São Paulo Research Foundation
(Brazil), that supports different types of projects
including in neuroscience (FAPESP, 2022)
Advancing the world’s understanding of the
brain has recently started to shift its focus on
the investment of neurotechnology and neu-
roinnovation, with different public and private
organizations investing in neuroscience startups
to stimulate these advancements. An example of
this investment is the Atlanta-based organization
NeuroLaunch, a 50-mentor program that partners
with Atlanta’s most prestigious universities with
strong suits in neuroscience and tech to aid start-
ups on developing products and advancing brain
(Coburn, 2015). This initiative has broadened
its activities to different cities in the US focus-
ing on different product development, such as a
more pharmaceutical focus on the east coast and
device focus on the west coast, allowing for the
rapid expansion of the neuroscience startup field
through its investments.
Another example of an organization joining
public and private forces to advance the neuro-
technology field is the Neurotechnology Industry
Organization (NIO). This is an American, lobby-
ing-focused institution that encompasses neuro-
science-mediated companies, academic research
centers, and organizations with the aim of promot-
ing investments, either through federal research
funding or private funding to make the neurotech-
nology field more accredited and established, to
facilitate product approval through advocacy and
promotion of the field (Robinson, 2019). It can
thus be seen that, as the neurotech startup field
advances, more opportunities are being created
for private organizations that sponsor and man-
age these initiatives, and lobby for better access to
their neuro-innovations.
INVESTMENT
Implementing the strategies discussed in this
chapter require not only planning but investments.
For startups, especially in neurotech, to establish
one’s business in the market and acquire a com-
petitive position in relation to others, it is neces-
sary to attract investors. When it comes to startups,
venture capital is a common type of investment at
its initial stage. The capitalists seek an opportu-
nity that is risky but provides the necessary tools
to grow (Zider, 1998). They motivate the entrepre-
neurs to structure their business by considering
the public and the scalability, taking part in the
management activities, and providing strategic
advice (Huse et al., 2005).
Efforts for investment in neurotechnology start-
ups are made from the private and public sectors
in an international scope. The different neurotech-
nology ongoing initiatives around the world mutu-
ally support one another to advance innovation
within the field. This combined effort stimulates
the participation of the private sector in invest-
ing, and thus, contributes to faster developments
that can be made on larger scales, given startups
receive these funds (Garden and Winickoff, 2018).
An interesting concept in the context of finance
is the so-called “valley of death,” which is the
startup life cycle period that typically happens
after the company launches a product but it’s still
not making money. A large percentage of startups
typically fail in this period. Therefore, proper
financial planning for this period is very important,
considering strategies that include crowdfunding,
joint ventures, incubators, contests, grants, and
philanthropy (especially for innovation that has
significant health impact but with low financial
gain).
For that reason, a crucial alternative to the
challenging financial period that the startups usu-
ally go through is the public–private partnership.
Different types of public grants inviting companies
to develop a new technology is a way to stimu-
late innovation and guarantee investments in what
may be a win–win situation. National Institute of
Health (NIH), a world leader in healthcare inno-
vation, offers different opportunities and partners
with industry and academia to promote medical
research in order to better understand and assist
human health. Examples of NIH public–private
 INNOVATION PATHWAYS AND REAL-LIFE NEUROSCIENCE STARTUPS
partnerships are: the Accelerating Medicines
Partnership, that brings together the Foundation
of the National Institute of Health (FNIH), the
NIH, the Food and Drug Administration (FDA),
and 10 different biopharmaceutical companies
to increase the new diagnostics and therapies
for Alzheimer’s and Parkinson’s disease, type 2
diabetes, and autoimmune disorders; the Partner-
ship for Accelerating Cancer therapies, that com-
bines the above-cited national institutions and 12
biopharmaceutical companies to invest in cancer
immunotherapy, anti-tumor immune response,
and imaging approaches to target metastatic
cancers, as well as the Biomarkers Consortium,
that helps to accelerate biomarkers’ development
and discovery in neuroscience, cancer, metabolic
disorders, immunity, and inflammation.
Promoting this kind of partnership favors
the companies that receive government budget
to develop a new technology and take fewer
financial risks, and favors the government stimu-
lating the progress, warming the economy, and
guaranteeing the development of a national pro-
duct, that afterwards may yield taxes and
economic, environmental, and cultural ben-
efits inducing advancements in several fields,
including neuroscience.
RESPONSIBLE INNOVATION AND ITS
CHALLENGES AMONG NEUROTECH
STARTUPS
Although producing innovation on a large scale
and at a fast past is thought to be a positive aspect
of neurotechnology startups, recent debates
regarding the neuroethical implications of this
rapid innovation have raised significant points.
Considering the field of neurotechnology encom-
passes neurological disorders deemed untreatable,
the innovative aspect is rushed as the demands for
effective therapeutic techniques for these disor-
ders increase. However, there is a lack of regula-
tion that comes with fast-paced innovation,
especially in the startup setting. Because they are
small, startups have limited resources and choose
not to focus on investing in neuroethical aspects
such as regulatory committees, or assessors that
can debate the safety or ethical implications of
neurotech innovations. This raises concerns
toward the quality of innovation and calls for a
consideration of neuroethical principles into the
research and development in neurotechnology
startups (Pfotenhauer et al., 2021).
These concerns are even greater when involving
neurotechnologies that are not medical devices but
53
interventions for healthy people to increase cogni-
tive and motor performance, and to improve emo-
tional balance. In these cases, products are often
marketed without adequate scientific evidence and
safety assessment since it is not regulated by the
strict criteria such as the US FAD. This situation is
even more worrying when involve the application
of electrical brain stimuli and other different not
innocuous interventions since indiscriminate use
can result in unknow adverse effects.
The United Nations Educational, Scientific
and Cultural Organization (UNESCO) recently
published a periodical with the title “Should we
be afraid of neuroscience?” (UNESCO, 2022). In
this publication, concerns were expressed regard-
ing brain–machine interface technology and arti-
ficial intelligence algorithms, which in theory can
monitor, modify, and even manipulate thoughts.
Moreover, discussed the need for specific laws
for these possible future scenarios, to protects
the “neurorights” of citizens, including physical
and mental integrity, mental privacy, freedom of
thought, free will, and enjoy the benefits of scien-
tific progress. As stated, the promising neurosci-
ence market can be as harmful as beneficial for
the society, investments by companies and mainly
the government should take place to audit and
control the development and correct exploitation
of these technologies. Chile is an example of the
first country that started to discuss and implement
neurorights in its constitution in order to pro-
tect the integrity of the mind and brain from the
advances in neurotechnology. Moreover, Spain,
USA, France, and Argentina have started to study
the issue (UNESCO, 2022).
Another challenge raised in the document is the
inequality in the neuroscience field largely domi-
nated by industrialized countries. Regions such as
Latin America and Caribbean, Central, West, and
South Asia, Oceania, and Sub-Saharan Africa still
make a lower contribution to the neuroscientific
literature as compared with their representation
in the world. Obstacles include limited access
to training, funding, and heavy teaching loads
(UNESCO, 2022). However, including those
regions in the research map is crucial to under-
stand the brain and validate research, since they
are responsible for an enormous genetic diver-
sity and representation of the world’s population.
Projects from more developed countries together
with private institutions may invest and develop
such places to acquire better and more valid neu-
roscience research.
With such an emphatic stimulation and invest-
ment in the neuroscience field in the last couple
of decades, it has been quickly demonstrated how
easy it can be to deviate into unethical manage-
ment of this field’s advancement. In fact, when
54 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
asked about the role of neuroethics in the neuro-
science startup department, neuro-entrepreneurs
have raised important areas where a code of con-
duct could be applied. These include data owner-
ship, autonomy, misuse of neurodata, and access
and justice. Data ownership has been emphasized
as a hard-to-manage topic within the neuroscience
domain because of its significant advancement,
considering that the findings within the field can
be so momentous, it is thought that data obtained
through this field should be made public domain
or be sold to larger companies within the indus-
try. Taking into account the lack of neuroethical
implications within neuroscience development
terrain, it is easy for larger companies to pressure
startups into selling their user-data, especially if
it comes with the promise of progress and inno-
vation through financial incentives (Moss et al.,
2021). Thus, the implementation of neuroethics
in this field could benefit startups in being able to
have more autonomy over their advancement in
the field. The seven different principles cited are
fundamental strategies for the startup development
and innovation as shown in Figure 4.1.
Real-Life Neuroscience Startups
The brain has been explored as the most complex
and mysterious organ of our species. Private
investments from the industry have advanced neu-
roscience and how we understand and assess brain
activity. The neuroscience industry invested 30.3
billion dollars in the year 2020 and is planning to
Figure 4.1 The seven principles for start up development and innovation chain.
Note: SIBM: Stanford Innovation Biodesign Method; LSUM: Lean Start Up Method.
increase this amount to 37 billion dollars by 2027,
growing in a compound annual growth rate
(CAGR) of 2.9%. Some sectors might be
highlighted since they have received more invest-
ments, also being the ones with more advance-
ments in the last years. Whole-brain imaging, for
example, is the main field recording 2.6% of the
CAGR and reaching 7.9 billion by the end of
2027. Other segments such as electrophysiology,
brain-computer interfaces, neurostimulation are
expected to have significant increases in their
budget (Neuroscience – Global Market Trajectory
and Analytics; NGMTA, 2021).
Brain Imaging
Brain imaging is also a relatively old technique
that has significantly advanced in the last few
years, especially due to the great importance in
clinical practice and due to the stimuli arising
from the large investments in neurosciences (as
described above). Besides the higher costs
involved in developing imaging techniques, this
challenge has been addressed by different startups
in the neuroscience field. Several techniques to
visualize the brain have been developed during the
years, like magnetic resonance imaging (MRI)
(Bernasconi et al., 1999, 2000; Cendes et al.,
1993; Mamani et al., 2012) and its functional
form, functional MRI (fMRI) (Poldrack, 2012;
Rana et al., 2016), functional near-infrared spec-
troscopy (fNIRS) (Chen et al., 2020), and positron
emission tomography (PET) (Lu and Yuan, 2015).
 INNOVATION PATHWAYS AND REAL-LIFE NEUROSCIENCE STARTUPS
All these techniques have improved our under-
standing of the brain structure and function, as
well as their relationships.
Behind the challenge of the higher costs of
these techniques in comparison to the other ones
explained here, several companies are aiming to
explore and improve them, and to create more effi-
cient ways of analysis to advance the understand-
ing of the CNS. Oxford Brain Diagnostics (OBD)
is a company founded in 2019 in the United
Kingdom. The startup raised US$1.94 million
to develop a software called Cortical Disarray
Measurement (CDM) to help clinicians in the
diagnosis of dementia through MRI (OBD, 2022).
Icometrix is another startup in Leuven, Belgium,
that has raised US$20.2 million to develop imag-
ing, guided and analyzed by artificial intelligence
software. The company was founded in 2011 and
its main product is the MSmetrix, which detects
and calculates brain lesions and atrophy volumes
(Icometrix, 2022). Additionally, PETcoil is a
startup founded in 2018 in Sunnyvale, California
that combines PET scan with MRI to achieve a
cost-effective high-performance PET/MRI. They
recently raised US$1 million in just one round of
funding (PETcoil, 2022).
Neuropharmacological Startups
Using pharmacological drugs may be a classical
and more common approach when we talk about
neuroscience and neuropsychiatry conditions.
However, the progress in the development of phar-
macological drugs has helped us to better under-
stand the complex biochemical pathways involved
in brain processing and brain diseases (Geerts
et al., 2020). Moreover, several improvements
must be done in the current pharmacotherapies
and a better understanding of the CNS biochemis-
try may raise for studies testing these types of
interventions and analyzing how they affect the
nervous system in diverse patterns. Currently,
some companies focus on developing neurophar-
macological interventions for disorders that have
no established treatment or where treatments
might be optimized, bringing more benefits and
less harm to patients. For example, Amylyx
Pharmaceuticals develops different pharmacologi-
cal treatments for neurodegenerative disorders
such as Alzheimer disease (Amylyx, 2022). The
company is located in Cambridge, Massachusetts,
one of the biggest centers of innovation and
research in the United States. In fact, Amylyx has
raised US$202.2 million in funding involving new
pharmacotherapeutic treatment for amyotrophic
lateral sclerosis (ALS), Alzheimer’s disease (SD),
55
and Wolfram (DIDMOAD) syndrome (cf.
NGMTA, 2021). Furthermore, Verge Genomics
was founded in 2015 in San Francisco, California
(Verge Genomics, 2022). The main activity of this
startup was using artificial intelligence and
machine learning to develop new drugs for the
treatment of Alzheimer’s, AML, Parkinson’s, Sch-
izophrenia, and other neuropsychiatry disorders.
Their therapy targets specific genes related to
those diseases. Amylyx has raised US$134.1
million in funding and has partnerships with 25
organizations, including universities, banks, insti-
tutes, and other pharmaceutical companies
(NGMTA, 2021).
Gene therapy that initially seemed unattainable
is now a reality. Ever since the creation of synthetic
insulin by the startup Genentech, more entrepre-
neurs have been investing on focusing in the devel-
opment of the gene therapy industry for different
conditions. Although faced with some challenges
such as delivery method and efficacious manufac-
turing, gene therapy startups are starting to focus
on improving these factors to reach complex CNS
disorders. Passage Bio (2022) is an example of a
company enhancing manufacturing techniques by
focus on accuracy of gene therapy targets for CNS
conditions such as amyotrophic lateral sclerosis,
frontotemporal dementia, and GM1 gangliodo-
sis, to name a few (Shaffer, 2020). Another inter-
esting example is the medically Spinraza from
Biogen, approved by United States Food and Drug
Administration (FDA) to treat spinal muscular
atrophy (SMA; Prakash, 2017). This medication
controls the mutations caused in the chromosome
5q, related to SMA, by selectively binds and tar-
gets RNA and regulates gene expression. The suc-
cess of this approach opens an important path for
treatment of many other genetically caused neu-
rological disorders. An interesting phenomenon
with gene therapy startups is that, being inserted
in this field and focusing on improving areas such
as delivery and manufacturing rather than solely
on specific products facilitates their expansion to
other conditions (Shaffer, 2020).
Electrophysiology Startups
The recording of electrophysiologic activity has
been a key tool in neuroscience with the potential
to provide a fair understanding of brain activity
with a high temporal resolution (Euler and
Schubert, 2021; Sanchez et al., 2014), allowing to
identify different stages during the information
process. Furthermore, different approaches can be
performed when collecting and analyzing EEG
data, such as resting activity, event-related
56 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
potentials (ERPs), event-related desynchroniza-
tion (ERDs), and so on (Euler and Schubert,
2021). Additionally, EEG’s potential in neurosci-
ence also relies on its portability and low cost,
being a very feasible tool to apply in research
studies and the clinical setting (Krigolson et al.,
2017; McWilliams et al., 2021). Moreover, mag-
netic encephalography (MEG) has been also an
important tool to analyze the magnetic field pro-
duced by the brain. With this technique, some-
times even together with the EEG, is possible to
detect patterns in the brain also with great tempo-
ral resolution through event-related magnetic
fields (ERFs; Lopes da Silva, 2013). Several com-
panies have been exploring inG in the last few
years. For instance, BioSerenety, a company
founded in 2014 in Paris, raised US$94 million in
funds to develop remote technologies to detect
brain signals such as the NeuroNaut, a remote
electroencephalography recording in the testing
phase. They have a goal to develop devices that
can accelerate research in targeted diseases
NGMTA, 2021). Cerible is another startup that
mainly invests in EEG systems intending to make
EEG devices more accessible and portable. It has
an important role in clinical practice specially to
make easier to detect non-convulsive seizure. The
company commenced in 2014 in Mountain View,
California and has raised US$121 million in fund-
ing to develop their product (Ceribell Rapid
Response EEG, 2022; NGMTA, 2021).
Another remote EEG system is the Dreem
headband, which allows longitudinal and house-
hold monitoring of important sleep parameters,
including sleep stages (Dreem, 2022). There are
technologies that use EEG signals to monitor
cognitive performance and mood. For example,
Focus SDK, EEG headband aiming to measure
the engagement and relaxation in educational
environments (Focus SDK, 2022). Many of the
new technologies use the EEG not only to moni-
tor, but also to train the brain in the context of the
brain–machine interface, as described below.
Moreover, neuroinnovation in the field of
electrophysiology also includes the creation of
products that facilitate interpretability and analy-
sis of electrophysiological findings. Considering
that EEGs and other electrophysiological tests
are becoming more applicable in the clinical set-
ting, it benefits clinicians to be able to quantita-
tively interpret their findings. This opens space in
the market for the development of software that
integrate different aspects of electrophysiology
analysis in ways that can help further the use of
these products (Suter et al., 2010). In addition,
the high demand of electrophysiological assess-
ments to understand brain behavior through
clinical research, has also created space for the
development of more practical, and easy to
navigate software that eases electrophysiologi-
cal analyses. An example of this opening is the
AnyWave software, a data visualizer that makes
the interpretability of neurophysiological findings
faster and easier for clinicians and methodologists
(Colombet et al., 2015).
Brain–Computer Interfaces Startups
Connecting brains with computers is an emerging
technique in the neuroscience field that allows
direct communication of the electrical signals of a
neuron for an external device (Mudgal et al.,
2020). Described here as one specific technology,
its use is highly dependent on the use of previous
technologies discussed here, such as EEG, MEG,
fMRI, and fNIRS (Mudgal et al., 2020). Therefore,
the development of brain–computer interfaces is
intrinsically related to the development of differ-
ent types of technologies that help the neurosci-
ence field to understand better than brain behavior
different companies have raised funds to develop
brain–computer interface technologies. The sys-
tems can be divided into invasive (with implanted
devices) or non-invasive.
Neuralink (2022) is a startup specialized in
developing brain–computer interfaces located
in Fremont, California. They focus on helping
patients with spinal cord injury in day-to-day
activities. Their main product is called “Link”
and captures and interprets neurons activity with
an invasive device. The company has raised
US$363 million to develop this technology
(NGMTA, 2021).
BCI Non-invasive systems are relatively sim-
pler and cheaper, and there are currently many
companies in the area. Some of the examples are
NextMind (2022) that invests in brain–computer
interfaces development, mainly using electro-
encephalography and headset to track real-time
visual experiences, translating them into digital
commands in real life through machine learn-
ing algorithms (NextMind, 2022). The company
founded in 2017 in Paris, France, has invested
US$4.6 million. The startup’s main product called
Dev Kit has earned the 2020 CES innovation
award (NGMTA, 2021; NextMind, 2022). Another
example is FocusCalm (2022) which proposes use
of EEG with neurofeedback to reduce stress and
improve one’s sense of well-being (FocusCalm,
2022); Another is Bitbrain that use BCI for cog-
nitive maintenance and enhancement (“Bitbrain –
Advanced neurotechnology,” 2018); and the
Emotiv which can even be used for entertainment,
but not as medical equipment (Emotiv, 2022).
 INNOVATION PATHWAYS AND REAL-LIFE NEUROSCIENCE STARTUPS
Neurostimulation Startups
Neurostimulation devices have been developed in
the past years targeting the treatment of neuropsy-
chiatry conditions stimulating the brain with dif-
ferent methods. Some examples of neurostimulation
techniques are the transcranial direct current stim-
ulation (tDCS), transcranial magnetic stimulation
(TMS), transcutaneous vagus nerve stimulation
(tVNS), between others with different applicability
in different conditions, such as chronic pain (Costa
et al., 2019; Moisset et al., 2020), depression
(Akhtar et al., 2016; Brunoni et al., 2010), and
stroke (Ting et al., 2021). Development of these
techniques, besides increasing the possibilities for
the treatment of relevant diseases, helps us to
understand better how the CNS works through
research studies that seek the brain response with
biomarkers, imaging, and clinical outcomes.
Among the startups investing in neurostimulation
devices, Thync is a company that designs devices
for non-invasive brain stimulation to help the
improvement of brain function. The startup already
raised US$13 million in funding and was founded
in 2011 in Los Gatos, California. Their main
product is called FeelZing designed to improve
the energy and performance of the users
(NGMTA, 2021; Thync, 2022). Additionally,
MicroTransponder is a startup focused in
developing neurostimulation devices as therapies
for specific neurological conditions. The company
was founded in 2007 in Dallas, Texas, and aims to
develop technologies to offer relief for chronic
pain, limb mobility, stroke, and tinnitus. Some
US$42.1 million has been raised in funding to
invest in the development of these techniques
(Microtransponder, 2022; NGMTA, 2021).
Calahealth is another example of a startup in this
field. The bioelectronic company was founded in
2014 in Burlingame, California, and have raised
US$148.3 million in funding to develop a periph-
eral nerve stimulation device called Cala Trio
mainly targeting patients with essential tremor
(Cala Health, 2022; NGMTA, 2021).
Table 4.1 Summary of real-life neuroscience start ups
Brain imaging Neuropharmacology Electrophysiology Brain-computer
Oxford Brain Amylyx BioSerenety,
Diagnostics, UK Pharmaceuticals, France
USA
Icometrix, Belgium Verge Genomics, Cerible, USA
USA
PETcoil, USA Passage Bio, USA Dreem, USA
Biogen, USA BrainCo, USA
57
Aside from the development of neurostimu-
lation devices, neurotechnology startups have
also been tapping into different neurofeedback
techniques related to neuromodulation target-
ing different conditions ranging from anxiety
to better focus. For instance, several neurotech-
nology startups have focused on developing
devices or phone applications related to mind-
fulness to improve workplace efficiency. Others
target themselves around improving focus for
studying. Nonetheless, startups conveniently tie
together lower cost neuro-innovations, such as
phone applications and neurotechnology to tar-
get different audiences for neurotech products
(NeurotechJP, 2022). A start up summary by field
is provided in Table 4.1.
Innovation Translation from
Academia to Industry
Another innovation core component is the acad-
emia. Universities are a huge generator of intel-
lectual property and innovative inventions.
However, translating the innovative invention
from years of effort and research in a profitable
product has been done with restricted efficiency
and success by the universities and research
organizations (Sanami et al., 2017; Yusuf, 2009).
Different reasons can explain the barriers for this
translation, as inadequate design to be easily
implemented in the health care setting, inadequate
marketing of the idea, or onerous regulations
(diSessa and Cobb, 2004; Sanami et al., 2017).
Furthermore, academics researchers usually have
reservations regarding commercialization, since
sometimes the intellectual property protection
goes against some knowledge sharing and demo-
cratic access principles. Therefore, there is a need
to balance between sharing knowledge and pro-
tecting the intellectual property in order to com-
mercialize and make the innovative process
profitable (Sanami et al., 2017).
Neurostimulation Cognitive and learning
interface neurotechnologies
Neuralink, USA Thync, USA MindStrong, USA
NextMind, MicroTransponder, Neurotrack, USA
France USA
FocusCalm, USA Calahealth, USA Virtuleap, Portugal
Bitbrain, Spain
58 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Nowadays, a trend model has been used by
different companies in partnership with research-
ers and universities. The open innovation model
is based on the collaborative network of trusted
researchers and companies in order to share
knowledge and be the middle-term between the
totally open model usually proposed by the aca-
demia and the old, closed innovation model,
proposed by to companies to protect the intel-
lectual property (Chesbrough et al., 2006; Trott
and Hartmann, 2009). In this model, the innova-
tion process would have benefits from both sides.
The creativity and potentialization of the trust-
able sharable knowledge, and the possibility of
commercialization provided by the protection of
the innovative product. To accomplish this pro-
posal, academia and industry need to count with
a multidisciplinary team, composed by academ-
ics, health care professionals, medical advice and
private sector product design companies, intellec-
tual property professionals, innovation managers,
and patients’ groups (Chesbrough et al., 2006;
Glasgow and Emmons, 2007; Sanami et al., 2017).
Different universities and research organizations
have been more focused on commercializing inno-
vations and participate on the academia-industry
relationship. Several online platforms can be used
to share knowledge, information, and engage with
industry creating solid relationships to commer-
cialize innovation (Sanami et al., 2017).
Translating an idea to a product is challenging.
Steps involve identifying areas requiring techni-
cal development, manufacture, clinical efficacy,
regulatory approval, financial viability, as well as a
large multidisciplinary team to address these differ-
ent areas of development. As Sanami et al. (2017)
suggested, a multi-partner approach, besides chal-
lenging, is required in order to accomplish all the
steps of development. During the process, clear
communication and definition of the specific role
of each stakeholder is required. As stated, before
on this chapter, an intrinsic relationship between
the academia, industry, and funding institutions/
government, this model allows to take advantage of
each one of the three entities strengths and over-
come their limitations, promoting accessible, effec-
tive, and financially feasible innovative ideas.
Startups Focusing on Cognitive and
Learning Neurotechnologies
Given increasing aging of the population and
higher prevalence of decay of mental health status
in the past years, a new era of neurotechnology
startups is starting to focus on developing tech-
nologies focused on cognitive improvement.
These startups have targeted the development of
practical, easy-to-use smartphone applications
and devices that aim for memory, and cognitive
improvement of healthy and disease burdened
individuals.
An up-and-coming area currently interesting
neurotech startups is the psychiatric field. With
the significant prevalence of anxiety and depres-
sion amongst today’s society, startups have
started to develop softwares aimed at improv-
ing or tracking individuals’ mental health status.
An example of a startup with this exact aim is
MindStrong, a company that developed a virtual
platform for the assessment of mental health sta-
tus and early detection of traces of psychiatric
disorders through an individual’s smartphone
(“MindStrong,” 2022). The company also pro-
vides virtual psychiatric services, for individuals
with already diagnosed psychiatric conditions.
Within the post-pandemic reality, the need for
more services that are practical, and that can be
done remotely has been elucidated, a reason to
why MindStrong is a good example of the mar-
ketable and achievable application of clinically
based neurotechnologies.
Another significant field catching the interest
of neurotech startups is the area of cognitive and
memory improvement. Considering brain training
exercises has become a significant trend within the
smartphone application realm, neurotech startups
such as Neurotrack and Virtuleap have envisioned
how to scientifically optimize these exercises with
the aim of conjuring memory and cognitive indi-
viduals in their product’s users.
Neurotrack is a Japan-based company with two
different products; an assessment of cognitive
function and a “brain care program”, both devel-
oped with the goal of preventing Alzheimer devel-
opment (“Neurotrack,” 2022). Whereas Virtuleap
is a virtual reality (VR) startup that has devel-
oped a VR product with the objective of improv-
ing memory function through the development
of games and tests that can engage motor skills,
attention, problem-solving strategies, informa-
tion processing, and other cognitive functions
that aid in memory improvement (Kadoi, 2022;
“Virtuleap,” 2022).
Considering the linear trend between technol-
ogy development and society advancement, it
makes sense that cognitive improvement is behind
so many neurotech developments to this day
(Cinel et al., 2019). Moreover, a large scientific
basis is provided for the development of products
aimed at cognitive augmentation given that studies
have shown that certain cognitive tasks employed
in these neurotech products can activate different
brain areas related to memory and cognition, and
thus allow space for the growth of these technolo-
gies and their startups in the market (Cinel et al.,
2019). The high demand for neurotech aimed at
 INNOVATION PATHWAYS AND REAL-LIFE NEUROSCIENCE STARTUPS
cognitive development also gives way for future
projections and more specific directions for tech-
nologies produced for these goals.
Applications of Neurotechnology
Startups
Historically, most of the focus of neuro-
entrepreneurs has been in generating neuro-
innovations targeted for diagnostic or screening
devices or devices designed for the clinical treat-
ment of specific neurological conditions. However,
these applications have given way for the advance-
ment of neurotech startups and their insertion into
the academic field, as clinically oriented neuro-
innovation has set a precedent for funding neuro-
cognitive research and expanding the production
of their creations. Neuro-innovations have created
a new demand for adjunctive devices for diagnosis
and treatment of neurological conditions (Moss
et al., 2021). Also, a qualitative study conveying
the insight of neuro-entrepreneurs on the role of
neuroethics in their field has suggested that neuro-
tech should not replace current practices, but
instead complement them (Moss et al., 2021).
Clinical applications of neurotechnology have
vastly contributed to the advancement of startup
development, leading these companies to be able
to expand their products applications to non-
clinical settings, including neurocognition.
With the growth and quick development of
the neurotech startup industry, entrepreneurs
have started to notice how neuro-innovation can
be applicable in other areas. Consequently, start-
ups are now focusing on neurotechnology uses
other than those involved with neurological dis-
eases, such as improving cognitive and memory
function, work efficiency, and wellbeing (Moss
et al., 2021). However, there is still some debate
regarding the ethics and applicability of expand-
ing neurotechnology to non-clinical fields such as
cognitive neuroscience.
SUMMARY AND CONCLUSIONS
Innovative advances in cognitive neuroscience are
extremely important to better understand the CNS
and the conditions that impact it, improving peo-
ple’s overall cognitive function and ultimately
their quality of life. Large, well-established com-
panies are not always able to meet innovation
demands within the neurotechnology field since
the management of these corporations has multi-
level complexity, and the process of innovation
59
undergoes major bureaucratic procedures, which
therefore slows down the development of new
technology. Startups are business models engaged
in innovation due to their more flexible and less
bureaucratic management. Since changes in sci-
ence and healthcare knowledge are rapid and
ongoing, these types of companies have been
gaining space in the sector developing novel and
innovative cognitive neuroscience solutions faster,
as well as scaling this important service and pro-
ducing new knowledge.
A core concept in translating innovation from
the neuroscience laboratories into population
hands is a well-stablished, trustable, and clear
partnership between academic research, industry,
and sponsors to promote feasible and effective
innovative ideas. However, it is important to ana-
lyze critically the biological plausibility and the
scientific basis of the cognitive neuroscience solu-
tions proposed by the plethora of business start-
ups. Moreover, with the rapid advancement and
progress of these startups, serious efforts are being
made to accredit and substantially advance the
cognitive neuroscience field by creating adminis-
trative opportunities as well as the direct imple-
mentation of neuroethics in the management of
these private initiatives.
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 PART II
Neuroscientific Substrates
and Principles
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Neural Processes and Activity:
Cultural Neuroscience
INTRODUCTION
The human brain abounds within the structure and
function of neurons (Koch and Poggio, 1987).
With approximately 105 neurons within each
cubic millimeter of cortical tissue, the central
nervous system (CNS) comprises more than 1012
neurons, 1013 synapses and up to 500 distinct
types of cortical neurons (Churchland and
Sejnowski, 2017). Neuronal activity occurs within
milliseconds and within a spatial scale of neuro-
anatomical organization (100μm). Organization of
the cortex of the brain is comprised of the struc-
tural composition of the dense population of cells
located within the CNS.
Neural communication involves the electrical
signaling of the cellular components of neurons
(Edelman et al., 1987). Synaptic transmission
consists of the differences in synaptic efficiency
and its inhibitory or excitatory neurotransmission
impact (Kuffler et al., 1984; Shepherd, 2004).
Neuronal activation involves approximately 10-15
joules of energy per action potential. Operation
of neurons and neuronal networks within spe-
cific cortical areas comprises the functional basis
of higher-level cognitive processes (Churchland
and Sejnowski, 2017; Hopfield, 1982). Sensory
input depends on the neuroanatomical basis of
information processing. Excitatory and inhibi-
tory interaction in the connectivity of neural
5
J o a n Y. C h i a o
networks contributes to the functional properties
of cognitive and sensory processes. The study of
cognitive systems in neuroscience entails under-
standing the functional specialization of the path-
ways or streams of cortical processing across
various levels of processing. At network levels,
patterns of cortical activity consist of the rep-
resentation and transformation of sensory input
and its perceptual interpretation into responses
of specific motor output or behavior. The struc-
tural and functional architecture of the cortex of
the brain is linked to cognition and behavior (cf.
Hubel and Wiesel, 1968; O’Reilly and Munakata,
2000). Investigation of higher-level function of
cognitive systems contributes to the understand-
ing of the functional expression of the brain and
its correspondence to behavior. Understanding
cellular and molecular mechanisms of the brain
contributes to understanding the cultural variation
of human populations and phenotypic expression
(Chaio, 2018; Cheon et al., 2018).
The brain’s structural neuroanatomy comprises
cortical and subcortical brain areas demarcated
within the major gyri and fissures of the occipi-
tal, temporal, parietal and frontal lobes (Angevine
and Cotman, 1981; Damasio and Damasio, 1989;
Huttenlocher, 1990). Cortical and subcortical
areas are demarcated conceptually via the tra-
ditional Brodmann designated areas (cf. Geyer
et al., 2011; Judaš et al., 2012).
66 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
STRUCTURAL PRINCIPLES
General and specific characteristics of the neuro-
anatomical structures of cognitive systems arise
from the structural and functional principles of
cortical organization. For instance, the structural
components of primary sensory modalities, such
as the visual system, consist of neuroanatomical
pathways of brain structures interconnected
through long fiber tracts. Each neuroanatomical
location of the visual system comprises part of the
sequence of information processing of sensory
inputs into the streams of visual pathways, which
detail the areas of the specific cortical areas
responsible for encoding and recognition of the
visual world.
Hierarchical levels of information processing of
cortical organization range from molecular to sys-
tems level neuroscience. The information process-
ing hierarchy demonstrates the flow of information
across levels of processing mechanisms from
molecular and cellular mechanisms of neurons to
the cortical systems and pathways of higher-level
processes and behavior. Multilevel processing of
the CNS demonstrates multiple levels of imple-
mentation of the functional components of mental
processes and their physical instantiation in the
structural and functional organization of the CNS
and its biophysical mechanisms.
The structural principles of CNS organization
consist of the understanding of the hierarchical
structure of information processing across levels
of implementation. The levels of information pro-
cessing of biophysical mechanisms illustrate the
stages of sensory processing of the environment
into representational content and its transforma-
tion and interpretation into patterns of motor out-
put and behavior. Structural properties of sensory
representation consist of encoding and decoding
of sensory input into the representational con-
tent of higher-level processes. Transformation of
sensory input into cortical patterns of functional
properties comprises the embedded distribution of
representational content across multilevel process-
ing mechanisms.
FUNCTIONAL PRINCIPLES
Mental and neural processes and their correspond-
ence reflect the functional principles of CNS corti-
cal organization. Functional localization of mental
constructs and functional mechanisms illustrates
the functional specialization of such states for
specific higher-level processes. Functional locali-
zation of mental and cortical modules involves
specialization of function for specific perceptual,
cognitive, affective, and social processes. Cortical
specialization of functional modules for special-
ized processes ensures the automatic, encapsu-
lated and innate processing of core capacities. The
physical instantiation of functional modules as
cortical localization entails that the functional
architecture of the brain enables the specialized
functional processing of the organism.
Response properties of populations of neurons
involve the levels of population activity of neurons
and their functional correspondence to higher-
level processes. Encoding of sensory input into the
neural code of the response properties of neurons
represents a structural and statistical problem to
determine the functional correspondence of neural
response. Observation of neural codes and their
interpretation as brain function relies on the decod-
ing of the information that is in the representation
of the response properties of neurons. Information
processing of the response properties of neurons
details the patterns of physiological signaling that
correspond to the sensory stimuli and their trans-
mission of information from neural responses.
Information flow of interconnected cortical
pathways reflects the aggregation of the neu-
ronal processing of populations of neurons that
comprise the cortical brain regions of neural net-
works. Feedforward and feedback connectivity of
cortical pathways demonstrates the unidirectional
and bidirectional information flow of the neural
processing of cortical networks across the inter-
connected functional pathways of cortical organi-
zation. Information processing of interconnected
cortical networks shows patterns of the functional
activation and inhibition of networks of neurons
and their functional correspondence to mental pro-
cesses and behavior.
Functional patterns of cortical activation are
comprised of the response of emergent properties
in response to the effortful processing during func-
tional task performance. Other cortical patterns of
activation reflect the intrinsic processing of cortical
mechanisms during resting state activation that cor-
responds with the structural properties of intercon-
nected cortical networks. Functional integration
of the cortical organization of the CNS consists of
the intrinsic and extrinsic properties of patterns of
functional activation from the basic mechanisms
of resting state activity and effortful processing.
DISTINCT TYPES OF NEURONS
The neuroanatomical evidence suggests approxi-
mately 50 to 500 distinct types of neurons within
 NEURAL PROCESSES AND ACTIVITY
the CNS cortical organization. Different types of
neurons show distinct patterns of neuronal firing
or firing rate ranging up to about 50 spikes per
second. Some types of neurons show multiple
firing patterns that are based on the activity pat-
tern of the cellular mechanism of a specific neuro-
anatomical location or neurotransmitter system.
Most neurons show spiking patterns of neuronal
activity that is spontaneous and intrinsic. Regular-
spiking neurons demonstrate the output of a
high-frequency spiking pattern of neuronal activ-
ity that declines to a sustained lower frequency of
activity. Repetitive-busting neurons demonstrate
the intrinsic pattern of neuronal firing activity that
is in response to a prolonged stimulus. The varia-
bility of neuronal activity pattern based on the
response properties of neurons illustrates the
multiple patterns of intrinsic and extrinsic activity
of neurons.
Cortical specificity of neurons further consists
of neurons dedicated to the neurochemical com-
munication of specific neurotransmitters located
within the limbic system and its interconnected
cortical projections. Neurotransmission involves
the norepinephrine system of the locus coeruleus
of the brainstem, the serotonin system located
within the raphe nucleus of the midbrain, the
dopamine system located within the substan-
tia nigra of the midbrain, acetylcholine located
within the nucleus basalis of the basal forebrain,
and the GABA neurotransmitter system located
within specific groups of cells of the mammil-
lary part of the hypothalamus. The neurotransmit-
ter neuron (e.g., serotonin neuron) shows distinct
neurochemical communication of the specific
neurotransmitter system. Different types of neu-
rons that originate within the specific regions
of the limbic system, such as the brainstem and
hypothalamus, project widely across the cortical
and subcortical regions of cortical brain streams
and perform specific types of neurotransmis-
sions involved in the regulation of higher-level
function processing.
Interconnectivity of neural networks is com-
prised of excitatory and inhibitory neurons respon-
sible for the electrophysiological signaling of
networks of neurons (Schmidt, 2012). Excitatory
neurons are important for feedforward process-
ing of neural networks; inhibitory neurons are
important for feedback and inhibitory processing
of neural networks. Bidirectionality of informa-
tion processing of neural networks demonstrates
the excitatory and inhibitory connectivity charac-
teristic of cortical neurons located as input, hid-
den and output layers of cortical organization. The
interconnectivity of neural networks is important
for the electrophysiological signaling of sensory
input and its representational content into an
67
interpretation that leads to patterns of cognitive-
behavioral response.
Encoding of distinct patterns of information
processing across cortical layers contributes to
the processes of pattern completion that facilitate
production of cognitive-behavioral response. The
amplification of specific neural activation patterns
of information processing mechanisms facilitates
the completion of the activity pattern to a specific
neural activation state. The constraint satisfac-
tion of functional patterns of neural activation is
responsible for the transformation of the represen-
tational content of sensory input into an adaptive
behavioral response. The transformation of the
neural activation pattern into an adaptive behav-
ioral response comprises the multitude of neural
responses underlying the higher-level processes of
cognition and sensation.
The functional properties of neurons involve
response properties that are part of the intrinsic
and extrinsic properties of the activity of neu-
rons. Functional properties of neurons encom-
pass the intrinsic properties of neural activity
that is spontaneous and deterministic as well as
the extrinsic properties of the activity of neural
networks that is effortful and task-based process-
ing. Emergent properties of the activity of neural
networks characterizes the patterns of functional
activity in response to environmental demands.
Functional patterns of neural activity detail the
bidirectional processing of neural networks that
constitutes the effortful processing of cognitive
and sensory processing mechanisms to environ-
mental stimulus and its transformation into adap-
tive behavioral response. Emergent properties of
neural activation patterns consist of the level of
neural activity that consists of the electrophysi-
ological response to the environment and its func-
tional correspondence to cognitive and sensory
states and observable behavior. Functional and
emergent properties of neural networks involve
patterns of electrophysiological signaling of cor-
tical networks and interconnectivity that encom-
passes the informational complexity of CNS
processing mechanisms.
The level of activity of networks of neurons
comprises interconnected neural networks that
consist of patterns of neural activation that show
functional correspondence to cognitive and sen-
sory processes responsible for observable behav-
ior. The cellular and molecular basis of neural
transmission emphasizes the notion that the
response properties of single neurons are neces-
sary and sufficient to ensure the characteristic
properties of networks of neurons and their inter-
connected responsivity. The response properties
of populations of neurons within specific corti-
cal regions further demonstrate the conditions
68 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
responsible for the functional specialization of
sensation and cognition.
DISTINCT TYPES OF REPRESENTATION
Different types of neurons constitute cellular
mechanisms with distinct types of representations
of a sensory stimulus. Local representation or
coding of a sensory stimulus in the cortical
representations of the environment describes the
selectivity of the cellular response of neurons for
a specific category of stimulus. For instance, local
coding of neurons illustrates the functional use of
one type of neuron for one type of representation
(e.g., “grandmother cell”). The distinct type of
neuron acts as a detector of the feature of the sen-
sory stimulus encoded in the level of activity of
the cellular mechanism. The notion of the neuron
as a feature detector reflects the specificity of
response selectivity of cells as a unit of processing.
Scalar coding of a sensory stimulus describes
the response properties of neurons as encoding
the representation of a sensory stimulus. The sca-
lar representation of a sensory stimulus consists
of the coding of features of the sensory stimulus
as a particular firing rate of the neuron. Coding
of features of the stimulus into scalar representa-
tions demonstrates the cellular selectivity of the
response properties of the neuron. Selectivity of
the firing rate of the neuron refers to the variability
of the timing and magnitude of electrophysiologi-
cal response of neurons to encode the representa-
tion of a particular stimulus.
Distributed representation of cortical organi-
zation refers to the coding of representational
content across multiple areas of the brain. The
vector coding of neurons depicts the selectivity
of a multitude of neurons to encode the represen-
tation of the sensory stimulus. The response of
many neurons encodes the features of the sensory
stimulus into representational content. The dis-
tributed pattern of response selectivity of neurons
illustrates the encoding of content across popula-
tions of neurons. Summation of activity level of
populations of neurons comprises the encoding of
features into distinct cortical representation. The
pattern of activation of populations of neurons
involves the configuration of relative weighing of
neuronal activity in the multidimensional or state
space representation of features within the cortical
organization. The many-to-one mapping of neu-
ronal representation consists of the level of activ-
ity of populations of neurons as a representation
into state space.
SENSATION AND PERCEPTION
The anatomical and physiological properties of
the visual system highlight the structural and
functional properties of visual processing streams
and the representation of the world within specific
neurons distributed across cortical organization
(Le Vay and Nelson, 1991; Van Essen, 1979).
Physiological processing of the visual world
describes the transformation of signal processing
from the retina to the primary visual cortex
(Hubel, 1998; Maunsell and Newsom, 1987).
Processing of visual information into the func-
tional organization of primary visual cortex entails
signal transduction of the image on the retina into
the representational content of the information
processing streams of primary visual cortex. The
main neurons that carry processing signals of
visual information from the retina to the primary
visual cortex consist of photoreceptors of the
retina, while the ganglion cells that comprise the
optic tract are located within the lateral geniculate
nucleus (LGN) of the thalamus and subsequently
project onto the primary visual (occipital) cortex.
Both principal pathways of visual processing
involve two types of neurons located within the
LGN of the thalamus that project onto the primary
visual cortex and its interconnected brain regions.
Parvocellular and magnocellular layers of the
LGN detail the distinct layers of cortical process-
ing within the thalamus that subsequently project
into distinct streams of processing within primary
visual cortices. Functional segregation of the two
processing streams of the visual system consists of
the information processing streams of the “what”
pathway that projects from primary visual cortex
into the inferior temporal cortex, and the “where”
pathway that projects from primary visual cortex
into the posterior parietal cortex (Ungerleider and
Haxby, 1994). Response properties of cortical
neurons of the ventral visual form pathway dem-
onstrate the basic function of the detection of vis-
ual form and color (e.g., “face cells”), while other
response properties of cortical neurons of the dor-
sal pathway are responsible for spatial location
(e.g., “place cells”).
Neurons within the primary visual cortex show
response selectivity that encodes the orientation of
an edge. Response properties of simple neurons
demonstrate a cellular basis of perceptual mecha-
nisms based on the elemental unit of edge orien-
tation (Figure 5.1). Other response properties of
neurons located within distinct structural regions of
primary visual cortex show response selectivity for
the other elemental units of perceptual features, such
as color and textures (Hubel and Livingston, 1987;
Ungerleider and Desimone, 1986; Zeki, 1983).
 NEURAL PROCESSES AND ACTIVITY
Figure 5.1a–b Stimulus-selective response of the receptive fields of single neurons in the
cat’s striate cortex.
Source: Adapted from Hubel and Wiesel, 1959.
FACIAL RECOGNITION
Face recognition is the perceptual and cognitive
process that underlies the capacity to recognize
the identity of others from faces. The concept of
face recognition comprises a fundamental ele-
ment of the recognition of complex visual infor-
mation. The cellular basis of cortical mechanisms
of facial recognition builds on the notion of
single neurons that show response selectivity to
the specific visual category of facial information
or to a specific facial identity. Functional spe-
cialization of cellular mechanisms for face rec-
ognition demonstrates the cortical specificity of
response selectivity to specific categories of
complex visual information that are important
for behavioral adaptation.
Identification of the cellular mechanisms of
face recognition demonstrates the functional
localization of specific cognitive processes
within the “what” pathway of visual processing.
For instance, the response properties of neurons
(e.g., “face cells”) located along the superior
temporal sulcus (STS) within inferior temporal
69
(IT) cortex shows selectivity to faces (Desimone,
1991; Desimone et al., 1984). The pattern of neu-
ronal activity of the STS neurons shows response
selectivity of a specific firing pattern that is spe-
cialized for faces (Figure 5.2). The pattern of
neuronal activity shows the encoding of response
selectivity for the detection of intact faces com-
pared with facial stimulus without parts of faces,
objects, and other complex visual stimuli (Allison
et al., 1994; Bentin et al., 1996; Hoffman and
Haxby, 2000; Kanwisher et al., 1997; McCarthy
et al., 1997; Puce et al., 1995). Response proper-
ties of single neurons located within STS high-
light the cellular basis of the cortical mechanisms
of face recognition.
SOCIAL PERCEPTION
The social capacity to recognize conspecifics is
important to the evolutionary adaptation of social
species. The perception and recognition of self
70 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 5.2a–b Response properties of inferior temporal neurons to faces in the macaque.
Source: Adapted from Desimone et al., 1984.
and others is a basic mechanism of the cognitive
processes of social capacities (Chiao et al., 2009,
2010). Social capacity to perceive and recognize
the social information of self and others is a fun-
damental component of the cognitive processes of
social capacities. Inferential reasoning of the
shared goals and intentions of others from the
social perception of the shared or joint attention of
others comprises a fundamental element of social
cognition (cf. Amodio and Frith, 2006). Implied
or actual motion of others contributes to the social
inferences of the shared goals and intentions of
social capacities.
Cellular mechanisms of the STS demonstrate
the response properties of functional specific-
ity for social cognition. The pattern of neuronal
activity of cellular mechanisms with the STS dem-
onstrates the response selectivity for the social
perception of social dimensions (Allison et al.,
2000). Response properties of STS neurons of
both hemispheres demonstrate the electrophysi-
ological pattern of activity that shows response
selectivity to the implied or actual motion of facial
and bodily movement. Increased pattern of activity
in response to the perception of implied or actual
motion of facial and bodily movement suggests
the importance of the facial and bodily orienta-
tion in the cellular mechanisms of social cogni-
tion. Electrophysiological patterns of activity of
STS neurons show response selectivity to the
face and gaze direction of facial expression and
social attention ((Perrett et al., 1985, 1992; Puce
et al., 1998). Response selectivity of STS neurons
to the implied motion of face and gaze direction
illustrates the perceptual cues of facial and bodily
movement in the social inferences of dominance
and submission. Selectivity of response patterns
to gaze direction contributes to the inferences of
shared attention. Patterns of response selectivity
of STS neurons illustrate the activity of cellular
mechanisms that are important for social percep-
tion and cognition (Perrett et al., 1982). The func-
tional specialization of the cellular mechanisms
located within the STS illustrates the response
properties of neurons responsible for social cog-
nition (i.e., cultural neuroscience; Chiao, 2016,
2017a,b, 2018; Chiao and Ambady, 2007; Chiao
and Blizinsky, 2016; Chiao and Immordino-Yang,
2013; Chiao and Mathur, 2016; Chiao et al.,
2010a,b, 2013, 2021a,b,c).
Other brain regions, such as the amygdala,
play an important role in the cellular and molecu-
lar basis of the cortical mechanisms of social
cognition. The cortical regions of STS show
structural and functional interconnectivity to the
amygdala receiving feedforward and feedback
projections. The amygdala consists of the cel-
lular mechanisms that are responsive to facial
 NEURAL PROCESSES AND ACTIVITY
and bodily movements, such as facial and bodily
expressions (Rolls, 1984). The amygdala which
receives bidirectional projections from the STS
shows in the response properties of populations
of neurons selectivity of activation patterns in
response to the movement of faces. Response
selectivity of neurons located within the amyg-
dala serve to enhance the electrophysiological
signaling of STS neurons that facilitates the per-
ceptual and social salience of facial and bodily
movements. Social salience of facial and bodily
movement demonstrates the facilitation of per-
ceptual salience of sensory input from the inter-
connected projection of the cellular mechanisms
located within the STS and the amygdala regions
of cortical processing.
Cellular mechanisms of the amygdala show the
response properties of neurons that are specific
to the detection of the expression and identity of
faces as complex visual stimuli. The pattern of
activity of neurons of the amygdala of monkeys
demonstrates the response selectivity to face iden-
tity and facial expression (Gothard et al., 2007).
Response properties of amygdala neurons fur-
ther show the specificity of response selectivity
to the identity or expression of faces suggesting
the distinct activity patterns of specific neurons
differentiate the featural characteristics of faces
(Figure 5.3). Increased electrophysiological sign-
aling of amygdala neurons that demonstrates the
identity-selectivity or expression-selectivity of
Figure 5.3a–b Stimulus-response properties of amygdala neurons in response to facial
expressions of macaques.
Source: Adapted from Gothard et al., 2007.
71
faces illustrates the specificity of activity pattern
that shows the functional specialization of cellular
mechanisms for specific cognitive and emotional
processes of social capacities. The increased fir-
ing rate of neurons located within the amygdala in
response to the detection of the threat expressions
of faces shows the category specificity of activity
patterns in the cellular mechanisms of social per-
ception and cognition.
Multilevel mechanisms of cortical organiza-
tion facilitate the cellular and molecular bases of
social perception. Neuronal mechanisms of social
perception show the firing pattern of activity of
cells that are important to the perception and rec-
ognition of social identity and social expression.
Functional pattern of circuit-based mechanisms
demonstrates the specificity of activity pattern
of social perception across interconnected brain
areas (Chiao, 2010; Pineda et al., 1994; Puce
and Perrett, 2003). Neural communication across
distinct types of neurons illustrates the capac-
ity of sensory and cognitive processes for the
bidirectional processing of social information.
Communication of electrophysiological signal-
ing of circuit-based mechanisms communicates
information of the response properties of the
stimulus of the social environment. The cortical
mechanisms of social perception demonstrate the
distinct patterns of activity of neurons that facili-
tate the sensory and cognitive processing of the
social environment.
72 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
CULTURAL NEUROSCIENCE
Culture consists of the processes and mechanisms
that are of importance to the shared meaning of
systems of values, practices, and beliefs of groups
of people defined by geography, ethnicity, ances-
try, language, and customs among others.
Multilevel processes of cortical mechanisms facil-
itate the distinct neuronal patterns of cells and the
aggregation of the level of activity of populations
of neurons located within interconnected brain
areas of cortical networks that comprise the iden-
tity and expression of culture within the organiza-
tion of the CNS (Chiao et al., 2008; Harada et al.,
2020). Variability in the timing and the rate of the
activity of neurons distinguishes the patterns of
activation of cortical mechanisms that are sponta-
neous and intrinsic to the identity and expression
of culture. Activity of distinct types of neurons
show variability in the timing and rate of neuronal
activity that encodes and transforms the stimulus
of the cultural environment into cultural patterns
of behavior. Functional specialization of cortical
mechanisms contributes to the functional and
emergent properties of the cognitive and neural
basis of culture.
Multilevel mechanisms of cortical organization
support the cognitive and neural basis of culture.
Neuronal mechanisms underlying the processes
of cognition and sensation demonstrate functional
expression in response to the cultural environment.
Cognitive capacity for the perception and recogni-
tion of cultural identity and cultural expression
serves as a foundation for the characterization of
the multilevel mechanisms of the fundamental
dimensions of culture. Functional and emergent
properties of neuronal mechanisms of specific
brain regions show response selectivity to the
cultural environment. Cortical specialization of
neuronal mechanisms contributes to the response
properties of cellular mechanisms underlying the
cognitive and sensory processes of culture. The
distinct electrophysiological signaling of cellular
mechanisms show functional specialization in the
differential activity patterns in the cortical net-
works of culture. Functional specialization of cor-
tical mechanisms shows the response selectivity of
the perceptual and cognitive processes of the facial
identity and facial expression of culture. Response
selectivity of the cortical specialization of specific
brain areas illustrates the distinct patterns of activ-
ity that distinguish the higher-level processing and
functional expression of distinct racial and ethnic
groups that comprise ethnocultural groups.
The level of activity of circuit-based mecha-
nisms illustrates the neural transmission of inter-
connected brain areas of the cortical networks of
culture. Functional activity of neuronal mecha-
nisms of interconnected brain areas demonstrates
the communication of information of distinct pat-
terns of activity of electrophysiological signaling.
The functional pattern of activity of interconnected
areas of cortical networks illustrates the sensory
and cognitive processing of culture. Bidirectional
activation of cortical networks facilitates the func-
tional processing of the information of the cultural
environment. The specificity of response selectiv-
ity of neural activity within interconnected brain
regions shows the functional activity of circuit-
based mechanisms that contribute to the sensory
and cognitive basis of culture.
The cognitive and sensory mechanisms of corti-
cal specialization support the functional and emer-
gent properties of cultural processes. Response
properties of neuronal activity within specialized
cortical mechanisms demonstrate the distinct pat-
terns of response selectivity to cultural identity
and cultural expression. Functional selectivity of
neural mechanisms in response to cultural identity
and cultural expression arises in the level of activ-
ity and its aggregation in cellular and molecular
mechanisms. Differential patterns of neurotrans-
mission of distinct systems of neuronal mecha-
nisms across levels of processing facilitates the
cognitive and neural basis of culture. From single-
neuron responses to populations of neurons, the
activity pattern of response properties of cellular
and molecular mechanisms formulates the cogni-
tive and neural basis of culture (i.e., cultural neu-
roscience; Chiao and Immordino-Yang, 2013).
COGNITIVE NEURAL NETWORKS
Interconnectivity of neuronal networks consists of
the excitatory and inhibitory connectivity of spe-
cific brain areas of cortical organization. Excitatory
and inhibitory neural connectivity demonstrates
bidirectional information processing of the encod-
ing and decoding of sensory input across layers of
cortical organization. Cortical responsivity of
neural networks consists of the encoding of infor-
mation of the stimulus in the populations of neu-
rons and the decoding of such information from
the activity of neuronal populations (Pouget and
Zemel, 2007). Decoding of the features of a sen-
sory stimulus from the cortical representation in
the pattern of activity of populations of neurons
relies on the selectivity of the response properties
of cellular mechanisms. Intrinsic connectivity of
neural networks reflects the spontaneous and
autonomous dynamics of neuronal activity,
 NEURAL PROCESSES AND ACTIVITY
describing the intrinsic properties of cortical
organization that arise from the structural brain
components. Spontaneous and intrinsic activity of
neural networks constitute the endogenous and
autonomous dynamic activity across nodes of net-
works, reflecting the spontaneous activity of neural
networks important to the maintenance of active
and itinerant cognitive representations.
Structural connectivity of cortical net-
works involves the white matter fiber tracts.
Functional organization of cortical networks
depicts the specific brain regions that comprise
networks of cortical function. Functional spe-
cialization of cortical networks allows specific
sensory and cognitive processes to contribute
to higher-level cognitive processing (Menon,
2012). Interconnectivity of brain regions reflects
the bidirectional processing of information
flow across the specific brain regions of corti-
cal networks. Functional integration of cortical
networks facilitates the excitatory and inhibitory
processing is of particular importance for the
transformation and interpretation of sensory and
cognitive representations across multiple brain
regions of cortical networks.
DISTINCT TYPES OF NEURAL NETWORKS
Core neural networks describe distinct types of
networks of neurons that are interconnected across
brain regions to serve specific higher-level func-
tion. Patterns of activation of core neural networks
contribute to the intrinsic and extrinsic properties
of the functional mechanisms of networks of neu-
rons. Activation patterns of neural networks are in
functional correspondence to the default mode of
resting state activity or the task-based processing
of functional tasks (Raichle, 2015). Intrinsic prop-
erties of core neural networks show correspond-
ence with the resting state activity of the default
mode network. Activation patterns of the intrinsic
properties of core neural networks characterize
the spontaneous and autonomous activity of net-
works of neurons that are based on structural
properties. Extrinsic properties of core neural
networks consist of the interconnected brain
regions that show functional patterns of activation
in response to the effortful processing of func-
tional tasks.
Intrinsic properties of networks of neurons
illustrates the importance of the interconnectiv-
ity of specific brain regions and the spontaneous
activity of populations of neurons located within
these cortical mechanisms. The default mode
network is a core neural network that consists
73
of interconnected brain regions located along
the cortical midline structures, such as the pos-
terior cingulate cortex and ventral portions of the
medial prefrontal cortex (Fox and Raichle, 2007;
Raichle et al., 2001). Activation of the default
mode network corresponds with the cognitive
functions that are important (He et al., 2008). The
activation pattern of the default mode network
shows decreased functional responsivity to cogni-
tive tasks that are not relevant to the recognition
and evaluation of the self. Intrinsic activity of the
default mode network is important to the func-
tional processes and basic mechanisms of social
and cultural capacities.
The extrinsic properties of networks of neu-
rons shows the interconnectivity of specific brain
regions and its exogenous activity in response
to the effortful processing of functional task
demands. One core neural network that is respon-
sible for the processing of salience consists of
the interconnected brain regions of the anterior
insula and dorsal anterior cingulate cortex. The
functional processing of the salience network is
important to the detection of the emotional and
motivational salience of the sensory environ-
ment (Menon and Uddin, 2010). The activation
pattern of the salience network facilitates the
processing of emotional and motivation salience
of sensory stimulus Adolphs, 2002; Davis and
Whalen, 2001). Another core neural network that
is important to the regulation and control of execu-
tive function consists of the interconnected brain
regions of frontoparietal cortices, such as the dor-
sal lateral prefrontal cortex and the posterior pari-
etal cortex. The functional pattern of activation
of the core neural network of executive function
contributes to the effortful processing of cortical
mechanisms that are responsible for the regula-
tory function of inhibitory control and executive
function (Miller, 2000; Miller and Cohen, 2001;
Pornpattananangkul et al., 2016). Across networks
of neurons, the distinct pattern of activation of
core neural networks demonstrates the functional
correspondence of the effortful processing of
cognition and the functional patterns of neuronal
activation that are important to the emergent prop-
erties of the neural basis of cognition (Cabeza and
Nyberg, 1997, 2000). The distinct patterns of the
exogenous activity of cognitive neural networks
is important to the functional processes and basic
mechanisms of the social and cultural environment
(cultural neuroscience; Chiao and Immordino-
Yang, 2013).
Other neural networks are important to the
higher-level cognitive brain processes. The acti-
vation patterns of neural networks contribute
to the higher-level processes of social (Blais
and Caldara, 2021; Chiao and Mathur, 2016;
74 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
de Gelder and Huis in’t Veld, 2016; Gianola and
Losin, 2021) and cultural capacities (Cheon and
Hong, 2016; Chiao et al., 2021). Functional acti-
vation of social neural networks demonstrates the
neuronal processing of social information within
specific brain areas of occipitotemporal, parietal
and frontal cortices. Localization of the neuronal
processing of social information of specific brain
areas demonstrates the functional specialization
of social processing. Interconnectivity of specific
brain areas further illustrates the regulatory con-
trol of social capacities. Functional activation of
cultural neural networks shows the neuronal pro-
cessing of cultural information within specific
brain areas of cortical and subcortical structures.
Functional localization of the neuronal processing
of cultural information illustrates the materializa-
tion of functional processes and basic mechanisms
for the processing of the identity and expression
of culture (Chiao et al., 2008; Harada et al., 2020).
Interconnectivity of specific brain areas contrib-
utes to the regulatory control of cultural capaci-
ties. Functional patterns of activation of social and
cultural neural networks illustrate the cognitive
and neural basis of social and cultural capacities
(cultural neuroscience; Chiao and Immordino-
Yang, 2013).
COGNITION AND HIGHER-LEVEL
PROCESSES
The large-scale CNS organization comprises
structural and functional principles that character-
ize the multilevel mechanisms of cortical organi-
zation. Structural principles of cortical
organization describe the hierarchical structure of
functional organization across levels of process-
ing. Functional principles of cortical organization
depict the functional specialization and integra-
tion of cortical networks based on localization and
interconnectivity of networks of neurons.
Systematic investigation of the structure and func-
tion of neurons entails understanding of its effect
within the networks of neurons that comprise the
neural pathways of cognitive systems. From single
neurons to local networks of neurons, understand-
ing the electrophysiological signaling of the
response properties of cortical mechanisms as
well as the neurotransmission of the functional
pathways of cognitive neural systems is important
in the characterization of the levels of CNS pro-
cessing and the link to higher-level cognition and
observable behavior (Churchland and Sejnowski,
2017; Haynes and Rees, 2005). The causal-func-
tional role of cortical mechanisms entails the
exploration of the functional correspondence of
neural processes and mechanisms and the link to
higher-level processes of cognition and observa-
ble behavior (Fodor, 1983; Marr 1982).
Multilevel processing entails correspondence
of the level of neural activity to the functional
activation pattern of cortical systems (Arcaro
and Livingstone, 2021). The convergence of
multimethod techniques in cognitive neurosci-
ence facilitates the multilevel observation of the
anatomy, physiology and connectivity of neurons
across spatiotemporal timescales (Friston, 1994;
Hillyard and Picton, 1987). The response prop-
erties of neuronal activity illustrate the response
selectivity of cellular mechanisms to the envi-
ronment. From single-cell recording techniques
to electrophysiological recording and functional
magnetic resonance imaging, the observation and
measurement of the response properties of neu-
ronal mechanisms ensures understanding of the
functional significance of the activity of neurons
across levels of processing and its link to observ-
able behavior.
Thus, the neuroscientific study of higher-level
cognitive processes involves systematic investi-
gation of the multilevel mechanisms of cognition
and its link to observable behaviors. The role of
the response selectivity of single neurons in the
encoding and decoding of the cortical representa-
tions of the environment illustrates the importance
of cellular and molecular mechanisms in the neu-
ral basis of cognition. The response specificity of
networks of neurons demonstrates the role of the
aggregation of the level of activity of populations
of neurons as population codes of the representa-
tional content of the environment. Response selec-
tivity of neuronal networks to cognitive change
reflects the adaptability of neuronal mechanisms
(Goh, 2021; Gutchess et al., 2021; Li, 2021;
Varnum and Hampton, 2021). Transformation
of the population codes of the environment into
patterns of motor output illustrates the functional
input and output of cortical mechanisms as the
physical instantiation of the functional processes
and basic mechanisms of cortical organization.
Understanding of the multilevel processing of cor-
tical mechanisms across the CNS structural and
functional organization is foundational to under-
standing the functional significance of the cortical
pathways of the higher-level cognitive processes.
Understanding of the cellular and molecular
basis of cognition and behavior contributes to the
generation of knowledge on neurons and its func-
tional significance to behavior. The demonstration
of neurons as the cellular and molecular basis of
the information processing of the CNS contrib-
utes to cognitive and systems neuroscience. The
theoretical foundations of cognitive and systems
 NEURAL PROCESSES AND ACTIVITY
neuroscience build from the systematic investiga-
tion of neurons and its functional correspondence
of patterns of activity as cortical representations of
the environment.
The role of neuronal mechanisms in cortical
brain organization and its higher-level processes
demonstrates the importance of the cellular and
molecular basis of cognition. Functional spe-
cialization of cellular mechanisms and its role in
cognition and higher-level processes contributes
to the structural and functional properties of corti-
cal organization. Systematic investigation of cel-
lular and molecular mechanisms contributes to the
understanding of electrophysiological signaling
and neural transmission as neural communication.
Response properties of cellular and molecular
mechanisms as representations of the environ-
ment facilitate the functional processes and basic
mechanisms of cognition as higher-level function.
Characterization of the multilevel mechanisms of
cortical organization contribute to the understand-
ing of the fundamental dimensions of human brain
organization and its link to observable behavior.
The patterns of activation of neuronal net-
works contribute to the functional processes and
basic mechanisms of cognition. Distinct activation
patterns of cortical neural networks are respon-
sible for the intrinsic and extrinsic processing of
populations of neurons. The distributed code of
neuronal populations demonstrates the category-
specific representation of the environment across
interconnected brain areas. Functional integra-
tion of cortical neural networks facilitates the
information processing across the structural and
functional connectivity of networks of neurons,
illustrating the importance of functional integra-
tion of cortical mechanisms in the higher-level
cognitive processes.
SUMMARY AND CONCLUSIONS
Study of neurons is foundational to the fundamen-
tals of cognitive and systems neuroscience.
Characterization of the structural and functional
properties of neurons contributes to the under-
standing of the cellular and molecular basis of the
human brain. The cultural and biological variation
of human populations contributes to the pheno-
typic variation of the human brain. Distinct types
of patterns of neuronal activity reflect the pheno-
typic expression of the functional architecture of
the human brain of distinct ethnocultural groups.
Systematic investigation of the phenotypic expres-
sion of the human brain advances knowledge of
the cultural and biological variation of human
75
populations (cultural neuroscience; Chiao and
Immordino-Yang, 2013).
Understanding the cellular and molecular basis
of the human brain is foundational to the study
of cognitive and sensory systems in neurosci-
ence. Moreover, the system-level approach to
the study of the human CNS and its phylogenetic
and ontogenetic origins enables a comprehensive
synthesis and analysis of functional processes
and basic mechanisms of the human brain. Study
of structural and functional principles of brain
organization contributes to the foundations of
cognitive and systems neuroscience. The human
brain as the neurobiological machinery of the
biological organism is a potent computational
machine with a myriad of causal-functional roles.
Understanding the causal-functional role of the
CNS in health and disease (cultural neuroscience;
e.g., Chiao and Immordino-Yang, 2013; Chiao and
Mathur, 2016; Chiao et al., 2008, 2017a,b, 2020,
2021a,b,c) is important in order to comprehend
the broader causal power of the human brain and
cognition in the structure of the natural world.
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Role of Neuroglia in Cognition
A l e x e i Ve r k h r a t s k y , A l e x e y S e m y a n o v,
Arthur Butt, and Olga Garaschuk
INTRODUCTION
The concept of Neuroglia (Nervenkitt, or nervous
putty) as a connective tissue of the brain and the spinal
cord was introduced by Rudolf Ludwig Karl Virchow
in 1856–1858 (Virchow, 1860), who advanced earlier
ideas of Karl von Rokitansky, who in 1854, described
the connective tissue of the nervous system as a store-
room (Lager), scaffold (Gerüste), and binding sub-
stance (Rokitansky, 1854). Neuroglial physiology and
pathology were investigated in great detail by almost
every prominent neuroanatomist and neurologist of
the nineteenth century, while the fundamental role of
neuroglia in brain homeostasis, nutritional support,
regulation of blood flow, sleep and conscience, as well
as in neuropathology, was widely recognized in works
of Camillo Golgi, Santiago Ramon y Cajal, Carl
Ludwig Schleich, Albert Kölliker, Wilhelm His,
Ernesto Lugaro, Alois Alzheimer, Franz Nissl, and
others (Chvatal and Verkhratsky, 2018; Kettenmann
and Verkhratsky, 2008).
MULTICELLULAR NATURE OF
NERVOUS TISSUE
The nervous system of vertebrates consists of the
central nervous system (CNS) and peripheral nervous
6
system (PNS), both of which are multicellular and do
not only contain neurones. Cell types in the nervous
tissue are broadly classified into cells of ectodermal
and mesodermal origin, according to their develop-
mental roots. The ectoderm derived cells are neural
cells (the progeny of common neuroepithelial precur-
sors), represented by neurones and neuroglia, includ-
ing astroglia and oligodendroglia in the CNS, and
Schwann cells, satellite cells, and enteric gliocytes in
the PNS. The mesodermal cells are subdivided into
CNS resident microglia and cellular elements of
blood vessels, including endothelial cells, pericytes,
smooth muscle cells, and fibroblasts. In pathological
conditions, the nervous tissue parenchyma can also
be invaded by blood-borne cells, such as platelets,
leukocytes, and various macrophages. All these cel-
lular populations are intimately interacting at struc-
tural and functional levels, thus creating the active
milieu of nervous tissue (Semyanov and Verkhratsky,
2021; also see Figure 6.1).
NEUROGLIA: DEFINITIONS,
CLASSIFICATION, AND NUMBERS
Neuroglia are defined as a heterogeneous popula-
tion of cells of ectodermal and mesodermal origin
providing for homeostasis and defence of the
80 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 6.1 Active milieu of the nervous tissue. A: Multicellular nature of the nervous tissue:
neurones and glia form neural networks. B: The concept of the active milieu of the nervous
tissue integrates multiple theories that address different aspects of local functional organi-
zation of the brain: multipartite synapse, neuro(glio)vascular unit, extrasynaptic signaling
and volume transmission. The active milieu is formed through dynamic interactions between
neuronal elements (somata, axons, dendrites, and spines), non-neuronal cell elements (astro-
cytic and microglial processes), vasculature (capillary), extracellular space (ECS), and extracel-
lular matrix (ECM). In an active milieu, synapses can contact, signal, and be homeostatically
controlled by astrocyte branches (a) or, by single or several leaflets (b). A single astrocytic
branch or leaflet may be contacted by several synapses (c). Dynamic changes in morphol-
ogy of astrocytic processes affect diffusional barriers, neurotransmitter clearance, and K+
dynamics, and supply of glutamine or energy substrates, thus regulating neuronal plasticity.
Astrocytic processes form loop-like structures through reciprocal gap junctions (GJ).
Source: (A) (from Kettenmann et al., 2013). (B) (from Semyanov and Verkhratsky, 2021).

nervous system; neuroglia are the ultimate sup-
portive cells, which keep nervous tissue in a func-
tional state (Verkhratsky and Butt, 2013). In
physiological conditions glial cells are responsi-
ble for housekeeping, whereas in pathology they
undergo functional remodelling to preserve and
restore brain homeostasis. Failure in glial function
exacerbates nervous tissue damage and facilitates
the development of neurological diseases (Pekny
et al., 2016; Verkhratsky et al., 2017). Homeostatic
and protective roles of neuroglia reflect evolution-
ary specialisation of the cellular components of
the nervous system. Neurones evolved as signal-
ling and information processing elements, which,
however, came at a price of losing essential house-
keeping functions, as neurones are generally inca-
pable of regulating their own immediate
environment and are vulnerable to many kinds of
environmental insults. The housekeeping and
protection therefore became the function of neuro-
glia (Verkhratsky and Nedergaard, 2016).
Neuroglia in the mammalian nervous system are
classified into PNS and CNS neuroglia (Verkhratsky
and Butt, 2013) (Figure 6.2). The peripheral nerv-
ous system glia are represented by the Schwann
cells (myelinating Schwann cells that myelinate
peripheral axons, non-myelinating Schwann cells
that surround multiple non-myelinating axons,
perisynaptic Schwann cells, which enwrap periph-
eral synapses (e.g., neuro-muscular junctions),
and nociceptive Schwann cells, which, together
with neuronal endings form sensory organs in the
skin), together with the satellite glial cells that sur-
round neurones in sensory and sympathetic gan-
glia, and enteric glia, which are a part of enteric
nervous system, the intrinsic nervous system of the
gastrointestinal tract. Also, there are several other
types of glial cells that are distinguished in organs
 Role of Neuroglia in Cognition
Figure 6.2 Classification of neuroglia.
of special senses, including olfactory ensheathing
cells, olfactory sustentacular (or supporting) cells,
supporting cells of the vestibular organ and organ
of Corti, and glia-like taste bud cells.
Neuroglia of the brain and the spinal cord
(the CNS glia) are subdivided into the macro-
glia of ectodermal (neuroepithelial) origin, and
the microglia of mesodermal origin (Verkhratsky
and Butt, 2013). Macroglia are further subclassi-
fied into astroglia and oligodendroglia. Astroglia
are primary homoeostatic cells of the grey and
white matter (Verkhratsky and Nedergaard, 2018).
Oligodendroglia are the myelinating cells of the
CNS (in both gray and white matter), together
with a significant population of adult oligoden-
drocyte precursors (OPCs, also known as NG2
glia, reflecting specific expression of nerve/glial
antigen 2), and perineuronal or satellite oligoden-
drocytes (Nave and Werner, 2014). Microglia are
myeloid cells that enter the embryonic neural tube
and ultimately transform into surveilling micro-
glial cells. Microglia in the CNS play numerous
physiological functions, participate in organisa-
tion of synaptic networks and provide for tissue
defence and tissue innate immunity. Although
microglial cells are myeloid progeny and retain
multiple features of immune cells, they are pro-
foundly adapted to the CNS environment and are
81
integral parts of neural networks (Kettenmann
et al., 2011).
The total numbers of glial cells and neurones
are approximately equivalent in the human brain,
which contains about 80 billion (80×109) neuroglia
and ~100 billion (100×109) neurones, but there is
substantial regional variation: in the cerebellum,
glia are outnumbered by neurones 1:10, whilst in
the cerebral cortex there are twice as many glia
as neurones (2:1), and the glia to neurone ratio
rises to ~ 10:1 in the brain stem and ~ 6-7:1 in the
human spinal cord (Verkhratsky and Butt, 2018;
von Bartheld et al. 2016). It is worth mentioning
that the largest white matter tracts, such as the cor-
pus callosum of the brain and dorsal (posterior)
columns of the spinal cord, contain only glia and
axons being devoid of neuronal cell bodies
ASTROGLIA
Diversity and Morphological
Appearance
Astroglia are a class of CNS neural cells that
are specialised for homeostasis and defence
82 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
(Verkhratsky and Nedergaard, 2018) (Figure 6.3).
Astroglia comprise “true” astrocytes and many
other related cells, ranging from radial glia
to ependymal cells lining the CNS ventricles
(Figure 6.4). As such, astroglial cells are highly
heterogeneous in form and function and demon-
strate remarkable adaptive plasticity that defines
the functional maintenance of the CNS in devel-
opment, adulthood ageing and pathology
(Figure 6.5). The class of astroglia (Figure 6.4)
includes (i) radial glia of the developing brain,
(ii) protoplasmic astrocytes of the grey matter,
(iii) fibrous astrocytes of the white matter, (iv)
velate astrocytes of the cerebellum and supraoptic
nucleus; (v) perivascular, marginal, and surface-
associated astrocytes responsible for formation
of the glia limitans; and (vi) radial astrocytes,
which include Müller glia of the retina, Bergmann
glia, and Fañanas glia of the cerebellum, radial
astrocytes of the supra-optic nucleus, tanycytes
of the third ventricle and pituicytes of the poste-
rior pituitary, and radial stem astrocytes (also
known as neural stem cells) found within the
neurogenic niches of the subventricular and sub-
granular zones. In addition, class of astroglia
Figure 6.3 Functions of astroglia.
Source: Adapted from Verkhratsky and Nedergaard, 2018.
covers ependymocytes, which include the epend-
ymal cells lining the CNS ventricles, together
with the choroid plexus cells and retinal pigment
epithelial cells. Notably, the brains of humans
and higher primates contain specific astrocytes
that are absent in other vertebrates: (i) interlami-
nar astrocytes, with small somata (~10 μm in
diameter) in layer I of the cortex and one or two
very long (up to 1 mm) processes that extend
through the cortex to end in layers III and IV;
(ii) polarised astrocytes, represented by uni- or
bipolar cells, the somata of which are located in
layers V and VI of the cortex; and (iii) varicose
projection astrocytes in layers V–VI of the
cortex, which send several (up to 5) long (up to
1 mm) unbranched processes that are endowed
with evenly spaced varicosities and extend in
all directions through the deep cortical layers
(Colombo and Reisin, 2004; Oberheim et al.,
2009). Human astrocytes are in general much
larger and much more complex compared to
astrocytes of other mammals (Oberheim et al.,
2009). Astrocytes account for 20–40% of all glial
cells depending on the brain region (Verkhratsky
and Nedergaard, 2018).
 Role of Neuroglia in Cognition
Figure 6.4 Classification of astroglia.
Source: Adapted from Verkhratsky and Nedergaard, 2018.
Protoplasmic astrocytes are the main homeo-
static glia of the grey matter, providing structure
to the neuropil, establishing intimate contacts with
synapses, and contributing to the regulation and
maintenance of synaptic transmission (Bushong
et al., 2002). A single protoplasmic astrocyte in the
rodent cortex contacts 4 to 8 neurones, surrounds
~300 to 600 neuronal dendrites and provides cover
for up to 20 000–120 000 synapses, whereas in the
human brain a single protoplasmic astrocyte cov-
ers ~ 2 million synapses (Oberheim et al., 2009).
Processes of protoplasmic astrocytes are classified
(Semyanov and Verkhratsky, 2021) (Figure 6.6),
into (i) branches (main or primary, secondary, etc.
astrocytic processes), (ii) leaflets, which are thin
membranous extensions 2–10 μm in length and
~100–200 nm in thickness devoid of intracellular
organelles, and (iii) endfeet, either subpial (ter-
minate beneath the pia mater) and perivascular
(terminate on blood vessels). The leaflets repre-
sent the major part of the surface area of an indi-
vidual astrocyte, accounting for ~ 80% of the total
astroglial plasmalemma, although being exceed-
ingly thin they contribute only a minor fraction
(~ 4–10%) to the cell volume (Reichenbach et al.,
2010). This is also reflected by an extremely high
surface-to-volume ratio of leaflets 2–3 times
larger than that of branches (Gavrilov et al., 2018).
Endfeet are specialised terminals of astrocytic
branches that form the glia limitans barrier at the
pia mater and brain vasculature. A single astrocyte
83
can possess one to several endfeet, which contact
the same or different blood vessels. Astrocytes
localised in superficial brain regions form end-
feet on the parenchymal side of the pia mater (Liu
et al. 2013). Astrocytic endfeet are highly plastic
structures containing smooth and rough endoplas-
mic reticulum, Golgi apparatus, and mitochondria
which support local biosynthesis contributing to
the maturation of membranes, protein secretion
and endfeet-vascular interactions (Boulay et al.,
2017). In addition, endfeet secrete vasoactive sub-
stances, which mediate astrocytic regulation of
local blood flow (MacVicar and Newman, 2015).
ASTROCYTIC NETWORKS OR SYNCYTIA
Astrocytes and oligodendrocytes are intercon-
nected into functional syncytia by gap junctions
to form a glial reticular network in the CNS. Gap
junctions form intercellular channels and several
hundreds of gap junction channels assemble into
large crystalline-like structures known as gap
junction plaques. Individual gap junctions are
formed by two aligned and closely apposed con-
nexons of adjacent cell membranes (gap of ~ 2 nm),
to form the intercellular channel, which has
a diameter between 6.5 and 15 Å and allows dif-
fusion of molecules with M.W. up to 1 KDa
84 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 6.5 Types of astroglial cells. The figure shows protoplasmic astrocytes from
hippocampus, fibrous astrocytes from the optic nerve, Bergmann glia and Fañanas glia
of the cerebellum (cerebellar radial astrocytes), and radial stem astrocytes of the
subgranular zone neurogenic niche.

(Giaume et al. 2021). Each connexon comprises
six subunits, known as connexins (Cx), which
comprise a large family of proteins. Homocellular
astrocyte-astrocyte gap junctions are composed
from Cx26, Cx30, and Cx43, of which Cx43
is the most abundant. Heterocellular gap junc-
tional channels connecting astrocytes with oli-
godendrocytes are represented by Cx32/Cx30,
Cx47/Cx43 complexes. Astrocyte-neuronal het-
erocellular contacts are restricted to developing
and early postnatal brain.
The concept of a panglial syncytium does not
presume an existence of a single “panbrain” net-
work connecting all glial cells, rather it envisages
regional connectivity of astrocytes, oligodendro-
cytes, and ependymocytes that brings them into
 Role of Neuroglia in Cognition 85

Figure 6.6 Morphological classification of astrocytic processes. Three-dimensional

reconstruction of astrocyte loaded with fluorescent dye Alexa Fluo 594 through a
patch-pipette. The cell consists of soma with optically resolved branches of primary,
secondary, and higher orders. These branches host fine terminal leaflets that cannot
be resolved with diffraction-limited optical imaging and appear as a spongiform cloud.
Astrocytic leaflets occupy most of the astrocyte territory also known as an anatomic
domain. Two insets (left and right) are zooming onto branches and leaflets reconstructed
from serial section transmission electron microscopy (TEM) image stacks. Astrocytic
branches contain organelles, whereas leaflets are organelle-free. Leaflets are interspaced
with dendritic spines, filling the space between them like paper cushions around pears
packed for shipping. Thus, most synapses hosted by dendritic spines interact with
organelle-free leaflets, while individual leaflets may interact with several synapses.
Some dendritic spines, however, reside in the vicinity of astrocytic branches and soma,
and those synapses may have a different effect on astrocytic Ca2+ activity.
Source: Adapted from Semyanov and Verkhratsky, 2021.

a functional unit, for example that which pro-
vides for K+ buffering in white matter (Giaume
et al., 2021). Panglial networks connecting astro-
cytes, oligodendrocytes, and ependymocytes are
functional in the thalamus, neocortex, and hip-
pocampus (Griemsmann et al., 2015). Astrocytic
syncytia are segregated into anatomical structures,
for example, confined to individual barrels of the
somatosensory cortex, individual glomeruli in the
olfactory bulb, or barreloid structures in the thala-
mus (Giaume et al., 2010). Glial gap junctional
connectivity may be regarded as a specialised
“analogue” intercellular signalling system (alter-
native to “binary” inter-neuronal communication),
which by utilising intercellular diffusion of multi-
ple molecules, can provide another level of infor-
mation processing within the CNS.
ION DISTRIBUTION, MEMBRANE
POTENTIAL, AND ION CHANNELS
Most mature astrocytes have a strongly negative
resting membrane potential (~ -80 to -90 mV),
reflecting the predominant resting K+ conduct-
ance (Verkhratsky and Nedergaard, 2018),
which maintains the membrane potential close
to the potassium equilibrium potential (EK). The
ion content of astroglia differs from neurones in
that astroglial cells have substantially higher
cytosolic Na+ (15–17 mM vs. ~ 8 mM in neu-
rones) and Cl- (30–60 mM vs. ~ 10 mM in
mature neurones), whereas the concentration of
K+ (~120–140 mM) and Ca2+ (<0.0001 mM) in
astroglia are generally the same as in neurones
86 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
(Verkhratsky and Nedergaard, 2018). The rever-
sal potential for Cl- is ~ –40 mV and activation
of Cl- permeable channels (e.g., GABAA recep-
tors) triggers Cl- efflux and depolarisation of
astrocytes (whereas in neurones, this results in
Cl- influx and hyperpolarisation). Astrocytes
express all major types of ion channels, includ-
ing voltage-gated K+, Na+, and Ca2+ channels
(in densities not sufficient to produce an action
potential), non-selective cation channels and
various types of anion channels (Verkhratsky
and Nedergaard, 2018). These channels gener-
ate ionic fluxes which contribute to astrocyte
intracellular signalling (see below).
RECEPTORS TO NEUROTRANSMITTERS,
NEUROMODULATORS, AND
NEUROHORMONES
Astroglia, being neural cells, are potentially capa-
ble of expressing all receptors to neurotransmitters,
neurohormones, and neuromodulators as neurones
do, which permits astroglial cells to perceive their
neurochemical environment and sense signaling
molecules released by neurones and other cells in
the nervous tissue (Verkhratsky, 2010). Glia, simi-
lar to neurones, are endowed with both ionotropic
and metabotropic receptors.
The complement of receptors expressed in
astroglia varies between different brain regions.
As a rule of thumb, the modality of neurotrans-
mitter receptors expressed by astroglial cells
matches that of their neuronal neighbors and is
most likely controlled by the local neurotransmit-
ter environment (Verkhratsky and Nedergaard,
2018). For example, astrocytes express glycine
receptors in the spinal cord, where glycine acts
as a main inhibitory mediator, whereas in basal
ganglia, which utilise dopaminergic transmission,
astrocytes express dopamine receptors. Therefore,
the expression of astroglial receptors in vivo is
regulated by neurochemical input, which makes
astrocytes perceptive to signals specific for each
particular region of the brain.
INTRACELLULAR EXCITABILITY
OF NEUROGLIA
Neurones are universally considered as the only
excitable cells of the nervous system; they gener-
ate fast action potentials, which are conducted
over large distances and initiate neurotransmitter
release responsible for synaptic connectivity.
Astrocytes are electrically non-excitable cells
that do not generate action potentials in response
to stimulation, and yet they possess a specific
form of excitability. Astroglial excitability (similar
to other glial cells) is based on spatio-temporally
organised fluctuations of intracellular ion con-
centrations and intracellular (second) messen-
gers (Verkhratsky et al., 2020). Moreover, the
gap junctional pathway allows propagating
waves of intracellular messengers, ions, and
metabolites, which endows astroglial syncytia
with a mechanism for intercellular long-range
signalling (Bernardinelli et al., 2004; Langer
et al., 2012; Scemes and Giaume, 2006).
Physiological stimulation of astrocytes produces
transient changes in all major ions, including
Ca2+ Na+, Cl-, K+, and H+, each of these ions can
mediate relevant signaling. In astrocytes, the
intracellular signaling role for Ca2+ is well docu-
mented (Bazargani and Attwell, 2016), for Na+ is
becoming generally recognised, for Cl- has been
proposed, and for K+ is yet to be considered
(Verkhratsky et al., 2020).
Astroglial Ca2+ signal generation is spatially
segregated (Figure 6.7). In the soma and branches
of protoplasmic astrocytes, Ca2+ signals primarily
originate from endoplasmic reticulum Ca2+ release
(Lim et al., 2021). The endoplasmic reticulum is a
dynamic Ca2+ store capable of accumulating Ca2+
ions through the activity of specific Ca2+ pumps
of sarco-endo-plasm reticulum (SERCA) type and
release Ca2+ through ER Ca2+ channels, which in
astroglia are mainly represented by inositol 1,4,5
triphosphate receptor (InsP3R) type II. The activity
of InsP3Rs is controlled by the second messenger
InsP3 which is produced following the activation
of numerous G-protein coupled (also known as
metabotropic) receptors linked to phospholipase
C as well as by cytoplasmic Ca2+ concentration.
Depletion of the endoplasmic reticulum Ca2+ store
triggers plasmalemmal Ca2+ entry through store-
operated Ca2+ channels (Verkhratsky and Parpura,
2014). Changes in cytosolic Ca2+ activate various
intracellular enzymes (also known as Ca2+ sen-
sors) that initiate or regulate cellular responses.
Waves of elevated Ca2+ can propagate through the
astroglial syncytium over long distances, either by
intercellular diffusion of InsP3 or by the release of
neurotransmitters such as ATP. These Ca2+ waves
are thought to represent long-range signalling
within astroglial networks and thus be function-
ally analogous to action potential in neurones
(Scemes and Giaume, 2006).
In the leaflets of protoplasmic astrocytes,
devoid of endoplasmic reticulum, Ca2+ signals
originate from plasmalemmal Ca2+ influx through
Ca2+ permeable ionotropic receptors (Palyginet al.,
 Role of Neuroglia in Cognition 87

Figure 6.7 Morpho-functional organization of Ca2+ signalling compartments in protoplasmic

astrocyte. Calcium signaling in soma and branches is mainly associated with Ca2+ release
from the endoplasmic reticulum (ER) with subsequent store-operated Ca2+ entry (SOCE). This
Ca2+ release is mediated by InsP3 receptors (InsP3R); InsP3 is synthesized by phospholypase C
(PLC) linked to G-protein metabotropic receptors. Calcium signaling in the leaflets is associ-
ated with Ca2+ entry through ionotropic receptors (NMDA glutamate receptors or P2X puri-
noceptors) or Ca2+-permeable channels (such as, for example, TRPA1 channels). Plasmalemmal
Ca2+ influx can also be mediated by the Na+/Ca2+ exchanger (NCX) operating in reverse mode.
Levels of free Ca2+ in the cytosol are also controlled by Ca2+-biding proteins (CBP), also
known as Ca2+ buffers.
Source: From Verkhratsky et al., 2020.

2010), transient receptor potential (TRP) chan-
nels (Shigetomi et al., 2012) or reversed Na+/Ca2+
exchange (Rose et al., 2020). Calcium signals in
leaflets, with their high surface-to-volume ratio,
allows larger net plasma membrane Ca2+ influx
and hence relatively larger (Ca2+)i fluctuations
within these tiny compartments (Semyanov and
Verkhratsky, 2021).
Another mechanism of astroglial ionic signal-
ling is based on rapid fluctuations in cytosolic
Na+ concentration (Rose and Verkhratsky, 2016).
These (Na+) transients result from activation of
various types of cationic channels (e.g., iono-
tropic receptors such as AMPA receptors or TRP
channels), or from the activity of Na+-dependent
transporters, most notably excitatory amino acid
(e.g., glutamate) transporters. Physiological acti-
vation of Na+ fluxes may increase cytosolic Na+
concentration by 10–20 mM. The transmembrane
Na+ gradient regulates many homeostatic molecu-
lar cascades expressed in astrocytes, including
Na+/K+ ATPase, Na+/Ca2+ exchanger, transporters
for glutamine, glutamate, and GABA, proton and
bicarbonate transporters, transporters for ascorbic
88 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

acid, Kir4.1 potassium channels, etc. (Verkhratsky
and Rose, 2020). Functionally, Na+ signalling is
fundamental for coordination of astroglial homeo-
static responses with neuronal activity.
The metabotropic branch of astroglial inter-
cellular excitability is mediated by second mes-
sengers, most notably by cyclic AMP (cAMP),
which mediates astroglial responses to noradrena-
line released from varicosities of catecholamin-
ergic projections from locus coeruleus neurones
(Verkhratsky et al., 2020).
FUNCTIONS OF ASTROGLIA
The main functions of astrocytes are summarized
in Table 6.1. Conceptually, astroglial cells are
responsible for every possible homeostatic task
(Verkhratsky et al., 2020). In addition, through
programs of reactive gliosis, astrocytes act as
principal cellular elements of CNS defence
(Escartin et al., 2021).
Astrocytes are major elements of extracellu-
lar K+ homeostasis (MacAulay, 2020). Neuronal
activity is associated with influx of Na+ and Ca2+
(depolarisation) and efflux of K+ (repolarisation);
extracellular K+ accumulation may significantly
alter neuronal excitability. The main system
responsible for K+ removal form the extracellular
space is associated with astrocytes and is repre-
sented by local K+ uptake and spatial K+ buff-
ering (MacAulay, 2020). Local K+ uptake is the
main mechanism of K+ clearance in physiologi-
cal conditions. Extracellular K+ is accumulated
by Na+/K+ ATPase (which in astrocytes contains
a specific α2 subunit highly sensitive to extra-
cellular K+ concentration (Larsen et al., 2014));
after cessation of neuronal activity K+ is released

Table 6.1 Main functions of astrocytes

Development of the CNS • Neurogenesis

Structural support
Barrier function
Homeostatic function
Metabolic support
Synaptic transmission
Regulation of blood flow
Brain defence, neuroprotection
and post injury remodeling
• Neural cell migration and formation of the layered gray matter
• Synaptogenesis
• Parcellation of the gray matter through the process of tiling
• Delineation of the pia matter and vessels by perivascular glia
• Formation of astroglio-vascular unit
• Regulation of the formation and permeability of blood-brain and CSF-brain
barriers
• Formation of glial-vascular interface
• Covering brain capillaries with endfeet
• Forming the fenestrated blood-brain barrier in hypothalamus allowing
neurosecretion.
• Control over extracellular K+ homeostasis through local and spatial buffering
• Control over extracellular pH
• Regulation of water transport
• Removal of neurotransmitters from the extracellular space
• Uptake of glucose; deposition of glycogen
• Providing energy substrate lactate to neurones in activity dependent manner
• Regulation of synapses maintenance and assisting in synaptic pruning
• Providing glutamate for glutamatergic transmission (through de novo synthesis
and glutamate-glutamine shuttle)
• Regulating synaptic plasticity
• Integrating synaptic fields
• Providing humoral regulation of neuronal networks through secretion of
neurotransmitters and neuromodulators
• Regulation of local blood supply (functional hyperaemia) through secretion of
vasoconstrictors or vasodilators
• Isomorphic and anisomorphic reactive astrogliosis
• Scar formation
• Catabolizing ammonia in the brain
• Immune responses and secretion of pro-inflammatory factors (cytokines,
chemokines, and immune modulators)

Source: Adapted from Verkhratsky and Butt, 2013.

 Role of Neuroglia in Cognition 89

Figure 6.8 Glymphatic system. Convective fluxes of cerebrospinal fluid (CSF) and interstitial
fluid (ISF) propel the waste products of neurone metabolism into the paravenous space,
from which they are directed into lymphatic vessels and ultimately return to the general
circulation for clearance by kidney and liver.

from astrocytes through inward rectifying K+
channels and shuttled back to neurones to restore
ionic gradients. Higher K+ loads, mainly associ-
ated with pathology, can be redistributed through
the astroglial syncytium by diffusion through
gap junctions (spatial K+ buffering (Bellot-Saez
et al., 2017)). Subsequently, excessive K+ ions
exit astrocytes into the interstitium or into the
perivascular space from where they are removed
to the blood.
Astroglial cells are critical for water move-
ments in the CNS: water channels, or aquapor-
ins, are concentrated in astroglial endfeet and in
perisynaptic processes; water entering astrocytes
is redistributed through gap junctions connecting
astroglial syncytia (Nagelhus and Ottersen, 2013).
Astroglial aquaporins also support the operation
of the brain glymphatic system (brain analogue of
the lymphatic system responsible for collection of
waste – see Figure 6.8; Hablitz and Nedergaard,
2021). Endfeet of parenchymal astrocytes cre-
ate the paravascular channels that provide for an
exchange between the interstitial fluid and the
cerebrovascular fluid thus providing the drainage
system for removing waste, which accumulates
in the brain parenchyma as a result of cellular
metabolism.
Through neuro-glio-vascular units (which inte-
grate parenchymal cellular elements and blood
vessels (Kugler et al., 2021)), astrocytes contrib-
ute to the regulation of local blood flow, being at
least in part responsible for functional hyperae-
mia, represented by a rapid rise in the local blood
flow in response to a local increase in neuronal
activity (MacVicar and Newman, 2015). These
changes occur in small vessels within ~200–250 μm
from the site of increased neuronal activity.
Glutamate, released during neuronal activity, acts
on astrocytic receptors, and induces Ca2+ signals.
These pass to astroglial perivascular endfeet and
initiate the release of vasoactive substances, which
regulate the tone of small arterioles and/or capil-
laries; astrocytes are capable of secreting both
vasoconstrictors and vasodilators (MacVicar and
Newman, 2015).
Astrocytes are also important elements of
metabolic support of neurones during periods
of intense activity. Astrocytes are able to syn-
thesize glycogen which acts as a CNS energy
reserve (Bak et al., 2018; Matsui et al., 2017).
In astrocytes, glucose is converted into pyruvate
and then into lactate in the presence of oxygen
(aerobic glycolysis). Glutamate released during
synaptic activity is accumulated by perisynaptic
astrocytic compartments though Na+-dependent
glutamate transporters thus leading to an
increase in cytosolic Na+ concentration. This, in
turn, activates the Na+-K+ ATPase, which expels
the excess Na+ into the extracellular space, and
stimulates phosphoglycerate kinase (PGK) to
trigger aerobic glycolysis that produces lactate.
Lactate is then released into the extracellular
space and finally taken up by neurones and used
as an energy substrate, this process being known
as astrocyte-neurone lactate shuttle (Pellerin and
Magistretti, 2012; Veloz Castillo et al., 2021).
90 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Astroglial Homeostatic Transporters
Astrocytes are actively engaged in the transport of
ions, neurotransmitters, hormones, various trans-
mitter and hormonal precursors, energy substrates,
amino acids, etc. Most of this transport is accom-
plished by plasmalemmal transporters, genes for
which are the most represented in the astrocytic
transcriptome. Membrane transporters are gener-
ally classified into (i) ABC transporters (Rees et al.,
2009), (ii) pumps or ATP-dependent transporters
(Apell, 2004), which hydrolyze ATP and use the
released energy to move molecules against their
electro-chemical gradients (e.g., Na+-K+-pumps)
and (iii) solute carrier transporters (SLCs)
(Pizzagalli et al., 2021), which can be secondary
active, utilising the electrochemical gradients of
different ions generated by the activity of pumps to
transport ions or other small molecules (e.g., Na+-
Ca2+ exchangers, NCX), or facilitative, in which
solutes move passively down their concentration
gradients (e.g., glucose transporters, GLUT).
Transporters can be uniporters, which transports a
single species of substrate (e.g., GLUT, Ca2+
pumps), co-transporters or symporters, which
transport two or more different substrates in the
same direction (e.g., excitatory amino acid trans-
porter 1, EAAT1, responsible for astroglial gluta-
mate uptake, and Na+/glucose cotransporter,
SGLT), and antiporters or exchangers, which trans-
port two or more different substrates in opposite
directions (e.g., NACX). The membrane transport-
ers expressed in astrocytes accomplish various
functional roles and are represented by: (i) trans-
porters responsible for ion homeostasis or ionosta-
sis; (ii) neurotransmitter transporters; (iii)
transporters of neurotransmitter precursors; and
(iv) metabolite transporters (Ugbode et al., 2017;
Verkhratsky and Rose, 2020).
ASTROGLIA AND SYNAPTIC
TRANSMISSION
Synaptic structures lie at the very core of informa-
tion transfer and processing in the nervous system.
Astrocytes are fundamental elements of synaptic
connectivity being involved in synaptic formation,
evolution, and maintenance (Augusto-Oliveira
et al., 2020). These multiple roles are generalized
in the concept of the astroglial cradle (Figure 6.9)
(Verkhratsky and Nedergaard, 2014). Astrocytes
contribute to synaptic connectivity through regu-
lation of (i) synaptogenesis; (ii) maturation of the
synapse; (iii) synaptic stabilization and mainte-
nance; and possibly (iv) synaptic elimination. The
major wave of emergence of glutamatergic syn-
apses in the mammalian brain occurs in early
postnatal period, immediately after massive
astrogliogenesis.
Astrocytic membranes cover the majority
of synapses in the CNS; in the hippocampus,
about 60% of all synaptic structures are closely
enwrapped by astroglia (Bernardinelli et al., 2014;
Ventura and Harris, 1999). A large area of peri-
synaptic leaflet membrane provides ample space
for receptors, channels, transporters, and pumps
that contribute to neuronal-glial signalling and are
responsible for homeostasis in the cleft (Figure 6.9).
The perisynaptic membranes contain multiple
neurotransmitter receptors, which are activated
by neurotransmitters released during synaptic
transmission and create localised transient Ca2+
and Na+ signals, also known as microdomains
(Verkhratsky and Nedergaard, 2014).
Astrocytes control the extracellular distribu-
tion of glutamate and maintain neuronal pools
of glutamate and GABA by supplying glutamine
(Figure 6.10). Glutamate concentration in the
synaptic cleft is controlled by astrocytes through
Na+-dependent astroglia-specific glutamate trans-
porters EAAT1 and EAAT2, which maintain low
glutamate concentration at rest and rapidly remove
glutamate released during synaptic transmission
(Vandenberg and Ryan, 2013; Zhou and Danbolt,
2013). After being taken up into astrocytes glu-
tamate is converted to glutamine, which subse-
quently is transported to neurones where it acts as a
precursor for glutamate and for glutamine (GABA)
glutamate shuttle (Hertz, 2013)). Astrocytes also
control the extracellular concentration of gly-
cine and are primary regulators of adenosine
levels in the CNS through the astroglial adeno-
sine cycle (Boison et al., 2010; Eulenburg et al.,
2010). Adenosine is transported to astroglia by
equilibrate ENT1 or concentrating Na+-dependent
transporters CNT2,3. Adenosine subsequently is
catabolised intracellularly by adenosine kinase
that in the CNS is expressed exclusively in astro-
cytes (Boison et al., 2010). Astrocytes also act as
a main sink for catecholamines, accumulated by
Na+-dependent norepinephrine transporter NET;
catecholamines subsequently are catabolised by
monoaminoxidase-B highly expressed in astro-
cytes (Saura et al., 1992).
GLIOCRINE SYSTEM: ASTROCYTES AS
SECRETORY CELLS OF CNS
Astrocytes are capable of releasing numerous
neuroactive substances that regulate various
 Role of Neuroglia in Cognition 91

Figure 6.9 Astroglial cradle and glial homeostatic support of the CNS synapse. A: The
majority of synapses in the brain and spinal cord are multi-partite being composed of (i) the
presynaptic terminal; (ii) the postsynaptic dendritic compartment; (iii) the perisynaptic
process of the astrocyte; (iv) the process of neighboring microglial cell that periodically
contacts the synaptic structure; and (v) the extracellular matrix (ECM) present in the
synaptic cleft and also extended extra-synaptically. Astroglial perisynaptic membrane
contains numerous transporters that control homeostasis in the synaptic cleft. B: Perisynaptic
glial membrane is densely packed with numerous homeostatic transporters that maintain
synaptic transmission by controlling ionostasis, removing neurotransmitters, and supplying
neuronal terminals with neurotransmitter precursors.
Abbreviations: EAAT – excitatory amino acid transporters 1 (SLC1A3) and 2 (SLC1A2); NKA – the Na+/K+ ATP-ase or
ATP-dependent Na+/K+ pump, the α2 subtype (ATP1A2) is predominantly expressed in astrocytes; NKCC1 – the Na-K-Cl
co-transporter (SLC12A2); NCX – the sodium-calcium exchanger expressed in 3 isoforms (SLC8A1, SLC8A2 and SLC8A3);
NAAT – the Na+-dependent ascorbic acid transporter (SLC23); NBC – the sodium-bicarbonate co-transporter (SLC4A4);
CNT2 – the high-affinity Na+-dependent concentrative adenosine transporter (CNT2); ASCT2 – the alanine-serine-cysteine
transporter 2; MCT-1 – the monocarboxylase transporter 1 (SLC16A1); Kir4.1 – inward rectifier Kir4.1 channels; NHE – the
sodium-proton exchanger 1 (SLC9A1); GAT – GABA transporters 1 (SLC6A1) and 3 (SLC6A11); SN1,2 – Na+/H+ dependent
sodium coupled neutral amino acid transporters 1 (SLC38A3) and 2 (SLC38A5); GlyT1 – glycine transporter 1 (SLC6A9).
Source: A: adapted from Verkhratsky and Nedergaard, 2014.

aspects of neuronal activity and also signal to
other cells in the CNS (Verkhratsky et al., 2016).
Astrocytes can release (i) classical neurotrans-
mitters (such as glutamate, ATP, and GABA),
(ii) neuromodulators (taurine or kynurenic acid),
(iii) neurotransmitter precursors such as glutamine
or L-serine, (iv) hormones, and (v) trophic and
immunocompetent agents such as growth factors
or cytokines. The discovery of astrocytic release
of neuroactive compounds has been of funda-
mental importance to our views on the role of
these cells in the nervous system. Indeed, this
implies a more active role for astroglial networks
in the CNS, since they can receive information
from neurones by neurotransmitter receptors,
convert this information into an alternative form
of long-range excitability in the form of Ca2+
waves, and finally release extracellular signalling
molecules (Araque et al., 2014). The concept of
regulated neurotransmitter release from astro-
cytes is generally known as gliotransmission
(Savtchouk and Volterra, 2018). Astrocytes
release neuroactive substances through several
molecular pathways which include Ca 2+-
regulated exocytosis, diffusion through several
types of membrane channels (connexon
hemichannels or anion channels), membrane
transporters and recently discovered ectosome
shedding, which represents shedding of
microvesicles from the plasma membrane. The
vesicles contain lipids, cell surface proteins, and
material from the cytoplasm or nucleus of the
cell, which all can be employed for intercellular
communication (Venturini et al., 2019).
92 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 6.10 Glutamate (GABA)-glutamine shuttle. Astrocytes take up (by glutamate

transporters EAAT1/2) glutamate released during synaptic transmission. Glutamate is
converted to glutamine (by glutamine synthetase, GS, highly expressed in astroglial
cells), which is shuttled to neurons for subsequent conversion into glutamate and
GABA.

OLIGODENDROGLIA AND NG2 GLIA FUNCTIONAL PROPERTIES OF

Oligodendrocytes are specialised to form the
insulating myelin sheaths around axons in the
CNS (Baumann and Pham-Dinh, 2001). The
myelin sheath is an insulating layer composed of
lipids and myelin proteins that provides for the
rapid conduction of nerve impulses and for the
miniaturisation of the vertebrate CNS.
Oligodendrocytes in the CNS send multiple pro-
cesses and myelinate up to 30 axons located in
their vicinity. Along the length of an axon,
myelin sheaths are interrupted by nodes of
Ranvier, the highly specialised region of the
axons where action potentials are generated. The
myelinated segments between nodes are called
internodes and are connected to the cell body by
a process that contacts each internodal myelin
sheath (or myelin segment) at its approximate
midpoint, giving the oligodendrocyte a symmet-
rical appearance (Baumann and Pham-Dinh,
2001; Verkhratsky and Butt, 2013).
OLIGODENDROCYTES
Oligodendrocytes, similar to all other glial cells,
are non-excitable. They maintain a negative rest-
ing membrane potential of about -80 mV; this
resting potential is mainly set up by inward recti-
fier K+ channels, which are abundantly expressed
in mature oligodendrocytes. Oligodendroglial
precursor cells (OPCs) also express anion chan-
nels and voltage-gated ion channels for Na+ and
Ca2+, which makes some of them excitable.
Activation of voltage-gated Na+ and Ca2+ chan-
nels in immature oligodendrocytes may contrib-
ute to initiation of myelination by detecting
active axons (the latter release K+ in the process
of electrical activity and local increases in K+
may depolarise oligodendroglial processes and
trigger cationic influx that signals to the cell
interior).
Oligodendrocytes and their precursors express
many types of neurotransmitter receptors including
 Role of Neuroglia in Cognition
receptors to glutamate, ATP, adenosine, acetylcho-
line, GABA, glycine, and dopamine (Butt et al.,
2019; Nishiyama et al., 2021). These receptors
are activated by neurotransmitters released from
axons (which secrete glutamate and ATP in the
process of action potential propagation), as wells
as by neurotransmitters released from neurones
and astrocytes. Oligodendrocytes are also cou-
pled to each other and to astrocytes through gap
junctions. These integrate oligodendrocytes into
neurochemical assemblies of brain cells (Giaume
et al., 2021).
MYELINATION
The main constituents of myelin are lipids (70% of
its dry weight) and proteins (30% of the dry
weight); cholesterol is a major component of
myelin (27%) and lack of cholesterol during devel-
opment can cause hypomyelination. Formation and
maintenance of nodal structure is a key function of
oligodendrocytes, and essential for directing axonal
potassium and sodium channels, which generate
the action potential, at the nodes of Ranvier (Nave
and Werner, 2014). In addition, oligodendrocytes
provide metabolic support for the axons they mye-
linate by releasing lactate into the periaxonal space
(Philips and Rothstein, 2017); metabolic support is
coupled to axonal activity through glutamate,
which activates oligodendroglial NMDA receptors.
The formation of the myelin sheath is a highly
complex process that involves multiple steps, from
mRNA transcription to protein translation and
assembly into the membranes (Nave and Werner,
2014). All of the myelin products have to be trans-
ported from the cell body and targeted to the
“workface” of the myelin sheath, over hundreds
and potentially thousands of microns. Notably,
disruption of myelination not only results in the
loss of action potential propagation, but also axonal
degeneration.
Myelination involves a number of axoglial recog-
nition and adhesion events that regulate the produc-
tion of myelin-related gene products and radial axon
growth. Myelination of axons occurs in a series of
distinct axoglial interdependent phases (Verkhratsky
and Butt, 2013): (1) axonal contact and recognition
by OPCs; (2) induction phase, in which OPCs extend
initiator processes along receptive axons to form
short ensheathing segments, triggering the differenti-
ation of OPCs into premyelinating oligodendrocytes
and the initiation of axonal ion channel clustering;
(3) remodeling phase, in which non-myelinating
processes within the unit are lost, and radial and
longitudinal growth of myelinating processes forms
93
incipient internodal segments, inducing axon radial
growth and establishes nodes of Ranvier; (4) matura-
tion phase, in which axons and myelin sheaths within
units undergo interdependent growth to establish
adult dimensions of axon diameter, myelin sheath
g-ratios, and intermodal lengths; (5) late developing
oligodendrocytes fill unmyelinated gaps along axons,
as part of normal growth into adulthood, as well as in
response to remodelling and demyelination or remy-
elination. Development myelination starts prenatally
and lasts well into adulthood (in humans it is com-
pleted by 30 years of age or even later).
OLIGODENDROCYTE PRECURSORS
(NG2-GLIA)
Oligodendrocyte precursors (OPC), also known as
NG2-glia, are identified by their expression of the
chondroitin sulphate proteoglycan NG2 (Butt
et al. 2005; Nishiyama et al., 2021). These cells
are present in the CNS throughout life. The OPCs
receives direct synaptic contacts from neurones.
The OPCs bear several primary processes; the
process-delineated domains have a certain degree
of overlap. In gray matter, OPCs are distributed as
a “mosaic,” whereas in the white matter, OPCs
have an elongated appearance, extending pro-
cesses along the axonal axis. OPCs constitute
8–10% of total glia.
The primary functional role of OPCs is the life-
long generation of oligodendrocytes, although they
may also subserve other unresolved functions,
for example at synapses (Nishiyama et al., 2021).
OPCs slowly divide in the adult brain to produce
daughter cells, one of which provides for self-
maintenance of the OPC population, and the other
differentiates into an oligodendrocyte under the
control of multifarious factors, helping to ensure
that disruption of any single factor does not result
in their loss of function. OPCs can also be reactive
and respond to CNS insults by increased prolifera-
tion and morphological remodelling, manifested by
shortening and thickening of cellular processes and
a strong upregulation of NG2 expression. OPCs
generate new oligodendrocytes in the post-lesion
period, thus contributing to tissue regeneration.
MICROGLIA
Microglial cells are commonly perceived as resi-
dent macrophages of the brain and the spinal cord
that define the innate immunity of the central
94 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

nervous system (Kettenmann et al., 2011; Tay
et al., 2019). This broad designation of microglia
seems to be in need of further elaboration,
because, as shall be discussed below, microglial
cells undergo specific adaptation to the CNS envi-
ronment and become a legitimate member of the
brain cellular architecture with numerous physio-
logical functions that far exceed and complement
their immune capabilities (Garaschuk and
Verkhratsky, 2019a). For multiple functions of
microglia, see Table 6.2 and Figure 6.11.
MORPHOLOGICAL PROPERTIES OF
MICROGLIA
After entering the CNS, microglial precursors
migrate and disseminate almost homogeneously
throughout the parenchyma of the brain and spinal
cord (Ginhoux et al., 2013). In total, microglial
cells account probably for ~ 10% of all neuroglia,
and their densities are similar in different CNS
regions. Migration of microglial precursors is
accompanied by a remarkable morphological and
functional metamorphosis: the myeloid progeni-
tors, generally similar to monocytes, convert into
microglial cells, which acquire “neural-like”
appearance. Differentiated microglial cells have a
small cell body (~ 4–5 μm) and several thin and
long processes with characteristic terminal arbori-
sation represented by numerous small secondary
processes (Augusto-Oliveira et al., 2021).
Microglial processes are in continuous motion
(thus being defined as ‘surveilling’ microglia),
moving through the surrounding CNS tissue at a
speed of ~0.7–1.5 μm/min. This movement of
microglial processes is accompanied by regular
extension/retraction (at 2–3 μm/min) of small pro-
trusions. Thus, microglial processes constantly
survey their neighbourhood. Microglial processes
also define a territorial domain of a single micro-
glial cell. There is generally little overlap between

Table 6.2 Diversity of microglial functions

Physiological
CNS development • Early synaptogenesis (?)
• Phagocyting redundant/post-apoptotic neurones
• Pruning unwanted/redundant/silent synapses
• Secreting trophic factors (e.g., cytokines, growth factors or neurotrophins)
Neuronal plasticity • Monitoring synapses
• Regulating synaptic plasticity/connectivity through secretion of cytokines, and/or
other factors
• Secretion of lipoprotein particles for maintenance of cell membranes and synapses
Defensive
Recognition of pathogens • Sensing pathogen-associated molecular patterns (PAMPs) through Toll-like receptors
• Recognition of damage through danger-associated molecular patterns through
purinoceptors
Phagocytosis: • Ingestion and destruction by digestive enzymes in lysosomes of:
(a) damaged cells, e.g., neurones (e.g., neuronophagia or Wallerian degeneration);
(b) micro-organisms (e.g., abscess); (c) virally infected cells (e.g., herpes simplex
encephalitis); (d) erythrocytes following haemorrhage
Antigen presentation • Presentation of pathogens (e.g., in bacterial, fungal, viral infections) bound to the
major histocompatibility complex (MHC) for activation of T lymphocytes
• Recognition of bound antibody (adaptive immune function)
Immune response • Secretion of pro-inflammatory factors e.g., chemokines or interferon-γ
Repair • Remodeling of extracellular matrix; Regulation of stem cell proliferation (e.g., granule
cell of hippocampus)
Pathological
Cytotoxicity • Secretion of glutamate; reactive oxygen species/respiratory burst
Tumour growth promotion • Secretion of matrix metalloproteinase
Demyelination • Myelin destruction/phagocytosis in e.g., multiple sclerosis
Infection • Viral entry into CNS; Hosting of HIV-1; Support mycobacteria, including their
intracytoplasmic survival (e.g., tuberculosis)
 Role of Neuroglia in Cognition 95

Figure 6.11 Main physiological functions of microglia. Microglia contribute to many

physiological functions in nervous tissue. Through synaptic pruning, microglia assist in
shaping synaptic connectivity; through secretion of numerous factors, microglia interact
with astrocytes and regulate synaptic transmission; microglia influence myelination in early
development and re-myelination in pathology; microglia support angiogenesis; microglia
phagocytose and clear the nervous tissue of apoptotic neurones and other cellular debris,
and microglia regulate adult neurogenesis.
Abbreviations: CD95L: CD95(Fas/APO-1) ligand, a 40-kd type II membrane protein and member of the tumor necrosis factor
superfamily of cytokines; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.

microdomains of microglia. Given the speed of ION SIGNALING

processes movement the microglial domain could
be completely scanned by these processes within
several hours. Microglial cells show a remarkable
degree of heterogeneity, both molecular and struc-
tural, between and within different brain regions as
well as at different developmental states (Stratoulias
et al., 2019); some physiological microglial mor-
photypes are presented in Figure 6.12.
After entering the CNS environment, microglial
cells undergo profound physiological remodeling
and acquire a receptive phenotype compatible
with the chemical environment. Arguably, rami-
fied microglia is the most “receptive” cells of the
CNS because they possess multiple receptors to
96 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 6.12 Some physiological microglial moprhotypes.
Source: From Augusto-Oliveira et al., 2021.
neurotransmitters and neuromodulators as well as
“immuno-competent” receptors characteristic for
myeloid cells (Garaschuk and Verkhratsky,
2019b). These latter receptors include P2X7 puri-
noceptors, receptors to chemokines and cytokines,
and receptors to various tissue mediators such as
platelet-activating factor, thrombin, histamine, or
bradykinin all being critical for triggering various
types of immune responses.
Most electrophysiological experiments on
microglia were performed in vitro in culture;
these experiments consistently reported resting
potentials of ~ -30 mV and therefore much more
positive than those of neurones and astroglia, but
similar to that of other immune cells. In healthy
brain, ramified microglia possess very few ion
channels, but upon activation the density of func-
tional ion channels increases considerably.
Microglial cells express almost all types of
receptors to neurotransmitters and neuromodula-
tors so far found in the nervous system, includ-
ing receptors to glutamate, purines and GABA
(Garaschuk and Verkhratsky, 2019b; Tay et al.,
2019). The purinoceptors (adenosine receptors,
ionotropic P2X and metabotropic P2Y purinocep-
tors) are, arguably, the most abundant in microglia
(Verkhratsky et al. 2009). Microglial cells consti-
tutively express P2X7 receptors that contribute to
numerous responses to neuropathology. The P2X7
receptors are a general feature of immune cells
where they mediate various immune reactions,
including the processing and the release of vari-
ous cytokines (Janks et al. 2018). The P2X7 recep-
tors are activated in conditions of massive ATP
release associated with neuronal damage and are
linked to immune responses of microglia, being
particularly important activators of cytokines
release. Incidentally, direct over-expression of
P2X7 receptors in microglia is sufficient to trigger
their activation in the in vitro system in complete
absence of any other exogenous factors. Microglia
also constitutively express P2X4 receptors (that
are activated by low μM ATP concentrations),
which are critically involved in mediating micro-
glial activation in conditions of chronic pain. In
addition, microglia express P2Y2, P2Y6, P2Y12,
and P2Y13 metabotropic purinoceptors, which
are mainly linked to Ca2+ signalling (Verkhratsky
et al., 2009). Whereas the UTP-sensitive P2Y6
receptors regulate microglial phagocytosis,
ADP-preferring P2Y12 receptors are fundamen-
tal for initiating the acute reactive microgliosis

Table 6.3 Pathophysiology of neuroglia
Pathology/Disease
Traumatic brain/spinal cord injury Activation of astrocytes and microglia; formation of astroglial scar isolating the
Ischaemia/Stroke
Neurodevelopmental disorders/Autistic spectrum disorders
Rett syndrome
Fragile X syndrome
Infectious diseases
Bacterial meningoencephalities
HIV and HIV-associated dementia
Demyelinating disorders
Multiple sclerosis
Toxic encephalopathies
Poisoning with metals (Manganese, Astrocytes are primary target; they preferentially accumulate metals via specific
Aluminium, Lead) or
metylmercury
Wernicke encephalopathy (Korsakoff Astrocytes are primary target and key component of pathology; the disease is caused
syndrome)
Hepatic encephalopathy
Neuropsychiatric disorders
Schizophrenia
Major depressive disorder
Role of Neuroglia in Cognition 97
Neuroglial contribution
area of damage; removal of cellular debris through microglial phagocytosis;
promotion of post-traumatic regeneration.
Activation of astrocytes and microglia; metabolic support and neuroprotection in
the penumbra; at the same time overactivated astrocytes and microglia can
contribute to neuronal death and infarct propagation; formation of post-stroke
astroglial scar; facilitation of post-lesion regeneration.
In Rett syndrome expression of mutant MECP2 gene in astrocytes disrupt their
supportive function and leads to abnormal development of dendrites.
Fragile X mental retardation protein expressed in astrocytes may alter their
supportive function and contribute to pathological synaptic connectivity.
Activation of microglia, which can, depending on the degree of activation, be
either protective (through elimination of pathogens) or toxic (through massive
release of pro-inflammatory factors and toxic substances such as NO and
reactive oxygen species).
Microglia are the primary target; virus infects exclusively microglial cells; which
release pro-inflammatory factors, that activate astrocytes, which in their turn
induce neurotoxicity.
Degeneration of oligodendrocytes lies at the core of myelin disruption and
aberrant action potential propagation. Pathologically activated microglia are
thought to induce oligodendroglial damage.
transporters, this down-regulates expression of glutamate transporters,
glutamine synthetase, and possibly GABA transporter. Failure in glutamate
homeostasis underlies excitotoxic neuronal damage and death.
by severe (up to 70%) down-regulation of astroglial expression of glutamate
transporters, which leads to accumulation of extracellular glutamate followed with
massive neuronal excitotoxicity and neuronal death in thalamo-cortical regions.
Liver failure causes hyperammonemia and rapid increase in ammonium
concentration in the brain. Astrocytes are primary target, being the main
system for ammonia removal and utilisation though glutamine synthetase.
Increased accumulation of ammonia in astroglial cells triggers metabolic and
homeostatic failure, cellular oedema, and disruption of glutamate homeostasis
with consequent severe disruption in neurotransmission.
Decrease in number of astrocytes and oligodendrocytes; impairment of astroglial
glutamate uptake and glutamine synthesis. Abnormal glutamate homeostasis
together with an increased astroglial production and release of kynurenic acid
(exogenous inhibitor of NMDA and ACh receptors) and altered synthesis of
D-serine (positive modulator of NMDA receptors) contributes to pathological
glutamatergic transmission implicated in pathogenesis of the disease.
Decrease in number of oligodendrocytes and astrocytes; microglial asthenia and
microglial apoptosis, abnormal glutamate homeostasis, decreased secretion
of growth factors and cytokines, altered gap junctional connectivity in glial
syncytia which all may contribute to abnormal connectivity in neural networks
and neurotransmission disbalance.
(Continued)
98 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Table 6.3 Pathophysiology of neuroglia (Continued)

Pathology/Disease Neuroglial contribution

Dementia and neurodegenerative disorders

Amyotrophic lateral sclerosis (ALS) Degeneration and atrophy of astrocytes at the early (pre-symptomatic) stages of
Alzheimer’s disease (AD)
Fronto-temporal dementia, Pick’s
disease, fronto-temporal lobar
degeneration, thalamic dementia
Huntington disease (HD)
Addictive disorders
Alcohol and drug abuse/addiction
the disease. Impaired astroglial glutamate uptake may account for glutamate
excitotoxicity. At later stages activation of microglial and astrocytes may
further contribute to neurotoxicity.
Astrocytic asthenia at the early stages of AD progression; mild reactive astrogliosis
of astrocytes associated with plaques. Reactive microgliosis is concomitant to
microglia dystrophy and loss of function (phagocytosis). General decrease in
glial neuroprotection may account for the dynamic and severity of the disease
progression.
Combination of astroglial degeneration and astrocytic death with astroglial
activation; secondary activation of microglia that contribute to
neuroinflammation.
The primary astroglial pathology in HD is associated with a decrease in expression
of glutamate transporters and impaired glutamate homeostasis; HD-affected
astrocytes have decreased ability to produce and release glutathione and
ascorbic acid, which reduces their neuroprotection through ROS scavenging.
Activation of microglia can be seen at the early, pre-symptomatic stages of this
disease.
Decrease in astroglial density and astroglial asthenia at the early stages of the
addictive disorders is complemented by secondary astrogliosis associated with
progression of pathology. Impaired glutamate uptake and release (through
cysteine-glutamate antiporter) may account for aberrant neurotransmission
and behavioural symptoms.

including rapid extension of microglial processes,
morphological alterations, membrane ruffling,
and chemotaxis while ADP-preferring P2Y13
receptors regulate microglial morphology, sur-
veillance, and resting levels of interleukin 1β
release. Intracellular Ca2+ signalling bridges the
surveilling or sensor functions of microglia with
their effector functions (e.g., directed process
motility, cytokine production). Under physiologi-
cal conditions and in conditions of minor tissue
dyshomeostasis, most microglial Ca2+ signals are
compartmentalized and occur only in microglial
processes. Microglial processes vividly react with
an increase in Ca2+ signalling both to hyper- and
hypoactivity in the surrounding neural networks.
Abundant somatic Ca2+ transients in microglia
reflect pathological conditions like status epilep-
ticus, aging, brain injury, amyloid pathology, or
peripheral inflammation.
PATHOPHYSIOLOGY OF NEUROGLIA
All diseases including neurological diseases can
be broadly defined as homeostatic failures.
Neuroglia are the principal homeostatic cells of
the nervous system. Accordingly, they are integral
to homeostatic failures in all neurological diseases
(Pekny et al., 2016; Verkhratsky et al., 2017).
Glial cells are involved in all types of neuropa-
thology, although they are not always the primary
targets. In its broadest sense, the function of glia
is homeostasis – maintaining a state of equilib-
rium both metabolically within neural cells, the
nervous tissue and the body as a whole, as well as
psychologically within the individual. Hence,
altered glial homeostatic function invariably con-
tributes to CNS neurological diseases, sometimes
as a principal element, but often secondary to
neural or environmental changes. In addition,
neuroglia forms CNS defence through intrinsic
evolutionary conserved defensive programmes
generally known as reactive gliosis. Such defence-
related reactive changes are expressed in all types
of glia and are represented by reactive astroglio-
sis, the reactive activation of oligodendroglial
precursors and the reactive microgliosis.
Pathological changes in neuroglia are complex and
diverse; they can be generic or disease-specific
and often vary at different disease stages. In the
context of human pathology, they are affected by
age and comorbidity. Pathological changes in
 Role of Neuroglia in Cognition
neuroglia can be broadly classified into (i) reac-
tive gliosis; (ii) degeneration with loss of function;
(iii) pathological remodelling, which results in
pathological phenotypes that drive neuropathol-
ogy; all these pathological reactions may occur
together or in isolation (Verkhratsky et al., 2017).
SUMMARY AND CONCLUSIONS
In the human brain glial cells are as abundant as
neurons. The relative number of glial cells has
increased with increasing complexity of the cen-
tral nervous system (CNS) during evolution. In
vertebrates three types of glial cells can be distin-
guished in the CNS, namely astrocytes, oligoden-
drocytes, and microglia. In the peripheral nervous
system glial cells are represented by Schwann
cells, satellite glial cells, enteric glial cells (EGCs),
and olfactory ensheathing cells. Astroglia are a
heterogeneous cell population that fulfil different
supportive and homeostatic tasks such as provid-
ing guiding structures during development, con-
trolling homeostasis of the extracellular space,
providing energy substrate for neurons, control-
ling blood flow, and modulating synaptic trans-
mission. Oligodendrocytes in the central and
Schwann cells in the peripheral nervous system
form myelin and thereby enable a high conduction
velocity within the axons. Microglial cells are the
immune competent cells of the brain and are acti-
vated during any pathologic process. The acti-
vated microglial cells can release many factors
which influence the pathologic process. Taken
together brain function is only possible by a con-
certed action of neurons and glial cells.
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Cognitive Neurogenetics
Jack van Honk, Zhang Li, Norihiro Sadato,
a n d J o a n Y. C h i a o
INTRODUCTION
Neuroscientific study of the phylogenetic and
ontogenetic bases of the central nervous system
(CNS) contributes to the understanding of the
structure and functional properties of the cogni-
tion and its evolutionary and cultural adaptation
(e.g., Chiao, 2016, 2017a,b; Chiao and Ambady,
2007; Chiao and Blizinsky, 2010; Chiao and
Immordino-Yang, 2013; Chiao et al., 2010, 2016,
2020, 2021a,b,c; Kandel and Schwartz, 1985;
Reinvang et al., 2010; Tandon, 2000). The role of
genetics in the higher-level cognitive processes
involves the functional role of cellular and molec-
ular mechanisms in the human brain (cf. Bartley
et al., 1997; Boyle et al., 2023a,b; Fossella et al.,
2006; also see Table 7.1). The distinct activation
patterns of neurotransmitter systems relate to the
functional role of genes within neurons.
Neurogenetics involved in cognitive neuroscience
(cognitive neurogenetics) pertains to how the
genetic code impacts on expressed cognitive
attributes (e.g., Green and Dunbar, 2012; Green
et al., 2008, 2012; Neumann et al., 2016). In this
chapter, we discuss specific neuroscientific find-
ings pertaining to cognitive and systems neurosci-
ence (cf. Boyle and Saklofske, 2004; Eising et al.,
2022) in attempting to address the important
7
question, “What are the underlying neural/neuro-
scientific circuits/pathways in higher-order cogni-
tive processes?”
Encoding and decoding of cortical representa-
tions of the sensory environment of cellular and
molecular mechanisms clearly demonstrates the
important role of genetics in human brain func-
tioning, including higher-level cognition. The nor-
mal cellular and molecular basis of human brain
activity corresponds functionally with conscious-
ness and the higher-level processes of cognition
and episodic memory (e.g., Aslaksen et al., 2018;
Bender and Raz, 2012; Bouazzaoui et al., 2013;
Crick and Koch, 1990; Golchert et al., 2019;
Green et al., 2013). Multilevel processing of neu-
ronal mechanisms consists of synaptic transmis-
sion that involves neurochemical signaling of
specific neurotransmitters, as well as enabling
computational cultural neuroscience; Chiao, 2011;
Churchland and Sejnowski, 2017; O’Reilly and
Munakata, 2000). The neurochemical signaling
directly affects the release of various neurotrans-
mitters at the presynaptic and postsynaptic junc-
tion of neurons. Specialization of the presynaptic
and postsynaptic structures illustrates the response
selectivity of distinct types of neurons and special-
ized information processes.
 Cognitive Neurogenetics
Table 7.1 Genes and brain function
Gene Polymorphism
Serotonin transporter (5-HTT) Variable number tandem repeat in the promoter region (5-HTTLPR) Amygdala
Dopamine receptor polymorphism Variable number of tandem repeats (VNTR) polymorphism
(DRD2, DRD4)
INTERFACE OF COGNITIVE
NEUROSCIENCE AND GENETICS
Genes influence cellular activity that comprise the
neurochemical signaling within the human brain
and its function. The functional specialization of
specific brain areas shows the prepotent, auto-
matic, innate, encapsulation of neuronal mecha-
nisms in the performance of the higher-level
function of cognition. Genetic regulation of neu-
rotransmission in the human brain is important in
cognitive processes and cortical organization.
The malleability of human brain function to the
interaction of genes and stimuli highlights the role
of genetic expression and neuronal plasticity in
neural and cognitive change. Genes are involved in
neuronal growth and maturation that accompanies
neurodevelopment. Interaction of genetic expres-
sion and environmental influences contributes to the
maturational processes that facilitate neurodevelop-
mental pathways. Genetic expression of human brain
function contributes to the processes of neurogen-
esis important in the neuronal growth and functional
maturation of cortical organization (with regard to
“neurogenetic effects on cognition in aging brains”
by Reinvang et al., 2010; cf. Aghamohammadi-
Sereshki et al., 2019; Chadjikyprianou et al., 2021;
Dixon et al., 2014; Lamar et al., 2003; Lundervold
et al., 2014; Parasuraman and Jiang, 2014; Villela
et al., 2018). Indeed, according to the Abstract on
the first page of Reinvang et al. (2010),
Knowledge of genetic influences on cognitive aging
can constrain and guide interventions aimed at
limiting age-related cognitive decline in older adults.
Progress in understanding the neural basis of cogni-
tive aging also requires a better understanding of
the neurogenetics of cognition. [We review] studies
aimed at deriving specific neurogenetic information
from three parallel and interrelated phenotype-
based approaches: psychometric constructs, cogni-
tive neuroscience-based processing measures, and
brain imaging morphometric data. Developments in
newer genetic analysis tools, including genome
wide association, are also described. In particular,
we focus on models for establishing genotype–­
phenotype associations within an explanatory
framework linking molecular, brain, and cognitive
103
Brain function
Ventral striatum
levels of analysis. Such multiple-phenotype
approaches indicate that individual variation in
genes central to maintaining synaptic integrity,
neurotransmitter function, and synaptic plasticity
are important in affecting age-related changes in
brain structure and cognition. Investigating pheno-
types at multiple levels is recommended as a means
to advance understanding of the neural impact of
genetic variants relevant to cognitive aging. Further
knowledge regarding the mechanisms of interac-
tion between genetic and preventative procedures
will in turn help in understanding the ameliorative
effect of various experiential and lifestyle factors on
age-related cognitive decline.
The functional integration of cortical organiza-
tion demonstrates the importance of the intercon-
nectivity of cortical brain regions in the functional
processes and basic mechanisms of the nervous
system. The structural and functional connectivity
of cortical organization detail the important role of
cortical networks and functional pathways in cog-
nitive and higher-level processes. The intercon-
nectivity of cortical networks provides regulatory
mechanisms that facilitate the control and regula-
tion of the level of activity of cortical mechanisms
and higher-level processes. The control and regu-
lation of level of activity of functional pathways
contributes to the bidirectional processes that
underlie the complexity of cognition and human
brain function. Genetic variation of human brain
function contributes to the understanding of the
individual and cultural differences that comprise
human variation. The impact of genetic and cul-
tural variation on the human brain illustrates the
overall adaptive preparedness of the organism
(i.e., comprising both human and infra-human
species) for biological and cultural adaptation
(Cavalli-Sforza et al., 1994; Chiao et al., 2010).
NEUROGENETICS OF COGNITIVE
NEUROSCIENCE
Research into the neurogenetics of cognitive neu-
roscience emphasizes the role of genotypes and
intermediate endophenotypes on the production of
104 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

complex phenotypes. Advances in behavioral cognition. Identification of the functional path-

genetics also have revealed the importance of
higher-level cognitive processes as intermediate
endophenotypes of complex behavior. Such
higher-level cognitive processes act as mediators
or moderators of the genetic expression of func-
tional pathways that underlie complex phenotypes
(Figure 7.1).
Identification of specific genes that regulate
levels of human brain activity highlights the func-
tional significance of genes on the functional
pathways of cognition and behavior (also see
Table 7.1). The interaction of genes with contex-
tual and environmental influences illustrates the
malleability of functional pathways involved in
ways of cognition and behavior contributes to the
understanding of the role of individual and cul-
tural differences on human variation. Functional
expression of specific genes in the neural path-
ways of human cognitive brain function dem-
onstrates the regulatory effect of the specialized
information processing of distinct neurons within
the brain’s cortical organization. In this chapter,
we focus on the role of neurogenetics in cognitive
and systems neuroscience.
Specific brain areas consist of distinct types of
neurons responsible for distinct types of neuro-
transmission. Patterns of electrophysiological sign-
aling of distinct types of neurons show response

Figure 7.1 The genotype-to-phenotype model of behavior.

(a) The behavioral genetics model describes the genotype-to-behavior pathway.
(b) The neurogenetics model characterizes the genotype-to-phenotype with the brain as an
intermediate endophenotype pathway.
(c) The cognitive neurogenetics model identifies the genotype-to-phenotype pathway with
cognitive brain function as an intermediate endophenotype; the cultural neurogenetics
model characterizes the role of genes and culture in the genotype-to-phenotype pathway.
 Cognitive Neurogenetics
selectivity to intrinsic and extrinsic processes.
Intrinsic processing of neurons illustrates the
spontaneous and intrinsic activity of electrophysi-
ological signaling based on the absence of input.
Extrinsic processing of neurons arises from the
activity of firing patterns in response to sustained
or prolonged sensory input, and the selectivity
of neuronal mechanisms in response to sensory
stimuli. Electrophysiological signaling of neuronal
mechanisms is responsible for the encoding and
decoding of sensory stimuli into cortical percep-
tual representations. The role of genotypes in the
endophenotypes of complex cognitive processes
recognizes the important intermediary role of
functional processes and underlying mechanisms
(Bogdan et al., 2012).
NEUROTRANSMISSION FROM NEURONS
TO COGNITION
Multilevel processing of neuronal mechanisms
consists of synaptic transmission involving the
neurochemical signaling of specific neurotrans-
mitters (Churchland and Sejnowski, 2017; Hille,
1984; O’Reilly and Munakata, 2000). Functional
processes and basic mechanisms of the CNS con-
sist of the pathways of the neurotransmitter sys-
tems that enable cognitive and higher-level
processes. Neurotransmission of specialized func-
tional pathways provides a molecular basis for the
chemical processes that underlie the genetic vari-
ations in human cognition. Synaptic transmission
consists of the intracellular changes to the mem-
brane potential of neurons and its release of spe-
cific neurotransmitters to produce the specific
effects of on cognition and working memory func-
tions (Ihne et al., 2016; Shepherd, 2004; also see
Figure 7.2).
The norepinephrine system is located within
the locus coeruleus of the brain stem and its inter-
connected brain regions. The serotonin system of
Figure 7.2 The brain as an intermediate
phenotype in the genotype-to-phenotype
pathway.
105
the raphe nucleus of the midbrain is responsible
for the neurochemical signaling of the serotonin
neurotransmitter system and its cortical projec-
tions. The dopamine system that is located within
the substantia nigra of the midbrain is responsi-
ble for the neurotransmission of the dopamine
neurotransmitter system and its interconnected
brain regions. In general, distinct types of neu-
rotransmitters reveal the selectivity of neuronal
mechanisms within the neurochemical signaling
of synaptic and neural transmission.
GENETIC BASIS OF COGNITIVE BRAIN
FUNCTION
Genes impact on the functional pathways of cog-
nitive brain function and observable cognitive
behavior (Heils et al., 1997). In general, the
genetic variants of specific functional polymor-
phisms show the functional variation of human
brain activity in response to task-based processes,
including various types of cognitive tasks (Canli
et al., 2006; Hariri and Weinberger, 2003a).
Genetic variants of specific functional polymor-
phisms illustrate the distinct types of functional
patterns of activation in response to the allelic
variation of specific genes (Brown et al., 2006;
Forbes et al., 2009; Hariri et al., 2002; also see
Figure 7.3). The functional correspondence of the
allelic variation of specific genes and the distinct
patterns of functional activation of specialized
brain regions, such as those involved in cognition
and memory, demonstrates the link of genotype to
endophenotype in the functional processes of
human brain function, including higher-level cog-
nitive function (Bogdan et al., 2017; Viding et al.,
2006). Thus, the distinct levels of functional acti-
vation of specific cortical brain regions in response
to effortful cognitive processes in the context of
genetic variation, illustrate the effect of genes on
neural transmission of phenotypic variation
(Bogdan et al., 2016; Brown and Hariri, 2006;
Fisher and Hariri, 2012; Hariri and Weinberger,
2003b; Hariri et al., 2005; Nikolova et al., 2014;
Zhou et al., 2008).
GENETIC AND FUNCTIONAL EXPRESSION
OF HUMAN BRAIN FUNCTION
Distinct patterns of genetic and functional expres-
sion in the functional pathways of neural trans-
mission illustrate the modifiability of genetic and
106 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 7.3 Genotype modulation of reward activity of the ventral striatum.
Source: From Forbes et al., 2005.
neural mechanisms and its intrinsic and extrinsic
properties. The modification of genetic and neural
mechanisms details the alteration of the functional
expression of basic mechanisms of cortical organ-
ization and its functional correspondence of geno-
type to phenotype (Canli et al., 2005). The
interaction of genes and environmental influences
enacts the functional processes and basic mecha-
nisms of cortical organization that underlie cogni-
tion and higher-level processes. The role of
cognition in the functional processes of cortical
organization facilitates modulation of the level of
activity of neuronal mechanisms based on intrin-
sic and extrinsic properties. The modification of
genetic and epigenetic expression contributes to
the regulation of the functional and behavioral
expression of cognition and higher-level processes
(Nikolova and Hariri, 2015).
The regulatory control of the efficacy of
presynaptic and postsynaptic activity of neuro-
transmitters provides a molecular basis for the
alteration of the excitatory or inhibitory input of
neuronal mechanisms and its interconnection.
Clearly, genes contribute to the control and regu-
lation of the efficacy of synaptic transmission and
its effect on the functional processes of neuronal
mechanisms. Thus, the regulatory control of genes
contributes to the neural activation of human cog-
nitive and memory function.
COGNITIVE NEUROGENETICS
The neurogenetics of cognition entails the genetic
variation of the functional activity of the brain
based on cognitive and higher-level processes.
Neurocognitive function describes the level of
activity of neuronal mechanisms in response to
the effortful cognitive processing. Cognition is
comprised of automatic and controlled processes
that show correspondence in the functional activ-
ity of human brain function and observable
behavior (Fodor, 1983; Gazzaniga et al., 2002;
Sejnowski and Churchland, 1989). The functional
response of the higher-level consciousness and
the regulation processes of mental activity consti-
tutes the role of cognition in the regulatory
mechanisms of the functional activity of the brain.
Information processing of sensory stimuli illus-
trates the malleability of neuronal plasticity to
learning and experience. The functional response
of cellular and molecular mechanisms to learning
demonstrates the importance of experience in the
functional processes of neuronal and cognitive
change, and underscores the importance of the
interaction of genes and environmental influences
in multilevel mechanisms.
Cognitive neurogenetics underscore the role of
the genotype to endophenotype in understanding
human brain activity. Neurogenetic models dem-
onstrate the genotype to endophenotype and the
role of genes in functional expression of the brain.
The conceptual model of the genotype to endophe-
notype highlights the importance of the functional
expression of genes in the cortical tissue. The role
of genes in the expression of human brain func-
tion shows the modifiability of CNS functional
processes and basic mechanisms.
The genetic variation of human brain activity
in response to a cognitive task illustrates the effect
of genes on the functional pathways of cognition
and higher-level processes. The role of genes in
 Cognitive Neurogenetics
the distinct functional patterns of activation illus-
trates the multiple patterns of activity of neurons
that comprise specific neurotransmitter systems
and their neurochemical signaling of localized
brain regions. The multiple patterns of activity of
neuronal mechanisms that genes regulate demon-
strates the role of neural transmission in the distinct
types of inter-connectivity that underlie cognitive
processes. Inhibitory or excitatory connectivity of
cortical neural networks suggests distinct types of
synaptic input based on the synaptic transmission
of neurotransmitter systems. Neural transmission
of cellular and molecular mechanisms provides a
putative mechanism for feedforward and inhibi-
tory processing of cortical neural networks. The
bidirectional processes of cortical neural networks
demonstrate a basic mechanism in the control or
regulation of cognition and higher-level processes.
The response selectivity of the distinct acti-
vation patterns shows the multiple functional
pathways that are responsible for the control and
regulation of cognition and higher-level processes.
The distinct types of neurotransmitter systems
show functional expression in the distinct func-
tional pathways of cognition and higher-level
processes. The functional pathways of neurotrans-
mitter systems are comprised of the neurotrans-
mitters located within specific brain regions and
their interconnected projections to cortical and
subcortical systems. The genotype to endopheno-
type that is observable in the multiple functional
pathways of distinct neurotransmitter systems
illustrates the cellular and molecular basis of the
functional processes and basic mechanisms of the
human brain.
GENETIC AND FUNCTIONAL EXPRESSION
OF COGNITION
Components of cognitive processes illustrate the
complexity of higher-level functions that com-
prise human cognition and memory. Cognitive
change involves the transformation and interpreta-
tion of cognitive representations based on the
encoding and maintenance of functional activa-
tion states that contribute to cognitive and behav-
ioral adaptation.
The genetic and functional expression of
cortical mechanisms comprise the cellular and
molecular basis for the control or regulation of
functional activity into distinct patterns of func-
tional activation of interconnected brain regions.
The distinct patterns of functional activation of
interconnected brain regions illustrate the func-
tional expression of the information processes of
107
cognition. The modulation of the level of activ-
ity of neuronal mechanisms based on the level of
mental activity of cognitive processes describes
the functional expression of the neuronal mecha-
nisms that underlie cognition and higher-level
function. The distinct patterns of activation of
interconnected brain regions of cortical neural
networks shows the modulation of neural activity
based on the functional task demand of cognitive
processes (Menon, 2012). The distributed pattern
of information processing of cortical neural net-
works details the multiple patterns of activity that
comprise interconnected brain regions and their
functional correspondence with cognition.
GENETIC REGULATION OF COGNITION
The genetic regulation of neurotransmission of
interconnected brain regions of cortical neural
networks involves the role of genetic variants in
the level of functional activity of interconnected
brain areas and the regulation of the efficacy of
neurochemical signaling of neuronal mechanisms
that underlie cognitive processes (Hariri et al.,
2003). The genetic regulation of the efficacy of
neurochemical signaling facilitates the synaptic
transmission of cortical mechanisms. The genetic
regulation of synaptic transmission constitutes of
putative mechanism for the amplification or inhi-
bition of the excitatory and inhibitory connectivity
of cortical neural networks. The regulation of the
bidirectional processing of the cognitive informa-
tion of cortical neural networks contributes to the
regulatory control of genes and its effect on neu-
ronal mechanisms.
Genetic and neural basis of cognition
The genetic and neural basis of cognition details
the mutual interactivity of cellular and molecular
processes in the cognitive representation of corti-
cal organization (Churchland and Sejnowski,
1988). The role of genes in the functional pro-
cesses of neuronal mechanisms is multifaceted
and illustrates the importance of the structure and
function of genes and its effect on the synaptic
transmission. The effect of genes in the functional
pathways of cognition demonstrates the genotype
to endophenotype of cognition and human brain
function. The effect of genes on the cortical
mechanisms of cognition implies a moderation or
mediation role of endophenotypes in the etiology
of complex traits. The cognitive neurogenetics
108 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
approach underscores the role of functional pro-
cesses in the control and regulation of cortical
mechanisms and the role of cognitive processes.
The modulation of the functional activity of neu-
ronal mechanisms based on learning and experi-
ence illustrates the importance of the dynamics of
the expression and regulation of genes in the
control and regulation of neural and cognitive
change (Figure 7.4).
Cognitive neurogenetics contributes to the fun-
damentals of cognitive and systems neuroscience.
Systematic investigation of the role of genes in the
control and regulation of the neurotransmission
of cortical mechanisms that are responsible for
cognition and higher-level function contributes to
the understanding of the neurobiological machin-
ery of biological organisms. The characterization
of multilevel mechanisms of the nervous system
entails the study of the functional processes and
basic mechanisms of the cellular and molecular
mechanisms of human brain function. Study of the
endophenotypes and phenotypes of complex traits
contributes to the understanding of the causal-
functional role of cognition and human brain func-
tion in functional and behavioral adaptation.
CULTURAL NEUROGENETICS: IMPACT ON
COGNITION
Research into cultural neurogenetics generates
novel knowledge of the role of genes and culture
in human brain/cognitive function (Chiao and
Ambady, 2007; Chiao and Blizinsky, 2010; Chiao
et al., 2010, 2016). Cultural neurogenetics is the
systematic investigation of the functional pro-
cesses and basic mechanisms of neuronal mecha-
nisms that show response selectivity to genetic
and cultural variation. Research into cultural neu-
rogenetics investigates how cultural variation
affects the functional expression of biomarkers
that underlie health and disease. International
comparative studies of cultural neurogenetics con-
tribute to the identification of endophenotypes and
phenotypes across various cultural settings (Chiao
et al., 2021a,b,c). The interaction of genes and
cultural environmental influences contributes to
the control and regulation of the functional pro-
cesses and basic mechanisms of the CNS and its
link to observable behavior (Cheon et al., 2014;
2021; Nomura, 2016; Sasaki et al., 2016; Stein
et al., 2016; Stevenson et al., 2016).
The study of cultural neurogenetics contributes
to the understanding of the interactivity of the
structural and functional connectivity of human
brain function. Cultural variation is important in
the control and regulation of the interaction of top-
down and bottom-up processes of specific brain
areas across multiple layers of cortical organiza-
tion. Cultural factors contribute to bidirectional
processing of the information of cortical neural
networks that control and regulate the perceptual
and motivational salience of sensory stimuli (Blais
and Caldara, 2021; Chiao and Mathur, 2016; De
Gelder and Huis in’t Veld, 2016). Cultural factors
are important in the understanding of the intrinsic
and extrinsic properties of functional processes and
basic mechanisms of human brain function and
cognition. Culture influences the regulation of
the processes of neural and cognitive change
(Goh, 2021; Gutchess et al., 2021; Varnum and
Hampton, 2021). The cultural expression of neu-
ronal mechanisms controls or regulates the func-
tional expression of complex cognitive processes.
Cross-cultural research into neurogenetics is
important in understanding of the role of cultural
factors that affect human brain function that con-
tribute to the fundamentals of cognitive and sys-
tems neuroscience. Cultural differences in the
functional processes and basic mechanisms of
human brain function illustrate the role of culture
in the structure and function of cortical organiza-
tion (Chiao et al., 2016). Cultural differences in
the distinct patterns of functional activation of
cortical neural networks show the distinct types
of processing of cultural information in the cog-
nitive and higher-level systems of the human
brain. Epigenetic expression of genes contributes
to modulation of brain function underlying social
behavior (Connelly and Morris, 2016; McGraw
and Young, 2010).
Processes of cultural transmission contribute to
the evolutionary adaptation of human populations
(Cavalli-Sforza and Feldman, 1981). Biological
and cultural transmission or inheritance of char-
acteristics illustrates the significance of the
functional architecture of the mind and brain in
behavioral and cultural adaptation. Cultural char-
acteristics of evolutionary change contribute to the
malleability of endophenotypes and phenotypes
of functional adaptation (Chen et al., 1999, 2016;
Uchiyama and Muthukrishna, 2021). The study of
neurogenetics also contributes to the fundamen-
tals of cognitive and systems neuroscience (Chiao
et al., 2021).
SUMMARY AND CONCLUSIONS
Evidence-based research into neurogenetics
builds knowledge-based resources of genes and
brain function. Understanding the fundamental
 Cognitive Neurogenetics 109

Figure 7.4 Neural correlates of epigenesis.

Source: Canli et al., 2006.
110 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
processes and basic mechanisms of the human
brain is foundational for understanding cognitive
and systems neuroscience. Cross-cultural study of
neurogenetics contributes to the understanding of
the interaction of gene and environmental influ-
ences on human brain function within different
nations, including the promotion of mental health
as well as cross-cultural differences in cognitive
and memory dexterity.
In summary, research into neurogenetics is
important in understanding the role of genes in
human brain function (including higher-level
cognitive and memory functions). Broadly, neu-
rogenetics research investigates the functional
genetics of neural pathways involving various
neuroanatomical components of the brain. Genes
regulate the functional neurotransmission of
molecular and cellular mechanisms within the
brain. Identification of specific genes or func-
tional polymorphisms that regulate neurotrans-
mission pathways involved in human cognition
and memory remains an important area of neuro-
cognitive research. Such research has the potential
to advance our understanding of the role of genetic
regulation within the neural mechanisms underly-
ing cognition and memory functions as well as the
role of neurogenetics in both individual and cul-
tural variation, more broadly.
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Dopamine System and Cognitive
Function across the Adult Life Span
Saana M. Korkki, Goran Papenberg,
Marc Guitart-Masip, Alireza Salami, Nina Karalija,
Lars Nyberg, and Lars Bäckman
INTRODUCTION
Following the discovery of dopamine (DA) as an
independent neurotransmitter in the 1950s, DA
has been recognized to regulate motor control,
higher-order cognitive function, as well as motiva-
tional and affective aspects of behavior (Björklund
and Dunnett, 2007; Salamone and Correa, 2012;
Tritsch and Sabatini, 2012). DA dysfunction is
implicated in the cognitive and motor symptoms
of several neurodegenerative (e.g., Parkinson’s
disease, Huntington’s disease), psychiatric (e.g.,
schizophrenia, obsessive compulsive disorder,
addiction), and developmental (e.g., attention
deficit hyperactivity disorder) disorders (Klein
et al., 2019), as well as in cognitive impairments
associated with healthy aging (Bäckman et al.,
2006, 2010).
In this chapter, we provide an overview of the
role of DA in higher-order cognition across the
adult life span. Specifically, we focus on the role of
DA in learning and memory, cognitive control, and
value-based decision making; cognitive processes
typically associated with dopaminergic neuro-
modulation (Ott and Nieder, 2019; Schultz, 2007;
Shohamy and Adcock, 2010). We further discuss
evidence for contribution of dopaminergic losses
to age-related impairments in these domains, with
8
an emphasis on molecular-imaging studies that
enable in vivo characterization of various compo-
nents of the DA system. Although studies concern-
ing these cognitive functions are largely discussed
separately, partly overlapping mechanisms likely
underpin the influence of DA on behavior across
domains (Diederen and Fletcher, 2021; Eriksson
et al., 2015; Gardner et al., 2018; Nyberg and
Eriksson, 2016; Westbrook and Braver, 2016). We
acknowledge that other neurotransmitter systems,
such as acetylcholine and noradrenaline, also play
an important role in cognitive function and age-
related cognitive deficits, as reviewed elsewhere
(Everitt and Robbins, 1997; Holland et al., 2021;
Rieckmann and Nyberg, 2020).
DOPAMINE SYSTEM AND
DOPAMINERGIC PATHWAYS
In the human brain, the majority of dopaminergic
neurons originate from the substantia nigra (SN)
and the ventral tegmental area (VTA) of the mid-
brain, from where they project to a range of corti-
cal and subcortical regions. Midbrain dopaminergic
projections are traditionally divided into three
 DOPAMINE SYSTEM AND COGNITIVE FUNCTION
pathways (Björklund and Dunnett, 2007). The
nigrostriatal pathway contains dopaminergic neu-
rons from the SN projecting to the dorsal striatum,
the mesolimbic pathway neurons from the VTA
projecting to the ventral striatum and other limbic
regions, and the mesocortical pathway contains
neurons from the VTA projecting to the cortex
(Figure 8.1A) (Björklund and Dunnett, 2007). A
fourth, tuberoinfundibular pathway comprises
dopaminergic neurons from the arcuate nucleus of
the hypothalamus that project to the median emi-
nence and is involved in controlling secretion of
prolactin (Vallone et al., 2000).
In addition to receiving dense dopaminergic
innervation from the midbrain, the striatum is
connected to cortical regions via topographically
organized cortico-striato-thalamo-cortical loops
(Alexander et al., 1991; Haber and Knutson, 2010;
Parent and Hazrati, 1995). Post-commissural
parts of the dorsal putamen receive input from
sensory-motor regions, pre-commissural putamen
and dorsal caudate input from associative regions,
and ventral striatum input from limbic regions.
Information from the striatum is relayed back to
the cortex via the thalamus, with DA playing a
key role in modulating signaling in the “direct”
and “indirect” pathways that facilitate and sup-
press thalamo-cortical connections, respectively
(Surmeier et al., 2007). Different parts of the
Figure 8.1 Dopaminergic pathways and pre- and post-synaptic components.
A The major dopaminergic pathways in the human brain.
Source: From Papenberg et al., 2019.
B Pre- and post-synaptic components of the dopaminergic system.
Source: From Cenci, 2014.
115
striatum are connected to each other via the mid-
brain, with the ascending spiral organization of
these connections enabling information flow from
the ventral striatum to associative and sensory-
motor areas of the striatum (Haber et al., 2000;
Haber and Knutson, 2010).
PRE- AND POST-SYNAPTIC
DOPAMINERGIC MECHANISMS
In contrast to fast-acting neurotransmitters that
mediate direct synaptic transmission, DA and
other monoamines act on a slower timescale that
ranges from hundreds of milliseconds to minutes
(Greengard, 2001). DA is synthesized in axon
terminals of dopaminergic cells, where the
enzyme tyrosine hydroxylase (TH) converts the
amino acid tyrosine into l-3,4-dihydroxyphenyla-
lanine (L-DOPA), which in turn is converted into
DA by aromatic-L-amino acid decarboxylase
(Elsworth and Roth, 1997; Klein et al., 2019).
Cytosolic DA is packaged into synaptic vehicles
by the vesicular monoamine transporter 2
(VMAT2) (Klein et al., 2019). After release of DA
from the presynaptic terminal, the DA transporter
(DAT) enables rapid reuptake of DA from the
116 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
synaptic cleft back into the presynaptic terminal
(Elsworth and Roth, 1997). DAT is abundant in
the striatum, but expressed at lower levels in
extrastriatal regions, where norepinephrine trans-
porter (NET) mediates DA reuptake (Borgkvist
et al., 2012; Morón et al., 2002). The enzymes
catechol-O-methyltransferase (COMT) and mon-
oamine oxidase (MAO) facilitate degradation of
DA into inactive metabolites (Elsworth and Roth,
1997).
On the post-synaptic cell, DA acts via G pro-
tein-coupled receptors that can be divided into two
main classes: D1-like receptors (D1DRs; compris-
ing D1 and D5 receptors) and D2-like receptors
(D2DRs; comprising D2, D3, and D4 receptors)
(Beaulieu and Gainetdinov, 2011). Although the
majority of DA receptors are located post-synap-
tically, D2DRs are also found in the presynaptic
terminal, where they function as autoreceptors to
regulate the synthesis, release, and reuptake of
DA (Ford, 2014). D1DRs are expressed in high
concentrations in both striatal and extrastriatal
regions, whereas D2DRs are found in high lev-
els in the striatum and in lower concentrations in
extrastriatal regions (Beaulieu and Gainetdinov,
2011). The cortical distribution of D1DRs appears
to follow a gradient of increasing density from
primary sensorimotor cortex to higher-order asso-
ciation areas (Froudist-Walsh et al., 2021). In
addition to differences in their regional distribu-
tion, D1DRs and D2DRs differ in their affinity
(i.e., strength of receptor binding) to DA (Beaulieu
and Gainetdinov, 2011). D1DRs have lower affin-
ity to DA and are thought to mediate phasic
actions of DA, reflecting large transient increases
in DA release that result from burst firing of dopa-
minergic neurons in response to excitatory inputs
(Goto et al., 2007). The higher affinity D2DRs
may be more important for detecting subtler
changes in tonic, or sustained, DA levels related
to pacemaker-like baseline firing of dopaminergic
neurons regulated by inhibitory inputs from the
ventral pallidum (Floresco et al., 2003; Goto et al.,
2007). Upon binding of DA to the post-synaptic
receptor, these two receptor classes are associated
with different intracellular signaling cascades,
with D1DR stimulation generally having excita-
tory, and D2DR stimulation inhibitory, effects
on the post-synaptic neuron (Greengard, 2001;
Surmeier et al., 2007; Tritsch and Sabatini, 2012).
In humans, molecular-imaging methods (e.g.,
positron emission tomography or PET; single pho-
ton emission computed tomography or SPECT)
using specific radioligands to target pre- and post-
synaptic components of the DA system allow char-
acterization of the DA system in vivo. Given the
sensitivity of radioligand binding to competition
from endogenous DA (Laruelle, 2000), these
methods can also be used to examine DA release
by assessing changes in DA receptor binding fol-
lowing cognitive or pharmacological manipula-
tions postulated to evoke DA release (Cropley
et al., 2006).
DOPAMINERGIC CONTRIBUTIONS TO
REWARD LEARNING AND VALUE-BASED
DECISION MAKING
Human and animal work indicate a critical role for
DA in reward-based learning and decision making.
Single-neuron recordings in the monkey midbrain
have shown dopaminergic neurons to fire in
phasic bursts in response to delivery of unex-
pected primary rewards, such as food or liquid
(Schultz, 1998; Schultz et al., 1997). Critically,
when a reward is consistently predicted by a cue,
dopaminergic activation gradually shifts to the
time of the cue presentation (Schultz, 1998;
Schultz et al., 1993). DA neuron activity signals
the difference between anticipated and obtained
rewards, thus providing a “reward prediction
error” (RPE) signal consistent with models of
reinforcement learning (Schultz, 2013; Schultz
et al., 1997). Increased burst firing of dopaminer-
gic neurons is observed when a reward greater
than predicted is received, whereas a dip below
baseline activity levels occurs in response to
reward omission or a reward smaller than expected
(Bayer and Glimcher, 2005; Bayer et al., 2007;
Schultz, 2013). Learning from positive and nega-
tive outcomes is thought to differentially involve
striatal D1DRs and D2DRs expressed in medium-
spiny neurons of the “direct” and “indirect” path-
ways (Surmeier et al., 2007). D1DR-expressing
neurons in the “direct” pathway are thought to
mediate learning from rewards and facilitate
reward-associated behaviors, whereas D2DR-
expressing neurons in the “indirect” pathway may
be critical for learning from negative outcomes
and inhibition of behavior (Cox et al., 2015; Frank
et al., 2004).
In human functional magnetic resonance imag-
ing (fMRI) studies, blood-oxygen-dependent
(BOLD) signal differences approximating RPEs
have been observed in the SN/VTA, but also in
mesolimbic regions beyond the midbrain, includ-
ing the ventral striatum and the medial prefrontal
cortex (D’Ardenne et al., 2008; Garrison et al.,
2013). While the involvement of dopaminergic
mechanisms in the RPE cannot be directly assessed
with fMRI, there is evidence that pharmacological
 DOPAMINE SYSTEM AND COGNITIVE FUNCTION
manipulations of the dopaminergic system impact
the neural expression of RPEs in the human stria-
tum (Pessiglione et al., 2006). Although lack-
ing the temporal resolution to isolate RPE-like
responses, PET studies have found increased
ventral striatal DA release during performance
of cognitive tasks that involve unpredicted mon-
etary rewards (Pappata et al., 2002; Zald et al.,
2004). Reward-related increases in ventral striatal
DA release have further been observed to corre-
late with ventral striatal fMRI activation during
reward anticipation (Schott et al., 2008). This sug-
gests that striatal DA release, and the subsequent
activation of D1DRs generally leading to excita-
tory post-synaptic effects, may be reflected in
increased BOLD signal in the striatum (Knutson
and Gibbs, 2007).
DA also appears to influence value-based
choices via motivational processes that direct the
allocation of effort to obtain rewards (Salamone
and Correa, 2012; Westbrook et al., 2021). In ani-
mal studies, DA depletion and DA antagonists
have been observed to increase rats’ preference
for low rewards requiring minimal effort in com-
parison to high rewards that require greater effort
(Cousins and Salamone, 1994; Salamone and
Correa, 2012). Similarly, markers of striatal DA
have been found to correlate with participants’
willingness to exert physical or cognitive effort to
receive monetary rewards in human PET studies
(Treadway et al., 2012; Westbrook et al., 2020).
Motivational influences of DA may reflect changes
in tonic DA levels (Niv et al., 2005, 2007). Tonic
DA has been proposed to encode the average rate
of rewards, signaling the opportunity costs of inac-
tion or sloth and impacting the vigor of responding
(Niv et al., 2007). Indeed, an association between
minute-to-minute fluctuations in DA levels and
average reward rate has been observed in rodent
studies (Hamid et al., 2016). In humans, increases
in reward rate decrease response times in a per-
ceptual discrimination task (Guitart-Masip et al.,
2011), with such effects being greater after admin-
istration of the DA precursor L-DOPA (Beierholm
et al., 2013), as well as for individuals with high
striatal DA synthesis capacity (and slow perfor-
mance) (Hofmans et al., 2022).
DOPAMINERGIC CONTRIBUTIONS TO
COGNITIVE CONTROL AND WORKING
MEMORY
Beyond reward, DA also modulates prefrontally
dependent cognitive control operations that guide
117
thoughts and actions in a goal-oriented manner
(Miller and Cohen, 2001). In the prefrontal cortex,
midbrain dopaminergic projections innervate both
excitatory pyramidal cells and inhibitory interneu-
rons (Ott and Nieder, 2019; Ranganath and Jacob,
2016). The more abundant D1DRs are expressed
in all layers of the prefrontal cortex, whereas
D2DRs are predominantly located in layer V
(Lidow et al., 1991; Ott and Nieder, 2019).
Early evidence for a role of DA in working
memory, a critical component of cognitive control
(Miller and Cohen, 2001), was provided by studies
showing depletion of DA from the monkey pre-
frontal cortex to result in similar working memory
deficits as seen after surgical removal of prefrontal
cortex tissue (Brozoski et al., 1979). Subsequent
human and non-human primate pharmacologi-
cal work has demonstrated a role for DA not
only in working memory (Kimberg et al., 1997;
Sawaguchi and Goldman-Rakic, 1991), but also
in other aspects of cognitive control, such as task
switching (Mehta et al., 1999, 2004), and selective
attention (Noudoost and Moore, 2011; ter Huurne
et al., 2015). Corresponding effects have been
observed at the neural level, with D1DR signal-
ing being critical for delay-period firing (Williams
and Goldman-Rakic, 1995) and D2DR signaling
for response-related firing (Wang et al., 2004)
of prefrontal neurons during working memory.
Human studies also implicate DA in supporting
the functional dynamics underpinning working
memory. For instance, administration of D1DR
agonists reduces fronto-parietal activation dur-
ing working memory in healthy young volunteers
(Fischer et al., 2010), with individual differences
in D1DR availability further correlating with the
degree of functional connectivity within this net-
work (Rieckmann et al., 2011a; Roffman et al.,
2016).
Interestingly, several studies have observed
opposing effects of dopaminergic drugs on cog-
nitive performance in different individuals (Cools
and D’Esposito, 2011). For instance, DA receptor
agonists have been found to enhance cognitive per-
formance in individuals with low working memory
capacity, but impair performance in individuals
with high working-memory capacity (Kimberg
et al., 1997). Given associations between DA syn-
thesis and working memory (Landau et al., 2009),
such findings have been interpreted to reflect an
inverted U-shaped relationship between DA and
cognitive performance, where both insufficient and
excessive DA levels can result in cognitive impair-
ments (Cools and D’Esposito, 2011). Consistent
with this proposal, in animal studies, dose-
dependent effects of DA stimulation have been
observed at the neural level, with low dose D1DR
118 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
agonists improving, and high dose D1DR agonists
degrading, spatial tuning of prefrontal neurons
during the delay-phase of a working-memory task
(Vijayraghavan et al., 2007). A recent computa-
tional model extended these findings by demon-
strating moderate levels of DA release to facilitate
persistent delay-period activity, a putative hall-
mark of working memory (Constantinidis et al.,
2018), in a distributed network of frontal, pari-
etal, and temporal regions, whereas insufficient or
excessive DA release resulted in a transient activ-
ity pattern in this network (Froudist-Walsh et al.,
2021). Moreover, recent evidence also suggests an
inverted U-shaped relationship between DA and
brain large-scale functional network organization,
with cortical regions showing intermediate levels
of D1DR availability demonstrating the greatest
nodal strength (i.e., strength of functional connec-
tions) (Nordin et al., 2022).
Variation in the effects of DA drug admin-
istration may also in part reflect differences in
the nature of cognitive processes investigated
(Floresco, 2013). Biophysically grounded compu-
tational models suggest distinct roles for prefron-
tal D1DRs and D2DRs in working memory, with
a D1DR-dominated state supporting robust main-
tenance of memory representations and a D2DR-
dominated state facilitating flexible switching
between representations (Durstewitz and Seamans,
2008; Seamans and Yang, 2004). Similar roles
have been attributed to prefrontal and striatal DA
(Cools, 2019; Cools and D’Esposito, 2011). While
prefrontal DA is thought to be critical for cogni-
tive stability, striatal DA may be more important
for mediating cognitive flexibility by gating infor-
mation in and out of working memory in accord-
ance with current task goals (Cools, 2019; Cools
and D’Esposito, 2011; O’Reilly, 2006). Indeed,
increased striatal DA release has been observed
following a working memory updating training
protocol (Bäckman et al., 2011b), with genetic
(Persson et al., 2015) and PET-derived (Nyberg
et al., 2009a) evidence further suggesting a similar
role for striatal DA in the updating of long-term
memory (LTM) representations.
DOPAMINERGIC CONTRIBUTIONS TO
EPISODIC MEMORY
The hippocampus, a key region for long-term
episodic memory (Eichenbaum, 2000; Squire,
1992), receives dopaminergic projections from the
VTA and, to a lesser extent, the SN via the mes-
olimbic pathway (Gasbarri et al., 1994). In addi-
tion, recent evidence suggests that co-release of
DA from locus coeruleus neurons (synthesizing
DA as a precursor for noradrenaline) may provide
another source of DA to the hippocampus
(Duszkiewicz et al., 2019). Animal studies indi-
cate a role for hippocampal DA in modulating the
persistence, or durability, of episodic memories,
likely reflecting the influence of DA on memory
consolidation (Lisman et al., 2011). Consistent
with a role in memory consolidation, intra-hip-
pocampal administration of D1DR antagonists
prior to memory encoding disrupts delayed (6–24
hours), but not short-term (20–30 minutes), spa-
tial-location memory (Bethus et al., 2010;
O’Carroll et al., 2006). Others have reported simi-
lar effects for expression of fear memory when a
DA antagonist was administered 12h after encod-
ing, but not at shorter post-encoding intervals
(Rossato et al., 2009). Indeed, DA-dependent
stimulation of protein synthesis is thought to be
critical for the late phase of hippocampal long-
term potentiation or LTP (Duszkiewicz et al.,
2019; Lisman et al., 2011; for dopaminergic
modulation of cortico-striatal LTP, see Calabresi
et al., 2007). LTP refers to activity-dependent
increases in synaptic strength and is considered a
key cellular substrate of memory (Bliss and
Collingridge, 1993). In rodents, late hippocampal
LTP is reduced by D1DR antagonists (O’Carroll
and Morris, 2004), and by genetic knockout of
D1DRs (Granado et al., 2008; Matthies et al.,
1997). Similar effects on LTP following D2DR
blockage have also been observed, with presynap-
tic D2DRs potentially playing a role in long-term
depression (LTD; activity-dependent decrease in
synaptic strength) (Rocchetti et al., 2015). In addi-
tion to modulating synaptic plasticity, rodent evi-
dence suggests that DA may contribute to memory
consolidation by promoting post-encoding hip-
pocampal reactivation of encoded memory repre-
sentations (McNamara et al., 2014). In humans,
post-encoding functional connectivity between
the VTA and the hippocampus has been found to
predict long-term, but not immediate, associative
recall (Tompary et al., 2015), providing indirect
support for dopaminergic modulation of hip-
pocampal post-encoding processes.
Dopaminergic modulation of LTM is thought to
serve an adaptive function, enhancing the retention
of novel, surprising, and motivationally relevant
aspects of prior experiences (Frank and Kafkas,
2021; Miendlarzewska et al., 2016; Shohamy
and Adcock, 2010). Exposure to novelty evokes
hippocampal DA release (Moreno-Castilla et al.,
2017), promotes memory retention, and induces
hippocampal LTP (Li et al., 2003; Wang et al.,
2010). Specifically, the CA1 subfield of the hip-
pocampus facilitates novelty detection by compar-
ing the sensory input arriving from the cortex to
 DOPAMINE SYSTEM AND COGNITIVE FUNCTION
memory-based predictions from the CA3 (Lisman
and Grace, 2005). Hippocampal novelty signals
are conveyed to the dopaminergic midbrain via
a polysynaptic pathway involving the nucleus
accumbens and the ventral pallidum (Lisman and
Grace, 2005; Lisman et al., 2011). This results in
reduced tonic inhibition of midbrain dopaminergic
neurons from the ventral pallidum and increased
baseline dopaminergic neuron firing (Floresco
et al., 2003), which in turn may facilitate phasic
burst firing (Lisman and Grace, 2005; Lodge and
Grace, 2006). Thus, the hippocampus itself can
regulate dopaminergic input from the midbrain to
the hippocampus.
DA is also thought to underpin value-related
enhancements of LTM seen for motivationally
relevant stimuli (Knowlton and Castel, 2022;
Shohamy and Adcock, 2010). FMRI evidence
indicates stimuli associated with monetary
rewards to result in increased activation of the
hippocampus, ventral striatum, and SN/VTA
during memory formation (Adcock et al., 2006;
Wittmann et al., 2005). Similarly, reward has been
shown to impact hippocampal post-encoding
processes, with the degree of post-encoding con-
nectivity between the hippocampus and the VTA
predicting memory benefits for stimuli learned
in high-reward contexts (Gruber et al., 2016).
Consistent with effects seen for DA stimulation
in rodents (McNamara et al., 2014), reward also
promoted post-encoding hippocampal reactiva-
tion of memory representations in this study
(Gruber et al., 2016). Beyond more general ben-
efits for reward-associated stimuli, recent work
has also reported the degree of RPEs experienced
during memory encoding to predict later episodic
remembering, with this effect being mediated by
RPE-related activation of the ventral striatum
(Calderon et al., 2021).
AGE-RELATED CHANGES IN THE
DOPAMINERGIC SYSTEM
Concomitant with decreases in many cognitive
domains, including episodic and working memory,
cognitive control, and decision making, the dopa-
minergic system exhibits age-related deterioration
(Bäckman et al., 2006, 2010). In contrast to some
clinical conditions that affect more selective
aspects of the DA system (Kim et al., 2002;
Laruelle et al., 2000), aging is associated with
relatively widespread declines in DA system
integrity. Loss of dopaminergic neurons in the SN
of approximately 3% per decade occurs with
aging (Fearnley and Lees, 1991; Bäckman et al.,
119
2006), with D1DRs, D2DRs, and DAT similarly
exhibiting age-related reductions (de Keyser et al.,
1990; Erixon-Lindroth et al., 2005; Kaasinen
et al., 2000; Seeman et al., 1987) that appear to be
correlated (Ishibashi et al., 2009; Volkow et al.,
1998b). Meta-analytic estimates of age-related
reductions in fronto-striatal DA receptor availabil-
ity and striatal DAT of 8.2–14.0% per decade have
been reported, with D1DRs slightly more affected
than D2DRs (Karrer et al., 2017). Findings regard-
ing striatal DA synthesis capacity are less consist-
ent, with no meta-analytic evidence for age-related
differences (Karrer et al., 2017). It is possible that
preserved DA synthesis capacity, in combination
with reduced DAT, may reflect a compensatory
mechanism, prolonging the availability of DA in
the synaptic cleft (Karrer et al., 2017). However,
associations between DA synthesis and release
have not been observed in younger adults (Berry
et al., 2018a), and evidence for relationships
between striatal DA synthesis capacity and func-
tion is mixed in older age (see section on
Dopaminergic contributions to age-related altera-
tions in cognitive control and working memory).
In addition to differences between pre- and
postsynaptic components (Karrer et al., 2017),
regional heterogeneity in the rate and trajectory of
age-related DA decreases may exist. While many
studies have reported linear age-related decreases
in PET markers of the DA system (Karrer et al.,
2017; Malén et al., 2022; Reeves et al., 2002),
non-linear patterns have also been observed, often
characterized by accelerated DA receptor losses
after midlife (Bäckman et al., 2006, 2010). A
recent study using the high-affinity radioligand
18
F-fallypride for characterization of both stri-
atal and extrastriatal D2DRs observed regional
heterogeneity in the degree of age-related recep-
tor losses, with the largest decline evident in the
temporal and frontal cortex (Seaman et al., 2019).
Interestingly, several regions also displayed non-
linear associations with adult age, which were
characterized by strong reductions in D2DR avail-
ability from young to middle age, followed by
more modest age-related differences in old age
(Seaman et al., 2019). This pattern contrasts some
prior findings from smaller cohorts, as well as typi-
cal age-related trajectories seen for other measures
of brain integrity, such as hippocampal volume
(Nobis et al., 2019). Regional variation in aging
effects is also suggested by findings indicating
D1DR availability across dopaminergic pathways
to be correlated in young, but to a lesser extent in
older age (Rieckmann et al., 2011b). An important
caveat to note, however, is that prior studies have
essentially relied on cross-sectional comparisons,
which may not map onto longitudinal changes in
DA-system integrity (Raz et al., 2005). Recently,
120 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
first 5-year longitudinal estimates of D2DR
declines in older age were reported, suggesting an
overestimation of striatal D2DR decline in previ-
ous cross-sectional studies (Karalija et al., 2022).
Aging-related losses were evident in the striatum
and in several extrastriatal regions (hippocampus,
anterior cingulate, orbitofrontal cortex) in this
study, with correlated D2DR declines observed
within associative and reward-related regions
(Karalija et al., 2022). Longitudinal data on D1DR
availability from a large life span cohort are cur-
rently underway (Nordin et al., 2022; see Marek
et al., 2011 for longitudinal data on DAT).
DOPAMINERGIC CONTRIBUTIONS
TO AGE-RELATED ALTERATIONS IN
COGNITIVE CONTROL AND WORKING
MEMORY
In addition to displaying negative associations
with age and positive associations with cognitive
performance, statistical control of PET-derived
markers of DA system integrity often accounts for
age-related variation in cognitive performance
(Bäckman et al., 2000; Erixon-Lindroth et al.,
2005, but see Juarez et al., 2019), suggesting a key
contribution of DA losses to cognitive deficits
associated with aging (Bäckman et al., 2006,
2010). Individual differences in DAT and DA
receptor availability have been found to positively
correlate with working memory, attention, set-
shifting, and other measures of cognitive control
in adult life span and older adult samples (Erixon-
Lindroth et al., 2005; Juarez et al., 2019; Landau
et al., 2009; MacDonald et al., 2012; Volkow
et al., 1998a). These associations may in part
reflect the influence of DA on maintenance of
functional integrity of fronto-parietal and cortico-
striatal networks important for goal-oriented
behavior. Older adults typically show diminished
modulation of fronto-parietal BOLD signal in
response to task demands, as well as reduced
functional connectivity within this network
(Geerligs et al., 2015; Nyberg et al., 2009b; Rieck
et al., 2017). Age-related reductions in striatal and
extrastriatal D1DR availability in part explain the
diminished load-dependent modulation of fronto-
parietal activation during working memory
(Bäckman et al., 2011a), with caudate D1DR
availability further correlating positively with
fronto-parietal functional connectivity during
working memory in older age (Rieckmann et al.,
2011a). Findings regarding the role of striatal DA
synthesis capacity in age-related deficits in
cognitive control have been more mixed, with
some studies showing positive (Landau et al.,
2009) and other negative (Klostermann et al.,
2012) associations to brain function. In a subset of
studies, relationships of DA synthesis to behavior
and brain function have also been limited to
younger adults (Berry et al., 2018b; Braskie et al.,
2011), suggesting a potentially age-varying rela-
tionship (Berry et al., 2016).
Candidate-gene studies have provided con-
verging evidence for a role of DA in maintaining
cognitive control abilities in later life (Papenberg
et al., 2015). One of the most commonly stud-
ied genetic polymorphisms in this context is the
COMT Val158Met that influences metabolic degra-
dation of DA in the prefrontal cortex and thereby
endogenous DA levels (Matsumoto et al., 2003).
Carriers of the advantageous Met allele, which is
associated with slower DA degradation and higher
endogenous prefrontal DA levels (Chen et al.,
2004; Lotta et al., 1995), display better perfor-
mance on tasks of executive function and work-
ing memory (Nagel et al., 2008; Störmer et al.,
2012), as well as more efficient prefrontal activa-
tion (Nyberg et al., 2014). Such effects are often
magnified in later life (Papenberg et al., 2015).
Critically, carriers of the COMT Val allele have
also been found to exhibit greater longitudinal
decline in executive function than Met carriers (de
Frias et al., 2005). In addition to COMT, variation
in D2DR-related genes has been associated with
inhibitory control (Colzato et al., 2013), and with
fronto-striatal working memory activation (Li
et al., 2019) in aging. Thus, converging molecular
imaging and genetic evidence indicates a contribu-
tion of DA to deficits in cognitive control in older
age, via impacting cortico-striatal function.
DOPAMINERGIC CONTRIBUTIONS TO
AGE-RELATED ALTERATIONS IN EPISODIC
MEMORY
PET studies have also demonstrated DA receptor
availability (Bäckman et al., 2000; Cervenka
et al., 2008) and DAT (Erixon-Lindroth et al.,
2005) to be positively associated with measures of
episodic memory across the adult life span.
Striatal DAT was further observed to predict lon-
gitudinal changes in episodic memory independ-
ent of the integrity of striatal resting state
functional networks over a period of 2–7 years
(Rieckmann et al., 2018). In genetic studies, ben-
eficial effects of advantageous DA-related poly-
morphisms have been observed for associative
 DOPAMINE SYSTEM AND COGNITIVE FUNCTION
recognition (Papenberg et al., 2017), backward
serial recall (Li et al., 2013), and updating of LTM
representations (Persson et al., 2015) in older age.
Consistent with the role of DA in memory con-
solidation (Lisman et al., 2011), older individual
carriers of advantageous alleles of D2DR and
DAT-related genes display enhanced retention of
visual information after long (1 week), but not
short (2.5 hours), study-test intervals (Papenberg
et al., 2013).
Fewer studies have examined associations
between PET markers of DA system integrity and
functional imaging measures of episodic mem-
ory processes. Some evidence suggests oppos-
ing relationships between D1DR availability and
BOLD signal in the ventral visual cortex during
face recognition across young and older adults
(Turner et al., 2020). Specifically, while D1DR
availability was positively coupled with BOLD
activation in younger adults, negative associations
were observed in older age, which may reflect
desynchronization of DA and BOLD activity in
aging (Turner et al., 2020). However, in pharma-
cological fMRI studies, L-DOPA (Chowdhury
et al., 2012), as well as DA receptor agonists and
antagonists (Morcom et al., 2010), have been
observed to modulate memory encoding-related
activity in medial temporal and fronto-striatal
regions in older age. Administration of DA recep-
tor agonists and antagonists further modulated the
specificity of hippocampal context representa-
tions in a baseline-dependent manner in one study
(Abdulrahman et al., 2017), aligning with com-
putational accounts that suggest a contribution of
DA to reduced fidelity of neural representations
in older age (Li et al., 2001). Despite prominent
dopaminergic losses, many studies have observed
preserved reward-related enhancement of episodic
memory performance in older age (Knowlton and
Castel, 2022), but also reported age-related reduc-
tions in mesolimbic activation during encoding of
stimuli associated with monetary rewards (Geddes
et al., 2018). Thus, further research is required to
assess the extent to which dopaminergic mecha-
nisms may continue to support value-based
enhancement of episodic memory in aging.
DOPAMINERGIC CONTRIBUTIONS TO
AGE-RELATED ALTERATIONS IN REWARD
LEARNING AND DECISION MAKING
There is growing interest in the contribution of
altered DA signaling to age-related changes in
reward-based learning and decision making
121
(Berry et al., 2019; Lighthall, 2020; Samanez-
Larkin and Knutson, 2015). While the processing
of basic rewards appears to be relatively well
preserved in aging, older adults typically display
impaired performance on tasks that require learn-
ing probabilistic, or dynamically changing, stimu-
lus-reward contingencies (Lighthall, 2020;
Samanez-Larkin and Knutson, 2015). Age differ-
ences in sensitivity to gains and losses when
acquiring and updating value representations have
been observed (Betts et al., 2020; Simon et al.,
2010; Sojitra et al., 2018), with older adults typi-
cally demonstrating slower learning of action-
outcome contingencies (Cutler et al., 2021; Mell
et al., 2005). At the neural level, these findings are
paralleled by fMRI studies demonstrating age-
related reductions of RPE-related activity in the
ventral striatum and the medial prefrontal cortex
(Eppinger et al., 2013; Samanez-Larkin et al.,
2014). Critically, L-DOPA administration was
found to improve reward-associated learning and
restore the ventral striatal RPE signal in older
adults who displayed drug-related performance
improvements (Chowdhury et al., 2013), implicat-
ing dopaminergic mechanisms in these age-related
cognitive impairments.
A recent multimodal neuroimaging study
(Dopamine, Aging, and Decision making; DAD)
assessed the role of D1DR availability in age dif-
ferences for various components of value-based
decision making (de Boer et al., 2017, 2019,
2020). One of the decision-making paradigms
included in this study was a two-armed bandit
task that required participants to choose between
two stimuli associated with fluctuating reward
probabilities. Behaviorally, older adults made less
optimal choices in this task, which was accom-
panied by diminished value-related activation
of the ventromedial prefrontal cortex (de Boer
et al., 2017). Importantly, value-related activation
of the ventromedial prefrontal cortex correlated
with D1DR availability in the nucleus accum-
bens across young and older adults (de Boer et al.,
2017). Independent of D1DR availability, struc-
tural integrity of the white matter tracts connect-
ing the nucleus accumbens to the ventromedial
prefrontal cortex also predicted prefrontal value-
related signals (de Boer et al., 2020), highlighting
an interplay of functional, structural and neuro-
chemical factors in contributing to age-related dif-
ferences in reward learning. In another paradigm,
participants were to execute or withhold a motor
response to obtain rewards or avoid punishments
(de Boer et al., 2019). On this task, individual dif-
ferences in dorsal striatal D1DR availability were
related to the degree of participants’ motivational
bias (de Boer et al., 2019), that is, the tendency
122 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
to perform an action to obtain rewards even when
the optimal choice is to withhold action, and to
withhold an action to avoid punishments event
when the optimal choice is to perform an action
(Guitart-Masip et al., 2012). Analyses of whole-
brain functional network organization during both
rest and decision-making tasks further indicated
that the regions exhibiting the greatest cross-sec-
tional age-related reduction in D1DR availability
also showed the largest age differences in func-
tional connectivity (Garzón et al., 2021), which
is consistent with other evidence linking DA to
maintenance of functional network integrity (Nour
et al., 2019; Rieckmann et al., 2011a; Roffman
et al., 2016).
COGNITION, BRAIN, AND AGING STUDY
Despite several cross-sectional studies supporting
a role for DA in age-related cognitive impair-
ments, longitudinal data on this topic remains
limited. This leaves the nature of longitudinal
changes in DA system integrity and their relation-
ship to cognitive changes in aging unclear. The
Cognition, Brain, and Aging (COBRA) study is a
large (N = 181; 64–68 years at baseline) multi-
modal neuroimaging study that involves longitu-
dinal assessment of D2DR availability, gray- and
white-matter integrity, brain function, and cogni-
tion over a 10-year period (Nevalainen et al.,
2015; see also Nordin et al., 2022 for an ongoing
longitudinal study on D1DRs). Findings from the
first 5-year follow-up in COBRA have been
recently reported, demonstrating longitudinal
declines in D2DR availability in several striatal
and extrastriatal regions (Karalija et al., 2022).
Moreover, cross-sectional analyses of the baseline
data have enabled well-powered investigation
of the replicability of prior cross-sectional
DA-cognition findings and the assessment of
potential modifying factors, such as genetic vari-
ance or lifestyle variables. Several key findings
from the baseline COBRA cohort are reviewed
next.
The distribution of cortical and subcortical
D2DR availability within the baseline COBRA
cohort was found to map onto known anatomi-
cal and functional organization of the DA system
(Papenberg et al., 2019a). Consistent with the
importance of DA for episodic memory (Shohamy
and Adcock, 2010), D2DR availability in the hip-
pocampus and the caudate correlated positively
with episodic memory performance across the
baseline cohort (Nyberg et al., 2016). The rela-
tionship between caudate D2DR availability and
episodic memory was further mediated by resting
state functional connectivity between the ventral
caudate and the medial temporal lobe (Nyberg
et al., 2016). Interestingly, no linear associations
between D2DR availability and performance on
tests of working memory, or perceptual speed,
were detected in this initial analysis (Nyberg
et al., 2016). Aligning with prior reports of non-
monotonic associations between DA and cog-
nition (Cools and D’Esposito, 2011; Floresco,
2013), results of a follow-up latent-profile analy-
sis indicated a non-linear multivariate association
between episodic memory, working memory, and
perceptual speed, and D2DR availability in the
striatum, hippocampus, and cortex (Lövdén et al.,
2018). While majority of the sample (N = 99)
displayed both high cognitive performance and
high D2DR availability, two smaller subgroups
with poor cognitive performance were detected.
In one of these subgroups (N = 42), reduced cog-
nitive performance was coupled with low D2DR
availability, whereas the other low-performing
subgroup (N = 40) exhibited high D2DR avail-
ability, especially in the striatum (Lövdén et al.,
2018). This latter group displayed low educational
attainment and high body-mass index, which are
also factors associated with psychiatric conditions
affecting DA signaling (Lövdén et al., 2018). In
addition to mean-level cognition, similar subgroup
differences were observed for moment-to-moment
variability in reaction time (Korkki et al., 2021).
Two studies further examined the role of
D2DRs in maintaining functional integrity of
brain circuits involved in working memory using
data from an n-back working memory paradigm
that participants completed in the MRI scanner
(Salami et al., 2018, 2019). Comparing two sub-
groups of older individuals that differed in terms
of their in-scanner working-memory performance
(high-performing group N = 113, low-performing
group N = 55), Salami et al. (2018) found
low-performing older adults to exhibit diminished
load-dependent modulation of fronto-parietal
activity, reduced fronto-parietal connectivity
during both task and rest, as well as decreased
frontal D2DR availability. Individual differ-
ences in D2DR availability were associated with
thalamo-striato-cortical BOLD signal during the
n-back task, with such associations being strong-
est when performing at maximum capacity limits
(i.e., the 3-back condition for the high-perform-
ing group, and the 2-back condition for the low-
performing group) (Salami et al., 2019). Nordin
et al. (2021) further observed D2DR availability
and episodic memory performance to be jointly
associated with hippocampal functional connec-
tivity with medial prefrontal, posterior parietal,
 DOPAMINE SYSTEM AND COGNITIVE FUNCTION
and striatal regions during rest. Associations
between D2DR availability and brain structural
integrity were also observed in the baseline cohort.
Specifically, whole-brain white matter lesion bur-
den was negatively related to D2DR availability in
the striatum and the hippocampus (Karalija et al.,
2019b). Individuals with the largest lesions were
also characterized by reduced episodic memory
and processing speed (Karalija et al., 2019b).
White-matter lesion progression also predicted
longitudinal losses in D2DR availability in asso-
ciative regions when examining data from the first
5-year follow-up, whereas reduction in cortical
perfusion was related to D2DR losses in limbic
regions (Karalija et al., 2022).
Another set of studies from the baseline
COBRA cohort focused on identifying potential
modifying factors impacting D2DR-cognition
relationships in older age, possibly contributing
to some inconsistencies in DA-behavior associa-
tions observed previously (Juarez et al., 2019). In
terms of genetic factors, Karalija et al. (2019a)
observed significant D2DR-cognition associa-
tions in C-carriers, but not T-homozygotes, of the
D2DR-gene polymorphism, C957T; likely reflect-
ing inflated D2DR binding via elevated recep-
tor affinity in the latter group (Hirvonen et al.,
2009). Similarly, positive associations between
hippocampal D2DR availability and episodic
memory were restricted to individuals carrying
beneficial alleles of the brain-derived neurotrophic
factor (BDNF) and the kidney and brain expressed
protein (KIBRA) polymorphisms (Papenberg
et al., 2019b), both of which have been associated
with hippocampus-dependent memory (Kambeitz
et al., 2012; Milnik et al., 2012). COMT was fur-
ther found to interact with D2DR availability to
influence memory performance, with the high-
est performance observed for individuals whose
D2DR availability matched their endogenous DA
levels, as indexed by COMT (Papenberg et al.,
2020). This highlights the importance of an opti-
mal balance between endogenous DA levels and
receptor availability. Accordingly, a DAT poly-
morphism, rs40184, presumably via regulating
DA availability, was associated with individual
differences in striatal and hippocampal D2DR
levels, as well as working memory performance
(Karalija et al., 2021a). Considering lifestyle fac-
tors, Köhncke et al. (2018) observed the intensity
of physical activity engagement to be positively
associated with caudate D2DR availability and
memory performance, whereas Karalija et al.
(2019b) observed negative associations between
elevated cardiovascular disease risk and D2DR
availability in the putamen. Sex differences in
D2DR availability and episodic memory in favor
123
of females were also observed in the baseline
sample (Karalija et al., 2021b), whereas women
exhibited steeper longitudinal decline in D2DR
availability in the nucleus accumbens (Karalija
et al., 2022).
Given the potentially different pattern of effects
(Nyberg et al., 2010; Raz et al., 2005), cross-
sectional observations from the COBRA baseline
assessment need to be corroborated by longitudi-
nal data from the 5-year follow-up. Indeed, first
longitudinal findings suggest that the magnitude
of age-related changes in D2DR availability
may have been overestimated in previous cross-
sectional comparisons (Karalija et al., 2022). The
longitudinal data further allow assessment of the
relationship between the degree of DA losses and
the degree of cognitive decline, as well as changes
in other brain parameters (e.g., grey-matter vol-
ume, white-matter lesions, blood flow, functional
activation patterns) with aging. As Rabbitt (1993)
queried, “Does it all go together when it goes?”.
This issue is at the heart of the COBRA project,
and the focus of ongoing analyses.
SUMMARY AND CONCLUSIONS
In this chapter, we have presented evidence for a
contribution of dopaminergic neurotransmission
to higher-order cognitive function across the adult
life span. Converging findings from molecular
neuroimaging, genetic, and pharmacological stud-
ies, support a role for DA in modulating human
memory, cognitive control, and value-based deci-
sion making. These diverse contributions may
reflect dopaminergic modulation of partly distinct
pathways, with the dorsal striatum and the pre-
frontal cortex implicated in cognitive control and
working memory, and the ventral striatum and the
mesolimbic system in reward-related processes
and long-term episodic memory. Evidence from
cross-sectional studies further indicates age-
related-deterioration of the dopaminergic system,
including loss of dopaminergic cells, transporters,
and receptors, that contributes to age-related cog-
nitive deficits in these domains. Recent efforts
from large-scale multimodal neuroimaging
cohorts have begun to elucidate potential modify-
ing factors, such as lifestyle and genetic variation,
that may influence associations between DA
system integrity and cognition in later life. While
longitudinal evidence on age-related DA declines
remains limited, ongoing longitudinal investiga-
tions (Nevalainen et al., 2015; Nordin et al., 2022)
will enable assessment of the cascade of
124 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
neurochemical, structural, and functional brain
changes associated with aging, and their relative
importance for maintaining cognitive performance
in later life.
Thus far, the majority of existing molecular
imaging studies have focused on assessing a single
pre- or post-synaptic marker of DA system integ-
rity. Given potential discordance of pre- and post-
synaptic components (Karrer et al., 2017), and the
importance of a balanced DA system in regulat-
ing behavior (Berry et al., 2019; Papenberg et al.,
2020), future studies incorporating assessment of
multiple pre- and post-synaptic markers within
the same individuals will be critical for gaining a
more mechanistic understanding of DA contribu-
tions to cognitive function, as well as of the exact
age-related trajectories of different pre- and post-
synaptic components. Moreover, parallel assess-
ment of DA system integrity along with other
neurotransmitter systems supporting higher-order
cognition and contributing to age-related cogni-
tive deficits (e.g., acetylcholine, noradrenaline)
will be important for delineating their interplay in
influencing cognitive function in both health and
disease.
In summary, the neurotransmitter dopamine is
implicated in a variety of functions, ranging from
motor control to higher-order cognition, as well
as motivational and affective aspects of behavior.
In this chapter, we have reviewed evidence for
dopaminergic contributions to cognitive function
across the adult life span, focusing on the domains
of cognitive control, learning and memory, and
value-based decision making. We have discussed
the general principles of dopaminergic modula-
tion of cognition based on integrated findings
from human pharmacological, neuroimaging, and
genetic studies, as well as experimental animal
work. In addition, we have reviewed evidence for
age-related decreases in DA system integrity and
the impact of such decreases on cognitive deficits
in aging. Taken together, although longitudinal
evidence is currently limited, the findings to date
support a dopaminergic account of age-related
cognitive deficits.
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Neurotransmission and
Neuromodulation of Recognition
Memory: Novelty vs. Familiarity
Daniel Osorio-Gómez, María-Isabel Miranda,
Federico Bermúdez-Rattoni, and
Kioko Guzmán-Ramos
INTRODUCTION
Many organisms, including human beings, require
modifying their behavior under variable situations
to promote and increase survival. Across evolutive
processes, memory has become an essential
mechanism to cope with environmental modifica-
tions. In general, organisms need to remember
adequate shelters, food sources, and dangerous
places or situations to avoid them. Usually, this
knowledge is conserved through a process called
memory, in which information is encoded, inte-
grated, and retrieved (Squire, 2009). Therefore,
memory promotes survival by shaping an organ-
ism’s behavior according to its acquired
experience.
Since the pioneering discovery in the 1950s by
Scoville and Milner of the loss of recent memory
following bilateral hippocampal lesions, consider-
able evidence suggests that memory could be clas-
sified depending on the duration and participation
of particular brain structures and circuits. In terms
of duration, memory can be divided into short-term
memory (STM) and long-term memory (LTM).
The neurobiological mechanisms involved in
maintaining STM and LTM differ; STM modifies
pre-existing brain networks by modulating exist-
ing proteins, while LTM demands morphological
9
and physiological changes through protein syn-
thesis to store information for extended periods,
even a lifetime (Dudai, 2004; Goelet et al., 1986;
McGaugh, 2000). Another classification of mem-
ory involves the use of memory systems or neural
networks and is divided into explicit (declarative)
and implicit (non-declarative) (Squire, 2004).
Explicit memory refers to information that can be
recalled consciously and is related to facts (seman-
tic) and events (episodic). Implicit memories are
related to information acquired through repetition,
such as habits or motor skills and conditioning; the
information is recalled without awareness. It has
been reported that explicit memory requires the
functional integrity of the medial temporal lobe.
In contrast, implicit memory usually involves
brain structures such as the cerebellum, amygdala,
and basal ganglia among others (Nadel and Hardt,
2011; Squire, 2004). In this chapter we focus on
recognition memory, an essential aspect of explicit
memory in which organisms judge that a recent
experience, including subject, location, or event,
has been previously experienced or encountered.
Long-lasting memories undergo different
stages: encoding, consolidation, retrieval and
updating (Abel and Lattal, 2001; Dudai, 2004;
Rodriguez-Ortiz and Bermúdez-Rattoni, 2017;
Sara, 2000). Memory encoding1 includes the
134 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

acquisition of information by learning events

during exposure to stimuli (McGaugh, 2000). Acquisition
As mentioned above, consolidation2 involves Information Encoding

changes in the structure of brain networks through

protein synthesis; in this process, memory is
stabilized into LTM suitable for future recalls
during memory retrieval (Bisaz et al., 2014;
McGaugh, 2000). Memory retrieval3 is defined
here as the process by which internal and external Consolidation
cues promote selection, reactivation, and assess-
ment of a behavioral outcome (Ben-Yakov et al.,
2015; Frankland et al., 2019). In addition, LTM
may go through a consolidation-like process after
memory retrieval. This process is known as recon-
solidation (Nader et al., 2000; Sara, 2000), and
it is when memory updating occurs (Lee et al., Retrieval
Reactivation Expression
2017; Rodriguez-Ortiz and Bermúdez-Rattoni,
2017; see Figure 9.1).
Various chemical substances carry information
between neurons at the synaptic level, underly-
ing neuronal communication within the brain.
Nevertheless, more than one hundred chemical
substances and even more receptors are involved
New information
in synaptic transmission (Holz and Fisher, 2012;
Hyman, 2005), promoting memory formation.
After the transduction4 of recently acquired infor-
mation, neurotransmitters are released into the
synaptic cleft, diffused across the synapse, and
bound to their respective receptors. According
Updating
to the neuroscience literature, there have been
attempts to categorize or group neurotransmit-
ters based on their chemical nature, function,
mechanisms, among other classifications. In this
regard, it has been proposed that neurotransmit-
ters are substances that produce rapid changes in
the membrane potential through the activation of
Figure 9.1 Long-term memory stages.
ligand-gated channels.5 In contrast, neuromodu-
lators are chemical substances that promote slow Exteroceptive and interoceptive informa-
biochemical changes in postsynaptic neurons, tion is encoded during acquisition and sub-
modulating presynaptic, and postsynaptic events. sequently stabilized into long-term memory
Unfortunately, this classification oversimplifies after structural changes within brain net-
the function and activity of neurotransmitters, works over memory consolidation. After the
since many neurochemicals activate ligand-gated integration of information, memories are
channels and metabotropic receptors6 (Hyman, recalled throughout retrieval, when they
2005). In this regard, we propose that neuro- are reactivated and expressed. Furthermore,
chemical substances can be identified as neuro- memory updating occurs only when new
transmitters and neuromodulators according to
information is integrated into the previ-
their effect on learning and memory processes.
Neurotransmitters are involved in signaling the ously formed memory traces.
functional properties of neural circuits required
for memory integration, whereas neuromodulators
modify the intrinsic characteristics of the neural
circuits regulating memory integration. Overall, required to promote and modulate cellular and
synaptic activity through neurotransmission and molecular mechanisms that subserve novelty
neuromodulation induces morphological changes detection and eventually transform novel stimuli
within brain networks for LTM establishment. into familiar stimuli necessary for recognition
Therefore, a series of neurochemical events are memory.
 NEUROTRANSMISSION AND NEUROMODULATION OF RECOGNITION MEMORY 135

RECOGNITION MEMORY regarding the brain structures involved in familiar-

Memory is an effective strategy to cope with envi-
ronmental changes; specifically, recognition
memory identifies different types of information,
including faces, places, sounds, objects, or changes
in the context to distinguish familiar events from
novel ones. It may be appropriate to distinguish
between assessment of explicit memory through
recall or recognition and their differences in pro-
cedure and effort involved. Recognition memory
plays a crucial role in episodic memory, which
comprises the acquisition, consolidation, retrieval,
and updating of information (Balderas et al., 2015;
Morici et al., 2015) about episodes experienced by
organisms in a space-time frame (Squire and Zola,
1996; Tulving, 2002). Recognition memory
involves two differential processes: familiarity and
recollection (Brown and Aggleton, 2001; Merkow
et al., 2015). Familiarity refers to the ability to
judge whether a particular stimulus or event has
already been experienced (Mandler, 1980).
Recollection is an independent process related to
recovering the characteristics (qualitative) of a
stimulus or event (Evans and Wilding, 2012; see
Figure 9.2). There is a comprehensive discussion
ity and recollection processes; evidence suggests
that both processes depend on distinct neural sub-
strates. The hippocampal formation and prefrontal
cortex are pivotal in recovering the qualitative
information of experienced events, while familiar-
ity relies on the parahippocampal (perirhinal,
entorhinal, and postrhinal) cortex of the brain
(Brown and Aggleton, 2001; Evans and Wilding,
2012; Merkow et al., 2015; Yonelinas, 2002).
Recognition memory has been studied using
different strategies and stimuli. A widely used
paradigm of taste recognition memory is the one
regarding identifying a familiar food. The poten-
tial to ingest harmful foods is reduced when
organisms restrict the consumption of novel tastes
(neophobia). With subsequent exposures, the
taste becomes familiar and organisms increase
the ingestion of the familiar stimulus (attenuation
of neophobia), since as pointed out by Michael
Domjan, this could be incorporated into their diet
as a safe source of nutrition. Accordingly, the defi-
nition of attenuation of neophobia indicates that
learning and memory events occur in organisms
promoting the recognition of novel and familiar
taste stimuli (Osorio-Gómez et al., 2018).

Figure 9.2 Recognition memory. Novelty/familiarity and recollection constitute recognition

memory. Familiarity is the ability to recognize if an experience, stimulus, or situation has
been encountered before, whereas recollection processes are associated with the contextual
integration of the characteristics of the event.
136 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Novel object recognition7 (NOR) and object
location memory8 (OLM) tasks are regularly
employed to assess the neurobiological mecha-
nisms of recognition memory, which involve
periods of handling and habituation to an empty
open field. During the sample phase, animals are
exposed to one or two identical novel objects;
afterward, animals are reintroduced to the
open field during the test phase and recognition
memory is evaluated either by presenting a dif-
ferent novel object, in NOR tasks, or by displac-
ing an object to a novel location, in OLM tasks
(Ennaceur and Delacour, 1988; Moreno-Castilla
et al., 2018). Both tasks allude to the ability of
animals to identify environmental changes by the
addition of an unknown object or a novel spatial
configuration, where researchers can assess novel/
familiar discrimination and the neurobiological
changes that subserve this process. Animal mod-
els are widely employed to evaluate learning and
memory processes. Behavioral tasks evaluate
the ability to recognize a previously experienced
stimulus or situation and are useful tools to repre-
sent human amnesia modeling. Although memory
is often evaluated in humans through language
(verbal and written), recognition memory is also
examined in humans through the visual-paired
comparison task. In this task, two identical pic-
tures are presented side-by-side during a brief
period; after a delay, one of the previous pictures
is presented alongside a new picture. Individuals
will look more at the new picture than the familiar
one (Manns et al., 2000). As explained later, NOR,
OLM and visual-paired comparison tasks rely on
brain structures involved in declarative memory.
Learning and memory require different neuro-
chemical substances to properly integrate infor-
mation into LTM. Recognition memory promotes
identifying different stimuli through acquisition,
consolidation, retrieval, and updating, which are
necessary for novel/familiar discrimination. In this
chapter, we review how neurotransmitters signal
information about novel and familiar stimuli and
how this signaling is regulated by neuromodula-
tors that enhance LTM formation. Many neu-
rotransmitters and neuromodulators may have
convergent functions, but for clarity, these are pre-
sented separately in this chapter.
NEUROTRANSMISSION RELATED TO
NOVELTY SIGNALING
As indicated before, organisms search for shelter
and food resources and constantly evaluate pos-
sible dangers (Ahmadlou et al., 2021); therefore,
they need to detect novel stimuli and discrimi-
nate environmental information. Novelty pro-
cessing is an essential cognitive function that
modulates other cognitive processes. For exam-
ple, novelty plays a crucial role in episodic
memory, as novel objects, context, gustatory
stimuli, among others are remembered better
than less distinctive stimuli due to familiarity
(Kishiyama and Yonelinas, 2003). Moreover, it
has been suggested that the novelty-familiarity
process modulates overall recognition memory
performance (Parker et al., 1998).
Novelty can be defined as the quality of being
new and unusual. It triggers attention, motiva-
tion, and memory processes (Bastin et al., 2019).
Thus, novelty refers to an attribute of simple
or complex stimuli that has never been experi-
enced; specifically, there are different types of
novelty depending on the nature of their pre-
existing representations (Kafkas and Montaldi,
2018). Absolute novelty implies that a stimulus
has never been encountered before, such as new
objects or a novel taste. In contrast, contextual
novelty detects an unexpected position/location
of the components of an experienced stimulus–
context pairing (Bastin et al., 2019; Kafkas and
Montaldi, 2018; Ranganath and Rainer, 2003).
Regardless of the type of stimulus, exposure
to a novel stimulus or context engages several
brain regions, including the prefrontal cortex
(Kishiyama and Yonelinas, 2003), insular cortex
(Bermudez-Rattoni, 2014), amygdala (Blackford
et al., 2010; Guzmán-Ramos et al., 2012b), and
medial temporal areas, including the hippocam-
pus and perirhinal cortices (Ranganath and
Rainer, 2003; Tulving et al., 1996).
As indicated above, a widely used paradigm
to study recognition memory is the attenua-
tion of neophobia. Presentation of a novel taste
stimulus enhances c-Fos expression in the central
(Yamamoto et al., 1997) and basolateral nuclei of
the amygdala (Lin et al., 2012), the perirhinal cor-
tex (Gómez-Chacón et al., 2015), the nucleus of
the solitary tract (Houpt et al., 1994), the thala-
mus and the insular cortex (Lin et al., 2012). In
addition, it has been reported that these structures
modify their electrophysiological responses after
the presentation of a novel taste stimulus (Adachi
et al., 1989; Carleton et al., 2010; Peng et al.,
2015; Verhagen et al., 2003). However, we will
focus on the neurochemicals involved in novel
taste recognition. Catecholaminergic denervation
by 6-hydroxydopamine9 (6-OHDA) administra-
tion within the olfactory bulb (Royet et al., 1983)
and dorsal bundle (Cole et al., 1988; Steketee
et al., 1989) reduces the neophobic response.
Similar lesions in the lateral tegmental area pro-
mote a decrease in the consumption of novel
 NEUROTRANSMISSION AND NEUROMODULATION OF RECOGNITION MEMORY
stimuli (Dunn and Everitt, 1987). On the other
hand, serotoninergic terminal denervation spares
the detection of novel gustatory stimuli (Royet
et al., 1983). Additionally, changes in several neu-
rotransmitters have been monitored during the
presentation of novel gustatory stimuli by using
in vivo microdialysis.10 Novel gustatory stimu-
lation induces an elevation of dopamine within
the nucleus accumbens, medial prefrontal cortex
(Bassareo and Di Chiara, 1999; Bassareo et al.,
2002), amygdala (Guzmán-Ramos et al., 2012b)
and insular cortex (Guzmán-Ramos et al., 2010;
Moreno-Castilla et al., 2016). There is also an
augmentation of norepinephrine in the amygdala
(Guzmán-Ramos et al., 2012b) and insular cortex
(Guzmán-Ramos et al., 2010). Moreover, novel
stimulus presentation is related to dopaminergic
activity within the insular cortex regardless of its
valence, since presenting either an innate aversive
gustatory stimulus (quinine) or an innate appeti-
tive gustatory stimulus promotes an elevation of
dopamine (Osorio-Gómez et al., 2021).
Norepinephrine administration into the baso-
lateral amygdala (Borsini and Rolls, 1984) or
insular cortex (Rojas et al., 2015) enhances the
neophobic response; in contrast, a blockade of
beta-adrenergic receptors within the basolat-
eral amygdala (Roozendaal and Cools, 1994) or
insular cortex (Rojas et al., 2015) diminishes the
rejection of a novel taste stimulus. Therefore,
norepinephrine release and the subsequent acti-
vation of beta-adrenergic receptors within the
basolateral amygdala and insular cortex occur in
novelty signaling. Similarly, a decrease in dopa-
mine levels within the insular cortex, as a result
of beta-amyloid accumulation in an Alzheimer’s
disease model, reduces the neophobic response;
this detrimental effect is ameliorated by the inhibi-
tion of dopamine reuptake (Moreno-Castilla et al.,
2016). The dopaminergic system is also involved
in neophobic response through D2 receptors, since
systemic administration of a D2 receptor agonist
reduces the rejection to novel stimuli (Muscat
et al., 1992). Hence, catecholaminergic activity is
required to modulate the novel response because
norepinephrine and dopamine levels increase after
presenting a novel gustatory stimulus. Therefore,
the activation of beta-adrenergic and D2 receptors
modulates novelty detection and the neophobic
response.
Concerning the cholinergic system and amino
acids, the presentation of a novel taste stimulus does
not promote any changes in the extracellular levels
of glutamate within the amygdala (Guzmán-Ramos
et al., 2012b; Miranda et al., 2002; Tucci et al.,
1998) and insular cortex (Guzmán-Ramos
et al., 2010; Miranda et al., 2002; Osorio-Gómez
et al., 2021). On the contrary, exposure to a novel
137
stimulus increases acetylcholine within the insular
cortex (Miranda et al., 2000; Rodríguez-García
and Miranda, 2016). Also, the administration of
scopolamine, a muscarinic receptor antagonist,
spares the neophobic response when injected into
the insular cortex (Gutiérrez et al., 2003), perirhi-
nal cortex (Gutiérrez et al., 2004), and nucleus
accumbens (Ramírez-Lugo et al., 2006). However,
administering a cholinergic agonist into the insu-
lar cortex generates a novelty signal that facili-
tates subsequent association leaning (Clark and
Bernstein, 2009). Moreover, systemic (Aguado
et al., 1994) or intra-amygdalar (Figueroa-Guzmán
et al., 2006) administration of a non-competitive
NMDA receptor antagonist does not affect the
neophobic response. Contrarily, administering a
competitive NMDA antagonist within the baso-
lateral amygdala diminishes the rejection of novel
gustatory stimuli (Burns et al., 1994). Altogether,
the presentation of novel gustatory stimuli elicits
an increase in acetylcholine, whereas glutamater-
gic levels remain unaltered. Additionally, cholin-
ergic activation promotes taste novelty signaling.
However, pharmacological manipulation of the
cholinergic system does not alter the neophobic
response, indicating that acetylcholine and gluta-
mate could act as an instructive signal required for
a transition from novelty to familiarity, as will be
discussed later.
As previously mentioned, besides recognizing
novel foods, animals must identify novel objects
or contexts. In this regard, NOR and OLM tasks
have been used as behavioral models to study
items and spatial recognition memory. Several
studies have reported that OLM and NOR depend
on different brain structures; in general, OLM
requires the hippocampal formation, particularly
the dorsal CA1 (Assini et al., 2009; Barrett et al.,
2011) and CA3 (Wagatsuma et al., 2018) por-
tions, to acquire, consolidate, and retrieve spatial
information (Mumby et al., 2002). Conversely,
NOR involves the insular cortex (Balderas et al.,
2008; Bermudez-Rattoni et al., 2005), perirhinal
cortex (Balderas et al., 2008; Winters et al., 2004;
Winters and Bussey, 2005), and ventromedial cor-
tex (Akirav and Maroun, 2006). Studies have also
reported the involvement of the hippocampus in
NOR (Broadbent et al., 2010; Cohen et al., 2013;
Furini et al., 2010, 2014, 2015; Mello-Carpes
et al., 2016; Myskiw et al., 2008; Reed and Squire,
1997). However, some controversy arises for its
participation in short but not long-term mem-
ory (Balderas et al., 2008; Haettig et al., 2011;
Mumby, 2001).
Microdialysis experiments have shown that
presenting a novel context does not promote either
glutamate or GABA elevation in the hippocam-
pus or prefrontal cortex (Giovannini et al., 2001).
138 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
However, exposure to novel objects induces
an elevation of acetylcholine in the hippocam-
pus (Aloisi et al., 1997; Ceccarelli et al., 1999;
Degroot et al., 2005; Ihalainen et al., 2010; Inglis
et al., 1994; Stanley et al., 2012) and frontal cor-
tex (Giovannini et al., 1998, 2001). Furthermore,
exposure to novel objects causes contradictory
results since elevated glutamatergic levels in the
hippocampus have been reported (Stanley et al.,
2012). In contrast, we reported no changes in
glutamate after the presentation of novel objects
(Guzmán-Ramos et al., 2012a). At the same time,
GABA levels remain similar to basal levels within
the hippocampus and insular cortex after present-
ing novel stimuli (Guzmán-Ramos et al., 2012a;
Stanley et al., 2012).
The catecholaminergic system is widely
involved in NOR and OLM performance; dopa-
mine is released within the insular cortex during
the presentation of novel objects in the sample
phase, whereas hippocampal dopamine remains
unaltered (Guzmán-Ramos et al., 2012a). On
the other hand, dopamine and noradrenaline
levels increase within the dorsal hippocampus
(Hernández-Ramírez et al., 2021; Mello-Carpes
et al., 2016; Moreno-Castilla et al., 2017), ven-
tral hippocampus (Titulaer et al., 2021), striatum
(Ihalainen et al., 1999), and prefrontal cortex
(Feenstra et al., 2000; Ihalainen et al., 1999) while
exploring a novel contextual configuration. In
addition, novel stimulus presentation elicits the
activation of the ventral tegmental area (Düzel
et al., 2010; Schultz, 1998) and the subsequent
release of dopamine in the nucleus accumbens
(Legault and Wise, 2001; Leonibus et al., 2006)
and prefrontal cortex (Feenstra and Botterblom,
1996; Feenstra et al., 2000). The locus coeruleus
also increases its firing response after presenting
novel objects or contexts (Pudovkina et al., 2001;
Sara et al., 1994; Vankov et al., 1995; Wagatsuma
et al., 2018).
The presentation of novel stimuli, indepen-
dently of the sensory modality, evokes several
neurotransmitters release, including acetylcho-
line, dopamine, and norepinephrine. Glutamate
and GABA activity in novelty detection during
NOR and OLM tasks is not apparent due to con-
tradictory results. This elevation induces a cascade
of learning and memory events (Hasselmo, 2006)
that could contribute to familiarity consolidation.
Thus, cholinergic signaling is involved in nov-
elty that instructs the integration of recognition
memory. In addition, changes in norepinephrine
levels could be associated with detecting salient
stimuli; the release of norepinephrine regulates
cortical function and mediates arousal, improving
subsequent cognitive functions such as attention
and motivation (Aston-Jones and Cohen, 2005).
Therefore, norepinephrine enhances behavioral
performance inducing exploration by modulat-
ing other effects of excitatory or inhibitory neu-
rotransmitters. Information about serotonin and
novelty detection is scarce, as the presentation
of a novel environment does not induce changes
in serotonin levels within the ventral midbrain,
basal ganglia, nucleus accumbens, or prefrontal
cortex (Jones et al., 1996). However, it seems that
serotoninergic denervation in a transgenic mouse
model for Down syndrome promotes an increased
response to novelty (Bell et al., 2003), suggesting
its involvement in novelty response modulation or
unspecific modifications in other neurotransmit-
ters, such as dopamine (Bortolozzi et al., 2005;
Díaz-Mataix et al., 2005).
Similarly, dopamine modulates learning signals
that facilitate the prediction of events (Montague
et al., 2004). Traditionally, dopamine has been
associated with the prediction and coding of
rewarding events (Schultz, 1998; Schultz et al.,
1993). Nevertheless, the dopaminergic response
could be a regulator of the behavioral response
and a modulator of learning signals that strengthen
associative events between novel predictor-stimuli
and their possible consequences.
NEUROCHEMISTRY INVOLVED IN THE
CONSOLIDATION OF RECOGNITION
MEMORY
After novelty detection, neurotransmitter release is
modified in response to a familiarity-consolidation
process. The catecholaminergic response induced
by the presentation of novel gustatory stimuli is
altered because of repetitive exposure to the same
stimulus. In this regard, once the taste stimulus is
familiar, the initial dopaminergic release is
reduced within the nucleus accumbens (De Luca,
2014), amygdala (Osorio-Gómez et al., 2016), and
insular cortex (Osorio-Gómez et al., 2017); like-
wise, noradrenaline release remains unaltered
within the amygdala and insular cortex after the
presentation of a familiar stimulus (Osorio-Gómez
et al., 2016, 2017). Thus, the dopaminergic and
noradrenergic response is no longer engaged due
to the recognition of familiar gustatory stimuli.
Additionally, denervation of the dorsal noradren-
ergic bundle accelerates attenuation of neophobia
(Sahakian et al., 1983), while the blockade of D1
dopaminergic receptors in the insular cortex
before the presentation of a novel stimulus impairs
attenuation of neophobia (David et al., 2014). This
evidence shows that catecholaminergic activity
diminishes after repeated presentation of the
 NEUROTRANSMISSION AND NEUROMODULATION OF RECOGNITION MEMORY
gustatory stimulus, suggesting that dopamine
(Duszkiewicz et al., 2019) and noradrenaline
(McIntyre et al., 2012) enhance the consolidation
of gustatory recognition memory during the initial
presentations of the stimulus.
Likewise, the extracellular levels of acetylcho-
line within the insular cortex decrease after the
consecutive presentation of a gustatory stimulus.
Decrements observed in acetylcholine are related
to the increased consumption of the familiar gusta-
tory stimulus (Miranda et al., 2000). Concerning
acetylcholine and consolidation of taste recogni-
tion memory, the blockade of muscarinic recep-
tors in the nucleus accumbens (Ramírez-Lugo
et al., 2006), insular cortex (Gutiérrez et al.,
2003), or perirhinal cortex (Gutiérrez et al., 2004)
has no effect on the neophobic response. Still, it
impairs consolidation of familiarity, observed
as a reduction in the attenuation of neophobia.
Therefore, the blockade of muscarinic receptors
prevents the novel stimulus from becoming famil-
iar. Significantly, cholinergic response within the
insular cortex is modulated by the nucleus basalis
magnocellularis, the main nucleus that provides
acetylcholine to several brain regions. The inac-
tivation of the nucleus basalis magnocellularis
disrupts familiar memory formation, preventing
acetylcholine release within the insular cortex
(Rodríguez-García and Miranda, 2016). Thereby,
cholinergic activity is widely involved in establish-
ing taste familiarity, suggesting that acetylcholine
encodes taste novelty triggering consolidation sig-
nals that promote gustatory recognition memory.
Concerning glutamate, we have previously
mentioned that the presentation of a novel or
familiar gustatory stimulus does not induce an
elevation of glutamate within the amygdala or
the insular cortex (Osorio-Gómez et al., 2016,
2017; Tucci et al., 1998). Nevertheless, it has been
observed that systemic (Aguado et al., 1994),
intra-amygdalar (Figueroa-Guzmán and Reilly,
2008), or intra-cortical (Figueroa-Guzmán et al.,
2006) administration of a non-competitive NMDA
receptor antagonist impairs attenuation of neo-
phobia. The administration of a specific mGluR1
antagonist accelerated the attenuation of neopho-
bia (Ramírez-Lugo et al., 2015). Therefore, even
though changes in glutamatergic levels are not
observed during exposure to novel or familiar
taste stimuli, it seems that glutamatergic receptors
are involved in the consolidation of gustatory rec-
ognition memory, demonstrating that basal gluta-
matergic signaling is needed to sustain the taste
memory trace.
Regarding object-location recognition memory,
the reduction of acetylcholine impairs NOR con-
solidation (De Jaeger et al., 2013). Additionally,
administration of a muscarinic antagonist into the
139
dorsal hippocampus (Hunsaker et al., 2007) or the
perirhinal cortex (Tang et al., 1997; Tinsley et al.,
2011; Warburton et al., 2003) hinders NOR forma-
tion (STM and LTM) when administered before
the sample phase. Besides, the inhibition of acetyl-
cholinesterase within the hippocampus maintains
acetylcholine activity, enhancing NOR (Hunsaker
et al., 2007). The administration of a muscarinic
antagonist into the insular or perirhinal cortices
immediately after the sample phase impairs NOR
consolidation (Balderas et al., 2008; Bermudez-
Rattoni et al., 2005) and object-in-context memory
recognition when administered in the hippocam-
pus (Balderas et al., 2008). Therefore, cholinergic
activity within the hippocampus and perirhinal
and insular cortices is responsible for learning and
consolidation processes associated with recogni-
tion memory, promoting the transition from nov-
elty to familiarity. For many years acetylcholine
has been described as an essential modulator of
learning/consolidation events through changes in
synaptic plasticity efficiency (Hasselmo, 2006).
However, there is evidence that activating mus-
carinic (Dennis et al., 2016) or nicotinic receptors
(Matsuyama et al., 2000) within the hippocampus
is sufficient to induce long-term potentiation, sug-
gesting that cholinergic transmission modulates
synaptic plasticity and makes a significant contri-
bution to memory-related events. Thus, it is prob-
able that acetylcholine release induced by novelty
initiates learning signals essential for recognition
memory regulated by neuromodulators such as
catecholamines.
As mentioned before, exposure to novel objects
or contexts induces an elevation of norepineph-
rine and dopamine within several brain regions.
Regarding dopamine, systemic administration
of a D1/D5 receptor agonist enhances NOR per-
sistence (de Lima et al., 2011) and facilitates the
retrieval of recognition memory (Hotte et al.,
2005). Conversely, the pharmacological blockade
of D1/D5 receptors within the perirhinal cortex
before the sample phase spares the acquisition
(intact STM) but impedes NOR consolidation
(hindered LTM). However, the administration of
a D1/D5 receptor agonist promotes NOR consoli-
dation (Balderas et al., 2013a). Moreover, novelty
enhances memory persistence by activating hip-
pocampal D1/D5 receptors (Takeuchi et al., 2016).
These results suggest that dopaminergic modula-
tion is responsible for strengthening recognition
memories. Initially, novelty induces dopamine
release that improves memory persistence through
the synthesis, tagging and capture of proteins
associated with synaptic plasticity (Frey and
Morris, 1998) generated by learning signals. In
the absence of a neuromodulator, synapses modi-
fied during learning could return to the baseline
140 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
level without establishing memories (Duszkiewicz
et al., 2019; Takeuchi et al., 2016).
Noradrenergic modulation of memories has
been widely described (McGaugh, 2000, 2015);
particularly, pharmacological manipulation of
the noradrenergic system enhances the LTM
of recognition tasks (Dornelles et al., 2007).
Norepinephrine administered into the hippocam-
pus immediately after the sample session pro-
motes NOR persistence (Mello-Carpes et al.,
2016). Likewise, noradrenergic activation of the
basolateral amygdala enhances the consolida-
tion of object-in-context recognition memory
(Barsegyan et al., 2014), object recognition mem-
ory (Roozendaal et al., 2007), and object location
(Song et al., 2021). Basolateral amygdala activity,
through modulation of the noradrenergic system,
facilitates the consolidation of recognition mem-
ory because of the regulation of arousal effects on
the dorsal hippocampus and insular and prelimbic
cortices (Barsegyan et al., 2019). We have previ-
ously described that the locus coeruleus responds
to novelty stimuli. Although this brain structure
has been classically associated with the produc-
tion of norepinephrine, recent evidence suggests
that hippocampal terminal activation coming from
the locus coeruleus increases spatial memory
consolidation through D1/D5 receptor activity
(Takeuchi et al., 2016). Surprisingly, the locus
coeruleus induces noradrenergic and dopaminer-
gic release in the dorsal hippocampus (Kempadoo
et al., 2016). Hence, novelty enhances recogni-
tion memory consolidation by the noradrenergic
modulation of the amygdala and the hippocampal
corelease of norepinephrine and dopamine via the
locus coeruleus.
NEUROCHEMISTRY DURING
MEMORY UPDATING: LEARNING
AND RE-LEARNING
Recognition memory is achieved through two
aspects: recollection and familiarity. Recollection
requires the maintenance of information related to
the specific characteristics of the context or stimu-
lus, and familiarity involves remembering if a sit-
uation, stimulus, context, or event has been
previously experienced. The transition from nov-
elty to familiarity is not a single event; novelty
promotes new information learning (Henson and
Gagnepain, 2010) and plasticity changes (Lisman
et al., 2011) that are required to shift gradually
toward familiarity. In this regard, it has been sug-
gested that novelty and familiarity are two sides of
the same coin since something novel cannot be
judged as familiar; this could be interpreted as
opposing signals that compete for the behavioral
outcome. However, evidence indicates that novel
and familiar stimuli induce the activation of sev-
eral brain regions in a graded manner (Kafkas and
Montaldi, 2014). Concerning neurotransmission,
novelty promotes an elevation in acetylcholine,
dopamine, and noradrenaline that gradually
diminishes after the consecutive exposure to the
stimulus (Miranda et al., 2000; Osorio-Gómez
et al., 2016, 2017; Rodríguez-García and Miranda,
2016). Thus, novelty elicits a maximum response,
but a progressive response reduction accompanies
the following presentations. This neurotransmitter
modulation promotes the transition from novelty
to familiarity (Kafkas and Montaldi, 2018; see
Figure 9.3).
After learning, information is stabilized into
LTM through protein synthesis. New proteins
promote changes in the structure and physiology
of synaptic connections that strengthen memory
over time (McGaugh, 2000, 2013). Nevertheless,
consolidated memories can undergo a reconsoli-
dation process11 (Nader et al., 2000) where memo-
ries are destabilized and restabilized after memory
retrieval (Lee et al., 2017; Rodriguez-Ortiz and
Bermúdez-Rattoni, 2017; Sara, 2000). Memories
require updating to incorporate relevant and recent
information about the environment into the previ-
ously integrated memory. Memory retrieval trig-
gers a period of lability where new information
is incorporated, inducing memory updating. The
evidence suggests that reconsolidation only initi-
ates after new information arrives and cannot be
induced without it (Garcia-Delatorre et al., 2014;
Lee, 2008; Lee et al., 2017; Rodriguez-Ortiz
and Bermúdez-Rattoni, 2017; Rodriguez-Ortiz
et al., 2005, 2008; Sevenster et al., 2014; Winters
et al., 2009). Therefore, the transition from nov-
elty to familiarity in recognition memory could
be explained as progressive information updating
through reconsolidating processes until complete
familiarization is accomplished.
It has been documented that recognition memory
undergoes reconsolidation (Balderas et al., 2015;
Kelly et al., 2003; Kwapis et al., 2020; Rodriguez-
Ortiz et al., 2005; Santoyo-Zedillo et al., 2014).
Thus, in taste recognition memory, each time a
taste stimulus is presented to the organism during
retrieval, memory is destabilized, and new infor-
mation (familiarity) is integrated into the memory
trace. The inhibition of protein synthesis after the
first sessions of attenuation of neophobia impairs
taste memory reconsolidation, and the familiar
taste is recognized as a novel again. Nevertheless,
when the stimulus has become very familiar, the
inhibition of protein synthesis spares taste rec-
ognition memory (Rodriguez-Ortiz et al., 2005).
 NEUROTRANSMISSION AND NEUROMODULATION OF RECOGNITION MEMORY
Novel
Memory updating
Unstable
memory
Novel
Familiar
Stable
memory
information
n
n
io
io
at
at
New
lid
lid
so
so
on
on
ec
C
Novel
Novel
Familiar
Figure 9.3 The transition from novelty to familiarity. Novelty promotes learning and memory
consolidation. Memory is destabilized and subsequently updated over reconsolidation when
new information is presented. The most significant amount of information is learned during
the first trials. Information updating during the last trials is diminished after the first sessions.
Interestingly, the blockade of muscarinic receptors
within the insular cortex before the second famil-
iarization session increases the neophobic response
and delays attenuation of neophobia (Gutiérrez
et al., 2003), suggesting that novelty-familiarity
updating is hindered. However, more studies are
required to elucidate the role of other neurotrans-
mitters in taste memory recognition updating.
Object recognition memory (Akirav and
Maroun, 2006; Balderas et al., 2013b, 2015;
Kelly et al., 2003; Rossato et al., 2007; Santoyo-
Zedillo et al., 2014) and object location memory
(Kwapis et al., 2020; Villain et al., 2016; Wright
et al., 2020) can also go through reconsolidation
processes. Inhibition of protein synthesis in the
perirhinal cortex in the hippocampus hinders the
information previously integrated when updating
with new information (Balderas et al., 2013b) or
the context (Winters et al., 2011) during the recon-
solidation process. Moreover, systemic blockade
of NMDA receptors impairs the reconsolidation
of NOR (Winters et al., 2009) depending on glu-
tamatergic activity. Conversely, after contextual
updating, the systemic administration of nicotine
enhances NOR reconsolidation when done imme-
diately after retrieval (Tian et al., 2015).
Like other memories, NOR updating could
occur in the absence of the behavioral outcome
during retrieval. Inactivation of the perirhinal cor-
tex during retrieval impairs behavioral response
141
Familiar
Novel Novel
Familiar
Familiar Familiar
information
n
information
io
io
at
at
New
lid
lid
New
so
so
on
on
ec
ec
R
Novel Novel
Familiar Familiar
since animals do not recognize the novel object.
However, during the next test session, animals can
discriminate a novel object from a familiar one,
indicating memory updating. Nevertheless, sup-
pose the inactivation of the perirhinal cortex is fol-
lowed by the administration of a protein synthesis
inhibitor during retrieval. In that case, animals do
not recognize the novel object during test sessions,
suggesting a failure in memory updating (Balderas
et al., 2013b, 2015). Similarly, the blockade of
AMPA receptors in the perirhinal cortex dis-
rupts memory expression during retrieval, while
the blockade of NMDA receptors impairs NOR
reconsolidation (Balderas et al., 2015; Santoyo-
Zedillo et al., 2014). Therefore, evidence suggests
that NOR reconsolidation occurs in the absence of
the behavioral output during retrieval when new
information is presented. NOR reconsolidation
requires NMDA receptor activation within the per-
irhinal cortex and subsequent protein synthesis.
The evidence related to catecholaminergic
activity during NOR reconsolidation is scarce. D1/
D5 receptors within the hippocampus are involved
in the destabilization process during reconsoli-
dation since the inactivation of D1/D5 receptors
impedes the amnesic effect of a protein synthesis
inhibitor (Rossato et al., 2015). However, more
data is necessary to comprehend the involvement
of dopamine and noradrenaline on the transition
of novelty to familiarity in recognition memory.
142 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
SUMMARY AND CONCLUSIONS
Learning and memory are critical cognitive pro-
cesses that enable organisms to store relevant
information obtained from the environment.
Learning and memory promote the acquisition,
storage and recall of data collected by sensory
organs. During these processes, information is
encoded and consolidated into LTM for subse-
quent use during retrieval. Memory is a dynamic
system in which stored information can be updated
after memory reactivation and reconsolidation
when new information is added. Importantly, the
consolidation, reconsolidation and updating pro-
cesses require complex interaction and modula-
tion between neurotransmitters, which promote
cellular and molecular mechanisms necessary for
morphological and physiological modifications
involved with information maintenance.
In this chapter, we have focused on one crucial
declarative memory – recognition memory – the
ability to discriminate or identify that something
has been previously experienced. Recognition
memory consists of two components: a collection
of contextual information, which makes the recol-
lection of the episode, where, and when the stimu-
lus was experienced, and the familiarity judgment,
which provides information on whether a stimulus
had prior exposure. Recognition memory requires
the functional integrity of the medial temporal
lobe’s brain structures such as the perirhinal, para-
hippocampal, entorhinal, insular cortices, and the
hippocampus. Recognition memory allows organ-
isms to remember specific characteristics (recol-
lection) and recognize the familiarity of an event.
Familiarity provides information on whether a
stimulus has been experienced previously with-
out the recollection component. The transition
from novelty to familiarity in recognition memory
might be explained as a piece of progressive infor-
mation updated through reconsolidation processes
until complete familiarization is accomplished.
Every time a new stimulus is presented to the
organism during retrieval, memory is destabilized
somewhat, and new information and familiar-
ity information is integrated into the updating
memory trace. Recognition memory depends on
cholinergic, glutamatergic, and dopaminergic sys-
tems that incorporate updated information into the
memory trace of “familiarity.”
Following the presentation of novel stimuli,
acetylcholine, noradrenaline, and dopamine
increase within multiple brain structures, includ-
ing the hippocampus and brain cortices (includ-
ing the perirhinal, entorhinal and insular cortices).
Acetylcholine encodes novelty and is also respon-
sible for triggering learning and consolidation
processes associated with recognition memory
formation, promoting the transition from novelty
to familiarity. Moreover, cholinergic signaling
is modulated by catecholamines and released by
the ventral tegmental area and locus coeruleus,
regulating the behavioral response associated with
novelty and also enhancing consolidation signals
that strengthen recognition. In addition, we have
discussed how the ventral tegmental area and the
locus coeruleus midbrain structures modulate nov-
elty detection and promote recognition memory
consolidation through their catecholaminergic
projections. As well, we have addressed gluta-
mate, GABA, and acetylcholine’s functional role
in acquiring, consolidating, updating, and retriev-
ing recognition memory. Also, we have discussed
the main findings relating to neurotransmission
as related to novelty signaling, neurochemistry
involved in the consolidation of recognition mem-
ory, and neurochemistry during memory updating.
Acknowledgments: We thank Gabriela Vera-
Rivera and Luis Rodriguez-Duran for technical
assistance, and we gratefully acknowledge Jessica
G. Norris for her generous help in proofread-
ing and editing the manuscript. DGAPA-PAPIIT
IN201420 and IN209122 to IM. Departamento de
Ciencias de la Salud to KG-R. DGAPA-PAPIIT
IN212919 and IN213123 to FBR, and DGAPA-
PAPIIT IA201420 and IA202922 to DOG.
Notes
1  Memory encoding: Attention-dependent stage
where information from sensory inputs is incor-
porated through mechanisms that preserve it.
2  Consolidation: Time-dependent process of sta-
bilization of synaptic connectivity in local circuits
and gradual reorganization of information at the
systems level.
3  Memory retrieval: Process by which internal and
external cues promote selection, reactivation and
assessment of a behavioral outcome.
4  Transduction: Conversion of a sensory stimulus
into an electrical impulse.
5  Ligand-gated channels: Integral membrane pro-
teins forming a pore allowing passage of ions
upon activation of a specific molecule.
6  Metabotropic receptors: Transmembrane proteins
that activate coupled G-proteins, initiating several
signaling cascades that modulate cell activity.
7  Novel object recognition: Behavioral essay that
relies on rodent’s innate exploratory behaviour
in the absence of externally applied rules or
reinforcement. In this task, animals discriminate
between a previously seen object and a novel
one.
 NEUROTRANSMISSION AND NEUROMODULATION OF RECOGNITION MEMORY
8  Object location memory: Hippocampus-­
ependent task where animals identify a familiar
object in a novel contextual distribution. It has three
components: (1) object processing, (2) spatial-loca-
tion processing, and (3) object to location binding.
9  6-Hydroxydopamine: A neurotoxin that leads to
catecholaminergic cell death.
10  In vivo microdialysis: Sampling and collecting
of small molecular weight substances from the
interstitial space. It allows the measurement of
neurotransmitters in neuronal extracellular fluid
in specific brain structures.
11  Reconsolidation: Stabilization process by which
active (or reactivated) memories are converted
into a lasting and stable long-term memory.
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Neurotransmission and
Neuromodulation of Memory:
Intensity and Valence
María-Isabel Miranda, Kioko Guzmán-Ramos,
Daniel Osorio-Gómez, and
Federico Bermúdez-Rattoni
INTRODUCTION
Learning is a fundamental function of survival
that induces behavior modifications. It requires
instructive brain circuits that trigger changes in
neural connectivity and adaptive changes in
behavior in response to environmental/internal
challenges. Numerous studies about aversive
associative learning have used different condition-
ing models to shed light on the neural mechanisms
of the aversive predictive and instructive signaling
required for learning and memory. Recently, it has
been proposed that the predictability of the aver-
sive experience tightly regulates parallel aversive
signaling in multiple circuits during behavioral
learning (Ozawa and Johansen, 2018).
Furthermore, during learning, neural circuits
transduce salient experiences (e.g., punishments,
aversive stimuli, motor errors, among others) into
instructive neural signals integrated into the
memory circuitries (Schultz, 2015). Therefore,
learning and recalling highly aversive or negative
experiences engages distributed brain networks.
This brain network activity is tuned by several
neurotransmitters, including acetylcholine (ACh),
glutamate, gamma-amino butyric acid (GABA),
dopamine (DA), and noradrenaline/norepineph-
rine (NA) (Hasselmo and Sarter, 2011; Hermans
10
et al., 2014; LeDoux, 2012; Luchicchi et al., 2014;
Picciotto et al., 2012).
CHOLINERGIC ACTIVITY
ACh activity has long been implicated in attend-
ing to and remembering emotional experiences.
The role of ACh signaling in the mnemonic pro-
cessing of highly salient events has been exten-
sively described (Dani and Bertrand, 2007;
Hasselmo and Sarter, 2011; Luchicchi et al., 2014;
Sarter et al., 2014; also see Chapter 13 this
volume). ACh release is related to different states
of arousal and associative conditioning (Acquas
et al., 1996; Miranda and Bermudez-Rattoni,
1999; Rasmusson and Szerb, 1976; Sarter and
Bruno, 1994). Accordingly, significant increments
of ACh release occur during appetitive condition-
ing,1 acquisition of discrimination performance2
(Butt, 1997), and operational tasks3 (Orsetti et al.,
1996), among other examples.
In both humans and experimental rodent
models, the amygdala and several cortical areas
receive a particularly significant cholinergic pro-
jection arising primarily from the nucleus basalis
magnocellularis (NBM) (Woolf, 1991). In this
152 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
regard, seminal findings indicate that M1 and M2
muscarinic receptor activation is necessary for
the modulation of memory consolidation induced
by cholinergic influences within the amygdala
(Power et al., 2003). Jiang et al. (2016) corrobo-
rated by optogenetics4 that endogenous choliner-
gic signaling modulates the excitability of putative
amygdala principal neurons via interaction with
both muscarinic and nicotinic ACh receptors
(Jiang et al., 2016). Thus, ACh modulates cortical–
amygdala synaptic plasticity and influences the
acquisition of fear-related behaviors (Jiang et al.,
2016). These results suggest that the NBM–­
cortical neuromodulatory pathway functions in
concert with ACh inputs to the basal amygdala,
which enhances the persistence of fear and aver-
sive memories, supporting the notion that ACh
modulation plays a crucial role in amygdala-based
learning (McGaugh et al., 2002).
Furthermore, cholinergic activity is required
for encoding spatial and aversive cues during
memory extinction5 or memory updating6 (Knox
and Keller, 2016), indicating that cholinergic basal
forebrain inputs also shape responses to aversive
cues, cue context, and extinguished cues. ACh
enhances cue detection across multiple regions
through inhibitory and excitatory currents that
amplify signal-to-noise ratios. In other words, dis-
tinct cholinergic inputs can convey salient infor-
mation to the amygdala and promote associative
biophysical changes that underlie emotional mem-
ories (Aitta-Aho et al., 2018; Pidoplichko et al.,
2013; Unal et al., 2015). Since aversive learning7
occurs during a heightened state of arousal, shift-
ing cortical sensory processing alters sensory-
perceptual thresholds and amplifies stimulus
generalization (Likhtik and Johansen, 2019b).
ACh intensifies cue encoding during increased
attention at cortical sensory sites that communi-
cate with the cortex and at cortical afferents to the
amygdala (Letzkus et al., 2011; Weinberger et al.,
2006), suggesting a cortical cholinergic impact
during aversive discrimination learning. However,
the role of ACh in memory cue/context discrimi-
nation requires further research. In summary,
associations during aversive experiences engage
distributed cholinergic activity. ACh intensifies
cue encoding during increased attention at corti-
cal sensory sites, enhancing the persistence of fear
and aversive memories.
NORADRENERGIC ACTIVITY
It is well known that aversive experiences produce
a surge of NA levels in the brain, including the
amygdala (Quirarte et al., 1998). This NA surge
promotes aversive associative learning and
memory through β-adrenergic receptor activation
(Uematsu et al., 2017). Evidence of β-adrenoceptors
located on vagal afferents to the nucleus of the
solitary tract (NTS) (Schreurs et al., 1986) sug-
gests that systemic epinephrine may modulate
neural processes through actions mediated by the
NTS. In this regard, epinephrine’s effects on
memory consolidation are initiated by peripheral
β-adrenoceptor activation (McInytire et al., 2006).
Extensive research suggests that the release
of peripheral adrenal hormones in response to a
stressor influences memory consolidation by acti-
vating central adrenoceptors (McGaugh, 2000).
NA activity and its interaction with circulating
corticosterone are required during memory con-
solidation (Roozendaal et al., 2006). Furthermore,
corticosteroids activate locus coeruleus (LC) pro-
jections to the amygdala, releasing noradrenaline
and enhancing anxiety (McCall et al., 2017). This
input may thus be specific to aversive learning. It
has also been demonstrated that pharmacological
stimulation of the NTS enhances aversive mem-
ory consolidation and NA levels in the amygdala
(Garcia-Medina and Miranda, 2013; Likhtik and
Johansen, 2019b).
Anatomical studies indicate that the pon-
tine tegmentum and NTS could activate the LC;
moreover, noradrenergic terminals from the LC
innervate the amygdala (Robertson et al., 2013;
Uematsu et al., 2017; Usunoff et al., 2006). These
findings corroborate a linear contribution of the
NTS–LC–amygdala NA pathway in aversive
learning. In general, NA enhances excitatory sign-
aling and neuronal plasticity,8 modulating aversive
memory acquisition and consolidation mecha-
nisms (Garcia-Medina et al., 2015; McIntyre
et al., 2003). Considerable evidence also indicates
that amygdala activation influences memory by
regulating consolidation in other brain regions;
thus, projections from the NTS to the amygdala
are critically involved in mediating adrenergic
influences on memory consolidation (Clayton and
Williams, 2000; Miyashita and Williams, 2002;
Williams et al., 1998). Interestingly, LC projec-
tion neurons participate in memory processes in
different brain areas. For example, LC neurons
enhance sensory cue responsiveness following
fear conditioning (Rasmussen and Jacobs, 1986)
since significant increases in NA are evident in the
amygdala after fear conditioning (Quirarte et al.,
1998). Additionally, pharmacological findings
demonstrated that endogenous NA released in the
amygdala during aversive and emotional arousal
training improves memory consolidation (Ellis
and Kesner, 1983; Hatfield and McGaugh, 1999;
Liang et al., 1986, 1990).
 NEUROTRANSMISSION AND NEUROMODULATION OF MEMORY
According to recent studies, the LC projects
strongly to the hippocampus, where it can release
both NA and DA, which are essential for contex-
tual and spatial forms of learning (Heath et al.,
2015; Takeuchi et al., 2016). As mentioned in
Chapter 13, presentation of relevant stimuli elicits
NA release from the LC (Robertson et al., 2013),
within the insular cortex (IC) (Guzman-Ramos
et al., 2010; Osorio-Gomez et al., 2021). This NA
activity could be associated with anxiety-related
responses (Galvez et al., 1996; Quirarte et al.,
1998). As reviewed, anatomical studies indicate
that NA neurons innervate several brain regions
from the LC, which in turn could be activated by
the pontine tegmentum and the NTS. Interestingly,
systemic epinephrine might modulate memory
consolidation by NTS activation. Epinephrine
exerts its effects on memory consolidation upon
peripheral β-adrenoceptor activation followed by
NTS stimulation. Furthermore, epinephrine pro-
motes an increase in NA in brain regions includ-
ing the amygdala, the hippocampus, and the IC,
enhancing aversive memory consolidation. These
data confirm the peripheral influence of epi-
nephrine on memory consolidation through the
activation of central NA activity. Therefore, stress-
induced activation of the NA system is pivotal in
enhancing memory consolidation.
It has been suggested that LC modulates rhyth-
mic activity, promoting neural coding involved in
cognitive processes (Swift et al., 2018; Walling
et al., 2011). This modulation could explain, at
least in part, the distributed oscillatory coupling
between LC, amygdala, and hippocampus dur-
ing emotional/aversive discrimination learning.
Further, the rhythmic activity modulated by NA
has been linked to sleep dysregulation in post-
traumatic stress disorder (PTSD), which affects
emotional memory (Hendrickson and Raskind,
2016). Additional studies are needed to under-
stand the relationship between sleep modulation
and aversive memory formation.
DOPAMINERGIC ACTIVITY
Different populations of dopaminergic neurons
project to individual target sites (Likhtik and
Johansen, 2019b). For instance, dopamine (DA)
neuron populations in the ventral tegmental area
(VTA) project to the medial prefrontal cortex
(mPFC), striatum and amygdala (Oades and
Halliday, 1987). Some of these neurons integrate
reward prediction error,9 responding primordi-
ally to unexpected rewards as an instructive
signal for appetitive learning (Keiflin and Janak,
153
2015; Watabe-Uchida et al., 2017). However,
some DA neurons in the VTA respond to aversive
stimuli or when encoding negative reinforcer
saliency for aversive outcomes (de Jong et al.,
2019; Matsumoto and Hikosaka, 2009; Menegas
et al., 2018).
These findings suggest that midbrain DA
regulates fear learning through projections to the
amygdala. The amygdala receives DA projections
from the VTA, increasing DA release during emo-
tional memories (Stevenson and Gratton, 2003).
Therefore, DA can regulate aversive learning
function by modulating the local synaptic, cellu-
lar, and microcircuit mechanisms of the amygdala.
In addition, during emotional/aversive learning,
complex neurotransmission interaction is apparent
because the amygdala sends a direct glutamater-
gic projection to the nucleus accumbens (NAc)
(Ricardo and Koh, 1978). Moreover, amygdala
modulation induces a long-lasting increase in DA
efflux in the NAc, a brain structure that regulates
both appetitive and aversively motivated behav-
iors. These behaviors modulate cortical ACh activ-
ity (Howland et al., 2002; Louilot et al., 1985) by
the activation of DA receptor activity in the NAc
(Moore et al., 1999). Besides, during emotional/
aversive learning, complex neurotransmission
system interaction is evident given that the amyg-
dala contributes to nociceptive sensory informa-
tion by processing negative emotional value, thus
supporting the association between an aversive
response and the environment in which it occurs
(Ansah et al., 2010; Gao et al., 2007; Kissiwaa
and Bagley, 2018; Tanimoto et al., 2003). The
amygdala sends a direct glutamatergic projection
to the NAc (Ricardo and Koh, 1978), which sug-
gests that amygdala–NAc interactions may lead
to changes in dopaminergic and glutamatergic
activity related to emotional component process-
ing during aversive memory formation (Howland
et al., 2002; Ramirez-Lugo et al., 2006; Stevenson
and Gratton, 2003, Yamamoto, 2006).
Furthermore, it seems that independent dopa-
minergic populations of VTA inputs to the mPFC
regulate aversive learning (de Jong et al., 2019;
Lammel et al., 2012; Likhtik and Johansen, 2019a;
Stubbendorff et al., 2019). Similarly, another set
of dopaminergic neurons respond to unexpected
aversive events and the cues that predict them.
These VTA DA neurons participate in aversive
processes including those projecting to the ventro-
medial shell of the NAc, substantia nigra and stria-
tum (de Jong et al., 2019; Menegas et al., 2018).
As mentioned, recent work suggests that the LC
releases DA in the hippocampus to modulate some
forms of contextual learning since VTA projec-
tions to the hippocampus are sparse (Broussard
et al., 2016; Takeuchi et al., 2016).
154 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
DA is involved in reward prediction error, unex-
pected rewards, and instructive signals for appeti-
tive memory formation, as well as in processing
negative emotional value and nociceptive sensory
information. Thus, DA contributes to the associa-
tion between an aversive response and the envi-
ronment in which it occurs. It should also be noted
that amygdala and NAc interactions may lead to
changes in dopaminergic and glutamatergic activ-
ity related to emotional/aversive processing during
memory formation.
GLUTAMATERGIC ACTIVITY
Nociception10 in all species is an essential defense
against dangers in the environment. Accordingly,
the experience of pain consists of somatosensory
elements of intensity and location, negative emo-
tional/aversive “feelings,” and subsequent nega-
tive behavior because of a learned association
between specific events and pain (i.e., association
of aversive and nociceptive components). This
associative learning integrates polymodal sensory
information and nociceptive information
(Mareket al., 2013; Moga et al., 1995; Neugebauer,
2015; Pape and Pare, 2010; Sah et al., 2003;
Vertes and Hoover, 2008).
Evidence indicates that the central amygdala
promotes aversive association. It receives noci-
ceptive information via the spino-parabrachial-
amygdaloid pathway and polymodal sensory
information via cortical and thalamic inputs
(Bernard et al., 1992, 1993; Bester et al., 1997).
Nevertheless, the final amygdala circuitry could
be required for pain-induced associative learn-
ing (Han et al., 2015; Sato et al., 2015; Watabe
et al., 2013). Both nociceptive stimulus and previ-
ously repeated subthreshold stimuli trigger gluta-
mate release from the parabrachial terminals. In
addition, nociceptive amygdala neurons increase
responsiveness, enhancing the aversive response
and the association between nociception and con-
text (Baliki et al., 2006; Bornhovd et al., 2002;
Cardinal et al., 2002; LeDoux, 2000)
The mechanism of nociception association is
not well described; however, some studies suggest
that it may be related to an increase in postsynap-
tic AMPA receptors (Cheng et al., 2011) that could
induce plasticity reeling upon the synthesis of new
proteins. These postsynaptic changes are similar
to those observed during stress when corticoster-
one produces an increment of AMPA receptors
(Groc et al., 2008; Martin et al., 2009). However,
it is still unclear whether additional neurochemical
changes in the amygdala participate in nociceptive
stimuli associated with the environment. Evidence
indicates that the anterior cingulate cortex pro-
jection to the amygdala is involved in descend-
ing pain modulation (Fuchs et al., 2014) and the
cognitive-affective component of pain (Johansen
et al., 2001).
As we will describe, the IC plays a crucial role
in the processing of interoceptive information such
as noxious stimulation intensity. Interestingly,
using conditioned taste aversion11 as an aversively
motivated learning model, studies have dem-
onstrated that novel taste stimuli fail to induce
changes in glutamate levels. However, glutamate
release is observed in the IC and amygdala with
gastric malaise induction (i.e., LiCl but not NaCl)
(Guzman-Ramos et al., 2010, 2012; Miranda et al.,
2002). Conversely, NaCl and LiCl administration
elicits cortical NA release (Guzman-Ramos et al.,
2010; Osorio-Gomez et al., 2017). However, in
experiments modifying the LiCl and NaCl concen-
trations, researchers observed that the changes in
NA release were related to the intensity of the peri-
toneal irritation. In contrast, glutamate was related
to the gastric irritation induced by LiCl regardless
of its concentration. Therefore, these results sug-
gest that glutamate could be associated with the
processing of gastric malaise by gastric irritation,
and NA could be related to the signaling of the
noxious salt intensity (Osorio-Gomez et al., 2017).
PEPTIDES AND ENDOCANNABINOID
SYSTEMS
Regarding pain modulation and learning, a recent
study suggests that the endocannabinoid system in
the mPFC plays a key role in mediating the
expression of fear-conditioned analgesia and con-
ditioned fear in the presence of nociceptive tone
(Rea et al., 2019). The results of that study are
consistent with evidence that cannabinoid (CB1)
receptors are essential in mediating the expression
of endogenous analgesia (e.g., delineating the
array of actions that the central nervous system
can use to reduce or, at times, augment pain) to
unconditioned aversive stimuli (Freitas et al.,
2013). However, the potential function of the can-
nabinoid system during the association of aversive
and nociceptive components has not been com-
pletely elucidated.
The endogenous opioid system is involved in
fear learning in rodents. It has been suggested that
an opioidergic transmitter signal, engaged through
conditioning, acts inhibitory on unconditioned
stimulus input (Eippert et al., 2008). Blockade of
endogenous opioid neurotransmission enhances
 NEUROTRANSMISSION AND NEUROMODULATION OF MEMORY
the acquisition of conditioned fear in humans
(Eippert et al., 2008). Opioid receptors and pep-
tides are expressed to varying degrees throughout
the amygdala (Poulin et al., 2008). Therefore, opi-
oidergic neurotransmission impacts not only on
aversive stimulus processing (Calcagnetti et al.,
1987; Fanselow et al., 1988) but also on appe-
titive conditioned associations (e.g., acquisition)
(Davis, 1979; McNally et al., 2004; Westbrook
et al., 1991; Young and Fanselow, 1992). Based
on neurophysiological simulations, Padlubnaya
and coworkers (2006) suggested that opioids can-
not exert their function alone, but need to work in
concert with a faster-acting inhibitory neurotrans-
mitter such as GABA (Padlubnaya et al., 2006).
Moreover, human studies suggest that the endog-
enous opioid system has an inhibitory role in fear
acquisition and is differentially involved in aver-
sive learning. The effect of endogenous opioids
may attenuate aversive/nociceptive impact via
conditioned hypoalgesia. They might also directly
regulate prediction errors during aversive learning
(e.g., conditioned fear) (Eippert et al., 2008). So
far, we can conclude that the opioidergic transmit-
ter signal could act as an inhibitory input of the
unconditioned stimulus. Thus, the blockade of
endogenous opioid neurotransmission enhances
the acquisition of conditioned fear memory.
VALENCE ASSOCIATION OF REWARDING
HEDONIC COMPONENTS: EMOTIONAL
BALANCE
The motivation to pursue happiness or pleasure
impacts greatly on our daily life behaviors.
Integral hedonic capacity requires undisturbed
interplay between several brain regions and neuro-
transmitter systems, including those underlying
associative learning (Hoflich et al., 2019). It
should be noted that there is growing evidence on
the difference between understanding “pleasure”
in humans and the hedonic response in animals
during rewarding events (Berridge and
Kringelbach, 2008). However, reward, hedonic
response, and pleasure are complex terms that
involve various subcomponents such as incentive,
motivation, and learning processing to obtain/
perceive wellness in response to a stimulus or
event and subsequently to remember it.
Accordingly, reward processing is a multi-step
phenomenon initiated by forming an association
between a given stimulus and a related reward.
After learning, it is followed by the development
or increase of attention, motivation and/or
155
anticipation, and defined by some as a “state of
readiness for a reward.” Moreover, during feed-
back based on rewards and learning, a proper
sequence of events is required for balanced inte-
gration between the expected value of a given
stimulus and the predicted effort to obtain a
reward, thereby emitting an adequate motivation
to initiate goal-directed behavior. The consumma-
tory phase of reward processing occurs when the
goal is achieved, leading to the hedonic response
(Kring and Barch, 2014; Rizvi et al., 2016).
SYSTEMS THAT REGULATE REWARD
Several systems that regulate reward and affective
processing also interact during associative learn-
ing and memory retrieval. Nevertheless, signifi-
cantly less is known about the role of reward and
hedonic processing in learning and memory.
Manipulation of numerous neurotransmitter path-
ways can simultaneously impact food intake and
reward. The main systems controlling homeostatic
and hedonic feeding are often treated as independ-
ent because homeostatic feeding is necessary for
basic metabolic processes and survival. In com-
parison, hedonic feeding is driven by sensory
perception or pleasure/hedonic stimulation.
Nonetheless, functional and anatomical aspects
of homeostatic and hedonic feeding overlap,
which indicates a significant interaction that has
been greatly overlooked in learning research. Non-
human animal research points to opioid modula-
tion of cognitive and decision-making processes
related to hedonic components. This emerging
evidence provides insight into how acute modula-
tion of opioids can influence cognitive function.
Opioid receptors are distributed throughout the
brain, including the more “cognitive” regions in
the frontal and parietal lobes (van Steenbergen
et al., 2019). Reports also highlight the impor-
tance of the opioid system in regulating not just
aversive experiences but also motivation and the
sense of hedonic impact (e.g., “liking”12) (Baldo,
2016; Pecina and Smith, 2010). In this regard, sev-
eral neural circuits thought to orchestrate feeding
behavior overlap with the reward circuitry (Rossi
and Stuber, 2018).
AVERSIVE LEARNING TASKS
In the presence of aversive stimuli, blocking
opioid signaling can enhance conditioned
156 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 10.1 A hypothetical scheme summarizes the interactions in a cortical synapse, where
stimuli with different valence and intensity can be integrated during memory formation and/
or complex retrieval associations.
responses in relation to learning tasks (Eippert
et al., 2008; Haaker et al., 2017). Reports agree
with the idea that opioid peptide neurotransmis-
sion causes a shift in the valuation of “hedonic
gradient,” ranging from displeasure to pleasure,
which is not limited to the liking of stimuli. For
example, micro-stimulation with opioid peptides
has been shown to increase motivation for differ-
ent reward types in rodents (Mahler and Berridge,
2012; Wassum et al., 2009). However, Laurent
et al. (2015) also show opioid modulation of
learning regardless of “liking” responses, suggest-
ing a dual role of this peptidergic system during
associative learning and hedonic integration
(Laurent et al., 2015). Overall, these findings
partly explain that learning and motivation typi-
cally increase together with reward valuation
(Berridge et al., 2009).
REWARD LEARNING TASKS
In rodents, reward learning can be modulated by
opioid receptor manipulation in several brain
regions related to memory processing like the stria-
tum and amygdala, among others (Berridge and
Kringelbach, 2015; Wassum et al., 2009a,b, 2011).
Furthermore, “hedonic spots” involved in sweet
taste “liking” responses also have been described
in the rat insula and prefrontal cortices (Castro
and Berridge, 2017). In this regard, rodent research
has argued convincingly for opioid involvement in
choice behaviors beyond the regulation of rein-
forcement and aversion (Laurent et al., 2015).
However, the role of opioid in associative hedonic
component processes and emotional memory
retrieval has not been clarified.
Several reports have suggested that the opioid
system profoundly affects reward-based decisions
by altering motivational processing and learning
(Jacobson et al., 2018). Thus, it is conceivable
that the opioid system regulates aversive arousal
(e.g., during aversive associations), influencing
cognitive control that tunes goal-directed behav-
ior (Dreisbach and Fischer, 2015; Valentino and
Van Bockstaele, 2015; van Steenbergen et al.,
2019). Evidence indicates that the endogenous
opioid system is involved in value-based decision-­
making, since blocking opioid receptors may
reduce motivational value when learning about
high-value stimuli (Berridge and Kringelbach,
2015; Eikemo et al., 2017; Laurent et al., 2015;
Lutz and Kieffer, 2013; van Steenbergen et al.,
2019; Weber et al., 2016).
Opioid activation and inhibition also affect
other neurotransmitter systems important for
 NEUROTRANSMISSION AND NEUROMODULATION OF MEMORY
cognition, such as DA and NA (Chaijale et al.,
2013; Fields and Margolis, 2015; Valentino and
Van Bockstaele, 2015). These systems are the
core of reward learning circuits and code reward
prediction error (Tian et al., 2016). Nonetheless,
mesolimbic and neostriatal DA systems do not
mediate the hedonic impact of rewarding stimuli
or hedonic reward learning and associative pre-
diction (Berridge and Robinson, 1998; Schultz,
2006). Conversely, the DA system may mediate
the incentive salience13 of rewards by modulating
their motivational value separately from hedonic
and reward learning.
According to recent studies, DA is neither nec-
essary nor sufficient to mediate changes in hedonic
“liking” for sensory “pleasures” (Berridge, 2000;
Pecina and Berridge, 2005). Further, DA is not
needed for new learning and is insufficient to
mediate learning by directly causing teaching or
prediction signals. By contrast, growing evidence
indicates that DA contributes causally to incen-
tive salience (Koob and Volkow, 2016; Lynch and
Ryan, 2020). Regardless, the debate continues
over the precise causal contribution of mesolim-
bic DA systems to reward (Berridge, 2007; Lin
et al., 2021). In this regard, the term “reward”
and its interpretation have various connotations
that are mainly linked to hedonic value, reward
motivation, learning and extinction processes, and
anticipation or expectation of rewarding stimuli
(Barbano and Cador, 2007; Salamone et al., 2007;
Schneider et al., 2010). These connotations make
it even more challenging to understand the neu-
rochemical processes involved in the complex
association of hedonic “pleasurable” components
during learning.
HEDONIC AND/OR REWARD PROCESSING
The endocannabinoid system has recently
emerged as another critical mediator for hedonic
and/or reward processing (Elphick, 2012). It is
well known that cannabinoid signaling has a regu-
latory influence over several neurotransmitter
systems that mediate reward-related behaviors
(e.g., DA, glutamate, and endogenous opioids).
Apparent involvement of cannabinoid signaling in
learning processes, neuroplasticity, motivational
behavior (e.g., operant conditioning), and reward
“wanting”14 has been reported (Ameri, 1999;
Fattore et al., 2010; Solinas et al., 2008). However,
just recently, studies have suggested that the
endocannabinoid system is central in hedonic
aspects of emotionally related learned behaviors,
specifically for the mediation of hedonic
157
component processing (Cota et al., 2006; Friemel
et al., 2014; Jarrett et al., 2007; Kirkham, 2009;
Mahler et al., 2007; Solinas et al., 2008), probably
by close interaction with the endogenous opioid
system (Cota et al., 2006). Detailed information
about neurocircuits and mechanisms involved in
the mediation of pleasure during learning is cru-
cial to gain a better a better understanding of
hedonic processing during emotional behaviors
(Berridge and Kringelbach, 2008; Esch and
Stefano, 2004; Kringelbach and Berridge, 2009).
Future research will help to elucidate the emo-
tional modulation that occurs during the associa-
tion of delightful experiences.
The systems that regulate reward and affective
processing interact during associative learning and
memory retrieval. Thus, current evidence indicates
that the endogenous opioid system is implicated
in determining the motivational value of stimuli
during learning. In contrast, the DA system may
mediate the incentive salience of rewards, modu-
lating their motivational value in a manner separa-
ble from hedonic and reward learning.
CONTEXT COMPLEXITY: EXTEROCEPTIVE
AND INTEROCEPTIVE MEMORY
MODULATION
According to recent studies, contextual changes
could significantly affect learning, retrieval and
memory updating (see Chapter 13 this volume),
suggesting a more complex scenario in any moti-
vational task during stimulus associations that
include opposite or different valences (e.g., a posi-
tive/appetitive or negative/aversive context).
Indeed, everyday learning entails a series of
changes in the context, temporality of experiences
and type of stimuli to be associated. In this regard,
interference paradigms15 in which stimuli are
associated with different stages of learning and
retrieval can modulate and update the strength of
memory performance at any point in the learning
process associated with contextual cues. For
example, testing memory in the same context in
which the memory was encoded leads to improved
retention relative to testing memory in a new con-
text (Bouton, 2019). Accordingly, context seems
to play a significant role in interference paradigms
such as memory extinction, countercondition-
ing16, discrimination reversal,17 and latent inhibi-
tion18 (Pearce, 1994; Pearce and Hall, 1980;
Wagner, 2003).
Context refers to the immediate environment
in which a memory is encoded (Roberts, 2019).
158 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Therefore, context is commonly defined as the set
of background stimuli that comprise the environ-
ment during a behavior. Similar stimuli can also
become foreground conditioned stimuli, depend-
ing on the task (De la Casa et al., 2018; Nadel and
Willner, 1980). Nevertheless, a suitable general
conceptualization of context should include vari-
ous exteroceptive and interoceptive stimuli that
are thought to be available in the environment and
play a key role. Theoretical approaches to inter-
ference have emphasized the possible influence of
many kinds of contextual stimuli (Bouton, 1993,
2019) that suggest the importance of context dur-
ing learning and memory.
EXTEROCEPTIVE INFLUENCES ON
CONTEXT
Standard exteroceptive context includes the room
and apparatus used during Pavlovian fear learn-
ing and context switching in different phases,
including extinction (Baldi and Bucherelli,
2015). As indicated above, the basal forebrain
cholinergic system provides dense neuromodula-
tory inputs to the basolateral amygdala complex,
targeting pyramidal neurons and interneurons in
this area (Lee and Kim, 2019; Muller et al.,
2011). The basolateral amygdala complex is
implicated in numerous cognitive functions, such
as associative context learning and extinction
processes. Particularly, cholinergic regulation
has been demonstrated in various studies using
systemic and region-specific pharmacological
manipulations during associative fear learning
and extinction paradigms (Gold, 2003; Gould
and Leach, 2014; Knox, 2016; Power et al., 2003;
Robinson et al., 2011; Tinsley et al., 2004;
Wilson and Fadel, 2017).
Some plastic mechanisms underlying the origi-
nal learning of the contextual or cue-conditioned
response suggest that extinction learning involves
disparate neuronal populations and signaling pro-
cesses specifically within prefrontal-amygdala
circuits (Baldi and Bucherelli, 2015; Herry et al.,
2008; Orsini and Maren, 2012; Rozeske et al.,
2015; Tronson et al., 2009). Studies on the optoge-
netic stimulation of cholinergic inputs and both
muscarinic and nicotinic cholinergic receptors
demonstrate that these circuits exert a significant
influence on cued fear extinction (Aitta-Aho et al.,
2018; Jiang et al., 2016; Unal et al, 2015).
Moreover, during acquisition, cholinergic
stimulation in the amygdala disrupts the extinc-
tion, but not the acquisition, of cued fear memo-
ries (Jiang et al., 2016). On the other hand, robust
behavioral evidence demonstrates that the hip-
pocampus and glutamatergic activity are crucial
for context-based memory (Kim and Fanselow,
1992). However, few studies have explored their
involvement in context complexity. In this regard,
some reports have indicated a role for hippocam-
pal function in the complex taste learning pro-
cess, such as blocking (Gallo and Cándido, 1995;
Moron et al., 2002), and in taste learning tasks
that critically depend on contextual information
(Gallo et al., 1999). The dorsal hippocampus has
been implicated in both learned taste aversions
to the physical context and the blocking of the
context in taste aversion learning (Aguado et al.,
1998) and extinction (Garcia-de la Torre et al.,
2010). Furthermore, dorsal hippocampal integ-
rity is required during the context dependency of
taste aversions and latent inhibition of taste aver-
sion (Baldi and Bucherelli, 2015; Manrique et al.,
2009a,b; Molero et al., 2005). DA activity has also
been reported in the consolidation of contextual
memories in the hippocampus. These reports sug-
gest that DA activity is modulatory in response
to environmental novelty within the hippocampal
neurons responsible for initial consolidation and
shifts after environmental novelty, when reward
expectancy or magnitude also changes.
In reward expectancy,19 DA is required for
executing learned actions until they become habit-
ual in a similar context (Kempadoo et al., 2016;
Takeuchi et al., 2016; Yamasaki and Takeuchi,
2017). Moreover, systemic administration of the
DA receptor antagonist disrupts context-­dependent
attenuation of taste neophobia (De la Casa and
Diaz, 2013; Grau-Perales et al., 2019). Despite this
evidence, the neurotransmission systems involved
in these processes have not been clearly described.
Various studies suggest that the histaminergic
system could play a significant role in regulating
contextual learning. Histamine, as a neurotrans-
mitter, is synthesized by neurons in the tubero-
mammillary nucleus and projects to the whole
brain. H1 and H2 potentiate excitatory inputs of
the four histamine receptors, while H3 receptors
down-regulate histamine synthesis and release
other neurotransmitters (Haas and Panula, 2003;
Panula et al., 1989). Histamine-induced cholin-
ergic, GABAergic and glutamatergic release, for
example, modulates several structures including
the supramammillary nucleus, NBM, diagonal
band nuclei, cerebral cortex, amygdala, and hip-
pocampus (Bacciottini et al., 2002; Baldo, 2016;
Inagaki et al., 1988; Panula et al., 1989). Thus, his-
tamine controls fundamental aspects of learning,
ranging from the sleep-wake cycle to nociception
(Passani et al., 2007). Histamine also modulates
hippocampal activity during aversive memory
processing (Brown et al., 2001). In this regard,
 NEUROTRANSMISSION AND NEUROMODULATION OF MEMORY
hippocampal histamine receptors are involved
in fear memory consolidation (Da Silva et al.,
2006; Zarrindast et al. 2002). In addition, increas-
ing ACh release in the BLA using histaminergic
agonists improves the expression of fear memo-
ries (Cangioli et al., 2002). Evidence corroborates
that intra-BLA administration of H3 antagonists
reduces both the freezing time of contextual fear-
conditioned rats and local ACh release (Passani
et al., 2001). Furthermore, histamine decreases
cortical ACh release, which has a differential
impact on taste aversive memory formation and
extinction. For example, an H3 agonist released
into the IC impaired conditioned taste aversive
memory and simultaneously decreased the local
release of ACh (Puron-Sierra and Miranda, 2014).
Conversely, CA1 infusion of the H2 receptor ago-
nist dimaprit facilitated the extinction of step-
down inhibitory avoidance (Bonini et al., 2011),
sustaining the hypothesis that histaminergic activ-
ity is required during context memory extinction.
Recent data illustrates that the central histamin-
ergic system is a necessary intermediary modula-
tor for arranging peripheral homeostatic signals
during emotionally salient cognitive processes.
It exerts its actions through the recruitment of
emotional cortico-amygdala circuits to generate
adequate behavioral responses (Provensi et al.,
2017). Accordingly, the cortico-amygdala circuit
is essential for appetitive behavior related to feed-
ing (Valdés et al., 2010) and other goal-directed
behaviors, like sexual behavior, drug seeking or
drinking (Contreras et al., 2016). Altogether, sev-
eral studies suggest that histaminergic neurons
detect aversive and rewarding signals in various
emotionally arousing contexts and relevant stimuli
that could help to regulate their impact on moti-
vated memory consolidation (Miklos and Kovacs,
2003; Passani et al., 2007; Taylor and Snyder,
1971; Torrealba et al., 2012). More studies are
needed to show that the effects of histaminergic
activity may depend on interactions with brain
structures that modulate the expression of learned
behavior in complex contexts and its mediation
with interoceptive signaling (Provens et al., 2020).
INTEROCEPTIVE INFLUENCES ON
CONTEXT
Interoception is defined as “a process by which
the nervous system senses, interprets, and inte-
grates signals originating from within the body,
providing a moment-by-moment mapping of the
body’s internal landscape across conscious and
unconscious levels” (Khalsa et al., 2018).
159
Accordingly, Schepers and Bouton (2017)
reported that interoceptive states produced by
hunger and satiety could control memory extinc-
tion. They observed that the renewed response in
the context of satiety went against traditional
notions about how behavior is motivated by
hunger and satiety. Since the hunger response was
extinguished during several sessions, the partici-
pants, which were evaluated individually in both
satiety and hunger states, exhibited a renewed
response when retrieval was tested in satiety
(Schepers and Bouton, 2017).
Furthermore, hunger and satiety states can pro-
vide discriminative cues for Pavlovian-conditioned
responses20 (Davidson, 1993; Davidson et al., 2005;
Kanoski et al., 2007; Sample et al., 2016). Similarly,
interoceptive cues provided by drug states could
modify extinction performance (Bouton et al.,
1990; Cunningham, 1979; Lattal, 2007). These
findings indicate that associative learning involving
interoceptive stimuli could induce physiological,
emotional, and perceptual changes during retrieval
and memory updating (Van Diest, 2019).
The IC has been implicated in a wide range of
conditions and behaviors. It seems that this cor-
tex translates and integrates external cues into
interoceptive states that regulate physiological
and cognitive processes (Craig and Craig, 2009).
Consequently, the IC functions as an integrative
hub due to the vast reciprocal connections that
exist between it and an extensive network of cor-
tical and subcortical structures (Benarroch, 2019;
Craig and Craig, 2009; Nguyen et al., 2016; Saper,
1982). As the IC area is responsible for the intero-
ceptive processing of multisensory information,
this region could be required for the processing
of internal states involved in memory formation
(Gu et al., 2013). The established role of the IC in
the processing of pain (Lu et al., 2016; Starr et al.,
2009) and negative affective states like anxiety
(Paulus and Stein, 2006) supports this hypothesis.
Moreover, the IC is also a necessary compo-
nent in reward and aversion learning (Bermúdez-
Rattoni et al., 2004; Casanova Castillo et al., 2016;
Guzman-Ramos et al., 2012; Toyoda, 2019; Sun
et al., 2020). It has been implicated in the media-
tion of several processes related to craving and
drug seeking (Contreras et al., 2007; Moschak
et al., 2018; Naqvi and Bechara, 2009). Several
findings present a potential mechanism whereby
upregulation of the IC by opioid signaling can lead
to altered subcortical function and downstream
activity (Pina et al., 2020). Also, recent data indi-
cate that combined effects of endocannabinoid
signaling can modulate long-term plasticity at
GABAergic synapses in the IC. This GABAergic
synaptic plasticity may be a crucial synaptic
mechanism in memory formation (Toyoda, 2020).
160 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
SUMMARY AND CONCLUSIONS
Identifying a stimulus with punishment or reward
is vital for survival throughout life. This associa-
tive process ultimately drives targeted actions to
prevent danger, such as avoidance behaviors or
appetitive responses essential for survival.
Consequently, the previous association of stimuli
alters future learning, allowing rapid response and
crucial adaptation to different situations. Several
studies indicate that the integration of nociceptive
stimuli requires a complex interaction of neuro-
transmission in brain areas related to the sensory-
discriminative components of pain and those that
contribute to the behavior associated with affec-
tive responses. In this chapter, we have discussed
the role of different neurotransmitters in several
brain areas which are crucial for cognitive func-
tions related to maintaining a balance between
reward and aversive learning.
Recent evidence shows that contextual changes
could affect learning, retrieval, and updating of
memory, suggesting a more complex scenario
during stimuli associations, including opposite
or different valences, relating to any motivational
task. Current knowledge points to the critical role
of integrating hubs, like the insular cortex, to
translate external signals into interoceptive states
that elicit complex physiological, affective, and
behavioral responses. This chapter has provided
an overview of some of the most important neu-
rotransmitter interactions that mediate aversive
and appetitive association in different brain areas.
Particularly important are those areas that play an
essential role during the formation of association
that require mediation of the affective/aversive
emotional balance according to their complexity,
resulting in the immense variation of valence and
intensity of memory.
In addition, these findings support the hypoth-
esis that the IC is an integrative hub combining
the opioid and cannabinoid systems during the
integration of associations of complex contexts.
Thus, the IC could be a substantial area to under-
stand exteroceptive and interoceptive memory
modulation with complex physiological, affective,
and behavioral responses. However, more studies
are needed to unveil the IC´s precise circuit and
signaling mechanisms during context complex-
ity learning to weigh the intensity and valence of
experiences.
Evidently, the conceptualization of context
should include a variety of exteroceptive and
interoceptive stimuli thought to be available in the
environment and which play a key role in mem-
ory formation. In this regard, it has been shown
that histamine controls fundamental aspects of
the sleep-wake cycle for the regulation of nocic-
eption, modulating the rhythmical activity of the
hippocampus during aversive learning processes.
Histamine is an excellent candidate for peripheral
homeostatic signals enabling cognition of salient
stimuli related to contextual environments.
Acknowledgments: We thank Gabriela Vera-
Rivera and Luis Rodriguez-Duran for techni-
cal assistance, and we gratefully acknowledge
Jessica G. Norris for her generous help in proof-
reading and editing the manuscript. DGAPA-
PAPIITIN209122, IN201420 to IM. Departamento
de Ciencias de la Salud to KG-R. DGAPA-PAPIIT
IN212919 and IN213123 to FBR, and DGAPA-
PAPIIT IA201420 and IA202922 to DOG.
Notes
1  Appetitive conditioning: A type of classical condi-
tioning in which the unconditioned stimulus is a
positive reinforcer.
2  Discrimination performance: Sensory decision-
making that focuses on relevant stimuli and ade-
quate signal/noise ratio and recognizes different
attributes in them.
3  Operational tasks: Involves behavior that “oper-
ates” on the environment according to the con-
sequences of the response output.
4  Optogenetics: A combination of genetic and
optical methods to excite or inhibit neuronal
function.
5  Memory extinction: Reduction of a response that
occurs because the conditioned stimulus is pre-
sented without the unconditioned stimulus and
no longer predicts it.
6  Memory updating: Strengthening the current
memory trace incorporating new information.
7  Aversive learning: Development of dislike or
unwillingness to display a behavior by pairing it
with an unpleasant stimulus.
8  Neuronal plasticity: Morphofunctional changes in
the cell that modify synaptic efficiency.
9  Reward prediction error: The difference between
received and expected rewards.
10  Nociception: Encoding and processing of noxious
stimuli.
11  Conditioned taste aversion: Learned rejection to
a particular taste after its association with visceral
illness.
12  Liking: The pleasurable/hedonic impact or vari-
ous expressions of subjective pleasure induced by
rewarded appetitive experience.
13  Incentive salience: Motivation for rewards that is
driven by both the physiological state and previ-
ously learned associations about a reward cue.
 NEUROTRANSMISSION AND NEUROMODULATION OF MEMORY
14  Wanting: Rewarding behavior that triggers atten-
tion-grabbing and attraction processes.
15  Interference paradigms: Tasks that activate non-
target memories, influencing learning or retrieval.
16  Counterconditioning: Behavioral modification
involving a new association with a stimulus of
opposite valence.
17  Discrimination reversal: Learning about contin-
gencies through the sensory properties of cues
that predict stimulus availability and the actions
required to experience the consequence provid-
ing discriminated behavior.
18  Latent inhibition: Process in which stimulus pre-
exposure attenuates the ability of that stimulus
to be associated with positive or negative conse-
quences.
19  Reward expectancy: When animals display a
behavior motivated by a particular positive out-
come.
20  Pavlovian conditioned responses: Association of a
conditioned stimulus with a biologically relevant
unconditioned stimulus where the subject learns
the predictive value of the conditioned stimulus.
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Neuromodulator Adenosine A2A
Receptor Control of Cognition
J i a n g - F a n C h e n a n d Ya n L i
INTRODUCTION
Adenosine is a ubiquitous nucleotide throughout
the body that is directly involved in the key intra-
cellular processes such as the energy metabolism
and biosynthesis of DNA and RNA. With this
intrinsic link to cellular metabolism, adenosine is
also widely used as an extracellular signal by
acting at four G-protein coupled receptors, namely
adenosine A1, A2A, A2B, and A3 receptors (Borea
et al., 2018; Fredholm et al., 2011). In the brain
where adenosine receptors are located more abun-
dantly than in other mammalian organs, adenosine
functions primarily as a neuromodulator. In par-
ticular, adenosine is traditionally considered an
inhibitory neuromodulator to decrease in the activ-
ity of excitatory synapses via feedback mechanism
(Cunha, 2016; Dunwiddie and Masino, 2001).
A2A receptors (A2AR) are expressed at high
levels in the striatum (dorsal striatum and nucleus
accumbens) (Svenningsson et al., 1999) and olfac-
tory tubercle and at low levels in neurons outside
the striatum and in glial cells (Christofi et al.,
2001). Adenosine A2A receptors are also one of the
best characterized GPCRs (Carpenter and Lebon,
2017; Goldfeld et al., 2011; Hino et al., 2012),
among the first to be crystalized and with 3D struc-
turally analyzed at nm resolution. As discussed in
detail below, the selective cellular localization of
11
A2A receptors to the striatopallidal neurons, the
molecular interaction with other neurotransmit-
ters such as dopamine and glutamate signaling
systems and their ability to modulate (striatal)
synaptic plasticity led us that the A2AR represents
a novel target for improving cognition in normal
and disordered brain. With the recent approval of
the A2AR antagonist istradefylline for treatment of
OFF-episode Parkinson’s disease (PD) by US FDA
(Chen and Cunha, 2020), we proposed to translate
the cognitive enhancement of A2AR antagonists in
rodents and non-human primates, and the safety
profile of A2AR in clinical phase IIB-III trials and
to reevaluate and repurpose the ability of the A2AR
antagonist istadefylline to control cognitive dete-
rioration in Alzheimer’s disease (AD) and PD.
STRIATOPALLIDAL A2A RECEPTORS
CONTROL THE NO-GO PATHWAY TO
EXERT “BRAKE” CONTROL OVER A WIDE
RANGE OF COGNITIVE FUNCTIONS
A2ARs are abundantly expressed in the striato-
pallidal medium spiny neurons (MSNs;
Svenningsson et al., 1999), 20-folds higher than
other cells and tissues. A2ARs are located
172 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
predominantly on the axon terminal and cell of the
striatopallidal neurons which constitute the output
projection pathway (i.e., striatopallidal pathway)
from the striatum to the external segment of the
globus pallidus (GPe). This selective expression
pattern is key to understanding the potential of
A2AR antagonism in the control of motor as well
as cognition. Striatal GABAergic projection neu-
rons are divided into the striatonigral pathway
(expressing dopamine D1 receptor) that receives
preferential innervation from the sensory cortical
and limbic structures and projects directly to sub-
stantia nigra pars reticulate (SNr), and the striato-
pallidal pathway (expressing dopamine D 2
receptor, D2R and A2AR) that receives preferential
innervation from motor cortex and projects to the
external globus pallidus (GPe) and indirectly to
SNr via subthalamic nucleus(Gerfen et al., 1990;
Wall et al., 2013). Striatopallidal projection neu-
rons are characterized electrophysiologically by
the strengthened and more excitable neural firing
patterns (Yin et al., 2009) and by specific form of
synaptic plasticity, long-term depression (LTD)
(W. Shen et al., 2008). At behavioral level, the
striatonigral pathway facilitates (i.e., “Go” pathway)
and the striatopallidal pathway inhibits (i.e.,
“No-Go” pathway) motor and motivational behav-
iors (Kreitzer and Malenka, 2008). Accordingly,
pharmacogenetic (Ferguson et al., 2011) and
optogenetic (Kravitz et al., 2012) activation of
striatopallidal pathways can suppress psycho-
stimulant sensitization and motivation-related
behaviors, including motor skill learning (Durieux
et al., 2012), the selection accuracy of learned
motor action (Nishizawa et al., 2012), and
decision-making in a probabilistic switching task
(Tai et al., 2012), sequence-learning initiation and
execution (Tecuapetla et al., 2016), and the
response initiation of instrumental behaviors.
Striatopallidal A2ARs are positively coupled to
Gs protein to activation adenylyl cyclase (Chen
et al., 2014), resulting in the increase in the
3’,5’-cyclic adenosine monophosphate (cAMP)/
PKA level. A2AR agonist (CGS21680) or an
adenyly cyclase activator forskolin significantly
increased cAMP accumulation, and activate
the miniature inhibitory postsynaptic currents
(mIPSCs) frequency of striatopallidal neurons,
resulting inhibition of GABA release in the GPe
(Fredholm et al., 2007; Morales-Figueroa et al.,
2019; Shindou et al., 2002). However, A2AR
activation also inhibit GABA release from intra-
striatal collaterals, leading to excitation of the
striatopallidal neurons (Mori et al., 1996). The
study with combined optogenetics, two-photon
microscopy, and glutamate uncaging shows that
this PKA-dependent mechanism result in Ca2 +
entry through NMDA-type glutamate receptors
at corticostriatal terminals, which is attenuated
by the D2R but enhanced by A2AR activation
(Higley and Sabatini, 2010). Thus, the striato-
pallidal pathway activity is regulated by multiple
A2AR-mediated actions via cAMP/PKA signaling
mechanisms (Mori, 2020): (a) generation of mIP-
SCs and (b) counting D2R inhibition of calcium
entry of striatopallidal neurons, (c) GABA release
in striatal collaterals and GPe output projections.
A2AR antagonists and adenyly cyclase or PKA
inhibitors blocked these effects, resulting in over-
all reduction of excitability of striatopallidal neu-
rons with increased GABA release in GPe. Thus,
the striatopallidal A2ARs are uniquely positioned
to selectively modulate the activity of the ‘NoGo’
pathway (Mori, 2020).
In functional terms, A2AR antagonism relieves
the ‘NoGo’ signal (a ‘brake’) and facilitating the
D2R effects. In contrast to most of neuropharmaco-
logical manipulations which often result in disrup-
tion of normal behaviors, this “brake” mechanism
by striatopallidal neurons enable A2AR antago-
nists to facilitate motor and a range of cognitive
behaviors, including working memory (Li et al.,
2018), reversal learning (Amodeo et al., 2018),
Pavlovian fear conditioning (Simoes et al., 2016),
set-­shifting (Zhou et al., 2019), and goal-directed
behavior (Li et al., 2016, 2018). This feature also
makes the A2AR antagonist a novel therapeutic
strategy for improving cognitive behaviors under
various neuropsychiatric conditions.
It should be noted that A2ARs in brain areas
outside the striatum may differently control cog-
nitions through distinct modulatory mechanisms
depending on different neural networks. Thus,
A2ARs in forebrain have been shown to exert oppo-
site effects on working memory (Li et al., 2018),
fear conditioning (Simoes et al., 2016; Wei et al.,
2014) and psychomotor activity (H.Y. Shen et al.,
2008, 2013) than the striatal A2ARs. This differen-
tial effects by striatal versus extra-striatal A2ARs
confers the A2AR an unique ability to balance each
of cognitive behavioral elements from becoming
extreme and rigidity control.
STRIATOPALLIDAL A2A RECEPTORS
INTEGRATE CORTICAL GLUTAMATE
AND NIGRAL DOPAMINE SIGNALS
TO CONTROL STRIATAL SYNAPTIC
PLASTICITY
Synaptic plasticity, including long-term potentia-
tion (LTP) and long-term depression (LTD), is
considered the neurophysiological basis of
 NEUROMODULATOR ADENOSINE
memory (Martin et al., 2000; Neves et al., 2008).
A2ARs are expressed at the cortico-striatal synapse
(i.e., post-synaptic sites of the striatopallidal neu-
rons) and in synapses throughout the rest of the
brain including excitatory (glutamatergic) syn-
apses (Rebola et al., 2005; Tetzlaff et al., 1987),
GABAergic (Cunha and Ribeiro, 2000; Rombo
et al., 2015; Shindou et al., 2002), and probably
other synapses. At the postsynaptic sites, striato-
pallidal A2ARs interact postsynaptically with D2Rs
(Canals et al., 2003; Hillion et al., 2002) in an
antagonistic manner as A2AR activation inhibits
D2R binding in the striatum, D2R-mediated neuro-
transmitter release, and immediate early gene
expression (Ferre et al., 1991, 1997). Functional
A2AR-D2R antagonistic interaction is further sup-
ported by the demonstration of A2AR-D2R heter-
odimers and A2AR-mGluR5 heterodimers using
FRET and coimmunoprecipitation analyses
(Canals et al., 2003) and proximity ligation assay
(PLA) analysis. There is also evidence for the pos-
sible postsynaptic A2AR-NMDAR crosstalk since
A2ARs can control expression, recruitment, and
the rate of desensitization, phosphorylation of
NMDAR and NMDA current (Franco et al., 2020;
Kouvaros and Papatheodoropoulos, 2016;
Temido-Ferreira et al., 2020). In additional, post-
synaptic A2ARs in the striatopallidal neurons syn-
ergistically interaction with metabotropic
glutamate 5 receptors (Coccurello et al., 2004;
Ferre et al., 2002; Kachroo et al., 2005) and can-
nabinoid CB1 receptors (Lerner et al., 2010) in the
modulation of NMDAR-mediated effects. At the
presynaptic sites, A2ARs are also present at cor-
tico-striatal projection terminals (Rebola et al.,
2005; Rosin et al., 2003) to modulate glutamate
release (Ciruela et al., 2006) and at striatopallidal
output projection terminals as well as striatal col-
laterals to modulate GABA release (Gomez-
Castro et al., 2021; Morales-Figueroa et al., 2019).
As NMDAR activity is required for long-term
potentiation (LTP and LTD) and D2R activation
is critical to induction of LTD, the postsynaptic
interaction between A2AR and D2R and mGluR5/
NMDAR, possibly through A2AR-D2R heterodi-
mer formation, provide a strong anatomical and
molecular bases for A2AR control of striatal syn-
aptic plasticity and cognition. Through these post-
synaptic and presynaptic mechanisms, adenosine
has been shown to provide homeostatic modula-
tion of synapse by providing the permissive condi-
tion to set the stage for Hebbian forms of plasticity
(Dias et al., 2013).
LTP: Striatal A2AR activity did not affect short-
term plasticity (such as the paired-pulse facilita-
tion index of presynaptic function) but plays an
important role in modulating striatal LTP since
pharmacological blockade or gene deletion of
173
A2ARs impair LTP at corticoaccumbal synapses
(d’Alcantara et al., 2001) and spike-timing-
dependent LTP at glutamatergic synapses onto
striatopallidal neurons (H.Y. Shen et al., 2008).
In the setting of FGFR coactivation, A2AR activa-
tion also promotes LTP at the corticostriatopalli-
dal synapses through a PKA-dependent pathway
(Flajolet et al., 2008).
LTD: LTD is the predominant and best-
characterized form of long-term synaptic plastic-
ity that is restricted to striatopallidal MSNs where
A2ARs are highly concentrated in the striatum.
In particular, endocannabinoid (eCB)-dependent
LTD is found to be restricted to striatopallidal
MSNs and is dependent on endocannabinoid
release and D2R activation (Kreitzer and Malenka,
2007). A2ARs interact with both D2Rs and CB1Rs,
likely contribute to the modulation of striatal LTD.
Indeed, we showed that A2AR activity preferen-
tially modulates LTD in striatal slices from R6/2
mice, a genetic model of Huntington’s disease
(Li et al., 2015; Villar-Menendez et al., 2013).
This impact of postsynaptic striatal A2AR activ-
ity on striatal LTD is key to our understanding of
A2AR control of cognition.
LTD-LTP shift: Interestingly, concomitant
stimulation of A2AR and D2R changes the stri-
atopallidal MSN plasticity from LTD to LTP
(W. Shen et al., 2008) and modulate a form of
striatal eCB-LTD that is dependent on endocan-
nabinoid release and D2R activation (Kreitzer and
Malenka, 2007). Notably, overactivation of the
A2AR under condition of aging and stress can led to
the LTD-to-LTP shift and increased NMDA recep-
tor gating in hippocampus (Temido-Ferreira et al.,
2020). Accordingly, A2AR blockade reverse this
plasticity shift and accompanied cognitive impair-
ment (Temido-Ferreira et al., 2019). It is sug-
gested that mGluR5 may act as a switch between
the A2AR and NMDAR by sensing glutamate
and translating it into NMDAR overactivation as
mGluR5 blockade prevents the LTD-to LTP shift
and the NMDAR overactivation (Temido-Ferreira
et al., 2020).
A2A RECEPTOR ACTIVITY IS NECESSARY
AND SUFFICIENT TO TRIGGER MEMORY
IMPAIRMENT
The ability of the striatopallidal A2AR to integrate
dopamine and glutamate signaling to control syn-
aptic plasticity and to exert the “brake” control of
cognition uniquely position the A2AR as important
therapeutic target for modulating cognitive behav-
iors in normal and neuropsychiatric disorders.
174 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
A growing body of evidence indicates that A2AR
activation inhibits various cognitive behaviors in
normal mice (Cunha et al., 2008; Ferre et al.,
2008; Schiffmann et al., 2007; H.Y. Shen et al.,
2008). For example, A2AR activation in the cingu-
late cortex impairs memory retrieval (Pereira
et al., 2005) and social recognition memory,
which is prevented by A2AR antagonists (Prediger
et al., 2005; Prediger and Takahashi, 2005). Over-
expression of A2ARs in the cortex impairs spatial
working memory without affecting spatial refer-
ence memory (Gimenez-Llort et al., 2007).
Optogenetic activation of A2AR signaling in hip-
pocampus is sufficient to trigger CREB phospho-
rylation and cognitive impairments (Li et al.,
2015). Optogenetic activation of A2AR signaling
in the striatopallidal neurons suppress value sensi-
tivity and inhibit goal-directed behavior as dem-
onstrated by increased habit formation (Li et al.,
2016). Similarly, the pharmacological activation
of A2AR in the hippocampus (Pagnussat et al.,
2015) or cingulate cortex (Pereira et al., 2005) can
trigger memory impairment.
Conversely, using three different A2AR KO
models (global, forebrain-specific and striatum-
specific A2AR KO), we recently showed that inac-
tivation of striatal A2ARs is sufficient to enhance
working memory (Wei et al., 2011; Zhou et al.,
2009), reversal learning (Wei et al., 2011), goal-
directed behavior (Yu et al., 2009), and Pavlovian
fear conditioning (Wei et al., 2014), Pavlovian-
to-Instrumental Transfer (Li et al., 2020), with-
out affecting spatial reference memory, motor
function, and anxiety-like behaviors. The pro-
cognitive effects of A2AR inactivation were dem-
onstrated using multiple behavioral tests: Eight
arm radial maze (working memory and reference
memory), the Morris water maze (reversal learn-
ing, working memory), instrumental learning
(goal-directed behavior) and Pavlovian fear condi-
tioning and motor sequence learning. These cogni-
tive enhancement in WM, goal-directed behavior
and motor sequence learning can be achieved
similarly by pharmacological blockade of the
A2AR (He et al., 2021; Li et al., 2018). Notably,
this precognitive effect of the A2AR can be isolated
to the striatopallidal A2ARs since selective dele-
tion of striatal A2AR (st-A2AR-KO) was sufficient
to bolster WM performance (Wei et al., 2011),
goal-directed behavior and fear conditioning
(Wei et al., 2014).
Thus, A2AR in striatopallidal neurons may
serve as an inhibitory control system for a range
of cognitive behaviors, including working mem-
ory (Li et al., 2018), reversal learning (Amodeo
et al., 2018), Pavlovian fear conditioning (Simoes
et al., 2016), Set-shifting (Zhou et al., 2019), goal-
directed behavior (Li et al., 2016, 2018), and motor
sequence learning (He et al., 2021) in normal
animals. Given the A2AR antagonists relieves
the ‘NoGo’ in the striatum and increase the stri-
atopallidal neuron activity, this “brake” effect of
striatal A2AR activation collaborates with the find-
ing that the activity of the striatopallidal pathway
provides inhibitory control for amphetamine sen-
sitization (Bateup et al., 2010), instrumental learn-
ing (Lobo et al., 2007; Yu et al., 2009), addiction
(Durieux et al., 2009; Lobo et al., 2010), and goal-
oriented behavior (Yu et al., 2009). These findings
not only herald the notion that the suppression of
A2AR activity is pro-cognitive, but also support
the possibility that in contrast to targeting hip-
pocampus-cortex by cholinesterase inhibitors, the
selective localization of A2AR in the striatopallidal
pathway would provide a novel and promising tar-
get for selectively alleviating cognitive deficits in
AD and PD.
However, conditional striatum-specific A2AR
knockout did not affect latent inhibition (LI)
and prepulse inhibition (PPI), two common
cross-species translational behavior tests for the
assessment of selective attention and sensori-
motor gating deficits reported in schizophrenia
patients (Singer et al., 2013). It should be noted
that A2ARs in the brain regions outside striatum or
in glial cells have been shown to produce oppo-
site effects on cognitions (H.Y. Shen et al., 2008,
2013). For example, selective deletion of the
astrocytic A2AR gene trigger working memory
deficits and the exacerbated responses to psy-
chosis-inducing drugs such as MK-801 (Matos
et al., 2015). Thus, astroglial and neuronal A2AR
interplay critically control glutamate homeosta-
sis and provide a mechanistic key link between
astrocytic dysfunction and abnormal psychomotor
and cognitive behavior. This indicates that rather
than through the postulated antagonistic interac-
tion between A2AR and D2Rs in neurons (Boison
et al., 2012; Rimondini et al., 1997; Shen et al.,
2012), astroglial A2AR may directly affect gluta-
mate transport activity as a primary target to drive
an astrocyte-to-neuron communication, leading
ultimately to the deregulated glutamate neuro-
transmission and cognitive impairments.
MULTIPLE BEHAVIORAL MECHANISMS
MAY CONTRIBUTE TO STRIATAL A2A
RECEPTOR CONTROL OF COGNITION
How does the striatal A2AR bring changes in cog-
nitions by modifying behavioral elements? Recent
studies coupled well-controlled, sophisticated
behavioral paradigms with pharmacological,
genetic, and optogenetics approaches have uncov-
ered multiple distinct behavioral elements/
 NEUROMODULATOR ADENOSINE
mechanisms underlying striatal A2AR control of
cognitive processes.
1 Value sensitivity versus action-outcome contin-
gency: One important finding is that striatal A2AR
affect neither acquisition of instrumental behav-
iors during the random interval training and out-
come-contingency as evident by the omission test
(Li et al., 2016, 2018), nor the encoding of working
memory information during the sample phase
(Li et al., 2018). Rather, striatal A2AR activity modi-
fied the animal’s sensitivity to the value of the
reward as evident by devaluation test. These results
are in line with the findings that A2AR antagonism
and genetic deletion can improve effort-based
decision making (Lopez-Cruz et al., 2018; Pardo
et al., 2012). The ability to control the animal’s
sensitivity to the value of the outcome may have
therapeutic implication since the deficits in this
NAc incentive processes can produce a range of
motivational dysfunctions (Salamone et al., 2016).
2 Motivation: As the striatum (nucleus accumbens
in particular) is the critical locus for motivational
control, inhibition of the striatopallidal pathway
in either the NAc or dorsomedial striatum (DMS)
leads to enhanced motivation (Carvalho Poyraz
et al., 2016), The view that NAc A2ARs may affect
goal-directed behavior by modulating the motiva-
tion is supported by the finding that pharmaco-
logical blockade of A2AR increases the breakpoints
and total lever presses in the progressive ratio
test (Li et al., 2020; Zhou et al., 2019), indicating
increased effort-related motivation that mice were
willing to expend to earn a reward. In the progres-
sive-hold down test, the A2AR antagonist KW6002
produces a greater number of responses, with the
main responding increases in the short durations
(<2 s). This increased general motivational effect
(with increased vigor) may explain an enhanced
sensitivity to reinforcement and rapid initiation of
lever pressing. Thu, A2AR antagonist may modulate
goal-directed behavior by modifying motivation
with increased vigor/responding rate and by invig-
orating the performance of instrumental actions
to gain rewards.
3 Cue-motivated behavior: Cue-(evoked) Pavlovian
incentive learning mediates the ability of a stimulus
previously paired with a reward to acquire incen-
tive motivational properties and thereby enhances
reward approaching behaviors, as well as invig-
orates the performance of actions to gaining
rewards (Aitken et al., 2016). Using a Pavlovian-
to-instrumental transfer test, Li et al. found that
NAc A2ARs controlled goal-directed behavior by
175
enhancing Pavlovian-to-instrumental transfer and
thereby promoted reward approaching behaviors,
that is invigorating the performance of instrumen-
tal actions to gaining rewards (Li et al., 2020). This
finding collaborates with recent study that the NAc
played a critical role in the motivational aspect of
instrumental behavior by a Pavlovian-instrumental
transfer (Yin et al., 2008). Thus, accumbal A2AR
activity also plays an important role in linking
value information with the sensory features of the
reward or reward-related cues and A2AR control
of goal-directed behavior by modulating animal’s
adaptive utility of cue-motivated behavior.
4 Behavioral inhibition: Down regulation of A2ARs
expression by shA2AR in the medial prefrontal
cortex which innervates NAc impaired the per-
formance of rat in a cost-benefit decision-making
task by controlling impulsive behavior (Leffa
et al., 2018). On the other hand, selective dele-
tion of the striatal A2ARs apparently improved
the control of impulsive behavior using the
omission test (Yu et al., 2009). Furthermore,
nucleus accumbal A2AR knockdown apparently
modulated the reversal learning with the reduced
regressive and perseverative errors, indicating
the enhanced control of impulsive behavior
accumbal A2AR (Zhou et al., 2019). Thus, the
A2ARs in the medial prefrontal cortex and stria-
tum may exert different effects on impulsive
behavior for control of goal-directed behavior.
5 Mood-related behaviors: Chronic stress shifted
behavioral control from goal-directed toward
habitual strategy (Radenbach et al., 2015),
mainly through corticostriatal pathway involving
the dorsomedial striatum and nucleus accumbal
circuits (Dias-Ferreira et al., 2009; Taylor et al.,
2014). Importantly, caffeine and A2AR specific
antagonists can prevent mood and memory dys-
function triggered by chronic stress (Kaster et al.,
2015). Thus, A2AR signaling in NAc might modu-
late the goal-directed behavior and the decision-
making processes triggered by mood-related
behavior, which need to be further investigated.
ABERRANT INCREASE OF A2A
RECEPTOR SIGNALING IN AGED AND
NEURODEGENERATIVE BRAINS
Increasing evidence have documented that patho-
logical brain conditions associated with memory
impairment (such as AD, stress, and inflamma-
tion) are characterized by a local increase of the
176 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
extracellular levels of adenosine and up-regulation
and aberrant signaling of brain A2ARs (Chen et al.,
2013; Cunha and Agostinho, 2010). A2ARs is up-
regulated in the brain of AD patients, detectable
by radioligand binding assay at early Braak stages
(Albasanz et al., 2008). A recent study demon-
strated that human with AD had increased level of
A2ARs selectively in astrocytes which may con-
tribute to memory impairments in AD (Orr et al.,
2015). Aging also induced upregulation of A2ARs
in hippocampal neurons of aged humans, a pheno-
type further exacerbated in AD patients
(Temido-Ferreira et al., 2020). Furthermore, the
density of hippocampal A2AR increases in aged
animals (Canas et al., 2009; Cunha et al., 1995;
Lopes et al., 1999; Rebola et al., 2003) as well as
in transgenic mice displaying memory impair-
ments (Cognato et al., 2010; Cunha et al., 2006;
Espinosa et al., 2013).
Similarly, there is aberrant increase of A2AR
signaling in postmortem brains of PD models
and human PD patients. For example, dopa-
mine depletion by mitochondrial neurotoxins
such as 6-hydroxydopamine (6-OHDA) and
MPTP increased ATP release and upregulated
ecto-5’-nucleotidase (CD73) and A2ARs in stri-
atal synaptosomes (Carmo et al., 2019) and in
the striatum of MPTP-treated mice (Meng et al.,
2019). A2AR upregulation in neurons and glial
cells of hippocampus is also induced by intra-
hippocampal injection of A53T α-Syn fibrils
(Hu et al., 2016). Furthermore, A2AR upregulation
has been documented in putamen of early stage
of PD (Braak stage 1-2) (Villar-Menendez et al.,
2014) and in PD with dyskinesia (compared to PD
patients without dyskinesia) by positron emission
tomography (PET) studies (Mishina et al., 2011;
Ramlackhansingh et al., 2011).
Therefore, increased adenosine-A2AR signal-
ing represents brain response to insults and thus a
novel therapeutic target for pharmacological inter-
vention to reverse cognitive impairment in AD
and PD.
A2A RECEPTOR ANTAGONISTS
REVERSE COGNITIVE IMPAIRMENTS
IN ALZHEIMER’S AND PARKINSON’S
DISEASE MODELS
A2AR antagonists can not only enhance cognition
in normal animals but also reverse cognitive
impairments in AD and PD models. The selective
A2AR antagonist SCH58261 and non-specific
adenosine receptor antagonist caffeine prevent
Aβ-induced cognitive impairments and
synaptotoxicity after intracerebroventricular Aβ
injection (Canas et al., 2009; Cunha et al., 2008;
Dall’Igna et al., 2007). Interestingly, long-term
(between early 4-9 months) administration of a
1.5 mg daily dose of caffeine (equivalent to 500 mg
in human) to AD transgenic (APPsw, Swedish
mutation) mice reduced brain A levels and protect
against certain cognitive deficits (Arendash et al.,
2006, 2009; Cao et al., 2009). A similar protective
effect of the A2AR antagonist SCH58261 was also
observed in AD transgenic (3xTgAD and APP/
PS1) mouse models (Silva et al., 2018; Viana da
Silva et al., 2016). Furthermore, conditional
genetic deletion of astrocytic A2AR enhanced
long-term memory in young and aging mice.
Conversely, chemogenetic activation of astrocytic
Gs-coupled signaling reduced long-term memory
in mice without affecting learning (Orr et al.,
2015). A recent study further demonstrates that
genetic deletion of or oral therapy of A2AR antago-
nists protect THY-Tau22 mice from Tau
pathology-induced deficits in spatial memory and
hippocampal plasticity, along with reduced Tau
hyperphosphorylation (Laurent et al., 2016).
Thus, A2AR blockade and caffeine can reverses
memory impairments in AD models.
In animal models of PD, dopamine depletion in
the prefrontal cortex produces cognitive deficits
in executive dysfunction (Brozoski et al., 1979;
Clinton et al., 2006), visuo-spatial and non-spatial
working memory that resemble those seen in PD
(Decamp and Schneider, 2004). The A2AR antago-
nist istradefylline reverses these cognitive defi-
cits, with increased level of dopamine content in
prefrontal cortex (Kadowaki Horita, et al., 2013).
A2AR antagonists or A2AR KO reverse working
memory deficits induced by intracerebral injec-
tion of alpha-synuclein (Ko et al., 2016). rescue
impairment of LTP associated with α-Syn expo-
sure through an NMDA receptor-dependent mech-
anism (Durante et al., 2019).
In animal models of Huntington’s disease,
A2AR blockade reverse working memory defi-
cits with selective reversal of LTD (but not LTP)
( Li et al., 2015). In animals chronically exposed
to cannabinoid (WIN 55,212-2), A2AR antago-
nists also revert memory deficits (as evident on
administration of the Novel Object Recognition
Test) and partially rescue impaired LTP of syn-
aptic potentials recorded from the CA1 area of
the hippocampus (Mouro et al., 2019). In cortical
controlled impact model of traumatic brain injury,
A2AR antagonists improved working memory
deficits with reduced neuroinflammation (Ning
et al., 2013, 2019). Interestingly, a recent study
show that A2AR overexpression triggers the HPA-
axis dysfunction, including loss of plasmatic cor-
ticosterone circadian oscillation, and promotes
 NEUROMODULATOR ADENOSINE
reduction of GR hippocampal levels (Batalha
et al., 2016) and memory impairments. This
memory and HPA-axis dysfunction was mecha-
nistically accompanied by a hippocampal LTD-
to-LTP shift and increased NMDA receptor gating
(Temido-Ferreira et al., 2020). Accordingly, A2AR
blockade reverse this plasticity shift and dysfunc-
tion in HPA-axis (Batalha et al., 2016), suggesting
that the pro-cognitive effects of A2AR antagonists
on age-related cognitive impairments may be
associated with its ability to modulate HPA-axis.
HUMAN STUDIES SUPPORT POSSIBLE
PRO-COGNITIVE EFFECTS OF CAFFEINE
IN AGING AND NEURODEGENERATIVE
Caffeine is doubtless the most widely consumed
psychoactive substance by more than 50% of the
world’s adult population, largely for its psycho-
stimulant (and presumably cognitive enhance-
ment) effect. Importantly, the cognitive beneficial
effects of caffeine attainable by regular human
consumption (around 200–300mg caffeine or 3–5
cups of coffee/day) are largely attributed to the
antagonism of the brain A2AR (Cunha and
Agostinho, 2010; Ferre, 2008; Fredholm et al.,
2005). At least six longitudinal studies support an
inverse relationship between caffeine consump-
tion and decreased memory decline associated
with aging as well as a reduced risk of developing
AD, including the Masssatricht Aging Study
(Hameleers et al., 2000; van Boxtel et al., 2003),
the Canadian Study of Health and Aging (CSHA)
study (Lindsay et al., 2002), the Finland, Italy,
Netherlands Elderly (FINE) study (van Gelder
et al., 2007), the French Three Cities study
(Ritchie et al., 2007), the Cardiovascular risk fac-
tors, Aging and Dementia (CAIDE) study
(Eskelinen et al., 2009), and the Honolulu-Asia
Aging study (Gelber et al., 2011). Human studies
show that plasma levels of caffeine in individuals
with mild cognitive impairment (MCI) who later
progress to dementia are lower than in those
whose MCI remains stable (Solfrizzi et al., 2015).
For example, the Honolulu-Asia Aging Study
involved 3494 men found that the men in the
highest quartile of caffeine intake were less likely
than men in the lowest quartile to have any neuro-
pathologic lesions at death in the 226 men with
dementia and the 347 men with cognitive impair-
ment who underwent brain autopsy (Gelber
et al., 2011).
Furthermore, among patients with PD, a
cross-sectional study involving 196 early-stage,
treatment-naïve PD patients reveals that coffee
177
drinking was associated with a reduced severity of
the mood/cognition domain of NMSS (p = 0.003)
(Cho et al., 2018). Curiously, caffeine is report-
edly to enhance the consolidation of long-term
memories in humans, 24 hours after a one-dose
(200mg) administration (Borota et al., 2014).
Despite the considerable strength of the corre-
lation in these large, longitudinal studies, epidemi-
ological investigation cannot definitively isolate
caffeine intake from other lifestyle choices that
potentially affect cognition. In fact, a recent clini-
cal trial with caffeine in PD has failed to confirm
a procognitive effect of caffeine in PD patients
(Postuma et al., 2017). Thus, it is importance to
further investigate the effect of chronic treatment
of caffeine on cognition in AD and PD.
Lastly, a human gene-based association analy-
sis in cognitively normal and impaired partici-
pants reported that a minor allele rs9608282 of
the ADORA2A gene is associated with larger hip-
pocampal volumes and better memory in mild AD
patients (Horgusluoglu-Moloch et al., 2017).
SUMMARY AND CONCLUSIONS
In summary, there is a striking convergence of
epidemiological evidence from multiple longitu-
dinal studies strongly establishing an inverse
relationship between chronic caffeine consump-
tion in humans and cognitive decline in aging, AD
and PD, with the animal studies demonstrating
that selective A2AR antagonists and caffeine have
the strong pro-cognitive impact in normal as well
as aging and AD and PD models. This led us
to postulate that propose that in addition to
hippocampal-cortex circuits, it may be possible to
selectively target the striatopallidal pathway of the
striatum to improve memory impairment in aging
and AD. The validity of this target is supported by
the up-regulation of A2ARs in the brain of AD and
PD patients (including astrocytes) and by the abil-
ity of A2AR antagonists to enhance conditioning in
normal and disease models including AD and PD.
The confirmation of this hypothesis will constitute
a novel view of the control of cognition including
working memory and goal-directed behaviors by
the targeting striatal A2ARs.
Over at least the last 15 years, at least six
double-blind, placebo controlled clinical trials of
istradefylline (KW-6002), altogether involving
a total of >2500 advanced PD patients and one
phase IIB trial with preladenant (SCH420814)
involving 253 PD patients, have been reported to
demonstrate motor benefits in PD (Hauser et al.,
2011). These clinical IIB-III trials have ultimately
178 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
led to the approval of istradefylline for treatment
of OFF-PD patients in both the United States
(2019) and in Japan (2013). Particularly relevant
to AD drug discovery, these clinical IIB-III trials
with the A2AR antagonists have shown a consist-
ent safety profile in more than 3000 advanced PD
patients (Hauser et al., 2011; Jenner et al., 2009).
This safety profile of A2AR antagonists is entirely
consistently with the widespread use of caffeine
among 70% of the human population. The effect
of A2AR antagonists on cognition deficits in PD
has not been, however, specifically assessed in
these large phase IIB-III clinical trials in PD for
motor effects (Aarsland et al., 2010; Chase et al.,
2003). With the approval of istradefylline (Chen
and Cunha, 2020), it would be critically important
within clinical trials to reevaluate the capability of
A2AR antagonists to reverse cognitive deficits in
PD patients.
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Hormonal Influences on Cognition
Linda Becker and Nicolas Rohleder
INTRODUCTION
Hormones are messenger molecules that are
released by endocrine glands within the body and
also by specialized neurons within the brain. Free
circulating hormones in the bloodstream or in the
interstitial fluid interact with the brain through
positive and negative feedback loops, which can
be related with changes in cognitive functioning.
In general, there are two different classes of hor-
mones, mainly distinguished by their biochemical
characteristics, which have direct effects on the
way they gain access to, and signal to target cells.
The two main classes are steroid hormones and
peptide hormones.
One class of hormones are steroid hormones.
They are synthesized from the precursor molecule
cholesterol. Important steroid hormones are glu-
cocorticoids (e.g., the stress hormone cortisol),
mineralocorticoids (e.g., aldosterone), and sex
hormones (e.g., testosterone, estradiol, and pro-
gesterone). Steroid hormones are highly stable and
typically bound to transport proteins in the blood.
In their free form (i.e., when they are not bound to
proteins), steroid hormones can pass through cell
membranes. Importantly, they can pass the blood-
brain barrier (BBB), and can therefore, affect neu-
ral and brain processing directly.
A further important class of hormones are pep-
tide hormones, short protein molecules, which
12
are composed of a small number of amino acids.
Relevant peptide hormones are adrenocortico-
tropic hormone (ACTH), epinephrine (EPI), nor-
epinephrine (NE), and oxytocin. As opposed to
steroid hormones, peptide hormones cannot eas-
ily cross cell membranes. Therefore, they cannot
pass the BBB either and can (in most cases) not
alter cognitive functions directly. However, mech-
anisms to circumvent this restriction have been
described (e.g., through activating nerves such as
the vagus nerve in the periphery that can then alter
brain function through this neural pathway; cf. van
Bochove et al., 2018).
In addition to the direct and indirect effects of
actual hormones, this chapter cannot provide a com-
prehensive overview without addressing neurotrans-
mitters that are part of intra-CNS pathways. These
pathways involve for example the locus coeruleus
(LC), which is the origin of noradrenergic projections
to the prefrontal cortex (PFC), as well as dopamin-
ergic projections to the prefrontal cortex originating
in the ventral tegmental area (VTA) (Chandler et al.,
2014). This pathway involves the norepinephrine as
a neurotransmitter, and thereby affects for example
executive functions located in the PFC. The LC also
projects to the amygdala, also with norepinephrine as
a neurotransmitter, providing regulation of memory
processes by arousal, which interacts closely with
stress hormones such as cortisol from the periphery
(McGaugh and Roozendaal, 2009).
186 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Brain Structures Involved in
Cognitive Functioning
The main brain structures, which are relevant for
cognitive functioning in general are the prefrontal
cortex (PFC), the hippocampus, and the amyg-
dala, of which the former is particularly relevant
for executive functioning and the others for
memory processes.
The prefrontal cortex (PFC) is part of the
cerebral cortex. The PFC receives projections
from the mediodorsal nucleus of the thalamus.
Different parts of the PFC can be distinguished.
One distinction is the differentiation between a
medial and a lateral part, of which the former can
be subdivided into a dorsal (dorsomedial PFC;
dmPFC) and a ventral one (ventromedial PFC;
vmPFC), and the latter a dorsolateral (dlPFC) and
a ventrolateral part (vlPFC; Carlén, 2017). The
PFC is involved in several functions, of which
cognitive functioning can be seen as the most
important ones. Besides it is involved in emo-
tional, motivational, and social processes. The
PFC plays a major role for executive functioning
(e.g., attention, working memory and -updating,
inhibition, and cognitive flexibility).
The hippocampus is a seahorse shaped structure
in the temporal part of the cerebral cortex, located
along the lateral ventricles. According to Lopes da
Silva and Arnolds (1978), it includes several ana-
tomical components – Ammon’s horn, the dentate
gyrus, and the subiculum (most inferior compo-
nent of the hippocampal formation). The main
function of the hippocampus is its involvement in
memory and learning.
The amygdala is an almond-shaped brain
structure, located in the medial temporal cortex
(Sah et al., 2003). It includes several nuclei, the
basolateral amygdala (BLA), as well as surround-
ing lateral nuclei. The amygdala is involved in
bottom-up processing of (e.g., emotional) salient
stimuli. It is highly relevant for emotional memory
foundation. Other structures involve for exam-
ple the anterior cingulate cortex (ACC) and the
inferior frontal gyrus (IFG).
HORMONE INTERACTIONS WITH SPECIFIC
COGNITIVE DOMAINS
Effects of any substance circulating in the blood,
including hormones, on any target tissue, depend
on the ability to reach the respective target tissue.
In the case of the brain, this either requires being
able to pass the BBB, as for example, steroid hor-
mones can do, while peptide hormones cannot.
Or it requires the circulating substance to exert its
effects on protected tissues (such as CNS neurons)
via mediating pathways, such as activating the
vagus nerve in the periphery, which can then
transmit a message into the brain. Any such effect
on cognitive function not only depends on the
ability of the hormone to enter the brain in
general, but more specifically, to reach an area of
the brain that is involved in performing the
specific cognitive function.
It is therefore necessary to differentiate
between (1) hormone effects in the classical way
(i.e., hormones being secreted into the periphery),
and finding their way into the brain; (2) hormone
effects through alternate mediating pathways
(i.e., hormones activate peripheral nerve endings
and signal to the CNS that way); and (3) intra-
CNS pathways as described above (e.g., the LC
noradrenergic system that can be activated by
stress or arousal, and projects to target areas in the
CNS relaying the arousal signal).
To study effects of hormones on cognitive func-
tions such as memory and EF, different methodo-
logical approaches have been used. The type of
method also depends on the structure and ability
of the hormone(s) of interest. Steroid hormones
can simply be administered to research partici-
pants via typical pharmacological techniques such
as pills, injections, or skin patches (Schlosser
et al., 2013). These methods are not feasible for
peptide hormones, because they would not be able
to penetrate the BBB and therefore will not reach
the brain. One alternative is the pharmacological
activation of the central noradrenergic system for
example by peripheral application of the alpha-2
receptor antagonist yohimbine (Roozendaal et al.,
2006). Another method is the application of recep-
tor blockers, such as the beta-adrenergic antago-
nist propranolol (Roozendaal et al., 2006). In
addition to pharmacological approaches, hormone
levels can also be experimentally manipulated by
behavioral paradigms in the laboratory, that for
example induce psychosocial stress, or negative
emotional arousal (Canli et al., 2000; Wolf et al.,
2004). Finally, natural fluctuations of hormones
during biological rhythms or hormone changes
over the lifespan can be investigated in observa-
tional studies (Pretscher et al., 2021).
Memory
One of the most important cognitive functions is
memory. Memory is important for remembering
and learning. Different types of memory can
be distinguished. One of these is the differentia-
tion between explicit and implicit memory
 Hormonal Influences on Cognition
(or declarative vs. non-declarative), of which the
former is happening consciously and the latter
unconsciously (Squire and Zola-Morgan, 1988).
Another neuro-biological distinction is whether the
hippocampus is involved in the learning process or
not (so-called hippocampus-dependent vs. non-
hippocampus-dependent memory (Henke, 2010).
In the case of memory, a well-known exam-
ple is the effect of the glucocorticoid cortisol on
declarative memory function (Wingenfeld and
Wolf, 2014). Cortisol, as a steroid hormone, is
able to pass the BBB and reach the hippocampus,
an area responsible for declarative memory forma-
tion. The effect of endogenous cortisol responses,
or glucocorticoid application before learning, on
the ability to later remember newly learned declar-
ative information is a robust finding (Wingenfeld
and Wolf, 2014). Furthermore, increased cortisol
levels (e.g., after acute stress exposure) are asso-
ciated with decreased declarative memory perfor-
mance (Becker and Rohleder, 2019; Wolf et al.,
2004). This is different for hormones that cannot
pass the BBB, which therefore can only indirectly
affect cognitive function, for example for EF such
as working memory (Becker and Rohleder, 2019).
The situation becomes more complicated when
different classes of hormones are involved. This is
the case for emotional memory. A robust finding
here is that information with negative emotional
content is more easily remembered than neu-
tral or positive information. This effect depends
on an interaction of two different systems, the
(intra-CNS) noradrenergic system, with the glu-
cocorticoid system, in the amygdala: Here results
show that memory is only enhanced if noradr-
energic activation is present at the same time as
glucocorticoids in the amygdala (Canli et al.,
2000; Roozendaal et al., 2006). This example
highlights not only the importance of co-signaling
of two pathways (i.e., glucocorticoids and nor-
epinephrine), but also the importance to differ-
entiate between central and peripheral effects of
norepinephrine.
Pharmacological hormone application
Application of hormones allows for the most
stringent experimental manipulation, used to
study cortisol effects on memory. As summarized
in a meta-analysis by (Het et al., 2005), which
includes 16 studies with a total of more than 500
participants, the effect of cortisol on declarative
memory depends on the timing of hormone appli-
cation relative to memory phase. It was found that
cortisol application before retrieval impaired
memory, while cortisol before learning had differ-
ent effects depending on the time of day, which is
related with the circadian rhythm of endogenous
cortisol. Impairment of memory formation was
187
found in the morning, when endogenous cortisol
is higher, but stimulating cortisol effects were
found in the afternoon, when endogenous cortisol
is lower. The importance of timing relative to
memory phase was also the result of a review of
findings from animal studies by (Roozendaal,
2002).
Glucocorticoid effects on memory retrieval
were traced to high glucocorticoid levels directly
affecting glucocorticoid receptors in the hip-
pocampus. Memory consolidation, in contrast,
was found to depend on more complicated inter-
actions with other brain regions, for example
the amygdala. In general, memory consolidation
appears to be enhanced by glucocorticoid hor-
mones. The key finding that cortisol, or gluco-
corticoids, enhance memory consolidation, but
impair memory retrieval, in healthy humans has
been confirmed (Wingenfeld and Wolf, 2014). In
this review, it was further elaborated that imme-
diate short-term effects of cortisol on the hip-
pocampus, which might be stimulating, need to be
distinguished from longer-term, inhibitory effects
on memory. One disadvantage of these pharma-
cological studies is that artificial hormone effects
are observed, for example because hormone con-
centrations achieved through pharmacological
application tend to be supraphysiological, and
that interactions with other systems that occur in
real-life situations of for example stress, cannot be
investigated.
Experimental manipulation of
hormone levels
Studies using experimental manipulations of hor-
mones mainly target the stress response system,
which includes increases in peripheral glucocorti-
coid concentrations, and activation of the central
LC-based noradrenergic system. The specific role
of location and timing, as well as interactions with
different hormone or neurotransmitter systems
and brain structures comes into play when think-
ing about the role of stress and stress hormones in
formation and consolidation, as well as retrieval
of emotional memories.
As an overall summary it can be noted that expe-
riences that elicit arousal and/or intense emotions,
in particular negative emotions, enhance memory
formation (i.e., consolidation; Canli et al., 2000).
This is mediated in particular by the interaction of
the intra-CNS pathways, specifically the noradren-
ergic system originating from the LC and project-
ing to the amygdala, with glucocorticoid hormones
from the periphery entering the brain (Roozendaal
et al., 2006). This expands the view presented above
that the effects of hormones depend on the memory
phase to also include the timing relative to an actual
188 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
experience. Through the interactions described
above and in more detail by (Joëls et al., 2006), it
can be concluded that declarative memory forma-
tion (consolidation) is enhanced by the interaction
of noradrenergic with glucocorticoid signaling,
which leads to even stronger memory enhancement
when stimuli or experiences are arousing, and /
or characterized by negative emotions. Memory
retrieval in contrast is impaired in the context of
negatively arousing experiences.
Associations with Natural Hormone
Fluctuations
A further way to assess the effect of hormones on
memory is to observe changes in memory in asso-
ciation with natural changes of hormone levels, for
example as part of natural rhythms or in association
with age-related changes in hormone levels.
Cortisol fluctuates significantly during the day,
with highest concentrations within the first hour
of waking up (Cortisol Awakening Response;
CAR) and continuous declines during the day.
During the CAR, memory consolidation appears
to be enhanced, and a missing or lower morning
cortisol increase seems to have negative effects on
memory, highlighting once again the role of cor-
tisol in memory formation (Law and Clow, 2020).
Less cortisol during the entire diurnal cycle fur-
ther relates to lower emotional memory formation
(Nagamine et al., 2017).
Results of longitudinal studies investigating
associations of changes in cortisol levels with
memory function revealed that older individuals
with higher cortisol levels experienced steeper
declines in declarative memory (Li et al., 2006;
Segerstrom et al., 2016). This underscores poten-
tial long-term effects of hormones on brain struc-
tures such as the hippocampus.
Executive Function
Executive functioning (EF) is one of the most
important cognitive functions for successfully
managing daily life. Executive functioning is a
higher-order neurocognitive control system ena-
bling individuals to organize actions, to plan and
engage in goal- and future-directed behaviour, and
to successfully adapt to changing environments
(Jurado and Rosselli, 2007). Executive function-
ing can be conceptualized as a multidimensional
construct, including several subdomains such as
inhibition, cognitive flexibility, working memory
and working memory-updating, verbal fluency,
and attention (Jurado and Rosselli, 2007; Snyder
et al., 2015). Inhibition refers to the ability to
inhibit automatic or inadequate responses.
Cognitive flexibility refers to switching between
tasks, operations, actions, or cognitions. Working
memory is a limited capacity cognitive system,
which is responsible for temporary storage and
processing of information (Baddeley, 2001).
Working memory-updating refers to the monitor-
ing of incoming information in working memory.
Verbal fluency is associated with cognitive flex-
ibility. At least two forms can be distinguished,
semantic fluency and second phonemic fluency.
Impairments in verbal fluency are in many cases
associated with frontal (phonemic and semantic
fluency) or temporal (semantic fluency only) brain
lesions (Henry and Crawford, 2004).
Attention involves both bottom-up and top-
down attentional processes. The former refers to
the automatic processing of salient (e.g., threat-
ening) stimuli, whereas the latter, which is also
called attentional control, is the ability to engage
and to sustain attention upon information that
is relevant to the current tasks or to one’s goals
(Engle, 2018). The most important brain structure
which is involved in EF is the PFC, which is in
particular modulated by dopaminergic, noradr-
energic, serotonergic, and cholinergic pathways
(Logue and Gould, 2014).
Pharmacological Hormone Application
The effects of pharmacological cortisol adminis-
tration have been investigated in a comprehensive
meta-analysis (Shields et al., 2015). One key find-
ing was that somewhat similar to cortisol effects
on memory, timing and domain are important, in
that different domains of EF are differentially
affected by early versus late after cortisol admin-
istration. Here, the effect of timing is based on
different mechanisms through which glucocorti-
coids affect target tissues, with rapid non-genomic
effects being different from the slower, genomic
effects (Joëls et al., 2006). Working memory was
impaired via rapid non-genomic cortisol effects,
but enhanced by slower, genomic effects. In
contrast, inhibition was stimulated by rapid
non-genomic effects, but impaired by slower,
genomic effects. Set-shifting was not affected by
cortisol (Shields et al., 2016).
Experimental Manipulation
of Hormone Levels
This already complex picture again becomes more
complicated when investigating the effect of
experimental manipulation of hormone levels on
different EF domains. Stress, which activates not
only cortisol but also affects the Autonomic
Nervous System and the LC-noradrenergic
system, has been found to negatively affect work-
ing memory and set-shifting (Plessow et al., 2011;
 Hormonal Influences on Cognition
Schoofs et al., 2008). When stress is induced with
the cold pressor test, a higher cortisol response
was associated with better updating flexibility and
with lower switching between different tasks
(Goldfarb et al., 2017). Targeting the central
noradrenergic system by vagus nerve stimulation
(VNS) showed that norepinephrine has positive
effects on inhibition (van Bochove et al., 2018).
Associations with Natural Hormone
Fluctuations
Similar to memory, studies have investigated the
relationship between natural hormone fluctuations
and executive function. A higher CAR seems to
have positive effects on EF, with better verbal
memory (Labad et al., 2020) and better task
switching performance (Law et al., 2020). Higher
diurnal total cortisol was found to be associated
with lower inhibition (stroop performance) but not
with cognitive flexibility (Pretscher et al., 2021).
Higher hair cortisol was further found to be
related with lower working memory in children
(Kim et al., 2022) and adults (van den Heuvel
et al., 2022). Similar associations were also found
with morning serum cortisol (i.e., higher cortisol
related with lower verbal memory and flexibility;
Echouffo-Tcheugui et al., 2018).
In older adults as well, higher diurnal cortisol,
flatter diurnal cortisol slopes and higher bedtime
cortisol have been found to be associated with
lesser function on all EF domains studied (Evans
et al., 2011; Franz et al., 2011; Lee et al., 2007;
Montoliu et al., 2019). Here as well, a higher CAR
is predictive of better EF (Evans et al., 2012). Here
as well, higher cortisol most likely relates to more
advanced brain aging in relevant structures.
Taken together, the effect of hormones on
memory and executive function has been mainly
investigated for stress hormones. Memory effects
of stress hormones cortisol and norepinephrine
are well-understood, in that timing and emo-
tional valence or arousal determine if memory
is enhanced or suppressed. Nevertheless, while
declarative memory is well-investigated, much
less is known about other forms, such as proce-
dural memory. More questions are open with
regard to executive function, which is, at least in
part, caused by the fact that many different sub-
domains need to be studied, and different tests
need to be administered to test a specific domain.
Since many of these tests are complicated and
also require full attention of the participants, it
is almost impossible to test all domains in one
experimental setup.
Despite these difficulties, research using hor-
mone administration or behavioral paradigms has
revealed that glucocorticoid effects on different
189
domains also depend on timing of hormone appli-
cation relative to testing. Here, fast, non-genomic
effects often have opposite effects from slow,
genomic effects. For both, memory and execu-
tive function it is relatively clear that age-related
changes, mainly in the form of cortisol increases
and flattening of diurnal curves are consistently
associated with declines in cognitive function.
ASSESSMENT OF HORMONE EFFECTS
ON COGNITIVE FUNCTIONS
The studies summarized above highlight the dif-
ficulties when aiming to assess the effects of hor-
mones on the brain, specifically, cognitive
function, or the associations of hormones with
cognitive function.
Experimental designs in which hormones are
either pharmacologically administered, or behav-
iorally manipulated allow establishing causality
and are therefore most powerful. However, both
study designs have their strengths and limitations.
Hormone application typically – at least in human
studies – only allows altering the concentration
of one specific hormone, for example glucocorti-
coids. While this is useful to establish the specific
effect of this specific hormone, it typically does
not reflect what happens in a real-life situation, in
which a whole network of hormones may interact.
Furthermore, hormone application often leads to
supra physiological concentrations, which limits
the generalizability of the findings. The opposite
is true in experiments that alter hormone concen-
trations through behavioral paradigms. Here, the
entire network of hormones and brain pathways is
altered in a natural way.
However, because humans respond very dif-
ferently to laboratory situations, hormone con-
centrations typically show large variations, which
requires large sample sizes. Despite the higher
external validity of behavioral paradigms, they still
do not reflect a real-life situation, which is where
observational studies can help. In these studies,
natural fluctuations of hormone concentrations
can be measured and associations with different
cognitive domains can be tested. These designs do
not allow establishing causal relationships.
To measure the associations between hormones
and cognitive functions, both must be measured
adequately. Because hormonal concentrations
in the brain cannot be measured non-invasively,
they must be measured in the periphery, e.g., in
blood samples. An alternative is the assessment
through saliva samples, which is much easier and
190 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
relatively stress-free for participants than collec-
tion of blood samples. Concentrations of steroid
hormones assessed in saliva are in many cases
proportional to hormone levels in the blood.
Therefore, salivary hormone assessment has
often become the method of choice, especially for
the assessment of steroids. However, most ster-
oid hormones are bound to transport proteins in
blood, and only the free fraction can be measured
in saliva fraction (about 10% for example of cor-
tisol). In contrast, due to the fact that peptides do
not cross the blood-brain barrier, peptide hormone
concentrations measured in the periphery do not
accurately reflect peptide hormone concentrations
in the brain. Some ways of measuring peptide hor-
mone levels indirectly through the assessment of
enzymes (that are related with hormones) from
saliva have been suggested. An example is the
assessment of the enzyme alpha-amylase from
saliva samples (salivary alpha- amylase, sAA)
as an indicator for sympathetic nervous system
(SNS) activity, which is associated with the acute
stress response (Nater and Rohleder, 2009).
Similarly, the application of hormones in the
periphery can only effectively be used for steroid
hormones that easily cross the blood brain barrier.
To test the effects of peptide hormones, such as
norepinephrine, peripheral administration would
not reach the desired brain structures. One worka-
round is to activate the desired target system in
the way through alternative pathways: The central
noradrenergic system, for example, can be stimu-
lated by administration of the alpha-2 adrenergic
receptor antagonist Yohimbine (van Stegeren et al.,
2010), which is safe to use in humans and reliably
activates the noradrenergic system, as well as the
peripheral sympathetic nervous system. Given the
importance of timing for hormone effects on cog-
nitive function, a main issue in all pharmacologi-
cal studies is to mimic natural hormone changes as
adequately as possible with regard to concentra-
tion and temporal response patterns. Here as well,
assessment of peripheral hormone concentrations,
as described above, is essential in ensuring proper
hormone concentrations.
When designing behavioral experiments
aimed at activating specific hormone systems,
a major issue is the selection of the experimen-
tal paradigm, and appropriate controls. Using
the example of experimental stress induction, the
research has the choice between a number of dif-
ferent stress paradigms, which all have strengths
and limitations. The most widely used stress
paradigm is the Trier Social Stress Test (TSST;
(Kirschbaum et al., 1993), which reliably activates
HPA axis and sympathetic nervous system, and for
which a non-stress control condition, the friendly
TSST is available (Wiemers et al., 2013). One of
the limitations of the TSST are the relatively high
number of personnel required.
Alternatives to the TSST are less personnel-
intensive, such as the socially evaluated cold
pressor test (SECPT; Boyle et al., 2016) or the
Montreal imaging stress task (MIST (Dedovic
et al., 2005)). With regard to cortisol, both SECPT
and MIST are limited by their lower effect on the
HPA axis, which sometimes requires eliminating
non-responder participants from the sample. Both,
TSST and SECPT can be applied in a group set-
ting, which somewhat reduces their limitations
(Becker et al., 2019; von Dawans et al., 2011).
Similar to pharmacological studies, measurement
of peripheral hormone concentrations is a neces-
sity, because of high inter-individual variability of
for example cortisol responses to stress (Kudielka
et al., 2009). Also, here as well, timing of stressor
application and careful timing of the respective
cognitive test is of major importance. Cortisol for
example peaks about 18 minutes after the end of
a TSST (Goodman et al., 2017), so that cognitive
testing of cortisol effects should be done in this
time window.
BIDIRECTIONALITY
One important fact to be aware of is that the asso-
ciation between hormones and cognition is bidi-
rectional, i.e., while hormones can have a
facilitating or deteriorating effect on cognitive
functioning as described above, cognitive abilities
can also affect the release and thereby concentra-
tion of hormones.
In longitudinal studies, results seem to support
that cognitive function can predict hormone con-
centrations much later in life. It was for example
shown that general cognitive ability measured
at the age of twenty was correlated with higher
overall diurnal cortisol 35 years later (Franz
et al., 2011). While in this study, no specific
domains were analyzed with regard to this long-
term relationship, results support the notion that
higher cognitive abilities might offer some level
of protection from long-term pathophysiological
hormone effects. Results from the Midlife in the
US (MIDUS) study point to a similar direction by
showing that higher executive function predicted
steeper diurnal cortisol declines at a later time
point (Stawski et al., 2011). Since steeper diurnal
slopes comprise a healthier pattern, here as well, a
better cognitive function seems to predict healthier
hormone secretion patterns. In experimental stud-
ies, higher scores on specific domains of execu-
tive functioning were found to be associated with
 Hormonal Influences on Cognition
lower acute stress cortisol responses. Specifically,
individuals with better working memory func-
tion showed a lesser stress response, pointing to
a potentially healthier ability to adapt to stressors
(Grimm et al., 2021).
SUMMARY AND CONCLUSIONS
The release of hormones can interact with the
brain through different direct and indirect path-
ways. This can result either in deterioration or
improvement of cognitive functioning. Of particu-
lar importance are steroid hormones (e.g., gluco-
corticoid and sex hormones), as well as peptide
hormones (e.g., norepinephrine). In this chapter,
we have described through which pathways these
interactions occur and how they can be assessed.
We started with an overview of different hormone
classes and brain structures that are particularly
relevant for cognitive functioning as well as for
the interaction between hormones and cognitive
functioning in general. We then examined differ-
ent cognitive domains and their associations with
peripheral concentrations of different hormone
types: First, we have described the hormonal
influences on different types of memory and,
second, the effects on executive functions (e.g.,
inhibition, working memory, and cognitive flexi-
bility). We then outlined how the hormonal effects
on cognitive functions can be assessed and what
should be considered in designing an empirical
study. Finally, we have briefly outlined the bidi-
rectionality of these effects whereby cognitive
functions can be affected by hormones on the one
hand, but cognitive functions can influence the
release of hormones on the other hand.
In summary, hormones circulating in the
periphery, as well as hormones and neurotrans-
mitter systems entering or being produced in the
brain have profound effects on cognitive function.
This is best established for stress hormones and
declarative memory, but also for other memory
domains and different executive functions. It
is important to note a high level of interaction
between different hormone systems, and the role
of timing of the ability to use a specific cogni-
tive function relative to a situation that changes
hormone levels. With regard to memory, it can
be assumed that stress hormone effects modu-
late memory in an adaptive manner, by enabling
easier long-term storage of information that is
important for survival, at the expense of informa-
tion that is of less importance. With regard to the
long-term effects of hormones on cognitive func-
tion, higher levels of stress hormones have been
shown to predict declines in cognitive function in
191
old age, later in life. Conversely, better cognitive
abilities in general, most notably executive func-
tions, help to dampen acute stress responses and
predict more adaptive cortisol concentrations in
later life. These facts highlight the importance
of understanding the bidirectional interactions of
hormones and cognitive functions, and the impor-
tant need to examine more deeply neuroanatomi-
cal brain areas affected by different hormones.
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 PART III
Neuroanatomical
Brain Systems
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Modeling of Basal Ganglia
Structure and Function
Anneke Alkemade, Bernadette C.M. van Wijk,
and Birte U. Forstmann
INTRODUCTION
Brain function can be studied from various per-
spectives, including computational modeling,
which has the potential to deepen our insight into
structure-function relationships, as evidenced by
the progress made in relation to the basal ganglia
(BG). In this chapter we provide an overview of
current knowledge regarding BG structure-func-
tion relationships, and highlight the role of com-
putational modeling in advancing our
understanding. Deciphering the neural processes
that the BG perform, as well as the overall behav-
ioral functions covered by this system, continues
to be a valid focus of research, as is the role of the
individual BG nuclei in disease, and case reports
of BG lesions.
RELATION BETWEEN ANATOMICAL
STRUCTURE AND FUNCTION
Imagine a satellite image of the world, which
provides detailed information on the items that
together form the landscape. This image provides
a high level of detail without highlighting specific
13
features, such as main infrastructure created by
humans. In order to understand how cities are con-
nected, one can start to map the traffic architec-
ture. Mapping how the roads are connected and
embedded in the landscape is crucial to model and
understand traffic behavior. The level of descrip-
tion can be limited to the identification of the
main roads, but could also include information on
framework characteristics that are required to
allow the system to function, for instance the
availability and location of gas stations, or bridges
connecting different roads. This relatively high
level of description can help us to understand how
the landscape architecture gives rise to function,
and can further be refined, for instance, through
the inclusion of information on speed limits.
Imagine that information is available on the dis-
tance between point A and B, together with the
speed with which a car travels. This information
now allows us to calculate how much time is
needed to get from point A to point B. If this cal-
culation results in a predicted seven-day drive,
while in reality the drive only takes three days,
this likely indicates that part of the architecture,
such as a bridge or tunnel has been omitted in the
created model. The mismatch between structure
(traffic architecture) and function (drive) will then
trigger the search for this bridge or tunnel on the
198 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
satellite image, and the description can be updated
accordingly. However, if the time needed to travel
from point A to point B in reality is only 30 min,
this indicates that the model used to estimate the
time of travel does not capture the data adequately,
and warrants a more thorough revision.
This principle of describing structure and link-
ing it to function can be applied to the brain in a
comparable manner. Studying the brain through
the microscope in sections that are stained using
histological techniques, or by applying structural
Magnetic Resonance Imaging (MRI) presents
information on the anatomical structures of the
brain. To understand how function rises from the
underlying anatomical architecture, the func-
tional neuroanatomy needs to be uncovered. The
relative contribution of specific brain areas can
for instance be addressed using functional (f)
MRI or electroencephalography (EEG), applied
in combination with behavioral or physiologi-
cal outcome parameters. This research process is
ongoing, and may never be completed. It is pur-
sued using a wealth of description levels, varying
from expert opinions for the recognition of struc-
tural features, which have already been linked to
specific functions, to techniques from the field of
molecular biology to identify specific signaling
systems, or individual proteins in cell popula-
tions. Using a variety of functional anatomical
studies, it is possible to identify main brain struc-
tures and anatomical networks that provide a
backbone for specific behavior. The basic ana-
tomical architecture identified can then be refined
based on studies providing information on brain
activation. As a next step, the anatomo-functional
models can be validated, adjusted, extended, or
rejected based on behavioral testing in combina-
tion with formal computational modeling stud-
ies. If the identified neural architecture does
not accommodate the observed behavior, or the
model is insufficiently able to predict behavior,
this can steer the descriptive anatomical research
toward the identification of the missing nodes
related to latent parameters identified through the
computational modeling, or it can trigger rigor-
ous paradigm shifts, thereby changing our under-
standing of brain processes.
Fully annotated anatomical descriptions cover-
ing all intricacies of the networks of the human
brain do not exist. If we compare anatomical
descriptions of the human brain to different geo-
graphical maps, distinct types of maps (BG maps
vs. maps of endocrine feedback systems) have dif-
ferent value for understanding function and inter-
preting behavior. High resolution satellite images
can form the basis for atlasing efforts to derive
a multitude of maps that can be reused for vari-
ous purposes. The challenge then is how to create
meaningful, reusable, instantly understandable
mapping of the brain for application in various
fields of research.
ANATOMY OF THE BASAL GANGLIA
We summarize a number of the major anatomical
characteristics, required for understanding and inter-
preting the underlying building blocks that are
incorporated in leading BG models. The BG is a
group of closely connected structures of varying
developmental origin. The main structures are the
striatum (STR), globus pallidus (GP), substantia
nigra (SN), and the subthalamic nucleus (STN). The
caudate (CAU) and putamen (PUT) together form
the dorsal striatum. The ventral striatum contains the
nucleus accumbens (NACC). Additionally, the
globus pallidus is divided in an external (GPe) and
internal segment (GPi) separated by the medial
medullary lamina (mml), each segment with differ-
ent in- and output connections and with distinct
functions. In turn, the substantia nigra is divided into
a compact (SNc) and a reticular (SNr) part (Yelnik
et al., 1987). The STN is located on the dorsolateral
aspect of the SN and has a characteristic almond
shape (Alkemade et al., 2015; also Figure 13.1).
The structure–function relationships are cap-
tured in today’s most prominent and successful
BG models describing direct, indirect and hyper-
direct pathways in the regulation of motor, cogni-
tive, as well as limbic behavior (cf. Helie et al.;
also Figure 13.2). This model represents a high
level of description, and can be used in various
ways within various disciplines including com-
putational modeling approaches. Researchers
studying brain function can use this model as a
basis to structure their research, and to refine their
understanding of the molecular underpinning of
BG function. Additionally, this box-and-arrow
diagram can form the basis for the design of for-
mal cognitive models that can be applied for the
prediction of behavior.
INDIVIDUAL NUCLEI OF THE BASAL
GANGLIA
In addition to the general architecture of the BG
nodes and their connections, the individual BG
nuclei each have their own complex internal make
up. A basic understanding of this architecture is
required as it delivers an anatomical backbone, as
well as biological plausibility for the formal
 Modeling of Basal Ganglia Structure and Function 199

Figure 13.1 Post-mortem anatomical images of the human basal ganglia.

A and B show the striatum (STR) and the globus pallidus interna and externa (GPi and GPe)
at different levels of magnification. C and D show the subthalamic nucleus (STN) and sub-
stantia nigra (SN), which are located at a more caudal level.

computational models of BG function, which are
used to explain both normal and aberrant behavior
resulting from BG-related disease. Information on
the number and the nature of neuronal connec-
tions between individual BG structures are com-
monly derived from neural tracing studies in
rodents and/or non-human primates. Neuronal
tracing studies are performed using molecules that
are taken up by neuronal cell bodies at the site of
injection, and which travel through the axons to
their terminal processes (Saleeba et al., 2019).
Dependent on the type of tracer, they may travel
antero- and/or retrogradely over the synaptic con-
nection or can be monosynaptically restricted
(Saleeba et al., 2019).
Although many studies have targeted the
BG, it is important to realize that the techniques
underlying the observations that form the basis of
the available anatomical models of the BG have
technical limitations. Tracing results are usually
obtained in rodents, and to a lesser extent in non-
human primates. These studies systematically
underestimate the extent and number of the pro-
jections (Alkemade, 2013). Immunohistochemical
results are often extrapolated from animal experi-
ments as well, which do not take potential inter-
species differences into account. Alternatively,
immunohistochemical results are derived from
post mortem human studies which have inherent
limitations imposed by ante mortem illness, cause
of death, tissue quality and antibody sensitivity
(Alkemade et al., 2019). Although it is unlikely
that these technical limitations will have resulted
in a misrepresentation of the underlying human
neuroanatomy, it is important to realize that some
differences may be present.
Striatum
The striatum (STR) is the largest structure of the
BG. The dorsal STR is formed by the CAU and
PUT, which share their histological characteristics
200 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 13.2 Basal ganglia models describing a direct, indirect, and hyperdirect pathway in
the regulation of motor, cognitive, as well as limbic behavior.
A Various studies have identified different parts of the cortico-basal ganglia-thalamic net-
work (indicated with shades of grey) as potential generators of neural oscillations.
B Using dynamic causal modeling, Moran et al. (2011) pinpointed the emergence of patholog-
ical beta oscillations (left panels) to altered connection strengths of the hyperdirect pathway
and STN-GPe circuit (light blue). Similar studies with data from human patients identified
additional connections: ‘+’ for Marreiros et al. (2013) and ‘*’ for Van Wijk et al. (2018). Overall,
findings suggest an increased activation of the hyperdirect and indirect pathway in PD.
Source: Adapted from Moran et al., 2011.

and functional profile, although they can easily be
distinguished anatomically due to their separation
by the internal capsule (ic). The NACC is located
ventral to the CAU and PUT, and its border to the
dorsal striatum can be visualized using histo-
chemical approaches (Meredith et al., 1996). The
NACC is often referred to as the ventral STR. The
STR predominantly contains medium spiny pro-
jection neurons (MSN) and a smaller proportion
of interneurons (Bishop et al., 1982; Matamales
et al., 2009; Plenz and Wickens, 2016). The STR
represents the main input nucleus of the BG and
receives information from multiple cortical areas
as well as the thalamus (THA), the brain stem and
GP (Aston-Jones and Cohen, 2005; Beckstead,
1983; Calabresi et al., 1996; Sharpe and Tepper,
1998; Soghomonian et al., 1989).
The microscopic appearance of the STR is
in-homogenous and patchy. The matrix is ana-
tomically distinct from the striosomes (patches),
forming areas that are functionally separate, with
differing neurochemical and connectivity pro-
files (Herkenham et al., 1984). The striosomes
have been identified as part of the limbic circuitry
based on their frontal cortical input regions, and
their projections to the SNc (Smith et al., 2016).
At the same time, the matrix of the striatum
receives input from the sensorimotor cortex, and
provides output via the SNr. It is important to
note that although this is an attractive anatomical
model, other studies have not been able to confirm
its validity (Voorn et al., 2004; Yin and Knowlton,
2006). More research is therefore needed to deter-
mine to what extent this compartmentalization
translates into functional outcomes, including spa-
tial weighting and regulated signaling.
The anatomo-functional specificity in the stria-
tum is attributed to the distinct function and dis-
tribution patterns of the dopamine receptors. Both
D1 and D2 receptors are expressed in striato-nigral
and striato-pallidal MSN of the STR, respectively
(Clark et al., 2005). Constitutive activity of the BG
reflects a situation in which the indirect pathway
is active, as a result of D2-receptor stimulation.
Striatal GABAergic enkephalin MSN that are part
of the indirect pathway, subsequently affect other
BG nuclei through polysynaptic connections to the
GPi /SNr via the GPe and STN (Shink and Smith,
1995). These output nuclei subsequently project
(indirectly) to the thalamus, the superior colli-
culus, brain stem, and other regions to modulate
behavior (Bolam et al., 2000). Activation is shifted
 Modeling of Basal Ganglia Structure and Function
in anticipation of movement when increased dopa-
mine availability in the STR shifts the balance
towards the direct pathway (Clark et al., 2005).
The direct pathway is activated via binding and
activation of the D1 receptors through dopamin-
ergic input originating from the SNc. Striatal
GABAergic substance P-positive MSN project
monosynaptically to the GPi and SNr (Shink et al.,
1996). Overall increases in striatal dopamine con-
centrations shift the balance toward activation of
the direct pathway, which is in line with increased
overall motor activity that is observed in rodents.
Additionally, topographical zonation has been
described for the STR. Functional differences
between dorsomedial and dorsolateral STR point
toward discrete roles in motor learning, habits,
action evaluation, and decision-making (Balleine
et al., 2007; Bloem et al., 2017; Castañé et al.,
2010; Wang et al., 2013).
SUBTHALAMIC NUCLEUS
The subthalamic nucleus receives direct cortical
input, and is the input nucleus for the hyperdirect
pathway of the BG (Temel et al., 2005). At the
same time the STN is part of the indirect pathway
of the BG (Temel et al., 2005). It conveys excita-
tory signals from the cortex directly to the GPi
and SNr via tonic glutamatergic signaling, provid-
ing a faster pathway than the direct and indirect
pathways (Nambu et al., 2000; Nambu et al.,
2002; Robledo and Féger, 1990; Rosales et al.,
1994; Smith and Parent, 1988). The STN has
received strong research attention in view of its
role as a target for deep brain stimulation in the
treatment of Parkinson’s disease (PD) (Temel
et al., 2005). The tripartite hypothesis dividing the
STN in a dorsolateral motor area, a ventromedial,
cognitive area, and a limbic tip has provided ana-
tomical guidance for deep brain stimulation
(DBS) surgery (Temel et al., 2005). Interestingly,
the discussion on the location and sharpness of the
anatomical borders of the putative subdivisions
has fueled anatomical research into the micro-
anatomy of this nucleus (Alkemade et al., 2019;
Alkemade and Forstmann, 2014; Lambert et al.,
2012, 2015). This has led to detailed accounts of
protein marker distribution patterns throughout
the human STN, although to date it remains chal-
lenging to link function directly to individual
protein expression. STN neurons display axon
collaterals that innervate both the internal and
external segment of the GP. Communicating neu-
rons both from the GPe and STN innervate the
201
same population of GPi neurons, suggestive of a
tight regulatory system to balance the direct, indi-
rect, and hyperdirect pathways of the BG (Nambu
et al., 2000).
GLOBUS PALLIDUS
GPi and SNr are output nuclei of the basal gan-
glia. The GPi plays a role in the direct, indirect as
well as the hyperdirect pathway of the BG. The
GPi receives extensive GABA-ergic input from
both the STR and GPe. Interestingly, the GABA-
ergic GPi neurons have only very limited local
axon collaterals (Ilinsky et al., 1997; Nakanishi
et al., 1991; Parent et al., 1999; Smith et al.,
1987). This specific organization of dendrites and
fibers has led researchers to attribute information
convergence to the GPi (Percheron et al., 1984;
Yelnik et al., 1984).
Single neurons of the GPe can project to all
nuclei of the BG, and through their extensive
GABAergic axon terminals, provide an anatomi-
cal framework allowing coherent network activ-
ity (Bevan, 2021; Bevan et al., 1994, 1996; Shink
et al., 1996). The GPe is innervated by GABA-
ergic fibers from the STR, as well as glutamatergic
fibers originating from the STN and the thalamus,
SNc, and brainstem (Deschênes, 1996; Fink-
Jensen and Mikkelsen, 1991; Hazrati et al., 1990;
Kita and Kitai, 1994; Parent and Hazrati, 1995).
GPe signaling can be modulated via the endocan-
nabinoid system through the altering of GABA
uptake (Di Marzo et al., 1998; Maneue et al.,
1994; Venderova et al., 2005). In the GPe and STR
the endocannabinoid signaling was reported to be
reduced in animal models of PD, as evidenced by
reduced CB1 receptor mRNA expression (Hurley
et al., 2003). Additionally, elevated levels of endo-
cannabinoid were reported, as well as positive
effects of receptor activation on the motor pheno-
type of primate models of PD (Ferrer et al., 2003;
Fox et al., 2002; Marzo et al., 2000).
SUBSTANTIA NIGRA
The substantia nigra (SN) is also an output
nucleus of the BG. The reticular and compact
parts of the SN receive largely comparable inputs,
but differ substantially in their output which is
exerted by chemically distinct neuronal types
(Gerfen and Wilson, 1996). The SN transmits
202 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
information received from the STR, via the pars
reticulata, to the thalamus, superior colliculus or
brainstem. Additionally, the SN provides feedback
to modulate information flow through the BG via
the STR. This modulatory feedback is mediated
by the dopaminergic nigrostriatal neurons that are
located in the pars compacta of the SN and that
has strong and diverse projections onto the STR
(Bolam et al., 1991).
USING ANATOMICAL INFORMATION TO
STUDY FUNCTION
The level of description of the BG nuclei and their
connections provided here is sufficient to under-
stand the major anatomical nodes incorporated in
leading models of BG function. We would like to
emphasize that the levels of description of the
internal anatomy provided here do not reflect the
full complexity of the BG. They can be compared
to the level of a single main road on a map telling
you in which direction you need to travel, but not
what you may encounter on the road. Additional
signaling pathways, which can be major regulatory
signals or ones that serve a more modulatory func-
tion are not included. Reasons for their omission
are either that the additional anatomical informa-
tion does not contribute to explaining behavior
captured in a model, or that the function of the
anatomical characteristics is currently unknown.
Isolated anatomical information including
connectomic data will not explain how the brain
works. However, when combined with data on
electrophysiological properties, synaptic strength,
neurotransmitter content, receptor expression
etc., anatomy provide insights into the general
mechanisms that underlie brain circuit function
(Rockland, 2015). Subsequently, the resulting
functional neuroanatomy can be integrated in fur-
ther research to understand individual differences
in brain and behavior. Creation of formal models
integrating all of this information allows us to
improve our understanding of how the brain gives
rise to complex human behavior. We will explain
how anatomy can funnel into computational mod-
eling of human behavior, and vice versa, how com-
putational models can shape anatomical research.
COMPUTATIONAL MODELS OF THE
BASAL GANGLIA
A straightforward approach to model BG function
is to quantify the number of excitatory and
inhibitory connections within a pathway and infer
the overall effect on cortical activation through
thalamocortical projections. As illustrated in
Figure 13.2, the direct BG pathway consists of an
excitatory corticostriatal connection, an inhibitory
striatopallidal connection, another inhibitory pal-
lidothalamic connection, and an excitatory projec-
tion from the thalamus to the cortex. Since the
resulting effect on the cortex is excitatory, this
pathway is often referred to as the ‘go’ pathway.
Conversely, the indirect pathway exerts an overall
inhibitory effect on cortical activity, and is there-
fore referred to as the ‘no go’ pathway. This basic
understanding of these pathways forms the under-
pinning of leading theories that offer an explana-
tion of hypo- and hyperkinetic movement
disorders and our general understanding of BG
function (Albin et al., 1989; DeLong, 1990). This
broadly applicable, but very general model does
not capture all experimental data on neuronal
activity patterns, and does not cover more specific
aspects of behavioral control such as action selec-
tion and learning. In this section, we will illustrate
how extension of available theories through
formal computational models based on BG anat-
omy could contribute to the elucidation of under-
lying brain processes.
A next level of detail is reached through cor-
relation of measures of task performance or indi-
vidual disease characteristics with recorded brain
responses using functional (f)MRI or electro-
physiological recordings. It is important to note
that the small size of a number of the individual
BG nuclei, their close proximity to each other and
other structures, and their dispersed location deep
inside the brain render it difficult to reliably record
activity from all network nodes simultaneously
(Forstmann et al., 2017). Moreover, such correla-
tions provide only limited insights into the contri-
bution of individual pathways as they might to a
large extent contain the same structures.
Computational models can provide an account
of the generative mechanisms that underlie
observed experimental data, motivated by current
theories in cognitive and systems neuroscience.
These descriptions include exact mathematical
equations, therefore leaving little room for seman-
tic ambiguities and facilitating scientific replica-
bility. The parameters of such models generally
represent biological quantities or psychological
constructs of interest, such as synaptic connection
strengths or learning rates. One important objec-
tive for using computational models is to quantify
the contribution of these individual parameters
to aspects of behavior. This can be achieved by
identifying the most plausible values for these
parameters for different (groups of) individuals
or experimental conditions, or by investigating
 Modeling of Basal Ganglia Structure and Function
the impact of individual parameters on model
predictions through simulations. Another major
objective is to formulate and compare alterna-
tive models to experimental data. Through this
approach, theories can be tested and further devel-
oped and refined.
Since computational models have diverse
applications in neuroscience, it is not surprising
that models are available in a wide range of forms
and level of detail. We can roughly distinguish
between models that aim to explain observed
behavior, models that explain observed neural
measurements, and so-called ‘joint’ models that
capture both behavior and neural measurements
(Turner et al., 2017). Behavioral models are
widely used in the field of mathematical psychol-
ogy, in which estimates of cognitive parameters
are often statistically linked to neural measure-
ments (Forstmann et al., 2015). These models
provide handles to understand the type of com-
putations implemented in the brain that underlie
cognition and behavior. At the same time, neu-
ral models are biophysical models that typically
describe the time evolution of neuronal membrane
potential or firing rates with differential equations.
These are valuable for investigating how neuronal
functions arise from biological properties such as
specific ionic currents or synaptic connectivity
patterns. We refer to (Dayan and Abbott, 2005;
Forstmann and Wagenmakers, 2015; Izhikevich,
2005) for excellent introductions on these topics.
Here, we will illustrate how the use of biophysical
models has provided more insights into the origin
of pathological neural oscillations in Parkinson’s
disease (PD), and how biologically inspired mod-
els of behavior have served to elucidate the neural
underpinnings of reinforcement learning.
BIOPHYSICAL MODELING IN
PARKINSON’S DISEASE
PD is associated with dysfunction of the basal
ganglia. Cardinal symptoms such as bradykinesia
(slowness of movement), rigidity, and tremor arise
as a result of the degeneration of dopaminergic
neurons in the SNc. According to current view-
points (Surmeier et al., 2007), D1 and D2 receptor
activation modulate the intrinsic excitability of
MSNs in distinct fashions: D1-receptor activation
in MSNs that belong to the direct pathway have
excitatory effects, whereas D2-receptor activation
in MSNs that belong to the indirect pathway give
rise to inhibitory effects on the excitability of the
MSNs. The reduced dopamine availability as
observed in PD would cause a disbalance between
203
direct and indirect pathway activation with an
overall exacerbated activation of the indirect path-
way, leading to inhibitory effects on motor control
and in the presentation of clinical motor symp-
toms. This theory fits with the observed changes
in neuronal firing rates in GPe, STN, and GPi
(Albin et al., 1989; DeLong, 1990), although it
cannot readily explain altered firing patterns in
these structures. In the Parkinsonian state, neurons
of the indirect pathway have been demonstrated to
exhibit an increased incidence of bursting and
oscillatory firing (Bergman et al., 1994;
Steigerwald et al., 2008). In particular, the local
field potential amplitude of beta band (∼13- 35Hz)
oscillations in STN is positively correlated with
severity of bradykinesia and rigidity (Neumann
et al., 2016; van Wijk et al., 2016) and its reduc-
tion in response to dopaminergic medication
(Kühn et al., 2006; Kühn et al., 2009; Ray et al.,
2008) or DBS (Kühn et al., 2008; Ray et al., 2008)
predicts observed clinical improvement.
Identifying the synaptic circuits involved in beta
generation is important for understanding the
pathophysiology of PD and the development of
targeted treatments.
Dynamical systems theory indicates that oscil-
lations in a neuronal network can emerge when
excitatory and inhibitory neurons are recurrently
connected. Considering the cortico-basal ganglia-
thalamus network, there are several ways in which
oscillations could potentially arise in the system
(Figure 13.2A). Many studies have focused on
the STN-GPe circuit. Several research groups
(e.g., Gillies et al., 2002; Holgado et al., 2010;
Humphries et al., 2006; Liu et al., 2016; Terman
et al., 2002) have applied computational models
to understand how the membrane potential or fir-
ing rate of individual neurons or populations of
neurons in this circuit responds to synaptic input.
This work shows that oscillations emerge within
certain parameter ranges of synaptic connection
strengths and transmission time delays within
the circuit. Notably, connections leading directly
to the STN-GPe circuit have a critical influence
(Holgado et al., 2010). A mere increase in striatal
inhibitory input to GPe could trigger oscillations
(Gillies et al., 2002; Kumar et al., 2011; Terman
et al., 2002). Alternatively, inhibitory interactions
between striatal MSNs (McCarthy et al., 2011) or
in combination with fast-spiking interneurons and
the feedback loop with GPe (Corbit et al., 2016)
have been proposed as a possible source of beta
oscillations. Long feedback loops involving cor-
tex can also generate oscillatory activity (Leblois
et al., 2006; Pavlides et al., 2015). Last, but not
least it is possible that oscillations originate else-
where in cortex or the cortico-thalamic circuit and
propagate through the BG (Hahn and Mcintyre,
204 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
2010; Pavlides et al., 2015; van Albada and
Robinson, 2009). Many of these studies motivate
their parameter values or validate their results with
findings from experimental studies.
The question then rises which of these pos-
sibilities most likely underlies the emergence of
beta oscillations in PD. Moran et al. (2011) used
dynamic causal modelling (DCM) to address
this question through computational analyses.
They constructed a generative model comprised
of coupled neural masses, one for each excita-
tory or inhibitory neural population included
in a cortico-basal ganglia-thalamus network.
Parameters derived from this model included
synaptic coupling strengths between neural pop-
ulations. Their values were estimated through
Bayesian model inversion by comparing model
predictions of power- and cross-spectral densi-
ties with experimental data. These data were
obtained from a group of 6-hydroxydopamine
(6-OHDA)-lesioned rats (an established model
of PD), and compared to an appropriate control
group. Electrocorticography and local field poten-
tials were recorded from four sites in the net-
work: cortex, GPe, STN, and the entopeduncular
nucleus (EPN, the rodent orthologue of the GPi).
6-OHDA-lesioned rats showed a marked spec-
tral peak in the beta frequency range that was not
observed in control animals (Figure 13.2B). The
difference between the two groups of animals was
best explained by a significantly increased input
from cortex to the STN and a reduced input from
the STN to GPe in the 6-OHDA-lesioned animals.
Later DCM studies using local field potentials
recorded with DBS electrodes in human patients
confirmed that the presence of beta oscillations is
associated with altered connection strengths of the
hyperdirect pathway and the STN-GPe circuit, as
well as other connections in the indirect pathway
and elsewhere (Figure 13.2B) (Marreiros et al.,
2013; van Wijk et al., 2018). These results are in
support of widespread effects of dopamine deple-
tion on synaptic transmission in the cortico-basal
ganglia-thalamus network. Multiple connections
are likely to contribute to the onset of pathological
beta oscillations in the indirect pathway.
ROLE OF THE BASAL GANGLIA IN ACTION
SELECTION AND REINFORCEMENT
LEARNING
The classical view poses that the direct and indi-
rect pathways serve to gait action representations
from frontal cortex by selectively facilitating one
of the action representations whilst inhibiting all
competing ones (Mink, 1996). Dopamine has
been implicated in learning to select the most
rewarding action given a particular context of
sensory input. Striatal neurons receive phasic
dopaminergic input from the SNc in response to
unexpected rewards to a conditioned stimulus
(Schultz, 1998). Conversely, the omission of an
expected reward leads to a dip in dopaminergic
signaling compared to tonic baseline innervation.
Synaptic plasticity has been demonstrated in stud-
ies where the stimulus-response combination
repeatedly leads to unexpected rewards. The
release of dopamine promotes long-term potentia-
tion by activating MSN D1 receptors (Surmeier
et al., 2007), resulting in the activation of the
direct pathway and increasing the probability for
selecting the same response option next time
(Cohen and Frank, 2009). The same action repre-
sentation in the indirect pathway weakens as
dopamine promotes long-term depression through
the activation of MSN D2 receptors. A decrease in
dopamine release would result in an inverse effect
through long-term potentiation of D2 MSN neu-
rons (Shen et al., 2008). This process creates a
dynamic balance between facilitation and inhibi-
tion of response actions and, although speculative,
could underlie reinforcement learning.
Frank et al. (2005, 2007) performed a series
of computational modeling studies to investi-
gate whether the BG neural architecture supports
action selection learning behavior as observed in
healthy individuals and can predict how behavior
relates to varying dopamine levels. Inspired both
by BG anatomy, and the computational properties
of neurons, a neural network model was designed
(Figure 13.3A) (Frank, 2005). The model learned
to select one of two behavioral responses for given
input stimuli. Each node in the network contained
a column of neurons that encoded activity for one
of the response options. Neurons were activated
through input from the previous node, incorpo-
rating the synaptic weight of the connection. The
balance in activity between the direct and indirect
pathway ultimately determined response option
selection at the output level of the network, the
premotor cortex. Hebbian learning as well as error
learning was included to drive the updating of syn-
aptic weights after receiving feedback whether the
selected response was correct.
Simulations under normal conditions revealed
a good learning performance (Frank, 2005).
Interestingly, the model performed significantly
worse if only the direct pathway was included
compared to the intact network, suggesting that
the enhanced contrast created by opposing modu-
lations in the direct vs. indirect pathway improves
discriminability between response options (Cohen
and Frank, 2009). Furthermore, the model could
 Modeling of Basal Ganglia Structure and Function 205

explain how an altered balance of tonic and phasic
dopamine leads to unequal learning effects from
positive vs. negative outcomes (Frank et al., 2004).
The model correctly predicted that PD patients are
better in learning from negative than from posi-
tive outcomes when in a low dopaminergic state, a
pattern that reverses after taking levodopa (Figure
13.3B). This finding may help explain why dopa-
minergic medication improves performance for
some cognitive tasks but yields opposite effects
in others. Next, the role of the STN was consid-
ered as it is one of the primary targets for DBS
treatment of PD. Projections from STN to GPi are
more diffuse than those from GPe to GPi (Mink,
1996; Parent and Hazrati, 1995), which has fueled
the hypothesis that the STN acts to globally sup-
press responses. Its monosynaptic input from
cortex via the hyperdirect pathway would serve as
a rapid signal to withhold all responses in case of
conflicting sensory input. This mechanism avoids
premature responses by allowing extra decision-
making time. To test this, Frank et al. (2007)
included the STN in their network and tested the
effect of STN-DBS on impulsive behavior in a
decision-making task. DBS did not affect learn-
ing but speeded up reaction times (RTs) for high-
conflict (difficult) trials. The modeling confirmed
that interfering with STN activity increases the
probability of premature responses triggered by
early firing in the direct pathway. These examples
highlight how computational modeling can aid in
identifying the BG anatomical pathways and bio-
logical processes involved in controlling aspects
of behavior.

Figure 13.3 A biologically constrained computational model of action selection correctly

predicts learning behavior in Parkinson’s disease.
A Network architecture of the model with example activation (in different grey shades). Each
cell represents a processing unit whose activation dynamics is inspired from real neurons.
Each column encodes one of two response options. Direct (“go”) and indirect (“no go”) path-
ways originate in the striatum. Relative activation in these pathways for the two response
options determines the final behavioral response (“R1” vs. “R2”). Synaptic weights in the
network are adjusted according to Hebbian and error learning after outcome presentation.
B Model predictions are tested against performance in a probabilistic decision-making task.
Individuals implicitly learn which of two stimuli in a training-pair is associated with the
higher probability of positive outcome. Subsequently, they are tested during presentation
of novel test-pairs of stimuli, to infer whether they rely more on learning from positive
(“Choose”) or negative feedback (“Avoid”). PD patients took part before (“OFF”) and after
(“ON”) receiving dopaminergic medication. Observed performance during the task is shown
top right (cf. model predictions bottom right). Note the reversal in learning from negative vs.
positive outcomes in PD with medication is well-captured by the model.
Source: Adapted from Frank et al., 2004. Reprinted with permission from AAAS.
206 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
CONSIDERATIONS IN COMPUTATIONAL
MODELING
By definition, computational models are simplifi-
cations of the biological system they reflect. For
example, despite evidence for anatomical projec-
tions from GPe to STR (Mallet et al., 2012), and
from GPe to GPi (Smith et al., 1998), both Moran
et al. (2011) and Marreiros et al. (2013) concluded
through formal model comparisons that incorpo-
rating these connections into the basal BG circuit
did not improve the model’s performance in
explaining beta oscillations beyond the cost of
added complexity. Similarly, initial models by
Frank et al. (2005) did not include the STN, pre-
sumably because the indirect pathway connection
between GPe and GPi was sufficient for obtaining
qualitatively correct model predictions of action
selection. On the other hand, leaving out relevant
components could significantly alter the behavior
of the system. Rubin (2017) provides an in-depth
discussion on the importance of biological details
in computational models of BG dysfunction.
Validation of computational models on the basis
of experimental data will remain crucial for reach-
ing reliable and robust conclusions. A challenge
for future research is to integrate neural and
behavioral models for finding even more direct
links between behavior and underlying biophysi-
ological processes.
SYNERGISTIC APPROACHES
Data from individual research fields will not
explain how the brain works. The field of descrip-
tive anatomy provides an account of the character,
form, size, and position of structures in the brain.
The combining of maps that contain multiple
levels of description, can grow into sizable atlas-
ing efforts which provide valuable resources.
These resources can be used by researchers from
other fields to retrieve the data relevant for their
theory formation, and provide anatomical validity
to their research findings. Through these integra-
tive efforts, descriptive anatomy is transferred to
the field of functional anatomy and computational
modeling, which in turn can indicate missing
nodes in the network models, which should be
retrieved via anatomical studies.
The combined research data can subsequently
be used for hypothesis generation. If the anatomi-
cal architecture and model behavior do not match,
this can either lead to the adjustment of the model,
or to additional research in the field of anatomy to
identify the missing part of the anatomical archi-
tecture. If we return to the comparison to the traffic
architecture, imagine the planning of a three-day
holiday trip, and a calculation of whether the traf-
fic architecture allows the completion of such a
trip. The hypothesis formulated could be that an
overnight accommodation should be included
along the set route. Identification of accommoda-
tion for overnight stays along the route would then
represent the equivalent of anatomical research
inspired by the modeling results.
Computational modeling could lead to the
description of the anatomical nodes beyond those
already in the model. The incorporation of addi-
tional structures into the model architecture may
not be needed to explain the main function of the
model, but could for instance allow the refinement
of specific models. One could for instance specu-
late that models based on dopamine signaling
would benefit from further refinement through the
incorporation of modulating systems. Although
speculative, the cannabinoid system is an interest-
ing candidate.
Conversely, hypothesis generation can be
driven by anatomy. Questions raised from the field
of anatomy include: What is the function of neu-
ronal populations or sources of neuromodulation
that are currently not included in circuit models?
For instance, what is the role of serotonergic mod-
ulation of STN function, and to what extent does
DBS affect serotonin signaling? Additionally,
does potential modulation of serotonergic signal-
ing contribute to the desired clinical effects, or to
the unwanted side effects of DBS (Temel et al.,
2005)? Can we identify additional anatomical
components that regulate behavior other than that
described in available models, or do they provide
additional modulatory components for the model?
Bringing together hypotheses from modeling and
anatomy is expected to contribute to the refinine-
ment of available models, the identification of
latent parameters, as well as the identification
of structures responsible for these parameters.
Ultimately these efforts can lead to a deeper
understanding of the BG nuclei and regulation of
their activity.
SUMMARY AND CONCLUSIONS
Understanding the role of the BG in human
behavior is the goal of many research groups
working in individual research disciplines world-
wide. Currently, we can integrate findings from
different fields using an interdisciplinary
approach. Individual research disciplines can
 Modeling of Basal Ganglia Structure and Function
benefit from other disciplines through the filling
of knowledge gaps that result from technical limi-
tations inherent to specific approaches, which are
present in every type of research, and which could
potentially lead to unwanted biases within specific
research fields.
Formal computational modeling is crucial in
this process, through providing a level of descrip-
tion that allows the translation of quantitative
research parameters between behavioral and
anatomo-functional data. Additionally, formal
modeling can lead to the identification of latent
factors that are needed to accurately explain and
predict behavior and behavioral changes. For BG
modeling, these interdisciplinary approaches have
already led to a deeper understanding of the brain
alterations that are observed in people with PD, as
well as more insight in the mechanisms underly-
ing reinforcement learning.
Crucial for the success of such efforts is the
availability of neural and behavioral data for com-
putational modeling. With increasing importance
of open science and open data, more research
groups are now sharing their data allowing reuse
and reanalysis of brain and behavioral data-
sets. The process of sharing data within the field
of cognitive neuroscience is further facilitated
through initiatives that aim to create uniformity in
data sharing structure that facilitates the algorith-
mic processing of individual datasets. An excel-
lent example of such efforts is the introduction of
the Brain Imaging Data Structure (BIDS) format,
which provides an intuitive and consistent method
for the arrangement of anatomo-functional and
behavioral data (Gorgolewski et al., 2016).
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Cerebellum: Advances in
Understanding of
Cerebellar Functions
INTRODUCTION
The cerebellum has intrigued scientists and phi-
losophers from the Antiquity. During the eight-
eenth century, Vincenzo Malacarne (1744–1816)
provided the first detailed macroanatomical
description of the human cerebellum (cf. Zanatta
et al., 2018). In particular, he suggested that there
was a correlation between the number of cerebel-
lar folia and the environment, which was the first
pioneering idea of neuroplasticity related to exter-
nal factors. He suggested that the number of folia
was linked with the degree of intelligence, provid-
ing the first hypothesis of the role of the cerebel-
lum in cognition. He also introduced the current
terminology of vermis, tonsil, pyramid, and uvula.
Subsequently, Luigi Rolando (1773–1831)
observed that cerebellar lesions can impair pos-
ture and voluntary movements (Schmahmann,
2016). Luigi Luciani (1840–1919) reported three
elemental deficits ipsilateral to a cerebellar lesion
performed in primates and in dogs: atonia, asthe-
nia and astasia. In the early 1800s, Jean Pierre
Flourens (1794–1867) was the first to associ-
ate cerebellar lesions with lack of coordination.
Likewise, Jan Evangelista Purkyně first identified
Purkinje neurons in the early 1800s. At the begin-
ning of the twentieth century, Santiago Ramón y
14
Mario Manto
Cajal (1852–1934) reported the fine network struc-
ture of the cerebellar cortex, and subsequently,
Gordon Holmes (1876–1965) described motor
deficits, underlining the clumsiness in patients
presenting with a cerebellar injury/lesion (cf.
Coco and Perciavalle, 2015). During World War I,
hundreds of soldiers suffered injuries to the occip-
ital region and cerebellum, because the issued hel-
mets did not cover these regions adequately. This
gave the opportunity to Gordon Holmes to observe
and report the clinical deficits in soldiers suffering
from acute cerebellar lesions (e.g., from gunshot
wounds). Subsequently, Olof Larsell (1886–1964)
identified the 10 lobules (I–X) of the cerebel-
lum (Larsell and Jansen, 1973). More recently,
toward the end of the twentieth century, Jeremy
D. Schmahmann reported the cognitive and affec-
tive deficits in cerebellar ataxias, thereby identi-
fying the third cornerstone of clinical ataxiology
(Schmahmann and Sherman, 1998; Manto and
Marien, 2015).
STRUCTURAL ANATOMY
Cerebellum occupies a large portion of the poste-
rior fossa, posteriorly to the brainstem. Although
 Cerebellum: Advances in Understanding of Cerebellar Functions
the human cerebellum contains about 60% of all
neurons of the brain, it occupies only 10% of brain
volume. Structurally, the cerebellum is composed
of four pairs of nuclei embedded in the white
matter which is surrounded by the cerebellar
cortex (Colin et al., 2002). By comparison with
the cerebral cortex, the cytoarchitecture of the
cerebellum is particularly uniform.
In terms of evolution, the cerebellum consists
of a single folium in amphibians and most teleosts
(Colin et al., 2002). The vermis is already visible
in reptiles and birds. The number of folia increases
markedly from birds to primates as a result of a
rostro-caudal expansion. The medio-lateral expan-
sion of the hemispheres follows the development
of the cerebral cortex. The phylogenetic expansion
of the neocerebellum is associated with expanding
interactions with the cerebral cortex, impacting
on information coding and processing capac-
ity (Huang and Ricklefs, 2013). Both in birds
and mammals, the expansion of the cerebellum is
nearly proportional to the telencephalon (Sultan,
2002). The constancy of the cerebellar fraction in
birds and mammals (about 10–15% of the whole
brain) has been interpreted as an argument to
consider that the cerebellum is a general-purpose
computational machine showing plasticity mecha-
nisms (Huang and Ricklefs, 2013; Herculano-
Houzel, 2010).
Anatomically, the cerebellum is highly con-
served across mammals, with a division of the
cortex by two fissures: (1) the primary fissure sep-
arating the anterior lobe from the posterior lobe,
and (2) posterolateral fissure separating the poste-
rior lobe from the flocculonodular lobe. The criti-
cal works of Jan Jansen, Olof Larsell, Robert Dow,
and Jan Voogd have founded our current under-
standing of the structural organization of the cer-
ebellum (cf. Larsell and Jansen, 1973; Voogd and
Koehler, 2018; Colin et al., 2002). Jansen divided
the human cerebellum on the basis of the fissures
into an anterior lobe, a posterior lobe and the floc-
culus/paraflocculus. Larsell subdivided the cer-
ebellum into 10 lobules (numbered I to X; Larsell
and Jansen, 1973; Colin et al., 2002). Dow used
the mossy fiber projections to the cerebellar cor-
tex to divide the cerebellum into three main areas:
the flocculonodular lobe (vestibulocerebellum),
the vermal anterior and posterior lobes receiving
spinal projections (paleocerebellum) and a medio-
lateral portion receiving mainly ponto-cerebellar
projections (neocerebellum).
The cerebellar cortex is arranged into three lay-
ers: the molecular layer, the Purkinje cell layer and
the granular layer. These three cortical layers con-
tain six main neuronal populations (Purkinje, stel-
late, basket, Lugaro, Golgi and granule neurons).
213
Whereas granule cells are excitatory, the other
neurons are all inhibitory and use principally
gamma-aminobutyric acid (GABA). Purkinje neu-
rons inhibit cerebellar nuclei, the sole output of
the cerebellar circuitry. Purkinje neurons form a
monolayer (ganglionic layer) between the exter-
nal molecular layer and the internal granular layer.
Their number is around 15 million in the human
cerebellum (Colin et al., 2002). They target cer-
ebellar nuclei and vestibular nuclei (considered by
some authors as belonging to cerebellar nuclei).
The single primary dendrite of the Purkinje neu-
ron is directed towards the molecular layer and is
divided into a rich arborization (width of about
300 microns) perpendicular to the folium axis.
The numerous spines along the arbor make excita-
tory synapses with parallel fibers emerging from
the parallel fibers arising from granule cells. The
climbing fiber embraces the smooth proximal
portion of the dendrite, forming one of the most
powerful synapses in the brain. There is a 1:1 rela-
tionship between one ascending fiber and the den-
dritic tree of a Purkinje neuron.
It can be considered that three types of fib-
ers enter in the cerebellum: The climbing fibers
arising from the contralateral inferior olive and
ascending in the inferior cerebellar peduncle (res-
tiform body), the mossy fibers having numerous
origins (somesthetic, vestibular, visual, acoustic,
and cortical) and the cholinergic/monoaminer-
gic afferents (noradrenergic fibers, dopaminergic
fibers, serotoninergic fibers). The inferior olive
nucleus is a complex of multi-lamella structure
packed with small-sized gabaergic neurons (Luo
and Sugihara, 2016). The large majority of oli-
vary neurons are projecting to the cerebellum and
each olivocerebellar axon gives rise to collaterals
targeting cerebellar nuclei and provide also thin
collaterals terminating in the granular layer with a
small number of swellings. The functional signifi-
cance of these collaterals remains undetermined
(Luo and Sugihara, 2016). Whereas the multiple
climbing fibers originating from a single axon are
distributed in a longitudinal band-shaped area, the
projection pattern of mossy fiber axons is trans-
versal and wide (Luo and Sugihara, 2016).
Whereas fish and amphibians have a single
unique cerebellar nucleus, reptiles and birds have
a medial and lateral nucleus. In lower mammals,
three nuclei are identified: a medial nucleus,
an interpositus and a lateral nucleus. In higher
mammals, the interpositus nucleus is subdivided
into an anterior and posterior part. In human, the
medial nucleus is the fastigial nucleus, the glo-
bosus nucleus corresponds to the anterior inter-
positus, the emboliformis nucleus to the posterior
interpositus, and the dentate nucleus to the lateral
214 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
nucleus. The dentate nucleus contains the majority
of nuclear neurons. It appears convoluted with a
medial hilus and contains mainly large multipolar
neurons. Nucleofugal fibers are excitatory, with
the exception of the nucleo-olivary tract which is
inhibitory. Collaterals from climbing and mossy
ascending tracts excite nuclear neurons.
Vestibular nuclei project on the flocculonodu-
lar lobe at the level of the flocculus-paraflocculus,
the nodulus/ventral uvula, and the dorsal oculo-
motor vermis corresponding to lobules V to VII.
It can be considered that vestibular nuclei are at
a sensorimotor crossroad (Barmack, 2016) since
they are influenced by visual information, pro-
prioceptive signals, cerebellar signals, and signals
from the cerebrum. They target thalamic nuclei,
brainstem nuclei, and also the spinal cord. The
descending routes to the spinal cord run through
the ventral funiculus (medial descending sys-
tems including the uncrossed corticospinal tract,
the tectospinal tract, the reticulospinal tract, and
the vestibulospinal tract) and the lateral funiculus
(lateral descending systems gathering the crossed
corticospinal tract and the rubrospinal tract). The
medial vestibulospinal tract terminates bilaterally
in the ventromedial aspects of the spinal gray mat-
ter, until midthoracic levels (Ruigrok, 2016). The
lateral vestibulospinal tract targets the ventrome-
dial laminae of the spinal gray matter. The first
tract influences motoneurons innervating neck and
axial muscles, the second influences motoneu-
rons controlling extensor or anti-gravity muscles
(Ruigrok, 2016).
PHYSIOLOGICAL ASPECTS
Simple Spikes and Complex Spikes
Purkinje neurons fire two types of action poten-
tials: conventional action potentials (simple
spikes) and stereotyped bursts of decrementing
spikes (complex spikes; Otis, 2016). Simple
spikes are typical voltage-gated sodium channel-
dependent action potentials. Complex spikes are
sodium channel driven spikelets on a depolarized
plateau potential.
Purkinje neurons fire spontaneously at rest at a
high frequency of about 40–80 Hz (simple spikes),
in a very regular fashion. This pace-making fea-
ture is fundamental for the cerebellar cortex, as
it allows the Purkinje neurons to inhibit tonically
the cerebellar nuclei and vestibular nuclei (Otis,
2016). Climbing fibers evoke a complex spike
(frequency about 1 Hz) at the level of the Purkinje
neuron by activation of voltage-gated calcium
channels densely distributed throughout the den-
drites. It is generally considered that complex
spikes slow the simple spikes firing (Otis, 2016).
The number of simple spikes is decreased after
a complex spike (“post-complex spike pause”).
Rates of complex spikes and simple spikes are
anticorrelated in response to sensory stimuli
(Barmack and Yakhnitsa, 2011).
Rebound Depolarization
Cerebellar nuclei neurons receive collateral excit-
atory projections from mossy and climbing fibers
and a strong inhibitory projection from Purkinje
neurons. Neurons in nuclei show a unique feature
of rebound in firing after hyperpolarization
(Dykstra and Turner, 2016). There is a first
increase in the firing frequency of about 100 msec
(role of T-type calcium currents), followed by a
late rebound lasting a few seconds (persistent
sodium currents). The rebound firing likely con-
tributes to the sculpting of nuclear commands
towards extra-cerebellar targets (Dykstra and
Turner, 2016).
Plasticity Mechanisms
The cerebellum is endowed with multiple forms
of plasticity at various synaptic sites. Learning
and compensatory mechanisms involve plasticity
mechanisms both in the cerebellar cortex and in
cerebellar nuclei. The various forms of plasticity
are integrated in order to fit with the environmen-
tal requirements and for learning purposes.
Concomitant stimulation at a low frequency of the
climbing fiber and a parallel fiber is associated
with a persistent attenuation of the parallel fiber-
Purkinje cell synapse (Ito et al., 1982). This paral-
lel fiber long-term depression (LTD) is associative,
saturable, and involves mGluR, clathrin-depend-
ent AMPAR endocytosis and subsequent rise in
internal Ca++ (Shen, 2016). This LTD is consid-
ered critical for motor learning.
If the parallel fiber stimulation preceded the
climbing fiber-evoked complex spikes by 50–250
msec, a spike-timing dependent plasticity (STDP)
occurs. The parallel fiber-Purkinje cell synapse
is also the site a homosynaptic LTP depend-
ing on the stimulus frequency which is applied
(1 Hz-post-synaptic LTP and 4–8 Hz pre-synaptic
LTP). Presumably, the 1 Hz LTP is used as a reset-
ting mechanism for motor learning purposes. LTP
occurs also between interneurons and Purkinje
 Cerebellum: Advances in Understanding of Cerebellar Functions
neurons, presumably to modulate the spike firing
pattern of Purkinje neurons (Hausser and Clark,
1997). Another form of LTP is observed at the
level of the mossy fiber-granule cell synapse,
modulating the local coding in the granular layer.
The Marr-Albus-Ito theory was based on com-
putational principle of the cerebellum related to
a blueprint of the cerebellar circuit (Yamazaki,
2021). The model was established following dis-
covery of LTD and has been challenged over the
years. Cerebellar plasticity is now considered as
distributed amongst the cerebellar cortex and
nuclei (D’Angelo, 2016). The original idea that
plasticity was restrained to the parallel fiber-
Purkinje neuron under olivocerebellar guidance
is not considered as valid nowadays (D’Angelo,
2016). The current theory considers that cerebel-
lar plasticity is distributed and dynamically trans-
ferred through the various synaptic sites during
a specific behavior and according to the needs
to achieve a task successfully (D’Angelo, 2016).
During learning, numerous forms of plasticity
occur in various sites of the circuitry, with plastic-
ity being organized in specific temporal patterns
starting in the granular layer, extending to the
molecular layer and finally to the cerebellar nuclei
(Shen, 2016).
CEREBELLAR MODULES
The cerebellum is divided into a series of olivo-
cortico-nuclear modules arranged longitudinally
in the rostro-caudal plane. Each module is defined
by its climbing fiber input from a specific subdi-
vision of the inferior olivary complex which tar-
gets one or more longitudinal zones of Purkinje
cells. Specific zones of Purkinje neurons send
inhibitory projections to defined clusters of neu-
rons in cerebellar nuclei/vestibular nuclei, which
themselves target the inferior olive neurons (via
inhibitory nucleo-olivary tract) which will project
to the Purkinje neuron (closed-loop triangulation:
inferior olive – Purkinje neurons – nuclei;
Ruigrok, 2011). One module may include multi-
ple microzones which correspond to clusters of
neighboring Purkinje cells coherently active
during a given operation (Broersen et al., 2016).
Each microzone is composed of a group of
approximately 1000 Purkinje neurons having the
same somatotopic receptive field and arranged in
a long narrow strip. The cellular interactions
within a microzone are much stronger than a
those between different microzones.
The inhibitory nucleo-olivary tract regulates the
degree of gap junction coupling between olivary
215
neurons. The level of simple spikes in the cer-
ebellar cortex modulates the complex spike syn-
chrony by acting remotely on the GABA release
at the olivary gap junctions (Marshall and Lang,
2009). In other words, a reduction in the rate of
simple spikes in the cerebellar cortex will disin-
hibit cerebellar nuclei, thus reducing the complex
spike synchrony via the nucleo-olivary tract. A
decreased rate of simple spikes will thus result
in a reduction of the rate of complex spikes in a
specific cortical region (Broersen et al., 2016).
Optogenetic manipulation confirm these observa-
tions (Witter et al., 2013).
Cerebellum is also organized into discrete
microcomplexes. Each microcomplex is the
recipient of a specific motor error signal from
the inferior olive, this signal being used to teach
the cerebellar cortex. Climbing fibers arising from
multiple subunits of the inferior olive target sev-
eral microcomplexes, all projecting on the same
subunit of cerebellar nuclei. The microcomplex
can be seen as an operating unit from the compu-
tational standpoint.
CEREBRO-CEREBELLAR CONNECTIVITY
Anatomical Cerebro-cerebellar Loops
Cerebro-cerebellar connectivity is organized into
multiple parallel loops arranged topographically.
Their existence is supported in particular by trac-
ing studies in animals and the technique of diffu-
sion tensor imaging (DTI) which allows to identify
white matter tracts in vivo. Cerebral cortex pro-
jects to the contralateral cerebellum via the pon-
tine nuclei (feed-forward loop through the middle
cerebellar peduncle: crossed pontocerebellar
tract). In monkeys, the majority of the cortico-
pontine fibers arise from the motor system,
whereas they arise from the prefrontal areas in
human (Ramnani, 2006; Ramnani et al., 2006).
The cerebellum projects back to the cerebral
cortex via the cerebello-thalamo-cortical pathway
(feedback loop through the superior cerebellar
peduncle). Distinct territories of the dentate nuclei
target distinct thalamic and cortical areas (motor,
premotor, associative) (Strick et al., 2009). The
ventral part of the dentate nucleus projects to pre-
frontal and pre-supplementary motor cortices
whereas the dorsal part project to the motor cortex
(Middleton and Strick 2001). Lobules III–VI and
VIII are connected to the motor cortex and Crus II
is connected with area BA46 (Kelly and Strick,
2003). Overall, the following closed loops run in
parallel (Habas, 2016):
216 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
• dorsal dentate nucleus, caudal ventro-lateral
thalamus, area BA4
• lateral dentate nucleus, X thalamus, area BA6
• caudal dentate nucleus, X thalamus, area BA8
• ventromedial dentate nucleus, caudal ventrolat-
eral and mediodorsal thalamus, area BA9
• ventralateral dentate nucleus, caudal ventro-
lateral and mediodorsal thalamus, dorsolateral
prefrontal cortex (BA46)
• lateral dentate nucleus, caudal ventrolateral
thalamus, BA7
In addition, striato-cerebellar loops have been
identified: indeed, the dentate nucleus projects to
the pallidum via the thalamus and the subthalamic
nucleus projects to the cerebellar cortex (crus II,
lobule VIIb) via pontine nuclei (Bostan et al.,
2010). Thanks to Strick et al. (2009), it is clear
that the cerebellum communicates with the basal
ganglia via disynaptic loops.
The spinocerebellar tracts convey the informa-
tion from the spinal cord to the cerebellum via
the inferior and superior cerebellar peduncles.
Lobules I–V, part of the lobule VI and lobule VIII
receive direct spinal afferents and spinal cord pro-
jects also to the inferior olive (spino-olivary tract).
Unlike these lobules which are directly connected
with the spinal cord (hence the terminology of
spino-cerebellum), the remainder of lobule VI and
lobule VII (VIIa, Crus I, Crus II, VIIb) receive no
direct spinal projection (Brodal and Brodal, 1981)
but are massively involved in cerebro-cerebellar
loops (prefrontal cortex, posterior parietal cortex,
superior temporal cortex, cingulate gyrus, para-
hippocampus) as reported above. A dichotomy of
cerebellar connections with the cerebral cortex,
brainstem and spinal cord has thus emerged.
Cerebellum receives numerous inputs from vis-
ual and eye movement-related regions via the pons
(Roth et al., 2016). The information is integrated
with proprioceptive and vestibular signals to adapt
spatial orientation. The cerebro-pontine projec-
tions originate from the frontal eye fields, the sup-
plementary eye fields, lateral intra-parietal area,
medial intra-parietal area, medial temporal area,
and middle temporal area (Roth et al., 2016). The
ponto-cerebellar projections terminate as mossy
fibers mainly in VI and VII of the posterior vermis
and the paraflocculus (Thier, 2011). The cerebel-
lum optimizes goal-directed movements not only
by acting on neck/trunk/limb muscles, but also by
controlling saccades, smooth pursuit as well as
ocular reflexes (Roth et al., 2016). Furthermore,
the cerebellum contributes to the adaptation and
recalibration of eye movements (see internal mod-
els below). Damage to lobules VI and VII of the
posterior vermis and paraflocculus are associated
with errors in saccades, irregular smooth pursuit,
and impaired adaptation.
Functional Anatomy
Important progress has been made these last 15
years in the understanding of resting-state net-
works and the mapping of motor versus non-
motor tasks in the cerebellum (Brissenden et al.,
2016; Buckner et al., 2011; Guell et al., 2018a,b;
King et al., 2019; Marek et al., 2018). Functional
imaging studies have confirmed that the cerebellar
circuitry is involved in multiple functions, beyond
the pure motor control. Functional maps can even
be extracted at a single-subject level (Marek et al.,
2018). Globally, the meta-analysis of neuroimag-
ing studies confirms the neuroanatomical findings
explained above (Stoodley and Schmahmann,
2009). The concept of task-dependent engage-
ment of specific cerebellar subregions is now
widely accepted.
The independent component analysis (ICA)-
based functional connectivity has delineated major
networks from resting-state fMRI data (Habas,
2016), including: the sensorimotor network
involved in sensorimotor operations, motor and
premotor cortex, lobules V–VI and VIII. Simple
movements or tactile tasks activate the sensori-
motor homunculi ipsilaterally: The right and left
executive networks, dorsolateral prefrontal and
parietal prefrontal cortices, Crus I/II – the lim-
bic “salience” network involved in interoception,
emotional, and autonomic regulation, frontal and
insular cortices, lobules VI/VII – the default-mode
network involved in self-agency, memory, and
mental imagery – dorsomedian prefrontal, poste-
rior cingulate, retrosplenial and parahippocampal
cortices, precuneus, lobules VII and IX. Regarding
language, clusters are predominantly right-lateral-
ized and involve lobules VI–VII. Verb generation
typically engages right-lateralized lobules VI–VII
(Ashida et al., 2019; Stoodley, 2012).
It has been proposed recently that three main
networks actively drive cerebellar activity (Guell
and Schmahmann 2018b): motor network: acti-
vation during movements; attentional/executive
network: stimulus-driven attention (ventral atten-
tion network, salience network), goal-oriented
attention (dorsal attention network), and related
executive functions (frontoparietal network);
default-mode network: mind wandering, and deac-
tivation during attention-demanding processes.
Guell and Schmahmann (2018a,b) suggested
that cerebellar functional anatomy is founded on
these three poles. There are two representations of
 Cerebellum: Advances in Understanding of Cerebellar Functions
motor processing in the cerebellar cortex: lobule
I–VI and lobule VIII. For the attentional/execu-
tive network and the default-mode network, there
are three representations: lobules VI-Crus I, Crus
II-lobule VIIB, lobules IX–X. Crus I-Crus II are
at the intersection of a first and a second default-
mode representation. It is plausible that the pro-
gression at a macroscale functional organization
evolves from (a) motor to (b) attentional/execu-
tive, and to (c) default-mode processing.
Our appraisal of emotion processing (engage-
ment of cerebellar vermis), vestibular functions
(engagement of cerebellar vermis and lobules
IX–X), language processing (lateralization on the
right side), and social cognition (engagement of
the default-mode network) still require further
research. Ongoing studies show that the social
mentalizing depends on CrusI/II (Van Overwalle
et al., 2020).
The functional organization reported here is
growingly recognized at the level of the cerebellar
cortex, but the functional organization at the level
of cerebellar nuclei still remains to be refined.
Recent data indicate that the human dentate
nucleus contains three distinct territories belong-
ing to the default-mode, salience-motor, and visual
networks (Guell et al., 2019). It is unclear whether
and how the interpositus nucleus and the fastigial
nucleus contribute to these networks.
Regional gray matter volumes in lobules IV–
VI are correlated with motor skills, whereas gray
matter in the posterior lobe is correlated with per-
formances on cognitive operations (Bernard and
Seidler, 2013; Moore et al., 2017). Older adults
have smaller cerebellar volume than young adults
and lobules in the anterior cerebellum are more
impacted by age. A disrupted cortico-cerebellar
resting state network connectivity has been identi-
fied in older adults (Bernard et al., 2013). There is
a disruption of cerebellar connectivity with both
the striatum and the medial temporal lobe in the
elderly. Engagement with the default mode net-
work and striatal pathways is associated with bet-
ter performance for older adults.
Assessment of Emotions
The example of emotions reflects very well the
importance of the numerous hubs of the brain and
the re-appraisal of their complex interactions
(Thomasson and Péron, 2022). The models of
Papez and MacLean stressed the cortical struc-
tures in the processing of emotions, with the
exception of the amygdala and the anterior nucleus
of the thalamus. Research has moved towards an
integrated cerebello-basal ganglia-cortical view of
217
emotion (Thomasson and Péron, 2022). For
instance, an integrated model of emotional pro-
cessing for prosody has been proposed and sug-
gests that the stimuli are processed by the cerebral
cortex, basal ganglia, and cerebellum (Thomasson
and Péron, 2022). Within each of the three struc-
tures, areas related to sensorimotor, associative,
and limbic tasks would be activated, with a func-
tional gradient. Temporal processing would be
divided into two functions: detection of global
similarity with previous responses by the basal
ganglia, and detection of irregularities in the tem-
poral pattern (violations in fine variations) by the
cerebellum. Emotions recruit lobules VI–VII,
with activation of lobules II–VI/VIII in relation to
motor responses, rostral and caudal vermal activa-
tions in case of autonomic regulation and associa-
tive learning in conjunction with amygdala
(Habas, 2022).
The anatomical connectivity of these networks
would allow the processing of emotions at a tem-
poral level and allow also to contribute to the
multidimensional aspect of the emotional expe-
riences of daily life (Habas, 2022). By using the
widespread connectivity with the cerebral cortex
and basal ganglia, the cerebellum would modulate
patterns of events in the time domain not only by
using predictions but also by taking advantage of
a reward-based error feedback, so that the cere-
bellum would help in the selection of emotional
responses which are the most rewarded in a given
context (Pierce and Péron, 2022). Even in the
emotional domain, prediction errors would be con-
veyed by the olivo-cerebellar pathway. This would
tune the sensitivity of the parallel fibers/Purkinje
neurons, resulting in reinforcement (or the reverse)
of projections towards the limbic system, the
orbitofrontal cortex, and the amygdala (Pierce and
Péron, 2022). Furthermore, cerebellum contrib-
utes to both biological motion perception and dis-
crimination in body emotional expressions, which
represent a powerful form of non-verbal com-
munication (Ferrari et al., 2022). Understanding
others’ emotional/mental states such as intentions
are particularly relevant (Adamaszek et al., 2017).
Although faces have been considered as a major
supply to transmit intentions and feelings, bogy
language contributes greatly as cues. The reper-
toire of emotional body postures has appeared as
extremely rich (Ferrari et al., 2022). Examples are
embarrassment, shame, pride, and anger.
When individuals are distant, the assessment
of body expressions becomes a major tool to infer
other’s intentions. In some cases, body signals are
critical to clarify ambiguous facial expressions.
The streams of information go through a ventral
path (the extra-striate body area and the fusiform
body area), a visuomotor circuit involving the
218 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
posterior superior temporal sulcus, the inferior
parietal sulcus, and the premotor areas (Ferrari
et al., 2022). The visuomotor circuit interacts
with the amygdala to assess body movements and
trigger adaptative behaviors. The posterior supe-
rior temporal sulcus is a key-structure to process
motion and integrates the signals with three net-
works: the mentalizing, the action-observation,
and the mirror networks. Furthermore, body
posture elicits reflex-like responses at the level
of the amygdala, the superior colliculus, and the
striatum. The amygdala can be envisioned as an
interface between the cerebral cortex and the sub-
cortical structures. Interestingly, the insula, the
somatosensory cortices, and the anterior cingulum
are closely connected with the amygdala, likely to
take into account visceral and attentional aspects
related to emotional processing (Ferrari et al.,
2022). Since the cerebellum is anatomically linked
to both the visuomotor circuit and the amygdala,
it is likely involved in the detection of viola-
tions during the assessment of emotions detected
through the analysis of body expressions. The
anterior-superior lobules of the cerebellum are
recruited when perceiving body expressions con-
taining emotional contents, likely by a resonance
mechanism (Agnew et al., 2007). Posterior lobules
are essential to process emotional body language.
The cerebellum is now considered a master-piece
of the connectome of nodes supporting behavior.
Identification of the functional networks open
up direct perspectives for clinical applications
both in terms of diagnosis, follow-up and thera-
pies of cerebellar ataxias such as neuromodulation
techniques targeting specific areas of the cerebel-
lar cortex. Cerebellar patients experience difficul-
ties to identify and classify basic emotions and
exhibit difficulties for social and affective behav-
ior. Overall, the disorders observed fit with the
general concept of a mismatch between internal
resources and the environmental demand, leading
to impaired homeostasis, extending the impact
of cerebellar dysfunction to structures regulating
general metabolic, visceral, and endocrine pro-
cesses such as the hypothalamus (Schutter, 2022).
CEREBELLO-CORTICAL CIRCUITS:
NEUROPHYSIOLOGICAL ASPECTS
Connectivity between the cerebellum and associa-
tive areas of the cerebral cortex is the anatomical
substrate of the contribution of the cerebellum in
higher cognitive functions including cognitive and
emotional behavior (Ramnani, 2012; Schmahmann
and Sherman, 1998). Dentate nuclei are anatomi-
cally connected with the prefrontal, temporo-
parietal and limbic areas (Schmahmann, 2010).
Each portion of the cerebellar cortex has specific
feedforward and feedback connections to the cer-
ebral cortex (Pisotta and Molinari, 2014). The
connectivity can be understood as a large set of
loops running in parallel (see above).
Using transcranial electrical stimulation and
transcranial magnetic stimulation (TMS), Ugawa
has demonstrated that stimulation over the human
cerebellum modulates the responses to a second
stimulus delivered over the contralateral primary
motor cortex (M1). Delivering a TMS pulse (con-
ditioning stimulus, CS) 5–7 msecs over the con-
tralateral cerebellar hemisphere before a second
stimulus over M1 (test stimulus, TS) inhibits the
TS (Ugawa et al., 1991; Ugawa et al., 1995). This
is called cerebellum-brain inhibition (CBI). The
reduction in the amplitude of the motor response
is interpreted as the consequence of the activa-
tion of Purkinje cells by the CS. This activation
of the cerebellar cortex inhibits cerebellar nuclei
which have themselves a disynaptic excitatory
connection with contralateral M1. These obser-
vations have served to explore the effects of the
neuromodulation of the cerebellar cortex (tDCS:
transcranial direct current stimulation, TMS)
upon CBI.
In patients presenting focal unilateral cerebellar
damage, Di Lazzaro et al. have observed reduced
excitability of the contralateral motor cortex, sug-
gesting that the cerebellum exerts a facilitating
tonic action on motor circuits (Di Lazzaro et al.,
1994a,b, 1995; Restuccia et al., 2001, 2007).
This has been confirmed in rodents (Oulad Ben
Taib et al., 2005). Application of cerebellar epi-
dural anodal tDCS decreases the excitability of
the motor cortex, reduces the excitability of F
waves, exerts a “smoothing effect” on corticomo-
tor maps and increases the afferent inhibition of
conditioned motor evoked responses (Oulad Ben
Taib et al., 2013). This study provided evidence
of a mechanism by which tDCS of the cerebellum
exerts a remote neuromodulatory effect upon the
motor cortex.
Tesche and Karhu (2000) and Ivry (2000) have
suggested that the cerebellum predicts incoming
somatosensory stimuli and tunes the activity of
the somatosensory cerebral cortex accordingly.
In patients with lateralized cerebellar lesions,
Restuccia et al. (2001) have demonstrated that the
cerebellum influences the activity of inhibitory
circuitries in the primary somatosensory cortex
(Restuccia et al., 2001). The cerebellum appears
to modulate the excitability of the primary sensory
cortex at very early stages of somatosensory input
 Cerebellum: Advances in Understanding of Cerebellar Functions
processing. Also shown is the implication that the
cerebellum operates in mismatch negativity. Also,
cerebellar patients show an impaired capacity to
correctly process somatosensory information at
the cortical level. Taken together, these observa-
tions indicate that the cerebellum exerts a remote
effect upon both the excitability of the motor cor-
tex and the processing of somatosensory inputs.
CEREBELLAR RESERVE
Cerebellar ataxias (CAs) result from various inju-
ries and manifest clinically with motor, oculomo-
tor and cognitive/affective deficits (see next
section). Cerebellar symptoms may recover
remarkably, as underlined by Holmes (cf. Mitoma
and Manto, 2021). Cerebellar reserve is defined as
the capacity for compensation and restoration fol-
lowing pathological changes in the cerebellar cir-
cuitry. The structural cerebellar reserve
corresponds to a compensation of a structural
damage in a limited area of the cerebellum (for
instance in case of stroke, traumatic injury or
tumor) by another area of the cerebellum (cerebel-
lar structures around the lesion, contralateral cer-
ebellar hemisphere), which is unaffected. The
functional cerebellar reserve refers to a compensa-
tion or restoration which occurs within the lesion
site (for instance in case of immune ataxias, meta-
bolic ataxias, degenerative ataxias) via a func-
tional reorganization.
Experimental studies show that motor recov-
ery may be substantial despite extensive cerebel-
lar lesions such as hemicerebellectomy (Federico
et al., 2006). However, a second lesion may
decompensate the symptoms, as observed for
a subsequent lesion at the level of the sensory
cortex (Mackel, 1987). When the sensory cor-
tex is removed secondarily to a cerebellar lesion
and following recovery from the cerebellar defi-
cits, the initially recovered motor performance is
much worse again (process of decompensation).
Furthermore, removal of the sensory cortex before
the cerebellar lesion increases the cerebellar defi-
cits and severely limits the recovery, suggesting a
functional interrelationship between the sensory
cortex and the cerebellum. Striatum and vestibulo-
spinal tracts are likely involved also. For instance,
NMDA blockade with MK-801 impairs the syn-
aptic rearrangement in the striatum and impacts
on motor recovery (Centonze et al., 2008). Thus,
extra-cerebellar lesions are involved in the recov-
ery process after a cerebellar lesion.
Cerebellar circuitry shows several plasticity
mechanisms such as LTP and LTD. This set of
219
plastic mechanisms is likely one of the neurobio-
logical substrates for the adaptation to errors. The
redundancy of information within the cerebellar
circuitry is another parameter. Indeed, the mossy
fibers extend widely in a medio-lateral fashion and
parallel fibers run through multiple Purkinje neu-
rons. In other words, the mossy fibers transmit the
information simultaneously to multiple functional
units and parallel fibers inform multiple Purkinje
neurons. This redundancy combined with multiple
plasticity mechanisms make of the cerebellum a
unique structure to adapt to the environment and
to lesions.
CEREBELLUM AS MODULATOR OF
MOTOR AND NON-MOTOR OPERATIONS
The mechanisms by which the cerebellum regu-
lates motor control, affect, and emotion is a funda-
mental topic for neurosciences. The concept of
motor dysmetria has now been expanded to cogni-
tive dysmetria (Schmahmann and Sherman, 1998).
On the basis of the homogeneous organization of
the cerebellar cortex, it is presumed that the cere-
bellum exerts a similar control over motor and
non-motor behavior. Schmahmann has proposed
the theory of Universal Cerebellar Transform
(UCT) that the major function of the cerebellum is
to maintain homeostasis around a baseline, acting
as a dampener which smooths out performance in
order to produce harmonious behavior
(Schmahmann, 2019). The cerebellum would reg-
ulate in a similar manner the rate, force and
rhythm of motor actions on one hand, and the
appropriateness of cognitive/affective/emotional
operations on the other hand. Emotional dysregu-
lation may be striking both in adults and in chil-
dren. Overall, motor dysmetria, dysmetria of
thought and emotional dysmetria would share the
same elemental mechanisms. The cerebellum
would perform unique computations in a topo-
graphically arranged fashion, according to the
loops involved.
A leading theory is that the cerebellum/cerebel-
lum-like structures play a key-role in the genera-
tion and maintenance of internal models allowing
predictive computations for motor, cognitive, and
affective operations. Predictions are necessary
given the inevitable noise and transmission delays
within the nervous system (Hardwick et al., 2016).
For motor control, response latencies are far below
those that can be achieved using feedback control.
There is compelling evidence from psychophysi-
cal studies, fMRI studies, and TMS studies that
the cerebellum is involved in motor and non-motor
220 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
predictions/anticipations. A typical example is
provided by the anticipatory changes in grip
forces during predictable manipulations of objects
(Johansson and Cole, 2013). The grip forces are
scaled without delay and therefore without the use
of sensory feedback. The lack of delay means that
the brain predicts the adaptations necessary to the
changes in viscous and elastic loads applied to the
arm (Ebner, 2013).
Adaptation of reaching movements to external
perturbing forces applied by a robotic manipulan-
dum or to Coriolis forces also provide a support
for the acquisition and updates of novel inverse
dynamic models in order to maintain the accuracy
(Shadmehr and Mussa-Ivaldi, 1994; Lackner and
Dizio, 1998). Cerebellar patients cannot compen-
sate to inertial loads (Manto et al., 1994). They
show delayed antagonist muscle responses (errors
in timing) and are unable to tune the magnitudes of
muscle discharges, suggesting that they cannot use
state estimation to control movement but rather
use outdated sensory information from feedback
processes (Hardwick et al., 2013). Application
of predictive strategies offer a clear advantage
in term of reactivity as compared to feedback
strategies. Furthermore, recordings of discharges
of Purkinje neurons show features of internal
models. According to Kawato et al. (1999), the
mossy fiber-granule cell-Purkinje cell circuit is
the anatomical substratum of the transformation
of the desired trajectory into the motor command
(inverse dynamic model). For Ebner (2011), the
firings of simple spikes fit with a forward inter-
nal model, the simple spikes firing preceding the
movement kinematics. Cerebellum-like struc-
tures, for instance the electrosensory lobe in elas-
mobranchs, show similar histological features to
the cerebellum with parallel fibers originating in
granule cells (receiving inputs from higher order
motor/sensory areas) and synapsing on principal
cells (analogous to Purkinje neurons). The mossy
fiber/granule cell/parallel fibers provide an effer-
ence copy of the corollary discharge of the drive to
the electric organ (Bell et al., 2008; Ebner, 2013).
A second input reaches the principal cells to relay
the sensory information from the periphery. This
is the equivalent of climbing fibers in the cerebel-
lum. There is evidence that cerebellum-like struc-
tures predict the upcoming sensory state and build
internal forward models (Bodznick et al., 1999).
Internal models provide representations of the
input-output properties of the motor apparatus
to adapt movement control (Manto and Habas,
2013). Forward models use the commands for
an action and information about the present state
to predict the consequences of an action (Ebner,
2013). Internal models attribute the capacity to the
cerebellar circuitry to produce and adapt motor
sequences. A mismatch between the predicted
and the actual sensory outcomes would cause
motor dysmetria. The internal model hypothesis
fits very well with the sequencing hypothesis of
Molinari (Leggio and Molinari, 2015). According
to this theory, cerebellar microcomplexes compare
sequences of movements with stored sequences,
thanks to working memory. If the sequence stored
matches the actual motor plan, cerebellum will
expect a sequence of elementary events arriving
in its circuitry. In case of mismatch, a signal error
is generated and the prediction scheme is cor-
rected. The efferent copy originating from M1 and
the incoming sensations are taken into account. A
similar sequencing mechanism with re-calibration
would operate for both motor and non-motor oper-
ations. This theory is congruent with the obser-
vation that cerebellar patients exhibit impaired
feedforward control, by contrast with the online
or reactive control which is relatively preserved
(Ebner, 2013; Manto et al., 1994). The sequenc-
ing hypothesis fits with the presumed role of the
cerebellum in predicting somatosensory events
(Bower, 1997). Cerebellar sequencing is not
linked to the elaboration of specific content and
likely different contents are processed in distinct
cerebello-cortical loops.
For language, cerebellar patients exhibit dif-
ficulties to generate lists of words according to
the phonemic but not the semantic rule. Impaired
verbal fluency appears specific for phonemically-
related retrieval strategies (Molinari and Leggio,
2013). Cerebellar patients show omissions and
repetitions of strokes and letters when they have
to dictate or copy words. The observation that
writing deteriorates when the eyes are closed
argues also for a use of visual feedback for writ-
ing. Regarding mental representations, Ito (2008)
has suggested that internal models are embedded
in the cerebellum with a close interaction with the
prefrontal cortex, but this experimental demon-
stration requires validation.
The numerous tasks of daily life require an
integration of the spatial and temporal informa-
tion in the msec range (Broersen et al., 2016).
Predictions for the future are intimately correlated
to the timing of elemental events. The brain con-
siders spatio-temporal cues to perform appropriate
anticipatory adjustments and perceptual decisions.
The cerebellum contributes greatly to these com-
putations as a platform involved in multiple net-
works including cerebral cortex, basal ganglia,
hippocampus, and spinal cord (Broersen et al.,
2016; Manto and Grimaldi, 2012). This is highly
demanding given that sensorimotor delays range
from 50 to 400 msec according to the modal-
ity and behavioral context (Grimaldi and Manto,
2012). Cerebellar patients exhibit errors in timing
 Cerebellum: Advances in Understanding of Cerebellar Functions
both for explicit and implicit tasks (Bares et al.,
2011). Given the micro-anatomy of the cerebellar
neurons, it is plausible that timing is an intrinsic
property of the circuitry. Unlike motor timing,
which is often assessed using rhythm production
tasks, predictive motor timing implies visuo-
motor coordination with anticipation of a future
event, and it is obvious in tasks such as catching
a ball or shooting a moving target (Bares et al.,
2011). Bares and colleagues have studied role of
the cerebellum and striatum in predictive motor
timing in a target interception task in healthy sub-
jects and in cerebellar patients. The performance
of the control subjects was better than that of the
cerebellar patients. Successful performance in
both groups was associated with increased activ-
ity in the cerebellum (right dentate nucleus, left
uvula (lobule V), and lobule VI), thalamus, and
in several cortical areas. The higher performance
in the control subjects was related to activation in
thalamus, putamen (lentiform nucleus), and cer-
ebellum (right dentate nucleus and culmen-lobule
IV), which were not activated either in the ataxic
patients or within the subgroup of controls with
poor performances. These findings highlight the
contribution of the cerebellum in visuo-motor
tasks where anticipation of timing is critical.
CLINICAL SYNDROMES AFTER 250 YEARS
OF CEREBELLAR RESEARCH
The current clinical view of cerebellar deficits con-
siders that cerebellar symptoms can be gathered
into a cerebellar motor syndrome (CMS), a vestibulo-
cerebellar syndrome (VCS) and a cerebellar cogni-
tive affective syndrome or Schmahmann’s syn-
drome (Cabaraux et al., 2021). The core feature of
cerebellar deficits is dysmetria, encompassing both
motor dysmetria and dysmetria of thought.
CMS is typically observed in lesions of the
anterior lobe (lobules I–V), whereas patients with
lesions of the lobules VI–X show relatively minor
motor deficits. There is a somatotopic representa-
tion as follows: lesions of the vermal/paravermal
lobules III–VI are correlated with ataxia of lower
limbs, lesions of vermal/paravermal/hemispheral
lobules IV–VI are correlated with upper limb
ataxia, paravermal/hemispheric lobules V–VI
are correlated with dysarthria, and lesions of the
superior vermis are correlated with ataxia of pos-
ture/gait (Schoch et al., 2006). Regarding nuclei,
lesions of fastigial nuclei are associated with
ataxia of stance/gait, lesions of the interposed
nuclei/adjacent dentate nuclei cause limb ataxia
and lesions of the dentate nuclei are associated
221
with dysarthria. The typical presentation of stroke
in the superior cerebellar artery (SCA) territory
includes ipsilateral motor dysmetria, dysarthria
and gait ataxia/lateropulsion, usually in absence
of cognitive deficits or in association with subtle
cognitive errors.
The vestibulo-cerebellar syndrome (VCS) com-
prises ocular instability, oculomotor movement
deficits, and ocular misalignment. Oculomotor
deficits are often prominent in cerebellar patients:
dysmetria of saccades, saccadic pursuit, impaired
vestibulo-ocular reflex (VOR), deficits in fixa-
tion, errors in vergence. Lesions are observed at
the level of the vermis and/or the flocculo-nod-
ular lobe. Although VCS impacts negatively on
the quality of life, it tends to be underestimated
by some influential clinical rating scales of cer-
ebellum-induced ataxia such as the Scale for
Assessment and Rating of Ataxia (SARA).
Schmahmann’s Syndrome
Lesions of the posterior lobe are associated with
various combinations of deficits in the executive
functions, in visuospatial performances, in lin-
guistic processing and regulation of affect
(Schmahmann and Sherman, 1998). Clinically,
this is discernible with the assessment of working
memory, ideational set shifting, perseverations,
drawings, verbal fluency, and prosodia. Severe
forms present with mutism, as observed in the
posterior fossa syndrome occurring in the imme-
diate postoperative phase following resection of a
posterior fossa surgery. Cerebellar mutism is typi-
cally associated with cognitive, behavioral, and
affective disturbances. Sequences are impaired in
the Schmahmann syndrome, including conceptu-
alization of figures. Patients with lesions in the
territory of the posterior inferior cerebellar artery
(PICA) or with vermian lesions often show a flat-
tening of affect, disinhibition, impulsivity, inap-
propriate comments which have been clearly
underrecognized in the past. A childhood-like
behavior may be observed.
Pathological laughing and crying also has
been observed following lesions of the pontocer-
ebellar tract, supporting the idea that cerebellum
contributes to the voluntary control of emotional
expression. Overall, the general consequence is
a lowering of intellectual functions, especially in
case of bilateral and acute lesions. The spectrum
of clinical deficits corresponds to a genuine link
between neurology and psychiatry (Schmahmann
et al., 2007). Social interactions are highly com-
plex and sophisticated. They require language
and communication skills. They are also under
222 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
cerebellar control and cerebellar patients may
exhibit an autistic-like behavior. Hypothetically,
the cerebellum builds internal models of human
social interactions, with the goal of optimiz-
ing social behavior. Cerebellum would allow the
anticipation of other person’s behavior, detect
violations in social links and trigger corrections
in the internal models. Such a mechanism would
have impacts far beyond humans, because it would
represent a model to understand social interactions
in the numerous species having a cerebellum.
Furthermore, the model could be used to esti-
mate the social cerebellar reserve, with the aim of
improving social skill set.
Social interactions might represent not only
adaptative behaviors following a selection pres-
sure, but also the sources of selection pressure
(Huang and Ricklefs, 2013). Social interactions
require and promote communication between
individuals, which implies a common language
acquired likely via imitation, a mechanism which
(1) recruits many regions of the brain including the
mirror neurons, and (2) necessitates a high degree
of plasticity for perception (Huang and Ricklefs,
2013). The cerebellum, through the numerous cer-
ebro-cerebello-cerebral channels, is a major node
for the information coding behind the acquisition
of complex behavior including language.
SUMMARY AND CONCLUSIONS
The human cerebellum contains about 60% of all
neurons of the brain, occupying 10% of brain
volume. Anatomically, the cerebellum is highly
conserved across mammals, with a division of the
cortex by two fissures: (1) primary fissure separat-
ing the anterior lobe from the posterior lobe, and
(2) posterolateral fissure separating the posterior
lobe from the flocculonodular lobe. The cerebellar
cortex is folded into 10 lobules (I to X) subdivided
into folia. Cerebellar hemispheres are particularly
developed in mammals. The cerebellar cortex is
arranged into three layers: the molecular layer, the
Purkinje cell layer and the granular layer. These
three cortical layers contain five main neuronal
populations (Purkinje, stellate, basket, Golgi and
granule cells). Whereas granule cells are excita-
tory, the other neurons are all inhibitory and use
principally gamma-aminobutyric acid (GABA).
Purkinje neurons inhibit cerebellar nuclei, the sole
output of the cerebellar circuitry.
The cerebellum is divided into a series of
olivo-cortico-nuclear modules arranged longitudi-
nally in the rostro-caudal plane. Each module is
defined by its climbing fiber input from a specific
subdivision of the inferior olivary complex which
targets one or more longitudinal zones of Purkinje
cells. Cerebro-cerebellar connectivity is organized
into multiple parallel loops. The current clinical
view of cerebellar deficits considers that cerebel-
lar symptoms can be gathered into a cerebellar
motor syndrome, a vestibulocerebellar syndrome
and a cerebellar cognitive affective syndrome. The
core feature of cerebellar deficits is dysmetria,
encompassing both motor and thought dysmetria.
Thus, the cerebellum plays a key-role in the gen-
eration and maintenance of internal models allow-
ing predictive computations for motor, cognitive,
and affective operations.
The cerebellum is involved in multiple seg-
regated cerebello-cerebral loops and it com-
municates directly with the basal ganglia. The
cerebellum is a critical structure in performing
motor predictions related to body dynamics and
to environmental changes. The predictions likely
apply to both motor and non-motor operations.
Cerebellar cortex sculpts cerebellar nuclei dis-
charges by a mechanism of inhibition/disinhibi-
tion and interacts closely with the inferior olive
through multiple olivo-cortico-nuclear modules.
The field of clinical ataxiology is now based upon
three groups of cerebellar symptoms gathered in
the CMS, the VCS, and the Schmahmann’s syn-
drome. All these clinical deficits can be under-
stood as the consequences of impaired predictions
leading to dysmetria.
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Amygdaloid Complex
Hans J. Markowitsch, Jens Borgelt, and
Angelica Staniloiu
INTRODUCTION
Karl Friedrich Burdach introduced in 1822 the
term amygdala to describe a nuclear mass in the
anterior portion of the human temporal lobes.
Being existent in probably all vertebrates
(de Olmos, 2004), it is – in the human brain and
that of higher mammals – composed of 13 telen-
cephalic nuclei which are grouped in three
­clusters: the basolateral, the cortical-like, and the
centromedial (Hortensius et al., 2017; Pabba,
2013; Sims and Williams, 1990; cf. Markowitsch
and Staniloiu, 2012b, Fig. 4, or Sarter and
Markowitsch, 1985b, Fig. 2, for a delineation of
amygdalar subregions). As it is a conglomerate of
several nuclei, one also speaks of the Amygdaloid
Complex, in order to emphasize this. Another
expression is corpus amygdaloideum. From the
functional side ‘emotional, olfactory, visceral,
somatosensory functions, an involvement in gen-
eral arousal and orienting reactions, and in sleep,
fight, defense, feeding and sexual activities have
been attributed to amygdaloid nuclei’ (Sarter and
Markowitsch, 1985). From the first half of the
twentieth century, it was proposed that the amyg-
dala processes sensory stimuli that already have
been pre-analyzed and modified by other centers
of the brain (Hilpert, 1928; Mittelstrass, 1937).
15
AMYGDALA AND LIMBIC SYSTEM
The amygdaloid complex constitutes one of the
major hubs (cf. Pessoa, 2008, Fig. 1) of the so-
called Limbic System. Though already introduced
by Broca in 1878 as le grand lobe limbique, it was
only MacLean in 1952 who coined the term
Limbic System for describing a combination of
phylogenetically older structures in the brain
(older cortical areas, nuclei, and interconnecting
fiber systems), which, so to say, constitute an
interface between the brain stem and the phyloge-
netically recent neocortex (Figure 15.1). In 1970,
MacLean refined this idea by proposing a pro-
toreptilian portion (principally from the spinal
cord to the basal ganglia), a paleomammalian one
(the Limbic System), and a neomammalian one
(the cortical mantle). Within the Limbic System
there are two major circuits which interact which
each other. One is the Papez Circuit (Papez,
1937), the other the Basolateral Limbic Circuit
(Figure 15.2) (cf. Markowitsch and Staniloiu,
2012a, b). While the first circuit has the hip-
pocampal formation in its center, the second cir-
cuit includes the amygdala, the septal nuclei/basal
forebrain, and the thalamic mediodorsal nucleus
(Sarter and Markowitsch, 1983, 1984). The (prin-
cipally) unidirectional ventral amygdalofugal
228 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 15.1 Schematical sagittal section through the human brain, showing the three divi-
sions, proposed by MacLean (1952, 1970): the neomammalian, paleomammalian, and reptilian
brain.

Figure 15.2 The basolateral limbic circuit. It links the amygdala, mediodorsal thalamic
nucleus, and area subcallosa together by distinct fiber projections, namely the ventral
­amygdalofugal pathway, the inferior thalamic peduncle, and the bandeletta diagonalis.

pathway leads from the amygdala to the medio- circuit evaluates the affective side of incoming
dorsal thalamus, from there fibers reach the sub- information and interacts with the second, the
callosal area, which then projects via the bandeletta medial circuit. Amygdala and septal nuclei act in
diagonalis back into the amygdaloid body. This opposition: activation of the amygdala increases
 Amygdaloid Complex 229

emotionality, activation of the septal nuclei
decreases it (and vice versa) (Cramon and
Markowitsch, 2000; Cramon et al., 1993;
Markowitsch and Staniloiu, 2012c). The medio-
dorsal nucleus (or – again – nuclear complex; cf.
Hassler, 1982) is implicated in many functions
from sleep and consciousness to memory and
decision making (Guilleminault et al., 1994;
Markowitsch, 1982, 2005; Markowitsch and
Staniloiu, 2012a; Mitchell, 2015).
Mesulam (2000) described the limbic system as
a group of interconnected cortical and subcortical
structures that
• bind “distributed information related to recent
events and experiences in a manner that sup-
ports declarative/episodic/explicit memory”
• channels “emotion and drives (…) to extraper-
sonal events and mental content”
• links “mental activity with autonomic, hormonal,
and immunological states”
• coordinates “affiliative behaviors related to
social cohesion”
• and is involved in the “[p]erception of smell,
taste, and pain.”
A nicely illustrated review of the structure and
function of the limbic system was written by
Catani et al. (2013). The connectivity and conse-
quently the functional involvement of the amyg-
dala is manifold. One example of input–output
relations of different amygdalar portions is given
in Table 15.1, another – more refined one – can
be found in Pessoa (2008). This author, for
instance, stresses sensory (visual) connections
and others which show that the amygdala partici-
pates in executive functions which makes sense
as from a developmental perspective the amyg-
dala belongs to the basal ganglia. The executive
control network is composed of the lateral pre-
frontal, the orbitofrontal and anterior cingular
cortices as well as of the nucleus accumbens and
the ventral tegmental area, which all are con-
trolled by in- or outputs from the amygdala.
AMYGDALA: FUNCTIONAL
INVOLVEMENTS
As already stated above the large number of fiber
connections of the amygdala of course implies a
similarly large functional involvement.
Furthermore, damage or hyperexcitation of the
amygdala lead to distinct disease pictures.
Though a bit overgeneralized, older portions of
the amygdala are more closely related to basic
functions such as olfaction and drive control
(Kose et al., 2021; Leitão et al., 2022), while
more recently evolved portions are engaged in
higher functions such as charging emotions to
memory (Cahill et al., 1995; McGaugh, 2005,
2015; Siebert et al., 2003). Over more than 100
years, theories on emotional processing have
been proposed and can be found in every text-
book on biopsychology (e.g., Cannon-Bard
theory of emotions, James-Lange theory of emo-
tions, Schachter-Singer and Lazarus’ theories of
emotions and cognitive appraisal).
Amygdala and Fear
Especially fear conditioning and other forms of
processing fear have been a major research topic
related to the amygdala. As modified in Figure 15.3,
the sketch of LeDoux (1994) is well-known
among researchers into the physiology of

Table 15.1 Connections of different portions of the amygdala

Nuclear mass Inputs Outputs

Lateral gustatory and visceral, somatosensory, auditory, prefrontal cortex medial temporal lobe nucleus
visual cortices thalamic and hypothalamic nuclei accumbens
Basal gustatory and visceral, somatosensory, auditory, prefrontal cortex striatum medial temporal lobe
visual cortices thalamic and hypothalamic nuclei
Central gustatory and visceral, somatosensory, auditory, bed nucleus of the stria terminalis, hypothalamus
visual cortices thalamic and hypothalamic nuclei midbrain, pons, medulla ascending cholinergic
brainstem and monoaminergic systems
Medial gustatory and visceral cortices olfactory system, bed nucleus of the stria
terminalis, hypothalamic, and thalamic nuclei
Mixed nuclei olfactory input

This list was created after Figure 1A of Pabba (2013).

230 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

emotions. Evidence for the repeatedly proposed
assumption of LeDoux (1994, 1996, 2000) that
there exists a subcortical route from the thalamus
to the amygdala is still sparse, although a mode-
ling study, based on the recording of magnetoen-
cephalographic activity in human beings, has
provided evidence for its existence (Garrido et al.,
2012). Other authors argue for a primary role of
the cortical structures (Pessoa and Adolphs, 2010),
or find at best, indirect evidence, as with the
method of diffusion tensor imaging, the direction
of fiber projections cannot be determined une-
quivocally (Tamietto et al., 2012).
Fear-and stress-related responses of the amyg-
dala – in particular its basolateral portion (Adhikari
et al., 2015; Sun et al., 2020; Yau et al., 2021) and
serotonin as an important transmitter in fear learn-
ing (Bocchio et al., 2016) – have been documented
in numerous publications (Bierbrauer et al., 2021;
Pare and Duvari, 2012; Simic et al., 2021). Though
a number of studies used sophisticated techniques
to trace the wiring of fear conditioning within indi-
vidual amygdalar nuclei and circuit configurations
(Lee et al., 2017; Pare and Duvari, 2012), a clear
picture is still not available, as was stressed in the
reviews cited before. This is in part attributable to
the high interconnectivity of the amygdalar complex
(“hub”; see above); Carlson et al. (2013), for exam-
ple, noted that individuals with a high attentional
predisposition to threat demonstrated a particu-
larly high anterior cingulate-amygdala connectiv-
ity. Similarly, Mao et al. (2020) found that social
anxiety is positively correlated with functional
amygdala-orbitofrontal connectivity, and Ferri et al.
(2016) established that attentional modulation is
related to amygdala-precuneus connectivity.

Figure 15.3 Proposed role of the amygdala in processing anxiety-related stimuli. Seeing a
tarantula implies visual information to pass from the retinae to the visual thalamus (lateral
geniculate nucleus) and then to the (primary) visual cortex. From there they reach via the
ventral visual pathway the polymodal regions of the temporal lobe and then the amygdala.
LeDoux (1994) proposed that there is an additional pathway from the visual thalamus to
the amygdala, providing a shallow, diffuse, coarse picture of the relevant environmental
stimulus, which nevertheless already alerts the amygdala to induce a counter-reaction – even
before the object becomes conscious (via the cortical processing mechanisms). For LeDoux
this stresses the role of the amygdala in fear conditioning.
 Amygdaloid Complex
Amygdala and Positive Emotions
While especially earlier investigations and studies
in animals emphasized the amygdala’s role in fear
and threat, later reports also established a substan-
tial role of the amygdala in processing positive
emotions (Baxter and Murray, 2002). The early
dominance of findings on fear and the amygdala
can also be explained from an evolutionary point
of view, as it is more important for survival of
individuals and species, to correctly analyze and
interpret threat signaling stimuli than those related
to joy and happiness. In fact, a study using a com-
bination of single unit recordings and fluores-
cence labeling of individual neurons in mice
found that there are antagonistic populations of
neurons in the basolateral amygdala that are
engaged in valence-specific behaviors (Kim et al.,
2016). This finding is in line to a related one in the
same species, also using a combination of meth-
ods (morphological, electrophysiological, and
optogenetic), and showing separate clusters of
basolateral amygdalar neurons for fear and reward
conditioning (Namburi et al., 2015).
Similarly, there are several findings in human
beings pointing to an amygdalar involvement in
positive emotions (though in humans, the orbito-
frontal cortex “phylogenetically” took over some
of these functions, as Edmund Rolls argued in
2021; cf. also Markowitsch et al., 2003, for emo-
tion-memory-related orbitofrontal activations and
the findings of Gee et al., 2022, indicating an
amygdala-frontal processing in childhood which
is reversed to top-down [fronto-amygdalar] pro-
cessing in adulthood).
Results of a resting-state functional magnetic
resonance (fMRI) study in humans demonstrated
a direct relation between reduced left amygdalar
activity and a heightened right orbitofrontal and
a bi-hemispheric precuneus connectivity for per-
ceived social support (Sato et al., 2020) – again
emphasizing the hub function of the amygdala
(see above). Related to the findings of Sato et al.
(2020) on left amygdalar involvement in emotion
processing, Puccetti et al. (2021) noted similarly
in normal individuals (also using fMRI) that “indi-
viduals demonstrating less persistent activation
patterns in the left amygdala to aversive stimuli
reported more positive and less negative affect in
daily life”. Aquino et al. (2020) studied via sin-
gle unit recording in the amygdala of patients
with epilepsy that social cognition and reward
learning engage the amygdala and also results
on mediation training (Kral et al., 2018), as well
as a meta-analysis on functional magnetic reso-
nance imaging studies that examined emotion reg-
ulation-modulated connectivity of the amygdala
(Berboth and Morawetz, 2021) demonstrated that
231
via amygdala – ventromedial prefrontal cortical
connectivity emotion regulation is controlled.
Together, these data confirm the conclusions of
reviews published a decade ago, stating that the
amygdala is necessary for processes of updating
representations of value (e.g., fear extinction or
reinforcer devaluation) (Morrison and Salzman,
2010). The authors commented that “The encod-
ing of affective significance by the amygdala
might be best described as a representation of state
value – a representation that is useful for coordi-
nating physiological, behavioral, and cognitive
responses in an affective/emotional context.”
Other Functions of the Amygdala
Smell accounts for 95–99% of chemosensation,
while the rest is processed as taste (Li and Lui,
2021). One of the major pathways of smell passes
from the piriform cortex to the entorhinal cortex
and amygdala to the hippocampus. Any destruction
of one of these regions results – according to
Li and Lui (2021) – in anosmia. The medial amyg-
dala seems to be the principal area involved in
threat-related odor perception, as a review of
Takahashi et al. (2005) suggests. A bit unexpected is
that also taste, namely oral texture features of vis-
cosity, fat texture, and temperature are processed via
the amygdala (and the orbitofrontal cortex) (Rolls,
2020; Rolls et al., 2018). While these findings were
obtained in the non-human primate, there is also
evidence that the human amygdala is activated by
the taste of glucose (Francis et al., 1999), as well as
in taste in general (Petekkaya et al., 2022).
There is also ample evidence for an amygdala
involvement in pain perception (e.g., Cai et al.,
2018; Thompson and Neugebauer, 2017) and in
social perception – particularly in the perception
of facial affect (Rutishauser et al., 2015; Wang
et al., 2014, 2021), but also in emotional scene
perception (Frank et al., 2019; Oba et al., 2020).
Particularly the right amygdala seems to play in
scene perception a more basic “ecological” role,
analyzing familiarity dimensions of the scene,
while temporal neocortical areas are engaged in
more integrative understanding of scenes, recruit-
ing the social role of the viewer (Oba et al., 2020).
The left amygdala, on the other hand, is related
to perceived social support, in particular its lat-
erobasal and superficial subregions. This was
found by Sato et al. (2016) in human beings on
the basis of applying to 49 healthy participants
a so-called Multidimensional Scale of Perceived
Social Support and measuring volume and shape
of the amygdala with structural magnetic reso-
nance imaging.
232 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Interestingly, a number of the studies, men-
tioned up to now, pointed to the fact that there
is a dominance of one amygdala over the other
with respect to a number of functions. This was
already addressed in a review from the end of the
last century (Markowitsch, 1998/1999). In this it
was stated that “the left amygdala is more closely
related to affective information encoding with a
higher affinity to language and to detailed fea-
ture extraction, and the right amygdala to affec-
tive information retrieval with a higher affinity to
pictorial or image-related material. Furthermore,
the right amygdala may be more strongly engaged
than the left one in a fast, shallow or gross analysis
of affect-related information.”
This statement directs to memory modula-
tion as another function in which the amygdala is
implicated. It has been known since long that the
amygdala modulates memory performance – both
during encoding and during retrieval (Sarter and
Markowitsch, 1985a, b; Cahill et al., 1995). For epi-
sodic-autobiographical memory, emotional tagging
is mentioned as a core feature of this memory system
(Markowitsch and Staniloiu, 2012a–c). Retrieving
episodic-autobiographical memories reactivates
(among other structures) the right amygdala as was
shown in a fMRI study on episodic-autobiograph-
ical memory retrieval in normal individuals (Fink
et al., 1996). This finding was confirmed in a later
study in which, in addition, it was found that only
true, but not fictitious memories engage the right
amygdala (Markowitsch et al., 2000).
Using a different approach, Rutishauser et al.
(2008) observed with single unit recordings
that there was a substantial activation within the
human amygdala during retrieval of what they
termed declarative memory in the title and epi-
sodic memory in the text (cf. Rutishauser et al.,
2015). Based on a study comparing the results of
temporal lobe-damaged patients and non-brain-
damaged individuals Buchanan et al. (2005) con-
cluded that the amygdala and surrounding cortices
of the medial temporal lobe may be a necessary
component in the neural circuitry necessary for
vivid recollection of unpleasant emotional events.
The interaction between emotion and explicit epi-
sodic memory was confirmed in a fMRI-study by
Katsumi and Dolcos (2020), while Bocchio et al.
(2017) concluded that “The neuronal circuits of
the basolateral amygdala (BLA) are crucial for
acquisition, consolidation, retrieval, and extinction
of associative emotional memories.” Canli et al.
(2000) identified a correlation between amyg-
dala activation and episodic memory for highly
emotional, but not for neutral stimuli. Thus, the
processing of memories with biological or social
significance via the amygdala is well established
(Markowitsch and Staniloiu, 2011).
PATHOLOGY-RELATED ASPECTS
AND DISEASE CONDITIONS OF THE
AMYGDALA
Various forms of pathological conditions, signifi-
cant deviations from the normal and diseases are
linked to the amygdaloid complex. Psychopathy-
related conditions – such as conduct disorder,
callous-unemotional behavior, and antisocial per-
sonality disorder – have been linked to changes in
the amygdala and its connections with anterior
cortical areas (Aghajani et al., 2016; Cardinale
et al., 2019; Fairchild et al., 2019; Kaya et al.,
2020; Yoder et al., 2015).
Amygdala and Aggression
As mainly based on data in rats and cats, Haller
(2018) argued that predatory aggression is con-
trolled by the central amygdala, rivalry aggression
by the medial amygdala, and violent aggression
by both medial and central amygdala. Whole and
centromedial amygdala–insular connectivity is
related to maternal aggressive behavior and later
major depressive disorder (Callaghan et al., 2017).
And also on the human level, there is a reduced
amygdala-orbitofrontal connectivity in youth with
disruptive behavior disorders (Marsh et al., 2011) –
pointing to a role of the amygdala in neuromoral
behavior (Raine, 2019), and again, to the hub
function of the amygdala in concert with areas of
the anterior limbic cortex.
Psychotic spectrum conditions such as schiz-
ophrenia and bipolar disorders lead to several
changes in amygdala shape, volume, and connec-
tivity (Ho et al., 2019; Sabharwal et al., 2021). Ho
et al. (2019) especially emphasized changes in the
uncinate fascicle (reduced fractional anisotropy in
diffusion tensor imaging), a bidirectional pathway
interconnecting frontal and temporal regions of the
brain (e.g., see Staniloiu and Markowitsch, 2010,
Fig. 1). Corresponding findings – that is, a reduced
amygdala-prefrontal connectivity – were obtained
by Tang et al. (2018) for individuals between 26
and 45 years of age and bipolar depression. Not
only in patients with bipolar depression, but also
in those with major depressive disorder (MDD),
functional connectivity changes between the
amygdala and other brain regions, in particular
also with the so-called default mode network were
obtained (Wackerhagen et al., 2020; cf. Redlich
et al., 2017, for therapy-related changes in the
amygdala in patients with MDD). Related find-
ings on a reduced functional connectivity in the
medial temporal and frontoparietal network were
obtained in patients with MDD and an anxiety
 Amygdaloid Complex
symptomatology, using resting resting-state MRI
(He et al., 2019). Other psychiatric disease con-
ditions in which the amygdala is involved are
OCD (Paul et al., 2019; Rus et al., 2016), PTSD
(Bijanki et al., 2020; Morey et al., 2020), and BPD
(Mancke et al., 2018).
Amygdala and Neurological Disorders
On the neurological disease side, there are a
number of disorders associated with the amyg-
dala. Frequently, autism-spectrum disorders
(Dziobek et al., 2010; Hennessey et al., 2018; Sato
and Uono, 2019) are related to the amygdala. It
seems that the development of the amygdala from
childhood to adulthood differs in individuals with
autism-spectrum disorders in comparison to
normals; the amygdala suddenly starts to signifi-
cantly increase in volume at around age 6.5 to 12
years in children with autism-spectrum disorders
(Xu et al., 2020).
Other gene-related disorders, associated with
changes in the amygdala and/or its connectivity,
are the fragile-X syndrome (Bruno et al., 2017;
Hessl et al., 2007; Olmos-Serrano and Corbin,
2011; Suvrathan and Chattarji, 2011), Williams-
Beuren’s syndrome, and Down’s syndrome.
Both the Williams’ and Down’s syndromes
(Murphy and Ellis, 1991; Porter et al., 2007; Pujol
et al., 2015) have been associated with changes in
the amygdala and/or its connectivity. Williams’
syndrome is an especially interesting condition,
referring (as does Down’s syndrome) to a specific
gene defect. This effect leads during develop-
ment to some intellectual disabilities, in particu-
lar learning problems, distinct facial features,
and cardiovascular and distinctive personality
features. Especially the last are probably related
to the amygdala, as in common sense, they are
characterized as particularly “social.” This implies
that they have a major tendency to approach other
persons, including strangers, a decreased social
anxiety and an increased attention for faces (e.g.,
Bellugi et al., 1999, 2000; Jones et al., 1999). Lew
et al. (2020) found in post-mortem amygdala tis-
sue opposing directions of change in the serotoner-
gic innervation in autism-spectrum disorder brains
and in those of individuals with Williams’ syn-
drome. The brains of the individuals with autism-
spectrum disorder had an increase in serotonergic
axons (compared to neurotypical brains), and the
brains of former Wilson’s syndrome individu-
als displayed a decrease. These opposite changes
were significant between the two syndromes
across multiple amygdaloid nuclei. The authors
assume that these differential changes contribute
233
to differences in the sociobehavioral phenotypes
of the two syndromes.
Furthermore, epileptic attacks (Beh et al.,
2016), the Klüver-Bucy’s syndrome (Caro and
Jiminez, 2016; Lanska, 2018), Alzheimer’s dis-
ease (Kim et al., 2020; Murray et al., 2021), and
Urbach-Wiethe disease (Hurlemann et al., 2007;
Koen et al., 2016; Markowitsch et al., 1994) are
accompanied by damage to or degeneration of the
amygdala (see below).
Amygdala and Functional
Neurological Disorders
So-called functional neurological disorders
(Carson et al., 2016; Edwards, 2016; Hallett,
2016) constitute a bridge between neurological
and psychiatric disorders and involve the amyg-
dala as well (Jungilligens et al., 2022; Voon et al.,
2010, 2011). This is also the case in dissociative
amnesia (also named functional amnesia or mnes-
tic block syndrome (Markowitsch and Staniloiu,
2016; Staniloiu and Markowitsch, 2014), where
we showed a reduced amygdala metabolism in
affected patients (Brand et al., 2009; Staniloiu
et al., 2011) and a lacking synchrony between
emotion- and fact-processing regions of the brain
(cf. Markowitsch and Staniloiu, 2022). This syn-
chrony is normally provided by the uncinate fasci-
cle, a fiber system interconnecting anterior
temporal regions (including the amygdala) with
the ventrolateral prefrontal cortex. Von der Heide
et al. (2013) pointed out that the uncinate fascicle
has prominent roles in mnestic processing, social
cognition, and emotional valence. Most likely, the
so-called overgeneral memory effect, which
implies that autobiographical memories lack the
usual emotional colorization and have a reduced
specificity, can be attributed to microstructural
changes in the amygdala and the uncinate fascicle
(Govindan et al., 2010).
AMYGDALA AND URBACH-WIETHE
DISEASE
Since 1993 we have studied patients with Urbach-
Wiethe disease – first in Germany (Babinsky
et al., 1993; Brand et al., 2007; Cahill et al., 1995;
Markowitsch et al., 1994) and later in South
Africa (Siebert et al., 2003). These patients are of
special interest, as they have quite selective – and
bilateral symmetrical – damage (calcification) of
the amygdaloid region; therefore, they provide a
234 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
unique “model” of the behavioral consequences of
bilateral amygdala damage in human beings.
A still unresolved question is whether the cal-
cifications of the amygdalae are already present
at birth or only develop in youth or young adult-
hood. We (Markowitsch et al., 2023) studied a
young patient both at age 9 years and at age 19
years and found that he – in spite of genetically
proven Urbach-Wiethe disease – did not show the
typical calcifications in his amygdalae, suggesting
that these develop only in adulthood and may vary
in density between individuals. Two other studies
addressed this question as well with in part nega-
tive evidence (Appenzeller et al., 2006; Dertlioğlu
et al., 2014). While the paper of Appenzeller et al.
(2006) only reported that calcification was more
evident in patients with longer disease duration,
that of Dertlioğlu et al. (2014) found absence of
brain calcifications in nine patients, aged between
2 and 20 years (mean age: 9 years, median age:
11 years), but positive evidence in one girl of
11 years of age. A third study, that of Pishnamazi
et al. (2016), demonstrated bilateral symmetrical
calcifications of the amygdalae in a 14.5-year-old
girl. Consequently, the factors favoring or inhib-
iting early amygdala calcification, have not been
unraveled.
We observed deficits with respect to the typical
amygdalar functions – from deficits in olfaction
(Siebert et al., 2003) to deficits in episodic-auto-
biographical memory performance (Cahill et al.,
1995) – but also deficits in decision making both
under ambiguity and under risk (Brand et al.,
2007). Patients with Urbach-Wiethe disease were
unable to keep social distancing and had a lack in
theory-of-mind functions. Interestingly, Bellugi
et al. (1999) compared the behavior of 25 individ-
uals with Williams’ syndrome with that of three
individuals with bilateral amygdala damage (one
with Urbach-Wiethe disease, two with encepha-
litis; Adolphs et al., 1998). They found both
groups to be friendly in normal life and tending to
approach people that would normally be avoided.
(One of us [HJM] had similar experiences with
Urbach-Wiethe individuals from South Africa.
One of them, after just having been introduced to
me, said: “Hans, you come from Germany. Why
didn’t you bring me a beer stein?”) In a face rat-
ing task, both groups gave abnormally positive
approachability ratings to unfamiliar faces (Bellugi
et al., 1999). However, while the individuals with
Wilson’s syndrome gave abnormally positive rat-
ings for all faces (approachable and unapproach-
able ones), the patients with complete amygdala
damage gave abnormally positive ratings only for
those faces that normally received the most nega-
tive ratings. The authors interpret these findings
as an inability of amygdala-damaged patients to
judge unapproachability, or to detect potentially
dangerous or threatening people. Again, this is in
conformity with our data that showed a remark-
able lack of fear in the Urbach-Wiethe patients
(Markowitsch et al., 1994; Siebert et al., 2003).
An impressive description of the lack of fear
by the Urbach-Wiethe patient of Adolphs et al.
(1998) was given by Feinstein et al. (2011). As
an example, they reported that the patient repeat-
edly wanted to touch snakes in an exotic pet house
(in spite of saying before that she disliked snakes
and spiders). Lilienfeld and co-workers (2018)
examined patient S.M. with Urbach-Wiethe dis-
ease (the same patient as studied in Adolphs et al.,
1998; Feinstein et al., 2011; Tranel and Hyman,
1990 and in other papers) and found that though
she seemed to be pretty fearless and deficient in
self-control, she did not fulfill other criteria of
psychopathy, such as cold-heartedness and mean-
ness. The authors concluded that extreme fear
deficits can co-exist with an absence of other
main psychopathic attributes. Pishnamazi et al.
(2016) noted from their single case report of a
young female patient with Urbach-Wiethe disease
that rapid attention to emotions was unchanged
compared to ten well-matched control individu-
als, but appeared to be crucial for assessing the
biological relevance of sensory events, and for an
efficient allocation of perceptual resources. This
was also the result of a study with two twin sisters
with Urbach-Wiethe disease, who showed faster
illusion onset and increased vividness ratings
towards the rubber-hand illusion (Spengler et al.,
2019). The authors concluded from their study
(which also involved oxytocin-based dampening
of the amygdala reactivity in normal individuals)
that a healthy amygdala protects from interpre-
tating potentially fatal threats due to a distorted
body-self.
Taken together, a malfunctioning amygdala not
only leads to severe changes in cognitive-affective
behavior, but also to long-lasting alterations in the
personality structure and consequently in well-
being, and in interpreting sensory signals. This all
the more, as a well-functioning amygdala is also
essential for social interaction, a capacity which is
the main feature of human beings.
SUMMARY AND CONCLUSIONS
Within the limbic system, the amygdala consti-
tutes the largest nuclear group. As a non-cortical
structure (i.e., in opposition to the hippocampal
formation, which is three-layered archicortex), it
is phylogenetically old and existent even in
 Amygdaloid Complex
teleosts, where it apparently already is dividable
into thirteen telencephalic territories – similarly as
in tetropods (Porter and Mueller, 2020). As for the
hippocampus, research from the nineteenth cen-
tury viewed olfactory processing as the primary
function of the amygdala. Later, a number of
additional functions were found showing that the
amygdala is central for emotional and social pro-
cessing and is indeed a central hub not only within
the limbic system, but within the central nervous
system as a whole.
The term ‘amygdaloid complex’ refers to the
fact that the subcortical nuclear mass in the ante-
rior portion of the temporal cortex of the human
brain (commonly named ‘amygdala’) is composed
of more than a dozen nuclei which usually are
combined within three subdivisions. Being heav-
ily interconnected with cortical, diencephalic and
brain stem structures, the amygdala is described as
a hub with multiple cognitive and memory func-
tions – from the interpretation of preprocessed
sensory information to the analysis of emotional
expressions and the colorization of memories. The
amygdala analyzes the biological and social sig-
nificance of incoming information and provides
valence or value to incoming sensory signals.
On the output side, amygdala activity influences
behavioral reactions, especially, but not exclu-
sively, with respect to emotional expressions.
Damage to or malfunctioning of the amygdala
can lead to numerous complex disease conditions
from epileptic attacks to syndromes which may
result in persistent and severe changes in the life
of the individual so affected.
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Hippocampal Formation
Rosanna K. Olsen and Mrinmayi Kulkarni
INTRODUCTION
The hippocampal formation, a bilateral neuroana-
tomical structure located deep within the temporal
lobe, is one of the most well studied regions of the
brain due to its central importance in critical cog-
nitive functions such as memory and spatial navi-
gation. In addition, this structure’s vulnerability to
damage and its relevance to many types of psychi-
atric, neurodevelopmental, and neurodegenerative
conditions, have made it a target of extensive
research (Boyle et al., 2012, 2023a,b; Li et al.,
2019; Terreros-Roncal et al., 2021). In this chap-
ter, we describe in detail both the macro- and
microstructural neuroanatomy of the hippocam-
pus, as well as the proposed neuroscientific func-
tions of its subregions. This chapter concludes
with a summary of the role of the hippocampus in
different types of memory and other cognitive
functions.
While the hippocampus is often treated as a
distinct anatomical unit, it is important to appre-
ciate that the hippocampal formation is not a
homogenous, unitary structure. Traditionally,
the hippocampal formation has been subdivided
into several distinct subregions, which can be
defined by their microstructural anatomical prop-
erties, most commonly derived from post-mortem
16
histological evidence (Duvernoy et al., 2013;
Insausti and Amaral, 2012; Lorente De Nó, 1934).
A parcellation scheme used by many neuroanato-
mists separates the hippocampus into the cornu
ammonis (CA) regions 1–4,1 the dentate gyrus,
and the subiculum. These hippocampal subre-
gions differ in their cellular composition, laminar
structure, as well as their internal and external
structural connections. The cytoarchitectural dif-
ferences across subregions can best be appreciated
using post-mortem histology staining techniques
(Ding and Van Hoesen, 2015; see Figure 16.1). In
addition to these structural distinctions, detailed
study of particular subregions of the hippocampal
formation using in vivo neuroimaging methods
has now provided evidence for distinct functional
contributions to different cognitive processes
(Carr et al., 2010; Olsen and Robin, 2020). For
example, high resolution functional neuroimag-
ing studies have indicated that the dentate gyrus
subregion may play a selective role in mnemonic
discrimination of visually similar scenes (Aly and
Turk-browne, 2016; Berron et al., 2016).
Another difference between the subregions of
the human hippocampal formation is that they
are differentially affected by distinct pathological
processes in a time-dependent manner (Braak and
Tredici, 2018). For example, it is well established
 Hippocampal Formation 243

Figure 16.1 Histological staining of post-mortem hippocampal tissue.

Left Panel: Two representative coronal slices through the hippocampal head which demon-
strate the internal and external digitations on the superior part of the head. Note that the
dentate gyrus is absent from the more anterior slice (upper) slice. The lower slice contains
the “vertical section” of the hippocampal head as well as uncal sections. The middle panel
is zoomed in so that the cell bodies can be visualized. The different size, shape, and density
of cells allow for differentiation of the CA subfields 1–4. Right panel: One representative
coronal slice through the hippocampal body, with subfields labeled based on histological
features of the different regions.
Source: Left image is adapted with permission from Ding and Van Hoesen (2015); Middle panel adapted from Duvernoy
(2005). Right panel adapted from Olsen et al. (2019).

that in people with Alzheimer’s disease, tau
pathology selectively affects particular hippocam-
pal subregions (CA1) in the earliest stages of the
disease (Braak and Braak, 1991). High resolution
structural neuroimaging studies have provided
complementary in vivo evidence for selective atro-
phy. These studies have used magnetic resonance
imaging (MRI) to identify grey matter volume loss
in the CA1 region of people who have mild cog-
nitive impairment, a condition that often precedes
Alzheimer’s disease (de Flores et al., 2015). CA1
is also thought to be more susceptible to hypoxic-
ischemic damage than more resistant areas such as
CA3 (Schmidt-Kastner and Freund, 1991).
In addition to the variability within the hip-
pocampal formation along its transverse axis
described above, the structural and functional
properties of the hippocampal formation also are
thought to differ significantly along its longitu-
dinal axis (Poppenk et al., 2013; Strange et al.,
2014). There is considerable evidence from mul-
tiple lines of research that indicates anterior and
posterior human hippocampal formation regions
play variable roles in different types of cognition
and are also differentially affected in development
and by disease (Lladó et al., 2018; Riggins et al.,
2018). Emerging research on the structural and
functional connectivity of the anterior and pos-
terior hippocampus (Libby et al., 2012; Vos De
Wael et al., 2018), as well as differential neural
responses in these regions (Grady, 2020; Robin
et al., 2019), and differential genetic expression
(Cembrowski and Spruston, 2019; Dong et al.,
2009; Vogel et al., 2020) has led to novel insights
into this long-axis organization of the hippocam-
pal formation (Genon et al., 2021). This chapter
provides an overview of the current understanding
of the macro- and microstructural properties of the
hippocampal formation, as well as current theo-
ries of its functional organization, with a special
emphasis on the cognitive functions supported by
distinct hippocampal subregions in humans.
ANATOMY OF THE HIPPOCAMPUS
Macrostructural Definitions
The hippocampus is comprised of two cortical
laminae (i.e. layered tissue) rolled up one inside
the other: the cornu ammonis and the gyrus denta-
tus (or “dentate gyrus,” also referred to as the
“fascia dentata”), separated from each other by the
hippocampal sulcus (Figure 16.2A). The term
“ram’s horn” was adopted to describe the shape of
the cornu ammonis regions, and accordingly,
244 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 16.2 Folding patterns in development and in the adult hippocampus.

The curved structure of the hippocampus originates from an initially flat piece of tissue that
folds medially during development. This fold forms the hippocampal sulcus, denoted by the
black arrow. The green arrow demonstrates the proximal-distal dimension of the folding pat-
tern, and the red arrow demonstrates the folding along the long-axis. The fully developed
hippocampus is shown on the right (pictured from above). Dotted lines indicate commonly
used long-axis divisions of the hippocampus into the head (uncal section), head (body-like
section), body, and tail. A = anterior, L = lateral, M = medial, P = posterior
Source: From DeKraker et al., 2018; adapted from Duvernoy et al., 2013.

these regions are named after the Egyptian god
Ammon (Ammun Kneph). Many anatomists and
neuroscience researchers also include the subicu-
lum (which is located between the cornu ammonis
regions and the adjacent entorhinal regions in the
medial temporal lobe cortex) as part of the hip-
pocampal formation, although some view the
subiculum as a transitional region between the
hippocampus and the rest of the temporal lobe.
The hippocampus proper, when dissected away
from the rest of the brain, resembles a seahorse
(Figure 16.2). The term “hippocampus” is the
Latin word for seahorse, in line with the Greek
term “hippokampos”. The cortical tissue that
makes up the hippocampus contains three pri-
mary layers of cells rather than the more common
regions of neocortex that contain six layers of
cells. This laminar structure of the hippocampal
formation classifies the cornu ammonis (CA) 1-4,
dentate gyrus (DG), and subiculum portions as
“allocortex” (sometimes also called archicortex;
cf. Insausti et al., 2017)
In the human, the hippocampus is located in the
medial aspect of the temporal lobe and bordered
anteriorly by the amygdala. Parts of the thalamus
(e.g., the lateral geniculate nucleus) border the
superior aspect of the hippocampal formation. The
lateral part of the hippocampus (mostly CA1) is
bordered by the temporal horn of the lateral ventri-
cle. The subiculum extends laterally and inferiorly
into the parahippocampal gyrus, which is a mac-
rostructural landmark for the inferomedial aspect
of the hippocampus. The tail of the hippocampus
is described as “disappearing” (i.e., narrowing)
beneath the splenium. The indusium griseum is a
structure thought to be a dorsal extension of the
hippocampus, narrow strip of grey matter running
dorsal to the corpus callosum in the subcingulate
 Hippocampal Formation 245

region. It is now recognized that the subiculum
can be separated from two distinct adjacent subre-
gions (e.g., the presubiculum, and the parasubicu-
lum; Insausti et al., 2017). The presubiculum and
parasubiculum are referred to as “periallocortex”
as they contain six layers, although one layer is
“cell-free” and is referred to as the lamina disse-
cans (Insausti et al., 2017).
Hippocampal Head
The anterior, middle, and posterior parts of the
human hippocampus are dramatically different
from each other in terms of macrostructural shape.
The anterior part of the hippocampus contains a
rounded “bulge” that extends medially; this part
of the hippocampal head is referred to as the
“uncus” which is named for its hook-like structure
(Figures 16.2 and 16.3). Like the other parts of the
hippocampal formation, the uncus is not a single
homogenous region; it contains different types of
hippocampal tissue, including gray matter
belonging to the CA, DG, and subiculum. The
position of these subfields within the uncus can be
explained by the folding pattern of the hippocam-
pus during development (DeKraker et al., 2018;
Ding and Van Hoesen, 2015; Duvernoy et al.,
2013; see Figure 16.2).
The superior part of the hippocampal head
contains “elevations” or “bumps,” which have
been described by Duvernoy as “the digitationes
hippocampi.” Ding and Van Hoesen (2015) have
described these digitations in detail, and also make
the distinction between the internal digitations
(those that extend inferiorly) and external digita-
tions (those that extend superiorly). Ding and oth-
ers have also described the “vertical digitation”
which is the most medial digitation. This part of
the hippocampus gets its name from its vertical
orientation (Figures 16.1 and 16.2). The number
and size of the digitations can vary across sub-
jects (DeKraker et al., 2021). There are also some
“transitional” structures in the anterior hippocam-
pus that connect it to the amygdala and entorhinal
cortex. One region, the hippocampal-amygdala

Figure 16.3 Hippocampal shape varies greatly across individuals. A: 3-dimensional render-
ings of different hippocampi, which demonstrate the variability of the hippocampal head
digitations, curvature, and overall shape. B: Two examples of two different individuals with
variable digitations in the hippocampal head. C and D: Two examples of hippocampal denta-
tions on the inferior surface of the hippocampus. These two individuals vary by the number
and depth of the dentations.
Source: A and B adapted from DeKraker et al. (2021). C & D adapted from Beattie et al. (2017).
246 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

transition area (abbreviated “HATA”), is often
located in or near the vertical digitation.
Compared with the hippocampal head, the
body of the hippocampus is more tubular or cylin-
drically-shaped, with a further narrowing that typ-
ically continues posteriorly into the hippocampal
tail. Like the hippocampal head, the anatomical
features (i.e., size and shape) of the hippocampal
tail vary from person to person, and in some indi-
viduals the hippocampal tail curves medially and
sometimes superiorly (Figure 16.3A).
An additional macrostructural feature of the
hippocampus that has recently been recognized
is the presence of “dentations” or “bumps” on
the inferior surface of the hippocampal body and
tail (Figure 16.3C and 16.3D; Chang et al., 2018;
Fleming Beattie et al., 2017). Note that these struc-
tures are thought to be distinct from the digitations
present on the superior aspect of the hippocampal
head. The functional relevance of these dentations
is not yet well characterized, especially because
they are difficult to visualize using current in vivo
neuroimaging protocols.
MICROSTRUCTURAL DEFINITIONS
Cellular Composition
As described above, the CA, DG, and subiculum
subregions of the hippocampus are composed of
three major layers of cells. The three major
layers of the CA are the stratum oriens, the stra-
tum pyramidale, and a third layer that combines
the stratum radiatum, lacunosum, and molecu-
lare, which is sometimes abbreviated as “SRLM”
(Figure 16.4), providing a useful landmark for
neuroimagers to separate CA layers from the
DG layers of the hippocampal formation (de
Flores et al., 2020; Wisse et al., 2020). For
example, in high-resolution T2-weighted MRI
scans, the SRLM can be visualized as a c-shaped
“dark band” in coronal sections (as shown in
Figure 16.4).
The pyramidal layer of cornu ammonis shows
regional variations, which has been used by neu-
roanatomists to determine the different numbers/
names for the different subfields. Lorente de No
in the early 1900s described four fields: CA1-CA4
(Figure 16.1, middle panel). CA1 contains pyram-
idal cells that are small, triangular, and more
“scattered” or widely spaced compared to CA2
and CA3. Conversely, the cells in CA2 and 3 are
larger and more densely packed compared to those
of CA1. The CA2 region has the most compact
and narrow pyramidal cell layer of the hippocam-
pus. Its cells are almost as large as those in CA3,
but there is far less space between the cell bod-
ies. The CA3 pyramidal cells are the largest of the
hippocampus and stain darkly in Nissl stains. CA3
also contains the unmyelinated mossy fibers of the
DG which form a supplementary layer in between
the statum radiatum and statrum moleculare,
called the stratum lucidum. The stratum pyrami-
dale layer of CA3 is approximately ten cells thick
and it has a relatively homogeneous appearance.

Figure 16.4 Left panel demonstrates the different types of layers in fascia dentata (dentate
gyrus) and cornu ammonis.
Right panel demonstrates the layers on high resolution postmortem MRI and on ­postmortem
histology. The SRLM layers appear as a dark band on T2-weighted MRI.
Source: Left panel adpated from Duvernoy, 2005; Right panel adapted from de Flores et al., 2019.
 Hippocampal Formation
Finally, the pyramidal cell layer of the subiculum
is 30 or more cells thick, and can be divided into
at least two sublaminae (sub-layers). Relative
to CA1, the subicular pyramidal cells tend to be
somewhat larger and more widely spaced.
Turning to the dentate gyrus, this subregion of
the hippocampus also contains three major layers.
The layers of the dentate gyrus are: the stratum
moleculare (molecular layer), the stratum granu-
losum (granular layer) and the polymorphic (or
multiform) layer. The stratum granulosum is con-
sidered the main layer of this structure and it con-
tains the somata of granular neurons, which are
small and round but densely packed, making the
layer easy to distinguish in post-mortem stained
(e.g., Nissl) slices. Mossy fibers are the axons from
these granular neurons and they traverse the poly-
morphic layer into CA4 and CA3 (Figure 16.4).
Neurochemical Composition of
Hippocampal Subregions
The cells within the hippocampus contain numer-
ous receptor types which are co-localized in differ-
ent regions and layers of the hippocampus.
Neurotransmitter types include noradrenaline/nor-
epinephrine, serotonin, acetylcholine, dopamine,
glutamate, and GABA. Peptides and other chemi-
cal markers have also been shown to localize cer-
tain populations of interneurons in the hippocampus.
Moreover, different calcium-binding proteins
including parvalbumin, calbindin, and calretinin
also bind to different subsets of GABAergic neu-
rons. Recent investigations have combined classic
cytoarchitectonic methods with receptor-mapping
methods to understand the chemoarchitecture of
the hippocampal subregions (Ding and Van
Hoesen, 2015; Palomero-Gallagher et al., 2020;
Zeineh et al., 2017). These investigations have
provided unique evidence for the existence of
unique subregions (e.g., CA4 and pro-subiculum)
not universally recognized by other neuroanato-
mists who rely on more traditional mapping meth-
ods which rely more heavily on cytoarchitecture.
INTRINSIC AND EXTRINSIC
CONNECTIVITY OF THE HIPPOCAMPUS
White Matter Structures Within
the Hippocampus
Recent advances in high-resolution imaging
techniques have helped define the afferent and
247
efferent white matter structures within and adja-
cent to the human hippocampus (Amaral et al.,
2018; Beaujoin et al., 2018; Ke et al., 2020;
Parekh et al., 2015; Zeineh et al., 2012, 2017).
These include the perforant path system, which
connects the entorhinal cortex to several differ-
ent regions of the hippocampus, including the
dentate gyrus, CA3, and CA1. The perforant
path system has many components, including
both transverse and longitudinal components
(Zeineh et al., 2017) which connect the more
anterior and posterior regions of the hippocam-
pal formation.
Current evidence of these white matter struc-
tures and their associated intra-hippocampal net-
works has influenced theories about hippocampal
functions. Until recently, the field has relied heav-
ily on tracer studies in non-human animal mod-
els (Bubb et al., 2017; Witter and Amaral, 1991).
Future improvements in neuroimaging technology
will help update any cross-species differences that
have evolved in humans. For example, the end-
folial pathway, which is an output pathway from
CA4, projecting to the Schaffer collaterals of
CA3, seems to exist only in primates (Lim et al.,
1997; Parekh et al., 2015).
HIPPOCAMPAL AFFERENTS
Entorhinal Cortex Inputs
The entorhinal cortex provides most of the input
into the hippocampus from both subcortical and
neocortical sites. However, there is a well-charac-
terized topographical pattern of projections from
distinct anatomical subregions of the entorhinal
cortex into the hippocampus (Witter, 2007). There
are at least two patterns that have been identified.
First, the lateral entorhinal cortices project to the
more distal part of CA1 (closer to the subiculum)
and the medial entorhinal cortices project to the
more proximal part of CA1 (closer to CA2).
Recent studies have also indicated that the differ-
ent layers of CA1 receive different inputs from
lateral and medial entorhinal cortex. The lateral
entorhinal cortices contribute excitatory synapses
in the superficial CA1 layers; whereas the medial
entorhinal cortex excite the deeper layers of CA1
(Masurkar et al., 2017). This layer-specific pattern
of connectivity suggests that the well-established
“tri-synaptic circuit” is more complex than origi-
nally proposed and that new models of hippocam-
pal function should evolve to incorporate the
heterogeneity of these circuits (Valero et al.,
2018).
248 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Hippocampal Efferents
The fornix is a major output structure of the hip-
pocampus, projecting from the subiculum to the
mammillary bodies, anterior thalamus and the
septum (Bubb et al., 2017). Distinct components
of fornix, including the pre-commissural fornix,
have been further characterized using diffusion
tensor imaging (Choi et al., 2019; Hodgetts et al.,
2020; Wei et al., 2017; Williams et al., 2020;
Zeineh et al., 2012). The alveus and the fimbria
are longitudinal fibers, which merge with the
fornix, which then projects to the mammillary
bodies, as well as the anterior nucleus of the thala-
mus. The alveus covers the intraventricular sur-
face and contains axons of the hippocampal and
subicular neurons. Similar to the gray matter of
the hippocampus, these white matter structures
can be measured volumetrically by using high-
resolution structural MRI. In Alzheimer’s disease,
the fimbria and fornix are reduced in volume, but
the alveus is not affected (Amaral et al., 2018).
Vascular Supply
The vascular supply of the hippocampus has been
well-studied in post-mortem studies (Erdem et al.,
1993) and more recently using MRI-angiography
(Spallazzi et al., 2019). The hippocampus is pri-
marily supplied by the posterior cerebral artery
(PCA), and to a lesser extent, the anterior choror-
idal artery (AChA; Duvernoy et al., 2013; Erdem
et al., 1993). It is believed that there are significant
individual differences in the patterns of the vascu-
lar supply to the hippocampus by the hippocampal
arteries that arise from these two main vessels.
Post-mortem studies originally demonstrated that
the contribution of the AChA to the hippocampal
arteries is quite variable and is sometimes absent
(Marinković, Milisavljević, and Puškaš, 1992).
This vascular variability has now been docu-
mented in vivo using MR angiography (Perosa
et al., 2020; Spallazzi et al., 2019).
It has long been recognized that the hip-
pocampus, in general, is vulnerable to hypoxia
and other conditions causing cerebral hypoper-
fusion (Duvernoy et al., 2013; Schmidt-Kastner
and Freund, 1991). It has also been recognized
that certain subregions of the hippocampus are
more sensitive to hypoxia than other subregions.
For example, the CA1 region was described by
Wilhelm Sommer in the late 1800s as the “vulner-
able sector” and the CA3 region as the “resistant
sector.” The reason for the differential sensitivity
to hypoxia among subregions may be explained by
the arrangement of the hippocampal vasculature.
The effect of hippocampal vascularization on neu-
rodegeneration is still an area of active investiga-
tion. Several recent in vivo studies in older adults
have demonstrated that “mixed” or “dual supply”
to the hippocampus (i.e. blood supply arising from
both the AChA AChA and PCA) might be protec-
tive against cognitive decline and hippocampal
atrophy (Perosa et al., 2020).
Hippocampal Long-axis Organization
While studies into differences in cytoarchitecture
have shed light on subfield organization along the
proximal-distal/medial-lateral axis, there is sub-
stantial evidence supporting systematic variation
in structure and function along the long-axis of the
hippocampus. In both rodent and primate studies,
the hippocampus is often divided into two seg-
ments, transitioning from the anterior hippocam-
pus in primates (ventral hippocampus in rodents)
to the posterior hippocampus (dorsal hippocam-
pus in rodents) at the last slice containing the
uncal apex (Poppenk et al., 2013). In humans,
several dichotomies for the functional specializa-
tion of the anterior and posterior hippocampus
have been proposed (Grady, 2020). Some have
suggested that the anterior hippocampus, through
its direct and indirect connections with the amyg-
dala, nucleus accumbens, hypothalamus, and ven-
tral tegmental area, is specialized for emotional
processing, whereas the posterior hippocampus
supports cognitive processing (Murty et al., 2011).
Some neuroimaging studies have reported selec-
tive activity in the anterior and posterior hip-
pocampus during memory encoding and retrieval,
respectively (Lepage et al., 1998). Still others
have suggested posterior hippocampal specializa-
tion in the representation of spatial information
and navigation (Woollett and Maguire, 2011).
However, evidence in support of these dichoto-
mies has been mixed, suggesting that differences
in functional specialization may be dynamic (i.e.,
dependent on moment-to-moment input from the
MTL and neocortex to the anterior and posterior
regions). Thus, the ability to probe this functional
specialization may be sensitive to the specific
tasks used to measure cognitive processes
(Poppenk et al., 2013).
In addition to differences in cognitive processes,
the anterior and posterior hippocampal subregions
also exhibit different profiles of connectivity with
the rest of the brain. Distinct brain networks have
been identified based on their correlated fluctua-
tions in activity (“functional connectivity”) with
other regions during task and rest. Regions in the
MTL cortex (adjacent to the hippocampus) such
 Hippocampal Formation
as the PRC and PHC are part of distinct functional
networks (Ranganath and Ritchey, 2012). The
PRC, considered a core component of the ante-
rior temporal (AT) network, exhibits connectivity
with the amygdala, lateral orbitofrontal cortex,
and the anterior temporal lobe. The PHC, on the
other hand, is part of the posterior medial (PM)
network, along with the retrosplenial cortex, pre-
cuneus, angular gyrus, posterior cingulate cortex,
and medial prefrontal cortex.
These networks contribute to different aspects
of episodic memory. Substantial evidence has
linked regions in the AT network to familiarity-
based, item memory, emotional and motivational
processing, and representation of conceptual and
semantic information. Together, these regions have
been proposed to support the use of prior experi-
ence to guide future behaviour (Ranganath and
Ritchey, 2012). In contrast, studies have shown
the involvement of regions in the PM network in
recollection-based memory (i.e., memory for con-
textual information, Yonelinas et al., 2010), spa-
tial navigation, and recall of event detail. Activity
in the PM network scales with the accuracy and
vividness of retrieved information (Cooper and
Ritchey, 2019; Kuhl and Chun, 2013; Richter
et al., 2016). Additionally, multivariate patterns
of activity in the PM network carry information
about the content of retrieved episodic memo-
ries (Robin et al., 2018). Moreover, studies have
shown the involvement of the PM network not
only in memory retrieval, but also episodic future
thinking and simulation (Cooper and Ritchey,
2020). Importantly, these networks exhibit differ-
ential connectivity with the anterior and posterior
hippocampus. The anterior hippocampus is more
highly functionally connected to the AT network,
whereas the posterior hippocampus is functionally
more connected to the PM network (Barnett et al.,
2021; Ranganath and Ritchey, 2012). Thus, the
anterior and posterior hippocampus may subserve
distinct cognitive processes through their differen-
tial connections with the rest of the brain.
Another feature of the hippocampus that has
been theorized to drive the long-axis organiza-
tion of hippocampal function relates to different
responsivity of neurons in the anterior and pos-
terior hippocampus. Neural responses along the
long axis of the hippocampus differ in the granu-
larity of their representation. In rodents, the spa-
tial receptive field sizes of neurons increase from
dorsal to ventral hippocampus (Kjelstrup et al.,
2008). This receptive field pattern, in conjunction
with findings about the type of input that subre-
gions receive from the entorhinal and perirhinal
cortices, suggests that the anterior hippocampus
supports coarse-grained representations of infor-
mation whereas the posterior hippocampus is more
249
capable of representing fine-grained, detailed
information (Poppenk et al., 2013). This distinc-
tion is also mirrored in humans. Activity in the
posterior hippocampus is higher for tasks relying
on retrieval of fine spatial details of an experience
(Hirshhorn et al., 2012), and conversely, more
activity in the anterior hippocampus is observed
when approximate or relative spatial information
is required (Poppenk et al., 2013; Strange et al.,
2014). Extending this dichotomy to the represen-
tation of non-spatial information, studies have
reported that retrieval of episodic details recruits
the posterior hippocampus, whereas retrieval of
gist or schematic representations is associated
with anterior hippocampal activity (Addis et al.,
2004). Thus, differences in local circuit organi-
zation across the hippocampus long-axis seem to
the reflected in the high-level representation of
information.
Overall, mounting evidence indicates differen-
ces in local information processing, intra-hippo-
campal and neocortico-hippocampal connectivity,
as well as functional specialization along the long
axis of the hippocampus. These studies, in addi-
tion to those demonstrating different trajecto-
ries of decline in normal and pathological aging
(Blujus et al., 2022; Langnes et al., 2020; Lladó
et al., 2018; Martin et al., 2010), suggest that the
long-axis is an important organizing principle
within the hippocampus.
Structure–Function Relationships
Experimental evidence from hippocampal amne-
sic cases (like the famous hippocampal amnesic,
“H.M.”) as well as lesions in non-human animal
models has indicated that the hippocampus plays
a critical role in the formation of new memories.
Certain types of memory, including autobiograph-
ical or episodic memory, are adversely affected by
damage to the hippocampus, which can occur as a
result of surgical procedures (e.g., temporal lobec-
tomy), strokes, anoxia, encephalitis, or neurologi-
cal conditions such as epilepsy and dementia.
Age-related atrophy or neurodegeneration in the
hippocampus also occurs as a natural consequence
of healthy aging in humans (Raz et al., 2004a,b).
Researchers have demonstrated that damage or
atrophy to the hippocampus results in changes in
certain types of memory function, although the
extent of the impairment can vary across patients.
The types of memory that are impaired and spared
due to hippocampal damage/atrophy has led to our
understanding of how memory is organized in the
brain. Most prominently, changes in long-term,
remote, episodic, or autobiographical memory
250 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
have been reported (Spiers et al., 2001), and other
types of memory (e.g., semantic memory, motor
learning) are either spared or less impaired. It is
important to recognize, however, that damage to
the hippocampus can also affect other cognitive
functions, outside of memory (see below).
Role of Hippocampus in Episodic
Memory
Episodic memory, which is thought to rely criti-
cally on the hippocampus, refers to memories of
unique events, which occur at a particular time
and place, and are typically only experienced once
(Tulving, 2002). Autobiographical memory refers
to memories of life events for a particular indi-
vidual and this type of memory is severely
impaired in persons with damage to the hip-
pocampus (Addis et al., 2007). Furthermore, epi-
sodic memory is associated with the ability to
experience what Tulving called, “mental time
travel.” This form of memory allows someone to
“re-experience” a previous event with high fidel-
ity, including associated thoughts and feelings, the
spatial context in which the episode occurred, and
other associated sensory details (sights, sounds,
smells). The hippocampus is thought to perform
important binding and indexing functions to form
these autobiographical memory associations and
later retrieve them.
Do Only Conscious Forms of Memory
Depend on the Hippocampus?
Autobiographical and episodic memory are typi-
cally grouped under the umbrella category of
“long-term memory.” Furthermore, these memo-
ries have been categorized by some researchers as
“declarative” or “explicit” types of memory as
opposed to “non-declarative” or “implicit.” These
definitions of memory loss have focused on the
notion that hippocampal damage primarily affects
memory that is available to our conscious aware-
ness (Squire and Zola, 1996). For example, indi-
viduals with hippocampal amnesia are impaired
when asked to consciously report a recent experi-
ence (e.g., verbally recall a list of words or recog-
nize a list of pictures). Other forms of memory
that are considered implicit, or non-declarative,
like skill learning (Milner, 1970), are not as criti-
cally impaired in hippocampal amnesia (Corkin,
2002). Interestingly, improvements in perfor-
mance of patients with hippocampal damage on
these tasks were evident up to several months
following initial learning (Gabrieli et al., 1993),
indicating that regions outside the hippocampus
may support forms of memory that do not require
conscious awareness.
More recently, researchers have argued that
non-conscious forms of memory are also critically
dependent on the hippocampus (Henke, 2010;
Moscovitch, 2008). For example, humans with
hippocampal damage do not demonstrate the same
type of implicit learning of object-location associ-
ations compared with people without hippocampal
damage (Chun and Phelps, 1999).
Similarly, the expression of memory in indirect
measures, such as viewing behavior, is absent in
patients with damage limited to the hippocampus
(Hannula et al., 2007; Ryan and Cohen, 2004),
whereas in neurologically intact individuals, this
effect is observed even without conscious aware-
ness of learned materials (Ryan et al., 2000). In
fact, in healthy young adults, hippocampal activity
is associated with the memory based eye-move-
ments even when explicit responses are incorrect
(Hannula and Ranganath, 2009). These results
suggest that implicit memory is tied to hippocam-
pal processing both during encoding and retrieval
(Hannula and Greene, 2012).
Role of Hippocampus in Relational
Memory
A key feature of episodic memory is that it con-
tains memory for individual elements of an epi-
sode, as well as the relations between the elements.
Thus, one’s memory for an event such as a music
concert, may consist of a bound representation of
elements such as the venue of the show, the band
that performed, the songs they showcased, and the
location of one’s seat in the audience with respect
to the stage. Studies have shown that this type of
memory, termed relational memory, critically
depends on the hippocampus (Cohen and
Eichenbaum, 1993; Davachi, 2006). Compelling
evidence for the involvement of the hippocampus
in relational memory comes from a neuropsycho-
logical study in which participants completed a
task which tested memory for individual items, as
well as memory for spatial, temporal, and associa-
tive relationships between items. Relative to age-
matched controls, patients with hippocampal
amnesia were impaired on all tests of relational
memory, whereas their memory for individual
items was relatively spared (Konkel et al., 2008;
cf. Giovanello et al., 2003; Hannula et al., 2007;
Ryan et al., 2000). These findings are supple-
mented by results from neuroimaging studies that
show greater hippocampal activation during
 Hippocampal Formation
encoding and retrieval of associations supported
by relational memory compared with encoding
and retrieval of item memory (Giovanello et al.,
2004; Kirwan and Stark, 2004; Prince et al.,
2005). Consequently, it has been proposed that the
role that the hippocampus plays in memory for-
mation is that of binding disparate elements of an
episode to form a coherent, bound representation
(Konkel and Cohen, 2009), with regions in the
surrounding MTL cortex (e.g., perirhinal cortex)
being recruited to support memory for individual
items (Davachi, 2006).
Episodic Versus Semantic Memory
Based on patterns of impaired and spared memory
in people with hippocampal damage, memory
researchers have often distinguished between epi-
sodic and semantic memory. Episodic memory
refers to memories for information that has been
experienced only once and occurs in a particular
place and time. Semantic memory refers to infor-
mation that has been experienced multiple times
(i.e., knowledge that is context-free). Some exam-
ples of semantic memory are memory for facts
about the world and knowledge of word meaning
(i.e., vocabulary). Semantic memory is relatively
spared in amnesia, especially in cases where the
damage is restricted to the hippocampus. However,
there is some retrograde amnesia for more recently
acquired semantic knowledge. This suggests that
the hippocampus plays a more time-limited role in
semantic memory compared to episodic memory
and that there is an important distinction between
episodic and semantic memory (Rosenbaum et al.,
2005).
Role of Hippocampus in Retrieval of
Recent and Remote Memories
As mentioned above, it is well established that
damage to the hippocampus affects the ability to
form new episodic or long-term memories (Cohen
and Eichenbaum, 1993). Memory loss for events
that occur after hippocampal damage is referred to
as anterograde memory loss. In addition to antero-
grade memory loss in patients with hippocampal
damage, numerous neuroimaging studies have
demonstrated consistent activity in the hippocam-
pus during memory encoding (Davachi et al.,
2003; Greicius et al., 2003; Prince et al., 2005).
Taken together, these results indicate that the hip-
pocampus plays a central and pivotal role in the
formation of new memories.
251
Similarly, neuroimaging studies have also
documented the involvement of the hippocam-
pus in the retrieval of recent episodic memories
(Greicius et al., 2003; Prince et al., 2005). The
extent to which the hippocampus is involved in the
recall of remote memories, on the other hand, is
less clear. There have been reports that damage to
the hippocampus affects the ability to recall mem-
ories which were experienced before the damage
occurred (i.e., retrograde amnesia; Squire et al.,
2001). In several of these cases retrograde amnesia
is limited to memories only from a few years prior
to the hippocampal damage (Kapur and Brooks,
1999; cf. Argyropoulos and Butler, 2020), which
suggests that the hippocampus plays a time-lim-
ited role in the consolidation and retrieval of past
events (Bayley et al., 2003; Boccia et al., 2019).
However, other evidence has indicated the hip-
pocampus is necessary for the retrieval of per-
sonally experienced detailed events even from
the distant past (Moscovitch et al., 2006). For
instance, results from neuroimaging studies have
shown hippocampal activation during retrieval
regardless of the age of the memory (Addis et al.,
2004; Ryan et al., 2001). For this reason, it has
been argued that episodic memories, in particular
memories tied to a particular spatiotemporal con-
text, are always dependent upon the hippocampus,
no matter how much time has passed since the epi-
sode (Moscovitch and Gilboa, 2021).
Role of Hippocampus in Short- and
Long-term Memory
While the role of the hippocampus in long-term
memory is well-established, more recent research
has provided evidence for its role in other types of
cognition, such as visual perception and “short-
term” or “working memory” (Graham et al.,
2010). Some scholars have proposed that the
underlying computations performed by the hip-
pocampal formation support a binding mechanism
that is critical for multiple forms of cognition,
including short-term memory and perception
(Olsen et al., 2012). Binding refers to the forma-
tion of an association among distinct elements of
an experience (e.g., a face and name).
The role of the hippocampus in the binding of
elements in service of long-term memory has been
outlined above. However, results from several
studies indicate that this computation performed
by hippocampus may be critical even at shorter
delays (Olsen et al., 2012). For instance, patients
with hippocampal amnesia are impaired on work-
ing memory tasks that require binding of multi-
ple features of a visual display (e.g., the color of
252 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
items and their locations), even when tested after
a 1s delay (Borders et al., 2022). In line with this
finding, among healthy young adults, the level of
univariate activity in the head and body of the hip-
pocampus was predictive of the precision of work-
ing memory decisions.
In addition to this binding mechanism, which
may play a more critical role during memory
encoding, the hippocampus also likely performs a
“comparison” mechanism during memory retrieval
(Chen et al., 2011; Kumaran and Maguire, 2007;
Vinogradova, 2001). Comparison refers to the pro-
cess of evaluating the current information with the
associated information stored in the brain. Thus,
the hippocampus contributes to multiple cogni-
tive processes that require several pieces of infor-
mation to be bound together or when currently
observed information needs to be compared to
information stored in memory.
Role of Hippocampus in Encoding and
Retrieval of Recent Memories
While some studies have focused on understand-
ing the particular mnemonic processes performed
by the hippocampus, such as binding and com-
parison, other groups have investigated whether
the hippocampus is more involved during particu-
lar task phases such as encoding (i.e., the initial
study episode) or retrieval (i.e., during the recog-
nition or recall stage). As mentioned above, meta-
analyses (Grady, 2020; Kim, 2011) have found
that the hippocampus is more active during
memory encoding compared to memory retrieval.
Moreover, the anterior hippocampus was more
active during encoding than the posterior hip-
pocampus (Grady, 2020; Lepage et al., 1998).
During memory retrieval the opposite pattern has
been observed, where the posterior hippocampus
is more active than the anterior hippocampus. It is
currently unclear if these patterns are reflecting
the relative position of the hippocampal subfields
along the hippocampus long-axis, or another
organizing principle (e.g., connectivity) of these
anterior and posterior hippocampal subregions
(Olsen and Robin, 2020). Empirical studies using
high resolution imaging have reported conflicting
results regarding which of the hippocampal sub-
fields are more involve in memory encoding
versus memory retrieval (Hrybouski et al., 2019).
Some studies have reported greater activity in DG
and CA2/3 during encoding and greater activity in
the subiculum during retrieval (Eldridge et al.,
2005; Suthana et al., 2015; Zeineh et al., 2003),
but this pattern has not been consistently reported
in studies that have used thinner slices, which
further allow for the analysis of both subfield and
anterior-posterior organization (Hrybouski et al.,
2019).
Material Specificity of Hippocampal
Representations
Other groups have focused on the type of materi-
als used as memory stimuli in different memory
experiments to better understand the contributions
of the hippocampus to these different aspects of
memory. While the adjacent MTL cortex shows
strong category selectivity, with the anterior MTL
cortex responding to faces and objects and the
posterior MTL cortex responding to scenes
(Litman et al., 2009), the hippocampus does not
demonstrate a similar dissociation along its long
axis (Liang et al., 2013). Instead, the anterior hip-
pocampus shows greater activity during the
encoding of visual activity across different stimu-
lus categories (faces, scenes, objects) overall
compared to the posterior hippocampus. Note that
some studies have suggested that the role of the
anterior and posterior hippocampus may vary by
brain hemisphere. For example, studies have
found that verbal memory was associated with
left-lateralized anterior hippocampus activation,
compared to pictoral memory which was associ-
ated with activity in the right posterior hippocam-
pus (Persson and Söderlund, 2015).
ROLE OF HIPPOCAMPUS OUTSIDE OF
LONG-TERM DECLARATIVE MEMORY
Role of Hippocampus in Spatial
Navigation
The discovery of “place cells”, which are cells
located in the CA1 and CA3 subfields that fire
when an animal is in a particular spatial location
or “place field” has led to several prominent theo-
ries of the role of the hippocampus in spatial
memory and the nature of hippocampal represen-
tations and the formation of a “cognitive map”
(O’Keefe and Nadel, 1978). While place cells
represent one important dimension of the hip-
pocampus’s role in cognition, it is clear that cells
within the hippocampus represent other types of
information besides spatial location of the animal
(Eichenbaum, 2000). Furthermore, hippocampal
cell firing reflects both the relevant spatial and
nonspatial features of a particular task or experi-
ence (Cohen and Eichenbaum, 1993; Eichenbaum
 Hippocampal Formation
and Cohen, 2001). In fact, research has demon-
strated that some cells within the hippocampus are
sensitive to particular combinations of experiences
(e.g. encountering a particular odor or item in a
particular location). Thus, it has been argued that
the cognitive map theory of hippocampal function
does not account for the diversity of representa-
tions which are supported by the hippocampus.
SUMMARY AND CONCLUSIONS
The careful study of patients with hippocampal
damage has set the stage for the modern neuroscien-
tific understanding of hippocampal function.
Recently, the study of this complicated brain struc-
ture using modern imaging tools such as high-reso-
lution structural and functional MRI have allowed
for a more thorough investigation of hippocampal
function in humans. However, there is still consider-
able uncertainty regarding (1) the particular types of
cognitive function affected by hippocampal damage
and (2) the contributions of specific subfields to dif-
ferent types of memory. Thus, future research
should adopt a variety of approaches, including
studies of patients and infra-human species with
targeted focal lesions, using high resolution imag-
ing that allows for the delineation of particular brain
subregions, as well as data driven methods that may
uncover critical novel organization of this important
brain structure (DeKraker et al., 2021; Genon et al.,
2021; Olsen and Robin, 2020).
ABBREVIATION LIST
AChA = Anterior choroidal artery
CA = cornu ammonis
DG = dentate gyrus (also called gyrus dentatus)
ERC = entorhinal cortex
FD = fascia dentata (part of the dentate gyrus)
HATA = hippocampal-amygdala transition area
MTL = medial temporal lobe
MRI = magnetic resonance imaging
PaS = parasubiculum
PCA = posterior cerebral artery
PHC = parahippocampal cortex
PRC = perirhinal cortex
PreS = presubiculum
ProS = prosubiculum
SRLM = stratum radiatum, lacunosum, and moleculare
Sub = subiculum
253
Note
1  Some anatomists do not recognize the CA4
region as a distinct subfield of the hippocampus,
and refer to this region instead as the “hillus”
region of the DG.
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Cerebral Lateralization and
Hemispheric Specialization
Luis M. García-Marín, Zuriel Ceja, Miguel E.
Rentería, and Albert M. Galaburda
INTRODUCTION
The discovery of cerebral dominance that one
hemisphere predominates over the other for the
control of a given motor, sensory, perceptual, cog-
nitive, or metacognitive function (Bear et al., 1996;
Finger, 2012; White et al., 1994), in turn, has given
rise to the concept of cerebral lateralization, the
notion that brain functions are differentially dis-
tributed between the cerebral hemispheres (e.g.,
Paul Broca’s nineteenth-century identification of
the left-hemisphere speech motor articulation
center). Despite more than 150 years of neuroana-
tomical research (cf. Harris, 1984; Vanderah and
Gould, 2020), the fundamental origins of cerebral
lateralization and its raison d’être still remain
essentially unknown.
Historically, cerebral lateralization has been
richly discussed. In early thinking, the size of each
part of the brain, in gross anatomical terms, was
thought to correspond to the strength of a particu-
lar mental faculty – phrenology was born! It is fair
to say that this set of assumptions, as competing
theories emerged, remained viable in scientific cir-
cles until the second half of the twentieth century
and, in clinical settings, even until today. At the
very outset, there was pushback against localiza-
tion from both a scientific and social perspective.
17
For instance, work on birds has suggested that the
brain operates as a unity, with the corollary that
sequential focal brain damage, irrespective of
location, results in the gradual weakening of all
functions. Nonetheless, the work of anatomists
has contributed by showing that underlying gyri
and sulci commonly are areas with distinctive
microscopic morphology (and distinctive func-
tion?), which has led to the creation of architec-
tonic maps, one of which (Brodmann’s) is still in
common use today (Vanderah and Gould, 2020).
These detailed maps of the human brain have
underscored the focally differentiated, non-uni-
form low-magnification microscopic anatomy of
the cerebral cortex, with areas displaying different
arrangements and sizes of neurons. Later, similar
mapping approaches were used to show size dif-
ferences in several of these areas between left and
right hemispheres. From quite early with blunt
dissection of the fixed post-mortem human brain
(Heimer, 2005), to the demonstration of white
matter connectivity by staining for degenerating
axons following damage (Talamonti et al., 2013),
followed by improved methods for tracing axonal
connections in the monkey (Heimer and Robards,
1981; Lanciego and Wouterlood, 2020), and cul-
minating with the current methods of imaging
tractography in living human beings, an extensive,
260 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
albeit directed and non-diffuse organization of
fiber pathways has been highlighted. While the
notion of individual focal brain areas support-
ing individual functions has largely given way
to circuits and networks composed of nodes and
connections, some asymmetric but mostly distrib-
uted between the two hemispheres (Behrens and
Johansen-Berg, 2009; Fox, 2018; Liu et al., 2009),
the notion that the brain works essentially as a
general-purpose computer supporting all functions
with the same machinery distributed throughout
the hemispheres has been discarded. Indeed, over
the past century, it has become established, for
example, that the right hemisphere is dominant for
many aspects of vision and attention, as well as
for emotional behaviors (Stone and Aybek, 2016).
Research into localization and lateralization has
continued until now, but there has been a growing
emphasis on describing the anatomy and physiol-
ogy of perception and cognition in terms of coop-
erating neural networks containing multiple and
bilaterally located nodes and connections (Fox,
2018). However, examining these networks still
supports a skewed distribution between the hemi-
spheres for some functions, with more nodes on one
side than on the other for a given function. Although
it remains undeniable that lateralized injury to the
brain, whether on the left or the right side of the
brain, leads to distinct syndromes, it is equally clear
that strict localization and lateralization of single,
focal brain areas as responsible for discrete cogni-
tive function is no longer a tenable concept.
Brain Lateralization and Hemispheric
Specialization
The human brain is one of the most intensely stud-
ied organs in the body and one of the least well
understood, reflecting its enormous complexity
and individual variability. One of the main charac-
teristics of the human brain is its profound func-
tional lateralization. Nevertheless, anatomically
speaking, the brain appears quite symmetrical on
quick inspection, even as a closer look clearly
shows structural differences between the two hem-
ispheres (Vanderah and Gould, 2020). In this sec-
tion, we list some of the prominent structural brain
asymmetries and their functional correlations (an
exhaustive catalog of asymmetric areas and their
variability is beyond the scope of this chapter).
Prominent Structural Brain
Asymmetries
Brain asymmetries have been studied for well
over a century, and findings show that the right
sylvian fissure is shorter and curves upwards
more sharply at its posterior end, whereas the
left is straighter and reaches further posteriorly
(Sherman and Galaburda, 1985; also see Figure
17.1). In addition, the banks of the posterior por-
tion of the sylvian fissure comprising the planum
temporale and parietal operculum, including the
supramarginal gyrus, are associated with phono-
logical encoding, speech notion, analyzing the
amplitude and frequency of sounds (Hickok and
Poeppel, 2007).
The finding of a larger left planum temporale in
most people also corresponds to a longer left syl-
vian fissure. The left planum temporale can be up
to ten times larger than the right. In fact, this is the
most striking asymmetry seen in the human brain
(Amunts et al., 1996). However, the relationship
of the sylvian and planum asymmetries to lan-
guage and handedness is not entirely straightfor-
ward (Dorsaint-Pierre et al., 2006; Foundas et al.,
1994). This may reflect a tendency to assume that
all right-handers are the same and all left-handers
are the same (Geschwind and Galaburda, 1985),
as well as the fact that different methodologies are
often employed to circumscribe and measure the
planum temporale in different studies (Kulynych
et al., 1993).
The planum temporale appears in higher non-
human primates and old-world monkey species,
including baboons (Becker et al., 2022), as does
the sylvian asymmetry. The fact that these non-
human primates lack language has cast doubt
on their validity for language capacity, although
it is likely that the asymmetry may be necessary
but not sufficient for language, in a majority,
although not in all humans. Thus, although the
posterior sylvian/planum temporale asymmetry
is a common accompaniment of linguistic capac-
ity in right-handers, there is variability within the
human population, so that some humans, more so
left-handers, may not be organized asymmetri-
cally for language in the posterior temporoparietal
regions (Annett, 2013).
Petalias comprise cerebral lobes that pro-
trude beyond the extension of their contralateral
homologs, leading to a stronger impression on the
inner table of the skull (i.e., protrusions of por-
tions of one cerebral hemisphere toward the other
hemisphere). Petalias have been demonstrated
in computerized tomography, magnetic reso-
nance imagies, and endocasts of the neanderthal
man. Right frontal/left occipital petalias are more
prominent in right-handers, and also have been
documented in ancestral human skulls and some
non-human primates (Amunts et al., 1996). Such
petalias are associated with an incursion of the
right frontal lobe into the left side of the skull and
the left occipital lobe to the right, thus conforming
 Cerebral Lateralization and Hemispheric Specialization 261

Figure 17.1 Cerebral features of the fetal brain.

to the so-called Yakovlevian counter-clockwise
torque. Additional studies have reported the asym-
metry present in non-human primates of the equiv-
alent of Broca’s area in the frontal operculum
(Cantalupo and Hopkins, 2001). However, these
asymmetries are subtle by comparison to those
seen in the human brain. Another issue regarding
non-human brain asymmetry that is not widely
discussed in the literature is that handedness,
language lateralization, and brain asymmetry are
not evenly distributed in the human population,
with a strong bias to some patterns of asymmetry
262 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
occurring more frequently than others; such strong
population biases do not seem to be present in
non-human animals (see below).
Lateralization of Emotions and
Cognition
The lateralization of emotions and cognition is of
interest in neuroscience. Based mainly on effects of
brain injury, cognitive abilities are more dependent
on intactness of the left hemisphere, whereas emo-
tional integrity depends more on right hemisphere
intactness (Corballis, 2014). Two neural hypothe-
ses explain emotional lateralization (Table 17.1).
Right hemisphere hypothesis (RHH) refers to the
proposed right-hemisphere dominance for emotion
perception and emotional behavior, which includes
processing of social interactions, and processing of
spatial information. Such lateralization has been
documented in primates, suggesting that there is an
evolutionary continuity dating back 30–40 million
years (Lindell, 2013). RHH is supported by obser-
vations of impairment due to brain damage to the
right hemisphere, including perception and inter-
pretation of, and response to, emotional stimuli
through diverse sensory channels, such as speech
prosody, facial expressions, and intrinsic arousal
responses to emotional stimuli (Ross, 2021).
However, lateralization can be violated in prosop-
agnosia, commonly seen with right posterior
infero-temporal lesions, whereby the cognitive
content of familiar faces is degraded while emo-
tional content is preserved.
The Valence Hypothesis (VH) is based on obser-
vations in patients during left and right-sided Wada
tests, and on results of frontal-lobe strokes vis-à-
vis depression (Harciarek and Mańkowska, 2021).
Technologies commonly used to evaluate this
hypothesis also include magnetic resonance imaging
(MRI) and neurophysiological studies. VH suggests
that there is a right hemisphere bias toward negative
emotions and a left hemisphere bias toward positive
emotions (Gainotti, 2019). VH refers mostly to a
loss of emotional indicators, instead of a reduction
Table 17.1 Right hemisphere and valence hypotheses
Emotions and cognition lateralization theories
Right Hemisphere Hypothesis (RHH)
Description • Left hemisphere for cognitive abilities
• Right hemisphere for emotion processing, geometric
processing, and social interaction development
Supported by Observation of damage to right hemisphere
Author Corballis, 2014
in ability to experience emotions, commonly pre-
served among patients who have experienced right
hemisphere trauma (Ross, 2021).
Emotional indicators include autonomic or
hypothalamic responses inducing changes in heart
rate, pupillary size, sweating, nausea, changes
in neuroendocrine secretions; somatic motor
responses such as arousal and fight–flight behav-
iors; changes in verbal-linguistic communication
arising mainly in left hemisphere; and affective-
prosodic communication disclosing right hemi-
sphere dominance (Ross, 2021). Some of these
responses implicate the anterior cingulate, medial
prefrontal cortex, dorsal prefrontal cortex, amyg-
dala, anterior insula, as well as areas associated
with empathy and theory of mind (TOM), where
laterality to the right hemisphere is often, but not
consistently, observed (Hillis, 2014). Fear and
pain mechanisms, which underlie much emotional
behavior, seem to be lateralized to the right amyg-
dala (Allen et al., 2021; Guadagno et al., 2020).
One RHH limitation is the apparent symmetric
neuroanatomy of structures including the amyg-
dala, hippocampus, and insula. This symmetry
might signify that both hemispheres participate
in different aspects of emotion, as per the valence
hypothesis. It has been suggested that the modu-
lating influence of the right hemisphere on affec-
tive-prosodic features of communication could be
complementary to left hemisphere dominance for
modulation of verbal-linguistic features (Ross,
2010). Whether RHH or VH can explain emotional
lateralization more accurately has been discussed
(Killgore and Yurgelun-Todd, 2007; Ross, 2021;
Sharma et al., 2020). Findings suggest that both
theories can potentially explain different aspects
of a complex distributed emotion processing sys-
tem (Killgore and Yurgelun-Todd, 2007).
Lateralization of Language
Language lateralization to the left hemisphere is
one of the least disputed examples of functional
asymmetry in the human brain, although the
Valence Hypothesis (VH)
Opposite dominance:
• Left hemisphere for positive emotions
• Right hemisphere for negative emotions
Observation in patients during left and
right-sided Wada test
Gainotti, 2019
 Cerebral Lateralization and Hemispheric Specialization
origin of this common phenotype is not known.
Language is a late arrival in evolution, at least in
its human form, so its left-sided localization may
reflect evolutionarily earlier lateralization of other
skills to the right in non-human vertebrates. For
instance, Denenberg et al. (1981) reported right-
sided lateralization for emotional behaviors in
rats, suggesting that, evolutionarily, this lateraliza-
tion preceded language lateralization. Language
lateralization to the left hemisphere may have
been necessitated by the previous lateralization of
emotions and attention to the right. On the other
hand, language lateralization to the left may have
been an adaptation of an earlier lateralization to
the left for conspecific vocalizations and motor
preference (Siniscalchi et al., 2018).
Initial findings related to language lateraliza-
tion were made in patients with brain injury as
well as epileptic patients. Defined pathologically,
Broca’s area usually includes the pars opercularis
and pars triangularis of the frontal operculum, as
well as the subcentral cortex, but more extensive
involvement is also implicated. Wernicke’s area
includes the planum temporale, plus various quan-
tities of the superior and middle temporal gyri and
the parietal operculum. Some individuals with
extensive injury to these regions, most of them
being left-handed, show no language deficits.
Lateralization of normal language function is
somewhat less striking than that documented by
acute brain injury, whereby most contemporary
functional studies implicate the participation of
the right hemisphere, even in right-handers and
especially in the absence of literacy (Dehaene
et al., 2010; Lecours et al., 1988). This is impor-
tant because although there is evidence that
lateralization reflects hardwired, biological
underpinnings, its full expression is also a reflec-
tion of learning. Age alone may affect language
lateralization, the mechanisms for which are not
understood, whereby lateralization first increases
in childhood, then remains stable in young adult
life, to gradually decrease in senescence (Brown
et al., 2005; Holland et al., 2001). However, not
everyone has reported this age-related change
(Wood et al., 2004). PET, transcranial Doppler,
and fMRI studies have evaluated language locali-
zation and lateralization in healthy subjects. These
noninvasive studies in healthy adults indicate that
approximately 95% of right-handers display left-
hemispheric language dominance (Knecht et al.,
2000), keeping in mind the variability reported
above, as well as factors such as handedness, fam-
ily history, and sex (Holland et al., 2001; Josse
and Tzourio-Mazoyer, 2004; Knecht et al., 2000;
Tzourio-Mazoyer et al., 2004). We anticipate that
some of the variability in the results of language
lateralization studies will be resolved when more
263
formal psycholinguistic parameters, such as gram-
mar, lexical knowledge, and pragmatic use of lan-
guage are further analyzed separately with regard
to cerebral lateralization (Heine et al., 2014).
Handedness
Handedness, also known as hand preference, is the
propensity to learn more easily and achieve greater
skill and comfort using one hand instead of the
other in the performance of tasks such as writing,
grasping an object, throwing a ball, or handling a
violin bow, for instance. Genetic and epigenetic
factors, including cultural factors, modulate the
expression of handedness in a given population
(Ocklenburg et al., 2017). Hand preferences,
whether right, left, or ambidextrous, are not abso-
lute categories, and instead, the degree of right-
handedness is commonly assessed by handedness
questionnaires such as the Edinburgh Handedness
Inventory (Schachter, 2000). Whereas the propor-
tion of right versus left-handers varies according to
the criteria used to determine handedness (as well
as according to culture, country, ethnic groups, and
other factors in western countries), 70% to 95% of
people are right-handed, whereas only 5% to 30%
of people are left-handed.
Handedness occurs at the individual level (e.g.,
a person is left-handed) and at a population level
(e.g., 15% of humans are left-handed). Handedness
(or pawedness or clawedness) occurs in individual
non-human species (Giljov et al., 2015; Ocklenburg
et al., 2013, 2014), but a population bias for hand
preference is usually associated with humans and
hominids, although more recently, population-
level asymmetries in non-human primates have
been reported (Lonsdorf and Hopkins, 2005),
especially favoring female right-handedness, both
in captivity and in the wild (Llorente et al., 2011).
Archaeological evidence suggests that human
ancestors such as Homo Heidelbergensis (Lozano
et al., 2009) and Homo Habilis (Frayer et al., 2016)
might also have had a hand-side preference.
Lateralization is a conserved feature of ver-
tebrates, and recent studies suggest lateraliza-
tion can be a feature of invertebrate species, too
(Frasnelli et al., 2012). In addition to the few clues
to lateralization’s phylogenetic history, some work
has been done on the ontogenetic development of
asymmetry. For instance, there has been discus-
sion about the possible genetic origin of handed-
ness. Nonetheless, genome studies have failed to
detect a simple genetic model able to explain all
of the lateralization (Armour et al., 2014), and
instead, it is more likely that many genes can
explain a fraction of the variance in handedness
data. Some studies suggest just one-quarter of the
264 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
variance can be explained by genetic variation,
among them the androgen receptor (AR) gene
(Arning et al., 2015), leucine-rich repeat trans-
membrane neuronal 1 (LRRTM1) (Francks et al.,
2007), and proprotein convertase subtilisin/Kexin
type 6 (PCSK6) (Scerri et al., 2011).
Most of the laterality research has focused on
the cerebral cortex. This is not unreasonable, since
the cortex is the brain system that differs most
between human and non-human animals. However,
at least part of lateralization is learned, and a fair
amount of learning involves subcortical systems.
Ontogenetically, handedness starts early in devel-
opment (at 10 gestational weeks) with 85% of
fetuses exhibiting predominance of right-hand
movements and right thumb sucking in 90% at 13
weeks (Hepper et al., 1990). Importantly, follow-up
studies show a positive correlation between early
thumb sucking preference and later handedness
(Hepper et al., 2005). Given that the motor cortex is
functionally linked to the spinal cord only after 15
weeks gestational age, it remains unlikely that the
cortex is the only driver of this form of lateraliza-
tion (ten Donkelaar et al., 2014). Instead, it remains
likely that lateralization begins in ontogenesis at
several independent induction nodes throughout
the nervous system and probably under the effect
of locally acting genes (Ocklenburg et al., 2017).
This proposed multiplex origin of lateralization can
increase the variability of outcome and diminish the
odds that lateralization is a simple binary system of
left- and right-handedness. Ocklenburg et al. (2017)
proposed that some time before 10 weeks post-con-
ception comprises the critical period of handedness
determination; throughout this period, asymmetrical
DNA methylation and posttranscriptional regulation
leads to a spike in RNA expression asymmetries
in the spinal segments that innervate the arms and
hands, which in turn is capable of influencing neural
circuit development throughout the nervous system,
provoking behavioral asymmetries after 15 weeks
when motor cortex and spinal cord are function-
ally connected (ten Donkelaar et al., 2014). In this
scenario, the cerebral cortex is at least partly slav-
ish to influences coming up from below. This is akin
to saying that cortical cognitive systems develop at
least partially in relation to inputs from the sensory
organs in a bottom-up fashion.
FACTORS ASSOCIATED WITH BRAIN
ASYMMETRIES
Body Asymmetries
The human body is seen to be symmetric during
early embryonic development (Figure 17.2).
However, at five gestational weeks, symmetry is
disrupted as the heart, originally a straight tube in
the midline loops and settles at its characteristic
left-sided position (Schmitz et al., 2019).
Comparable twists result in the liver becoming
right-sided and the stomach left-sided by the sixth
gestational week (Schmitz et al., 2019). By seven
gestational weeks, the lung divides into right and
left buds. These buds will eventually split into two
lobes on the left side of the midline and three
lobes on the right side (Schmitz et al., 2019).
Development of visceral asymmetries reaches
completion by the tenth gestational week, which
marks the end of the embryonic period.
Initially, the ectoderm gives rise to the earli-
est neural tissue, the neural plate, which folds
into the neural tube, a symmetric midline struc-
ture. The rostral end of the neural tube grows
ventrally, leading to the formation of the prosen-
cephalon, mesencephalon, and rhombencephalon
by the sixth gestational week. The prosencepha-
lon, in turn, gives rise to the cerebral hemispheres
by eight gestational weeks, and structural brain
hemispheric asymmetries emerge after the begin-
ning of the fetal period at 11 gestational weeks
(Schmitz et al., 2019). Between 11 and 13 gesta-
tional weeks, the earliest structural hemispheric
asymmetry is noted: Enlargement of the left cho-
roid plexus. This asymmetry in length, area, and
circumference has been suggested to be a precur-
sor of other hemispheric asymmetries (Corballis,
2013; Schmitz et al., 2019). In addition, at 20 ges-
tational weeks, a leftward asymmetry emerges in
the volume of the occipital lobes, as does for the
entire left hemisphere (Schmitz et al., 2019). The
asymmetry of the sylvian fissures becomes visible
even before the fissure is fully closed, soon after
the twentieth week of gestation, and finally, the
leftward planum temporale asymmetry, percepti-
ble at 31 gestational weeks, is claimed to result
from interhemispheric differences in cerebrospi-
nal fluid production and accompanying asym-
metries in cytokines, growth factors, and peptides
(Schmitz et al., 2019).
Ciliopathies
Cilia consist of hundreds of proteins organized
around a microtubular scaffold and have key roles
in cell locomotion, fluid movement, including the
propulsion of seminal fluids containing sperm, and
sensory functions (Ferkol and Leigh, 2012). Cilia
are involved in the development of the entire human
organism and play an essential role in the develop-
ing central nervous system. Notably, cilia function
determines visceral asymmetry in vertebrates
 Cerebral Lateralization and Hemispheric Specialization 265

Figure 17.2 Formation of body asymmetries during embryonic development.

Body symmetry is first disrupted at the heart during embryonic development, and brain
asymmetries become observable at 11 weeks.

(Trulioff et al., 2017). During embryonic develop-
ment, clockwise rotation of cilia creates transient
leftward fluid flows that contribute to left-right pat-
terning. These flows are known to guide the asym-
metric activation of the Nodal (TGFβ) signaling
pathway transforming growth factor-β (TGFβ),
which directs asymmetric morphogenesis in devel-
oping organs (Dasgupta and Amack, 2016). Two
hypotheses have been proposed for how nodal flow
is perceived by nodal and perinodal cells. The che-
mosensory hypothesis suggests that the nodal flow
produces a gradient of left node vesicular parcels
with hedgehog proteins, resulting in a downstream
signaling cascade of nodal in the left-side perinodal
cells (Tanaka et al., 2005). In contrast, the mecha-
nosensory hypothesis proposes that the left nodal
flow leads to the asymmetrical increase influx of
Ca2+ ions in the sensory cilia cells, which in turn is
associated with the nodal activation in the left-side
perinodal cells (McGrath et al., 2003; Tanaka et al.,
2005). Both proposals can explain asymmetric gene
expression and asymmetric organogenesis, although
more detail is needed. Cilia malfunctioning can
induce abnormalities in left-right patterning, infer-
tility, and the clearance of secretions from the lung,
resulting in severe medical conditions known as
ciliopathies (Table 17.2).
The Bardet-Biedl syndrome, Meckel syn-
drome, Joubert’s syndrome, Senior-Loken syn-
drome, Jeune’s syndrome, Siewert’s/Kartagener’s
syndrome, and Alstrom syndrome are examples
of ciliopathies, where genetic mutations result
in abnormally formed or malfunctioning cilia
(Waters and Beales, 2011). Ciliopathies may
include, to a varying extent, heterotaxy, which
is the abnormal arrangement of the thoracoab-
dominal organs across the left–right axis of the
human body (Kim, 2011). Cilia disruption, both
anatomical and functional, has also been seen in
association with the developmental dyslexia can-
didate gene DYX1C1, when its homolog, dyx1c1,
is deleted in the mouse, where developmental dys-
lexia itself is associated with brain asymmetry var-
iants (Galaburda et al., 1985; Tarkar et al., 2013).
266 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Table 17.2 Ciliopathies overview

Importance Cilia plays an essential role in the central nervous system development and determines
visceral asymmetry in vertebrates (Trulioff et al., 2017).
Related growth factors The nodal (TGFβ) influences asymmetric morphogenesis in developing organs (Dasgupta
and Amack, 2016).
Hypotheses Chemosensory Hypothesis Mechanosensory Hypothesis
The nodal flow produces a gradient of left The left nodal flow leads to the asymmetrical
node vesicular parcels with hedgehog increase influx of Ca2+ ions in the sensory
proteins, resulting in a downstream cilia cells, which in turn is associated
signaling cascade of nodal in the left- with the nodal activation in the left-side
side perinodal cells (Tanaka et al., 2005). perinodal cells (McGrath et al., 2003;
Tanaka et al., 2005).
Malfunctioning • Abnormalities in left-right patterning
implications • Infertility
• Lung secretions clearance
Examples of ciliopathies • Bardet-Biedl syndrome
• Meckel syndrome
• Joubert’s syndrome
• Senior-Loken syndrome
• Jeune’s syndrome
• Siewert’s/Kartagener’s syndrome
• Alstrom syndrome
• Heterotaxy

Although cilia are distributed widely in the CNS
and characterize the morphology of fluid propel-
ling ependymal cells lining the ventricles, a role of
cilia in the formation of brain asymmetry remains
to be confirmed.
Genetics and Heritability
Brain asymmetry is heritable, but the genetic
foundations of human brain asymmetry remained
largely unknown until recently. Genome-wide
association studies (GWAS) have helped eluci-
date whether genomic variation in large popula-
tion datasets relates to variation in adult brain
asymmetry using MRI scans and genetic data.
Although these are correlational data, they repre-
sent a good step toward finding the biological
cause or causes of brain asymmetry. A GWAS is
performed to identify regions of the genome asso-
ciated with a given phenotype, in this case, brain
asymmetries. Thousands of individuals with and
without specific brain asymmetries are recruited
and classified as cases and controls. Then, their
DNA is genotyped and analyzed for the frequency
of genetic variants in the form of single nucleo-
tide polymorphisms (SNPs) across the entire
genome. If a genetic variant is statistically more
common among individuals who show brain
asymmetry than for those who do not, taking into
account multiple comparisons, then that suggests
the genetic variant is associated with brain
asymmetries.
GWAS have identified 27 independent lead
SNPs across 21 genomic loci associated with
different aspects of brain asymmetry (Sha et al.,
2021). These lead SNPs were also associated with
cortical surface area, cortical thickness, or sub-
cortical volumes (Sha et al., 2021). Furthermore,
the loci associated with brain asymmetries were
mapped to several genes, including those respon-
sible for encoding proteins involved in the reor-
ganization of the actin cytoskeleton and the
stabilization of microtubules (Sha et al., 2021).
Similarly, some of these loci were mapped to
genes related to brain phenotypes or develop-
ment. For instance, ZIC4 is involved in the devel-
opment of visual and auditory pathways, and
NR2F1 is associated with neural activity during
cortical patterning, BBS9 causes Bardet–Biedl
syndrome when mutated, and COL18A1 plays a
major role in neural tube closure and is mutated in
Knobloch syndrome, potentially resulting in skull
abnormalities (Sha et al., 2021). The assays that
disclose SNP variants are, of course, hypothesis-
free, so it is rewarding to see the emergence of
brain-related genes in the analyses. However, as
can be seen from the examples listed above, there
is no obvious connection between what is known
about the functions of these genes and the emer-
gence of brain asymmetry. One exception may be
the association with genes involved with the actin
 Cerebral Lateralization and Hemispheric Specialization
cytoskeleton, as the latter is crucial for cilia func-
tion, and cilia are implicated in asymmetry forma-
tion (see above). Additional help is obtained by
analyzing the expression patterns of these candi-
date genes, both spatially and temporally. In this
way, for instance, genes expressed, say, only after
puberty could be excluded from further study.
Thus, it is informative to note that by using GWAS
results, scientists found higher mRNA expression
of genes related to brain asymmetry during early-
and mid-prenatal brain development, ranging
from 9 to 24 post-conceptional weeks (Sha et al.,
2021), a timeframe overlaping with the emergence
of detectable gross anatomical asymmetries in
the human brain. That said, it would be reward-
ing to observe that some of the asymmetry can-
didate genes are also expressed in somatic organs
that also develop asymmetrically (e.g., the liver,
the spleen, the heart, although the mechanisms for
body and brain asymmetry may be different). One
reason for stating this is that, although brain areas
are asymmetrical in size, they are present on both
sides of the brain, whereas, for instance, there is
no tiny right-sided spleen or a small mirror image
liver on the left.
Single nucleotide polymorphism (SNP) herit-
ability describes the extent to which variance in
brain asymmetry is linked to common genetic
variation across the entire genome (Kong et al.,
2021; Sha et al., 2021). In genetic epidemiological
studies, brain asymmetry heritability has ranged
from 2.2% to 24% in specific brain structures
(Kong et al., 2018, 2021; Sha et al., 2021), while
twin and family studies have estimated heritabil-
ity for brain asymmetry measurements up to 37%
(Jahanshad et al., 2010), suggesting that genetic
variation is partly responsible for global brain
asymmetry. Similarly, for velvet monkeys, global
brain asymmetry has been reported between 10%
and 30% (Fears et al., 2011). In contrast, estimates
for the heritability of asymmetry in specific brain
structures range from 21% to 32% for chimpan-
zees, with a total brain asymmetry heritability of
41% (Gómez-Robles et al., 2016). These findings
suggest a genetic origin behind the level of brain
plasticity within higher primates and monkeys,
which, in turn, shows that brain asymmetries are,
at least in part, heritable, and that they did not arise
de novo with humans and are instead part of a phy-
logenetic history.
Experiential and Environmental
Factors
Although lateralization of handedness and lan-
guage have been demonstrated to have a heritable
267
genetic component, they are also considered plas-
tic since they can be reversed early in life. If
functional lateralization can be switched early,
what does it say about the relationship between
functional lateralization and anatomical asymme-
try, which does not switch? Some growth of the
smaller side is possible from use, as suggested by
Merzenich et al. (1996). Alternatively, the quality
of the recovered skill may not be as high as if
there had not been any injury causing a switch, or
the switch may be only partial (Buetefisch, 2015).
On the other hand, there has been disagreement
about whether anatomical asymmetries predict
functional lateralization strongly and consistently
(Beaton, 1997; Foundas et al., 1994).
Twin and family studies have estimated that
shared environmental factors account for up to
36% of the variance in brain asymmetry in specific
regions (Yoon et al., 2010). What does appear to
be the case is that, even though anatomical asym-
metries are present early, it may take language
experience, especially written language learning,
to help express this laterality at the functional
level (Dehaene et al., 2010). Another example of
a putative environmental effect may be the season
of conception. For instance, more left-handers
have been found among males born during winter
(Duboc et al., 2015). This phenomenon could be
explained by the seasonal variation in the mother’s
hormones. Higher levels of androgens during fetal
development in spring could contribute, along
with genetic factors, to a left shift in handedness
(Duboc et al., 2015). However, cultural pressure
has also been shown to push a shift from left to
right-handedness during early life (Fagard, 2013),
but to our knowledge, there are no examples of any
particular culture pressing a large-scale change of
hand preference from right to left.
Sex Hormones
Testosterone has been a focal point of interest
when studying brain lateralization because it may
play an important role in handedness among
males (Galaburda et al., 1985; Hampson and
Sankar, 2012). However, while some have impli-
cated testosterone in the shift to left-handedness
(Galaburda et al., 1985), others have observed that
left-handed males have lower bioavailable testos-
terone levels than right-handed males (Hampson
and Sankar, 2012). Notably, males with mixed
handedness have weaker androgen receptors;
however, this does not seem to impact testosterone
levels compared to right-handers (Hampson and
Sankar, 2012). One of the complex issues to
resolve relates to the exact timing during develop-
ment when steroids may modulate laterality
268 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
effects and the distinction between absolute tes-
tosterone levels and variable testosterone sensitiv-
ity to a given testosterone level, which is also
controlled by the genes.
BRAIN ASYMMETRIES IN BRAIN
DISORDERS
Neurodevelopmental Disorders
Dyslexia
Developmental language disorders and learning
disabilities such as dyslexia have been linked to
anatomical disruptions of brain asymmetry
(Altarelli et al., 2014; Galaburda et al., 1985;
Leonard and Eckert, 2008). The planum temporale,
a region of interest in dyslexia asymmetry studies,
is found directly posterior to Heschl’s gyrus, which,
in turn, contains the primary auditory cortex
(Galaburda et al., 1985). The planum temporale
overlaps, at least in part, with Wernicke’s temporo-
parietal language area. In particular, it contains the
auditory association cortex, which has a role in
representing and processing a necessary skill for
fluent reading (Leonard and Eckert, 2008).
Therefore, a structural anomaly in this region may
be expected to alter efficient phonological repre-
sentation and processing and, consequently, fluent,
efficient treading. Anatomically, the planum tem-
porale is typically larger in the left hemisphere than
the right hemisphere, and this manifestation of
asymmetry is altered in individuals with develop-
mental dyslexia (Altarelli et al., 2014; Galaburda
et al., 1985). During the 1980s, Galaburda acquired
a series of postmortem brains from individuals with
dyslexia and reported an enlargement of the planum
temporale in the right hemisphere, which abolished
the typical asymmetry of this region (Galaburda
et al., 1985; Leonard and Eckert, 2008). This was
taken as an example of larger not being better, and
anti-phrenological bend. Later studies using mag-
netic resonance imaging have replicated these find-
ings in males but not in females (Altarelli et al.,
2014). Developmental dyslexia is less common in
women than in men, and when it occurs, the pathol-
ogy may, in fact, be different (Galaburda et al.,
1985; Humphreys et al., 1990).
Attention Deficit-hyperactivity
Disorder
Attention deficit-hyperactivity disorder (ADHD)
is the most commonly reported neurodevelopmen-
tal disorder in children, which may extend into
adulthood. ADHD symptoms include lack of
attention, concentration, focus, disorganization,
and sometimes hyperactivity (Magnus et al.,
2022). A case-controlled study claimed that an
anatomical asymmetry of the caudate nucleus
might play a role in developing ADHD (Dang
et al., 2016). Another correlational study, in an
effort to shed light on the relationship between the
brain’s white matter and ADHD, used diffusion
tensor imaging data to estimate the mean frac-
tional anisotropy (FA) of 40 brain regions (Wu
et al., 2020). Among the findings, an increase in
leftward lateralization of the posterior thalamic
radiation was associated with ADHD in children
(Wu et al., 2020). Similarly, a magnetic resonance
imaging study demonstrated that individuals with
ADHD show increased leftward lateralization in
the inferior orbitofrontal cortex and decreased
rightward lateralization in the medial orbitofrontal
cortex and rectus gyrus (Zou and Yang, 2021). It
is not clear why these areas are implicated, as the
physiology of this disorder points instead to the
dorsomedial, dopaminergic cortex (Brown et al.,
2010). Furthermore, these same authors found dif-
ferent asymmetry manifestations between men
and women, where the clinical manifestations also
differ.
Autism Spectrum Disorder
Disruption of standard anatomical brain asym-
metries has been suggested to be one of the factors
influencing the development of autism spectrum
disorder (ASD) (Postema et al., 2019). ASD is
characterized by impaired communication,
impaired reciprocal social interactions, and
restricted and repetitive behaviors or interests
(Faras et al., 2010). Postema et al. (2019) mapped
differences in brain asymmetry between individu-
als with ASD and controls. They found altered
asymmetries in seven regional cortical thickness
measurements among individuals with ASD, pre-
dominantly involving medial frontal, orbitofron-
tal, inferior temporal, and cingulate regions
(Postema et al., 2019), areas implicated in theory
of mind, risk assessment and reward, and sociali-
zation. In particular, the rightward asymmetry of
the medial orbitofrontal surface area was
decreased in individuals with ASD, as was the
leftward asymmetry of the lateral orbitofrontal
surface area. Also, individuals with ASD showed
increased leftward asymmetry of putaminal
volume (Postema et al., 2019). Understanding the
neuroanatomical biology of ASD, including brain
asymmetries, could potentially lead to earlier
diagnosis, clinical subgrouping, and the develop-
ment of individually targeted treatments.
 Cerebral Lateralization and Hemispheric Specialization
Neurodegenerative Disorders
Corticobasal degeneration
Corticobasal neurodegeneration or corticobasal syn-
drome, one of the degenerative brain disorders
known as tauopathies, was initially considered to be
strictly a motor disorder; however, it is currently
categorized as a complex condition that includes
sensorimotor and cognitive features (Parmera et al.,
2016). Symptoms may include language dysfunc-
tion, left-sided apraxia, sensory and visual neglect
affecting the left side of space, apathy, disinhibition,
extrapyramidal stiffness, myoclonus, difficulty
swallowing, poor balance, and coordination
(Parmera et al., 2016). Corticobasal degeneration is
widely known for presenting asymmetrical cortical
atrophy in magnetic resonance studies, including
diffusion-tensor imaging, being more pronounced
in the right hemisphere (Constantinides et al., 2019).
Volumetric studies have shown that cortical atrophy
is primarily observed in the pericentral region,
including the pre- and post-central gyri and poste-
rior portions of the frontal lobe and anterior portions
of the parietal lobe (Constantinides et al., 2019).
Pick’s Disease
Pick’s disease, one type of frontotemporal lobar
degeneration or frontotemporal dementia, is
another example of tauopathy. It is characterized
by behavioral changes and language dysfunction
owing to frontal and temporal cortical neurode-
generation (Pippin and Gupta, 2023). The pathol-
ogy of Pick’s disease mimics to a fair degree the
clinical symptomatology, whereby when language
is particularly strongly affected, the left temporal
lobe shows greater pathology, and when behavior
aberrations are a prominent manifestation, the
pathology is worse on the right side. While the
disease is often asymmetric in presentation, there
is much individual variability (Irwin et al., 2018).
PSYCHIATRIC DISORDERS
Schizophrenia
Schizophrenia is a chronic psychiatric disorder
characterized by delusions, hallucinations, dis-
organized thought and behavior, and impaired
cognitive ability (Kahn et al., 2015; Patel et al.,
2014). Most theories around the pathophysiol-
ogy of schizophrenia point to abnormalities in
neurotransmission, paying particular attention to
269
the excess or deficiency of neurotransmitters
such as dopamine, serotonin, and glutamate
(Patel et al., 2014). Notably, other theories sug-
gest that hemispheric laterality plays a signifi-
cant role in the pathophysiology of schizophrenia.
For instance, it has been argued that schizophre-
nia may result from a genetically determined
failure of normal cerebral lateralization (Oertel-
Knöchel and Linden, 2011). Thus, the authors
observed that individuals with schizophrenia are
left-handed more often than the base rate in the
general population. Magnetic resonance imaging
and postmortem studies of gray matter volume
asymmetry indicate that reduced or reversed
asymmetry of the planum temporale is part of
the anatomical phenotype of schizophrenia, as is
the reduction or absence of normal right frontal
and left occipital petalias (Oertel-Knöchel and
Linden, 2011). In addition, studies have reported
that people with schizophrenia have a higher
likelihood of being mixed-handed, also a devia-
tion from the standard pattern of lateralization
(Sommer et al., 2001). Schizophrenic individu-
als actively experiencing hallucinations do not
show a right ear advantage to external auditory
stimuli, suggesting that auditory hallucinations
could be arising in the left hemisphere (Hugdahl
et al., 2008).
Bipolar Affective Disorder
Bipolar affective disorder is a psychiatric disorder
characterized by severe mood swings, including
manic, hypomanic, and depressive episodes (Leow
et al., 2013). Convergent evidence suggests that
abnormalities in the structural network organiza-
tion have a role in bipolar disorder. For instance,
brain white matter analysis has revealed lower
integrity in the corpus callosum among bipolar
individuals (Leow et al., 2013). Similarly, the left
hippocampus, the left lateral orbitofrontal cortex,
and the bilateral cingulate isthmus, which are part
of the limbic system, display abnormalities in
nodal network measures in bipolar subjects (Leow
et al., 2013).
Magnetic resonance imaging studies show
asymmetries of the right and left cerebral hemi-
spheres in individuals with bipolar disorder, and,
specifically, the disturbance of the right hemi-
sphere has been mainly associated with mood
regulation. In contrast, simultaneous disturbances
of the right and left hemispheres are most likely
related to mania, which in turn explains the coex-
istence of psychotic and affective symptoms in
bipolar disorder (Caligiuri et al., 2004).
270 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Major Depressive Disorder
Major depressive disorder (MDD) is commonly
known for persistent low mood and anhedonia,
fatigue, and sleep disturbances (APA, 2013).
Electroencephalogram measures of hemispheric
asymmetry have shown abnormalities among indi-
viduals with MDD (Bruder et al., 2016). For
instance, individuals at a higher risk for MDD
have a hemispheric asymmetry for electroen-
cephalogram measures at rest (Bruder et al.,
2005). Studies have demonstrated that MDD is
associated with right asymmetry in the frontal
brain activity (Bruder et al., 1997). Robinson and
colleagues brought attention to the laterality of
strokes and their effects on mood, with the left
inferior prefrontal region and right posterior
regions being particularly relevant in depression
causing lesions (Robinson et al., 1984; Robinson
and Starkstein, 1990).
Obsessive-compulsive Disorder
Obsessive-compulsive disorder (OCD) is a psy-
chiatric disorder known for the presence of repeti-
tive obsessions and persistent thoughts or urges
that are intrusive and related to anxiety (Stein
et al., 2019). Functional laterality research for
OCD has suggested psychometric deficits in the
visual-spatial domain (Maril et al., 2007) and
altered emotional processing (Schienle et al.,
2005). Both right- and left-sided dysfunction have
been observed among individuals with OCD. For
instance, studies have reported greater impairment
in the visuospatial memory than verbal memory in
OCD (right-sided dysfunction). In contrast, the
detection of left-sided dysfunction is based mainly
on neuropsychological and neuroimaging obser-
vations (Kong et al., 2020).
Recent work performed by the Enhancing
Neuro-Imaging Genetics through Meta-Analysis
(ENIGMA) consortium used magnetic resonance
imaging scans to investigate alterations of brain
asymmetry in individuals with OCD (Kong et al.,
2020). Their findings highlight volume asymme-
try of the thalamus and pallidum influencing OCD
(Kong et al., 2020).
SUMMARY AND CONCLUSIONS
The fact that our species has two hemispheres is
not surprising, given that all vertebrates and many
invertebrates consist of two paired, joined struc-
tures across a vertical meridian. What is more
puzzling is why the two sides of the brain are not
simply mirror images of one another, both struc-
turally and functionally. One of the most widely
accepted theories is that our brain is asymmetric
to conserve energy. Repetition or redundancy
across the hemispheres can be costly in an organ
that already consumes 20% of the cardiac output.
Furthermore, more efficient packing permits a
greater supply of skills. One could also argue that
callosal transmission is a challenging function,
fraught with potential errors, and should be kept at
a minimum, thus the packing of networks as much
as possible within a hemisphere, but why so often
within the same hemisphere in the species?
Much work has been done to document ana-
tomical and functional instances of normal brain/
mind asymmetry. Given this asymmetry, injury to
the left or right side of the brain results in differ-
ent patterns of functional loss. Even though much
of this knowledge has been acquired over the past
nearly 200 years, the fundamental underpinnings
of brain/mind asymmetry are unknown. With the
advent of newer and more powerful tools, some
clues are emerging as to how asymmetry origi-
nates during development, but why there is a need
for asymmetry in the first place remains unknown.
One could argue that to build perfectly symmetri-
cal brain regions would require additional machin-
ery for comparing and controlling left and right
growth, and it is unclear what that would accom-
plish, at least for cognitive functions. Thus, sensa-
tion must be roughly equal from the two sides of
the body, lest one side becomes more vulnerable
to injury, but this is less clear for functions such as
language. So, instead of precisely controlling for
symmetry, development consists of launching the
growth of areas on both sides and allowing the two
sides to progress stochastically at their own speed
to whatever degree. However, this would not
explain why asymmetries have a preferred direc-
tionality at the population level. Thus, it is not
asymmetry that needs an explanation, but rather
the preferential asymmetry seen in the population
(e.g., most people are right-handed).
It may be the case that asymmetry is inevita-
ble at the population level because chemical and
physical systems are inherently asymmetric in
this region of the universe. Thus, electromagnetic
fields have directionality, and all planets in the
solar system move in the same direction and by
and large rotate in the same direction too; biologi-
cal molecules are of only one enantiomeric kind;
for instance, levorotatory sugars and dextro-rota-
tory amino acids are left out of biological systems,
and when introduced artificially, they are inactive;
cilia move in only one direction and can set up
molecular gradients of only one asymmetric type;
and so on.
 Cerebral Lateralization and Hemispheric Specialization
Perhaps we should be less interested in why
brain systems are asymmetric and more inter-
ested in those examples that appear less asym-
metric, such as seen in individuals with bilateral
brain representation for language and bimanual
“dexterity.” It also remains of great interest as to
why some patterns, including a more symmetric or
reverse asymmetric organization, are often associ-
ated with negative functional consequences, such
as a tendency to developmental cognitive-percep-
tual disorders. Yet, this may be a false impres-
sion. For instance, adding say five left-handers
with language problems to the whole population
of left-handers is more noticeable than adding
five right-handers with language problems to the
whole population of right-handers, given that
the former is a much smaller population than the
latter, giving the impression of pathological left-
handedness when there is, in fact, an equal number
of pathological right-handedness. So, studies of
pathological association with one or another pat-
tern of laterality are confounded by the absence
of standard and variant laterality markers. An
important step, we believe, will be to learn how
to identify pathological left- and right-handers
and predict their deficits at an early age, better to
test them and implement preventive and treatment
modalities.
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 PART IV
Neural Dynamics and Processes
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Mirror Mechanism in Cognition
Giacomo Rizzolatti and Leonardo Fogassi
INTRODUCTION
The main objective of this chapter is to show how
the mirror mechanism represents a basic mecha-
nism endowed with unique functional characteris-
tics. Essentially, the mirror mechanism transforms
sensory representations of others’ behaviors into
motor representations that the observers would
use if they were to make the same behavior. As the
anatomical and functional properties of the areas
endowed with mirror mechanism can differ sig-
nificantly one from another, the incoming sensory
information and the outgoing motor representa-
tions may vary. Responses recorded from the
premotor areas are different from, for example,
those of the insula or the amygdala. In spite of
these differences, all centers endowed with the
mirror mechanism use the motor representations
involved in a given behavior to process informa-
tion about similar behavior observed in other
people. This transformation is not related to the
merely visual aspects of actions being observed
nor to a specific sensory modality, but rather
depends primarily on the capacity of the observer
to motorically represent possible action goals.
One important discovery concerning the mir-
ror mechanism has been that it is not a preroga-
tive of the motor areas, but is also present in
18
centers involved in producing motor and visceral
responses characteristic of specific emotions such
as disgust, fear, and hilarity.
The mirror mechanism is also underlying our
capacity of recognizing the forms of actions.
Indeed, an action can be performed in a gentle
or in a brusque way; one can show an irrepress-
ible or a slight sense of disgust; the anger can be
explosive or repressed. The recognition of these
“vitality forms,” as named by Stern, is at the basis
of social life.
Finally, we will expound the theory that mirror
responses play a distinctive role in understanding
actions, vitality forms and emotions we observe
in others. In developing this idea, we will put for-
ward the notion of understanding from the inside
(Rizzolatti and Sinigaglia, 2008). This way of
understanding others is in contrast with the classi-
cal logical-inferential way, which is used too, but
only for actions for which there is no motor repre-
sentation (e.g., dog barking, bird flights).
HISTORICAL PREMISE
The discovery of mirror neurons was published
for the first time in 1992 (Di Pellegrino et al.,
280 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

1992). Mirror neurons are motor neurons that
activate both during execution of a motor act and
during observation of the same motor act per-
formed by another individual. This discovery did
not come out from a completely unexplored back-
ground but was prepared by a previous, long
investigation on the cognitive properties of the
cortical motor system, based on neuroanatomical
and single neuron data. For this reason, it is neces-
sary, before describing in depth the mirror neuron
mechanism, to frame it within the properties of
the motor system.
CORTICAL MOTOR SYSTEM AND ITS
COGNITIVE PROPERTIES
Since the first parcellation by Brodmann (1909) of
the agranular frontal cortex of the macaque
monkey, who described two cytoarchitectonic
areas 4 and 6, the anatomical picture of this corti-
cal sector has considerably changed. Although in
the twentieth century several neuroanatomists had
already shown that the agranular frontal cortex
can be further subdivided into a higher number of
cytoarchitectonic areas, more recently, the com-
bined use of architectonic and neurochemical
techniques has allowed a better definition of the
architectonic borders between distinct areas
(Belmalih et al., 2007; Geyer et al., 2000). Here,
we will use the parcellation introduced by our
neuroanatomical group, that subdivided the motor
cortex into seven different areas, named with an
“F” followed by progressive numbers (Rizzolatti
et al., 1998; Figure 18.1). In this classification,
area F1 corresponds to the primary motor cortex
(M1), the area from which it is possible to elicit
movements of all body parts with electrical micro-
stimulation at low intensity thresholds (Porter and
Lemon 1995). Areas from F2 to F7 correspond to
the traditional premotor cortex. Electrical micro-
stimulation shows that these areas are completely

Figure 18.1 Lateral view of the monkey brain showing the subdivisions of the agranular
frontal and posterior parietal cortices. Intraparietal and arcuate sulci are shown unfolded.
Agranular frontal areas are defined according to Matelli et al. (1985, 1991) and Belmalih
et al. (2009), frontal eye fields (FEF) according to Bruce and Goldberg (1985), and areas of
posterior parietal convexity according to Pandya and Seltzer (1982) and Gregoriou et al.
(2006). The areas buried inside the intraparietal sulcus and V6A are defined on the basis of
functional properties (see Rizzolatti et al. 1998).
AI, inferior arcuate sulcus; AIP, anterior intraparietal area; AS, superior arcuate sulcus; C, cen-
tral sulcus; DLPF, dorsolateral prefrontal cortex; IO, inferior occipital sulcus; IP, intraparietal
sulcus; L, lateral fissure; LIP, lateral intraparietal area; Lu, lunate sulcus; MIP, medial intrapari-
etal area; P, principal sulcus; ST, superior temporal sulcus; VIP, ventral intraparietal area; VLPF,
ventrolateral prefrontal cortex.
 Mirror Mechanism in Cognition
or partially excitable. Of them, caudal premotor
areas (F2, F3, F4, and F5) have strong anatomical
connections with F1, while the rostral ones (F6
and F7) are not connected with F1, but show
stronger connections with the other premotor
areas and with prefrontal cortex (Rizzolatti and
Luppino 2001; Rizzolatti et al., 1998).
Similar to the agranular frontal cortex,
the posterior parietal cortex, from its first
Brodmann’s subdivision into areas 5 and 7, also
has been later parcellated into several cytoarchi-
tectonic areas forming the inferior (IPL) and the
superior (SPL) parietal lobules. The relevance of
these areas for the motor system derives from
their strong reciprocal connections with motor
areas. Although neurophysiological data showed
the presence, in these parietal areas, of many
sensory, unimodal, and polymodal features,
that traditionally led to the concept of “associa-
tive cortex” (Critchley), the evidence of the last
three decades showed that these sensory aspects
are mostly related to the motor control of dif-
ferent effectors (Rizzolatti and Luppino 2001;
Rizzolatti et al., 1998). Neuroanatomical find-
ings show that each posterior parietal area has
a main reciprocal connection with a specific
motor area, forming a dedicated circuit; thus,
several dedicated parieto-premotor circuits
have been described (Rizzolatti and Luppino
2001; Rizzolatti et al., 1998; Rozzi et al., 2006).
Broadly speaking, areas of SPL are connected
with dorsal premotor cortex, while areas of IPL
are linked with ventral premotor cortex. Single
neuron studies demonstrated that in the two
nodes of each parieto-premotor circuit there
are neurons sharing similar sensory and motor
properties that are exploited for the organization
of motor acts/actions performed with different
effectors such as the arm, hand and eyes. These
studies revealed two main functions of these
neuroanatomical circuits: the capacity to operate
several types of sensory-motor transformations
and that of coding motor cognitive properties.
These two functions are always strictly linked
within the same circuit, as it will be exemplified
below. In conclusion, these parieto-premotor cir-
cuits can be considered as the functional bases
of the cortical motor system (Rizzolatti and
Luppino 2001; Rizzolatti et al., 1998).
The parieto-premotor circuits have also strong
connections with both dorsolateral and ventrolat-
eral sectors of prefrontal cortex. Generally speak-
ing, the connections of dorsolateral prefrontal
cortex with the agranular frontal cortex are mainly
with area F7, while those of ventrolateral pre-
frontal cortex are with area F5, and both prefron-
tal sectors project to F6 and supplementary eye
281
field (SEF) (Gerbella et al., 2010; Lu et al., 1994;
Luppino et al., 1993). Concerning the connec-
tions with posterior parietal cortex, dorsolateral
prefrontal cortex is connected with area V6A and
PGm (Borra et al., 2019), while ventrolateral pre-
frontal cortex is connected with inferior parietal
areas AIP, PFG and PG, plus second somatosen-
sory area (SII) (Borra et al., 2011, 2019; Gerbella
et al., 2013). Altogether, these connections allow a
high-level control exerted by prefrontal cortex on
the parieto-premotor circuits related to reaching in
space and object grasping.
CODING THE GOAL OF MOTOR ACTS
One of the main functional properties demon-
strated in the last decades in the premotor cortex
is that its neurons do not mainly code movement
parameters, as maintained in the traditional view,
but rather the goal of motor acts.1 For example,
neurons of area F5 code hand related motor acts,
such as grasping, manipulating, tearing, holding,
while neurons of area F4 code proximal and axial
motor acts such as reaching or orienting (Rizzolatti
et al., 1988). This means that premotor areas store
several types of motor goals that can be then
implemented, depending on the context, through
their connections with F1 or through direct
­cortico-spinal or cortico-brainstem descending
pathways.
As already suggested by the above described
parieto-premotor connections, similar properties
have also been demonstrated in the inferior pari-
etal cortex, leading to a change of interpretation
of the role of this cortical sector, now to be con-
sidered as part of the motor system (Rozzi et al.,
2008).
Based on these concepts and on a series of neu-
rophysiological investigations, it has been possi-
ble to study in depth the properties and the role of
two circuits, one linking ventral intraparietal area
(VIP) with premotor area F4, the other linking
anterior intraparietal area (AIP) with area F5. The
former circuit is involved in the transformation of
the spatial location of objects into the appropri-
ate arm movements necessary to reach objects.
Neurons of this circuit code space in a motor for-
mat (Fogassi et al., 1996; Gentilucci et al., 1988).
The second circuit is involved in the transfor-
mation of the physical properties of objects into
the appropriate hand motor acts, and it has been
called the grasping circuit (Jeannerod et al., 1995;
Murata et al., 1987, 2000). Neurons of this circuit
provide a “pragmatic” description of objects.
282 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

MIRROR NEURONS IN THE MONKEY
Mirror neurons were first described in area F5 of
the macaque monkey (Di Pellegrino et al., 1992;
Gallese et al., 1996; Rizzolatti et al., 1996) and
then in the inferior parietal lobule (area PFG)
(Fogassi et al., 2005; Gallese et al., 2002, Rozzi
et al., 2008). The motor properties of these neu-
rons are not distinguishable from those of F5
hand-related motor neurons (Rizzolatti et al.,
1988), thus they also code the goal of motor acts.
However, they also show a visual response when
the monkey observes a motor act (e.g., grasping)
performed by another individual (another monkey
or a human being) similar to that coded, motori-
cally, by the same neuron (Figure 18.2). The
observed hand motor acts more effective in pro-
ducing mirror neurons response are grasping,
manipulating, holding, tearing, hands interactions.
In later studies it has been shown that, in a sector
of F5 lateral to that initially explored, there are
mirror neurons responding during execution and
observation of mouth motor acts, such as grasping,
licking, chewing, or even of both hand-and-mouth
motor acts having the same goal (e.g., grasping
with the hand or the mouth) (Ferrari et al., 2003).
Among the acts coded by mirror neurons, grasping
is the most represented. Although most mirror
neurons are invariant with respect to many details
of observed motor acts, the original observations
showed that some mirror neurons can be modu-
lated by the space in which the motor act is per-
formed, the type of grip used to grasp an object,
the hand of the agent (left or right) performing the
motor act, or the direction (contra-ipsi or ipsi-
contra) in which the motor act is performed
(Gallese et al., 1996; Rizzolatti et al., 1996).
Since its first description, based also on their
motor properties, it has been suggested that the
visual response of mirror neurons code the goal of
another’s motor act. However, it was important to
assess whether this type of coding strongly depends
on the complete pictorial description of the motor
act performed by the observed individual, as it is
for most visual neurons of inferotemporal cortex,
or whether it can also occur when the observed
act is only partially visible. In order to directly
test this experimental issue, Umiltà et al. (2001)

Figure 18.2 Example of mirror neuron discharging when the monkey grasps a piece of food
(B) and when it observes the experimenter performing the same grasping act (A). On the
right, the neuronal discharge in five trials for each condition is shown. The arrows indicate
grasping onset, on which the neuronal discharge is aligned.
Source: From Di Pellegrino et al. 1992.
 Mirror Mechanism in Cognition
compared two conditions, one in which the mon-
key could directly see the grasping act, the other
in which part of grasping (hand-target interaction)
was hidden behind a screen. The results showed
that mirror neurons show the same discharge in
both conditions. Interestingly, in the control con-
ditions, in which grasping was pantomimed, both
in full vision or hidden behind the screen, the same
neurons did not discharge. This demonstrates that
mirror neurons can code the goal of motor act even
when part of it is not visible, likely based on the
stored motor representation, and on the available
contextual information (initial vision of the hand
and memory of the object presence).
A further confirmation that the main property of
mirror neurons is that of coding the goal of others’
acts came from the study of Kohler et al. (2002),
showing that many mirror neurons can respond not
only to observation of motor acts, but also to the
sound/noise produced by them (for example pea-
nut breaking or noisy object manipulation). This
category of mirror neurons also responds to the
sound alone. This finding confirms that through
mirror neurons it is possible to access the meaning
of a motor act by using different sensory modali-
ties in which this act can be presented.
Although the early studies carried out on mirror
neurons were focused on their motor responses and
on visual responses to motor acts performed with
biological effectors (hand, mouth), more recently
two studies showed that these neurons can also be
sensitive to motor acts done with artificial effec-
tors (e.g., tools). Umiltà et al. (2008) described F5
single-neuron activity in monkeys trained to grasp
objects by means of two different types of pliers,
direct and reverse. The important feature was that
the two types of pliers required an opposite pat-
tern of finger movements (opening-closure or vice
versa) in order to grasp a piece of food. Very inter-
estingly, when tested while the monkey grasped
food with the hand or with the pliers, motor neu-
rons in area F5 discharged during the attainment
of the goal (grasping the object) independently
of the used effectors (either the hand or the pli-
ers) and of the pattern of finger movements used
to achieve it (closure or opening of the fingers)
(Figure 18.3). The same type of response was
also found during the observation of motor acts
performed with the hand and both types of pliers
(Rochat et al., 2010). Altogether, these findings
demonstrate that after motor learning mirror neu-
rons can generalize their visual response, likely
relying on the training-induced expansion of the
motor repertoire.
The “key” property of mirror neurons is the
congruence between the effective observed and the
effective executed motor act. Independent of whether
283
the congruence is based on both the goal of the
motor act and the means used to achieve it (“strictly
congruent” mirror neurons) or mainly on the goal
(“broadly congruent” neurons), in both cases these
neurons represent a mechanism matching observed
and executed acts, since the visual (or auditory)
description of a motor act can access the motor rep-
resentation of that motor act. This mechanism would
allow the observing individual to understand oth-
ers’ motor acts. In other words, when an individual
observes others’ behaviors similar to those s/he is
able to produce, thanks to the “mirror mechanism”
s/he automatically understands this behavior (see
section on the Mirror System in humans).
One could think that, during observation, the
retrieval of the motor act representation could lead
to the overt execution of that motor act, since the
output of these neurons could activate other neu-
rons directly involved in driving movement execu-
tion (Mazurek and Schieber, 2019). This does not
happen, likely because of an internal mechanism
inhibiting this automatic motor reproduction. A
possible neural basis for this inhibitory mecha-
nism has been described by Kraskov et al. (2009),
who showed that half of F5 mirror neurons pro-
jecting to the spinal cord had a strongly excitatory
response during grasping execution, but an inhibi-
tory response during grasping observation. They
speculated that during observation of several types
of motor acts this suppression of activity could
cause a “disfacilitation” of motor neurons.
Recent studies showed that mirror neurons are
also capable to encode specific visual features of
the observed motor acts. A first study (Caggiano
et al., 2009) was aimed at assessing whether the
visual discharge of mirror neurons is influenced
by the space (near or far) where the motor act is
executed by the observed agent. It has been found
that half of F5 mirror neurons had a different dis-
charge depending on whether a grasping act was
performed by an experimenter in the monkey
reaching space (peripersonal space) or outside it
(extrapersonal space), while the other half were
not modulated by the distance. Interestingly, by
inserting a transparent barrier between the mon-
key and the observed motor act, “extrapersonal”
mirror neurons began to discharge also within the
peripersonal space, while “peripersonal” neurons
stopped their response, suggesting that space-
induced modulation is also plastically related to
the operational monkey space. As a whole, these
data suggest that the modulation of mirror neu-
rons activity due to the distance of the observed
act could be attributed to the possibility of the
observing individual to socially interact with the
performing agent, for example to cooperate or to
compete.
284 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 18.3 Example of an F5 neuron active when a monkey executes a grasping act with
normal (A) and reverse (B) pliers. Rasters and histograms are aligned with the end of the
grasping closure phase of the motor act (asterisks). The curves below each histogram indi-
cate the hand position as a function of the distance between the pliers handles. When the
curve goes down, fingers close; when it goes up, fingers open. Vertical axes indicate the
measure of finger closure/opening, performed with a potentiometer. Neuron activity is
expressed in spikes per second.
Source: From Umiltà et al. 2008.

A second study (Caggiano et al., 2011) allowed,
first of all, to show that F5 mirror neurons can also
respond to motor acts presented by means of vide-
oclips, although in a lower percentage with respect
to those presented in a naturalistic setting. The
presence of a response to videoclips allowed, in a
subsequent experiment, to present to the monkey
videos of grasping motor acts seen from different
perspectives (frontal, lateral, subjective), with the
advantage that in all trials related to a specific per-
spective the video was identical, thus avoiding the
variability intrinsic to naturalistic presentation.
The results showed that three-quarter of mir-
ror neurons were modulated by visual perspective
and that the three different perspectives were rep-
resented, in terms of preferential discharge, by not
statistically different percentages of neurons. As a
conclusion of this study, it has been proposed that
view-dependent neurons could either constitute an
intermediate step in the formation of invariant neu-
rons or could participate in encoding particular per-
spectives through the feedback interaction with high
level visual areas (see below), in which pictorial
descriptions of these perspectives are represented.
PARIETO-FRONTAL MIRROR NEURON
CIRCUIT
Both premotor area F5 and inferior parietal area
PFG contain mirror neurons, that is neurons in
which both visual and motor responses are present.
 Mirror Mechanism in Cognition
However, their visual input must be provided by
high order visual areas. The main candidate for this
role is the anterior region of the superior temporal
sulcus (STSa), that contains neurons responding to
the presentation of biological stimuli in motion,
such as walking, head rotation, forelimb movements
(Barraclough et al., 2006; Perrett et al., 1989).
Among them there are also neurons discharging
during the observation of goal-directed hand move-
ments similar to those activating mirror neurons, but
devoid of any motor-related discharge. Likely, this
visual input is sent to inferior parietal cortex, to
which the inferotemporal region is strongly con-
nected (Borra et al., 2008; Rozzi et al., 2006).
The presence of mirror neuron circuits start-
ing from temporal visual areas is also confirmed
by functional magnetic resonance (fMRI) studies
in monkeys. In fact, Nelissen et al., (2005; 2011)
recorded the BOLD activation of the brain of
awake monkeys trained to observe movies, show-
ing grasping actions, where either the hand or the
entire agent could be seen. They found that the
convexity of F5 (F5c) (Figure 18.1), where mirror
neurons are usually recorded, was more activated
by the observation of the entire agent performing
the grasping act, while areas F5a and F5p (Figure
18.1), buried in the depth of the arcuate sulcus,
activated stronger during the observation of a
grasping hand. Furthermore, they demonstrated
that, in the inferior parietal cortex, the activation
was stronger in area PFG during observation of
the whole person grasping an object, while area
AIP was more activated by the view of a grasp-
ing hand. Finally, during grasping observation,
several areas of STS, including both upper and
lower banks, were active. Thus, this study revealed
that also AIP, an area having a strong role in the
grasping circuit, is part of the mirror system. More
generally, these findings show that the visual input
about the observed action originating from STS
can follow two different anatomo-functional path-
ways, one linking the upper lip of STS with area
PFG that in turn would project to area F5c, the
other linking the lower bank of the STS with area
AIP, then projecting to areas F5a and F5p. The first
pathway would be more related to the observed
agent, while the second would allow to understand
observed acts exploiting the details on the type of
hand grip and on object meaning (Figure 18.4).
OTHER CORTICAL AREAS SHOWING
MIRROR PROPERTIES
Since their first discovery in area F5, many stud-
ies consolidated the notion that this latter area
285
and the inferior parietal area PFG are the main
node of the mirror neuron system. These two
anatomical locations are also in line with the idea
that the mirror mechanism is based on a motor
scaffold formed by neurons coding the goal of
motor acts, well demonstrated both in F5 and
PFG. However, in the recent years, neuroana-
tomical and neurophysiological evidence showed
that the “grasping network,” involving neurons
related to grasping execution, is larger than previ-
ously thought, including further areas of premo-
tor and parietal cortex (Borra et al., 2017).
Similarly, single neurons studies showed that
other cortical areas contain neurons with “mirror”
properties.
FRONTAL CORTEX
Two studies showed neurons that discharged
during observation of a video, although the motor
act was not directly visible. Cisek and Kalaska
(2004) have described neurons of dorsal premotor
cortex (PMd) that activated both when a trained
monkey moved a cursor to reach a target on a
screen and when observed the cursor, moved by
the experimenter (not seen from the monkey),
achieving the same target. They proposed that this
visual discharge could represent a rehearsal of the
related motor act.
In another study, Tkach et al. (2007) described
neurons of MI and PMd that activated when
the monkey used a cursor to reach a target on
a screen and when it observed the replay of the
same movement. If only the cursor movement
without the target was presented, the response
was absent. This neuronal behavior resembles the
differential discharge recorded in mirror neurons
when comparing the goal related motor act with
its pantomime.
More recently, a very original study was car-
ried out by Yoshida et al. (2011). They used a
task in which two monkeys, positioned one in
front of the other, alternated their action in a
common task. Single neurons recordings from
pre-supplementary and cingulate cortex showed
the presence of neurons activated only during
own execution (“self”), during observation of
other’s movement (“other”) or in both cases.
This latter category resembles mirror neurons.
They suggested that this part of the mesial cor-
tex is important for self-other distinction. A
recent study (Livi et al., 2019) carried out in
area F6 (pre-supplementary cortex), using a go/
nogo grasping execution and observation task,
besides showing neurons categories similar
286 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 18.4 Grasping observation circuits in the monkey brain. A. Lateral view of the
monkey brain indicating the sulci shown unfolded in (B). Black and gray arrows link areas
belonging to the STPm–PFG–F5c circuit and the LB2–AIP–F5a/p circuit. Parietal areas PF, PFG,
PG, and Opt are defined according to the parcellation of Pandya and Seltzer (1982) and
Gregoriou et al. (2006), prefrontal areas 45a and 45b according to Gerbella et al. 2010.
AIP, anterior intraparietal area; FEF, Frontal eye fields; F5c, F5 convexity; F5p, F5 (bank)
posterior; F5a, F5 (bank) anterior; FST, lower superior temporal area; IAS, inferior arcuate
sulcus; IPS/IPL, intraparietal sulcus/inferior parietal lobule; LIPa, anterior part of the lateral
intraparietal area; MSTd, middle superior temporal area, dorsal part; MT, middle temporal
area; MTp, middle temporal area, peripheral part; STPm, middle superior temporal polysen-
sory area; STS, superior temporal sulcus. LB1, LB2, UB1, UB2 are defined according to Nelissen
et al. (2011).
Source: From Nelissen et al. 2011.

to those reported by Yoshida et al., found that PARIETAL CORTEX

the “mirror-type” neurons responded to object
presentation when this latter was the target of The confirmation of the presence of neurons with
another’s actions. mirror properties in AIP came from some single
 Mirror Mechanism in Cognition
neurons studies. Maeda et al. (2015) recorded
neurons from area AIP responding to videoclips of
the monkey own hand action and of the experi-
menter’s action. They proposed that the activity of
both categories of neurons can be important for
monitoring the hand position based on visual
feedback. Lanzilotto et al. (2016) confirmed that
neurons in the posterior part of AIP respond to
visual presentation of several types of static and
dynamic hand acts. Among them, grasping is the
most represented, but also other acts, such as
dragging, dropping, or pushing are coded.
A different consideration must be made relative
to possible mirror properties in prefrontal cortex.
It is well known that visual responses in prefrontal
cortex are often recorded when they are linked to
a subsequent behavioral reaction, although there
are also neurons activated by passive visual stimu-
lation, such as presentation of faces (Romanski
and Diehl, 2011; Scalaidhe et al., 1997). Simone
et al. (2017) recording from ventrolateral prefron-
tal cortex, a cortical sector strongly connected
with inferior parietal areas PFG and AIP and with
infero-temporal, found neurons specific for the
presentation of videos of goal-related motor acts
performed by another monkey or a human agent,
as compared to non goal-related biological move-
ment or object motion. Interestingly, these neu-
rons were also activated when part of the video
was obscured, suggesting a high order represen-
tation of the observed action. Although many
of these neurons did not show a corresponding
motor response, they have been found in sectors in
which neurons activated during action execution
(Simone et al., 2015). Thus, it is possible that the
response to observation of goal-related motor acts
is exploited for the planning of behavioral reac-
tions in a social context.
Altogether, all these new data on frontal and
parietal areas suggest the existence of a network,
more extended than the core circuit of the classi-
cal mirror neuron system, composed by areas that
can exploit their response to obervation of motor
acts/actions for several roles, from those contrib-
uting the details necessary for the recognition of
the acting hand to those allowing the distinction
between the self and the other or that exploit social
information for planning appropriate responsive
behavior.
HUMAN MIRROR SYSTEM
Single neurons recording studies in monkeys
demonstrated the existence of the parieto-frontal
287
mirror neuron mechanism. In humans, it is very
difficult, for ethical reasons, to provide a direct
demonstration of this mechanism at the single
neuron level. The possibility to directly perform
intracortical recording is permitted only in par-
ticular types of patients, such as epileptic
patients, with the aim to localize the epileptic
locus. However, also in this case, the implanted
probes usually allow to record electroencephalo-
graphic (EEG) data from a small population of
neurons close to the recording electrode. Only in
a few cases, it has been possible to record single
neuron activity from a brush of electrodes at the
tip of the probe (see below) (Mukamel et al.,
2011).
The above considerations explain why the mir-
ror mechanism in humans has been studied and
demonstrated using electrophysiological (TMS,
EEG, MEG) and neuroimaging (PET, fMRI) tech-
niques that reveal the activity of populations of
neurons.
The first publication demonstrating that the
motor cortex activates during observation of motor
acts was provided by a transcranial magnetic stim-
ulation (TMS) study by Fadiga et al. (1995). They
applied single pulse magnetic stimulation at low
threshold to the hand and arm representation of
the motor cortex of participants, who were asked
to attentively observe an experimenter grasping an
object or, as control, the same experimenter per-
forming meaningless arm movements in the air.
The results showed a specific enhancement, dur-
ing grasping, with respect to control conditions,
of the EMG activity (motor evoked potentials,
MEPs) of extrinsic and intrinsic hand muscles
normally used to execute the observed motor act.
Furthermore, it was also observed an enhanced
activity during observation of meaningless arm
movements. The same pattern of activation was
found when the observing participants executed
the same hand and arm movements. These find-
ings suggest that the motor representations of
hand motor acts are activated in the observer
during observation of the same acts, thus indi-
cating the presence, also in humans, of a mirror
mechanism. Furthermore, the activation of motor
cortex during observation of meaningless move-
ments suggested that in humans, differently from
monkeys, also non-goal directed movements can
be recognised through a similar matching mecha-
nism. In a subsequent TMS study, Gangitano et al.
(2004) stimulated the hand motor field at different
time points of the observed movements (e.g., hand
starting movement, finger opening, finger closure,
etc.), showing that the pattern of cortical activa-
tion was congruent with the timing of the observed
finger movements.
288 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

A further TMS study by Cattaneo et al. (2009)
compared the MEPs produced in participants
observing grasping an object or closure-opening
without object, executed by means of normal
and reversed pliers (cf. monkey study by Umiltà
et al., 2008). The TMS pulse was given above
the field of representation of the opponens pol-
licis. The results showed that during observation
of goal-directed grasping, MEPs were enhanced
when both types of pliers took possession of the
object, independently of the movement performed
(extension with the inverted pliers, flexion with
the normal pliers). Yet, during observation of non-
goal directed movements, MEP activation always
occurred during observation of finger closure,
independently of the type of pliers. Thus, the for-
mer activation was due to the goal of the observed
movements.
Although the TMS technique clearly reveals
the presence of the mirror mechanism likely
underpinned by mirror neurons, it does not pro-
vide the precise anatomical location of the motor
sectors that are directly activated by observation.
Since 1996, several positron emission tomography
(PET) and fMRI studies showed that, during obser-
vation of goal-directed motor acts there is always
an activation of three main cortical nodes: a sec-
tor around the STS, the supramarginal gyrus (part
of IPL), and the ventral premotor cortex/posterior
sector of the inferior frontal gyrus (IFG) (Frey
and Gerry, 2006; Grafton et al., 1996; Iacoboni
et al., 1999; Koski et al., 2003; cf. Caspers et al.,
2010; Rizzolatti et al., 2014; Figure 18.5). These
three nodes are homologues of the monkey areas
responding to observed motor acts. Specifically,
the STS sector corresponds to the monkey area
containing neurons responding during observa-
tion of biological movements but devoid of motor
properties (Perrett et al., 1989). The IPL sectors
correspond to area PFG, while the frontal nodes
correspond to F5 region. These studies provided
a good confirmation of the phylogenetic origin of
the human mirror neuron system from the monkey
one. However, most of them were limited to the
observation of hand and mouth motor acts. On the
other hand, the mirror neurons described in mon-
keys are mainly related to these latter effectors. In
most recent years the investigation also extended
to other effectors.
SOMATOTOPY OF OBSERVED ACTS
One of the first studies trying to assess which
motor sectors are activated by the observation of
acts performed with different effectors is that of
Buccino et al. (2001). Participants to this study
had to observe goal-related motor acts performed
with the mouth (e.g., biting an apple), the hand
(e.g., grasping a glass), and the leg (e.g., kicking a
ball). The results showed a somatotopic activation
of premotor and parietal cortices. Observation of
mouth motor acts activated IFG and the lateral-
most part of ventral premotor cortex, that of hand

Figure 18.5 Lateral view of the two hemispheres of the human brain, in which the areas
usually activated by action observation, as a result of a metanalysis, are indicated. The main
activations are in a sector of the superior temporal sulcus (pMTG-V5), in the inferior parietal
lobule (hIP3 and PFt) plus a small part of the superior parietal lobule (7A); in the ventral pre-
motor cortex (BA6), plus the posterior part of the inferior frontal gyrus (BA44-45).
Source: From Caspers et al. (2010).
 Mirror Mechanism in Cognition
motor acts activated a most medial sector of ven-
tral premotor cortex, while observation of feet
motor acts activated dorsal premotor cortex. This
activation resembled the Penfield’s motor homun-
culus, indicating that motor cortex mirrors the
observed motor acts also in terms of effectors. A
somatotopic activation was also observed in the
posterior parietal cortex, following a rostro-caudal
direction (mouth represented more rostrally, fol-
lowed by hand and foot), but in this case a higher
overlap between fields of adjacent effectors was
observed.
Other studies, focusing on reaching movements
or on movements of several body parts, including
the trunk and the leg, substantially confirm the
somatotopic concept derived from Buccino et al.
(2001). Filimon et al. (2007) asked participants
to execute, imagine, and observe reaching move-
ments. Except for the areas that are only typical of
a specific condition (e.g., the primary motor cortex
in the execution condition) in all conditions there
was an activation of a dorsal cortical network,
including dorsal premotor cortex and superior
parietal lobule. Calvo-Merino et al. (2005) asked
participants expert in two categories of dance
(classic ballet or capoeira) to observe videoclips
showing steps of the two types of dances. Naïve
subjects were the control group. The results show
that, during observation, all groups of subjects
presented an activation of a temporo-parieto-
frontal circuit, but the activation was higher in
dancers (expertise effect). In particular, the activa-
tion included ventral and dorsal premotor cortex,
inferior and superior parietal lobule and posterior
STS. It is very likely that the activation of different
premotor and parietal areas reflected the observa-
tion of movements of different effectors. A further
study supporting the concept of somatotopy is that
of Abdollahi et al. (2013), who asked subjects to
observe manipulation, locomotion, and climbing.
They found that while the regions of overlapping
activation are restricted, observation of manipula-
tion tended to activate more area AIP, while obser-
vation of climbing activated more the rostral part
of the dorsal superior parietal lobule.
CODING OF THE GOAL
Several evidence point to the most relevant role of
the human mirror system, as that of the monkey,
in representing the action goal. Firstly, in the
study by Gazzola et al. (2007), participants were
presented with videos of grasping executed by a
human or a robot hand. The data showed a very
similar activation of the parieto-frontal mirror
289
system in both conditions, in spite of the differ-
ence in shape and kinematics of the two effectors,
suggesting that this system decodes more strongly
the achieved aim of the action rather than the
details of the effector. Additional evidence in
favour of goal coding is provided by an experi-
ment carried out on two aplasic patients and
healthy control subjects who observed videoclips
showing hand grasping actions. The two aplasic
individuals also made actions with their feet and
mouth. It was found that in the aplasic individuals
the parieto-frontal mirror circuit activated during
observation of hand grasping acts. These activa-
tions overlapped with the premotor and the pari-
etal sectors active during the execution of foot and
mouth movements. Since these patients had never
executed the observed hand actions, the matching
between observation and execution was not based
on the effector, but on the common action goal
(Gazzola et al., 2007).
ELECTROPHYSIOLOGICAL STUDIES
A further interesting issue concerns the time
course of cortical activation during action obser-
vation. This issue can be better addressed using
EEG and magnetoencephalographic (MEG) tech-
niques. Using these techniques, independently,
Altschuler et al. (1997) and Cochin et al. (1999)
confirmed that during both action observation and
action execution there is an activation of motor
cortex, as shown by a desynchronization of the μ
rhythm, while Nishitani and Hari (2000) showed
that during action observation the activation of the
IFG followed that of visual cortex, and preceded
that of primary motor cortex.
In humans, ethical reasons do not allow a direct
demonstration of the existence of mirror neurons
at the single neuron level. Some studies, however,
verified the overlap between activations occurring
during observation and execution, by applying
single-voxel analysis, demonstrating the activa-
tion of the same voxels in the two conditions in
single participants (Gazzola et al., 2006).
Despite the difficulty to record single neurons
in humans, Mukamel et al. (2010), using a special
probe, were able to record single neurons from
epileptic patients required to observe and execute
reaching-grasping motor acts and facial expres-
sions. The recorded areas were mesial cortical
structures, namely pre-supplementary (pre-SMA)
and supplementary (SMA) motor cortex, anterior
cingulate cortex, hippocampus, parahippocam-
pal cortex, and entorhinal cortex. They found,
in SMA and hippocampus, neurons responding
290 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
during both observation and execution, some of
them being excited during execution and inhibited
during observation. Areas on the medial wall such
as SMA seem relevant to movement initiation and
movement sequences, while neurons recorded in
hippocampus could be involved in the memory of
the action formed during action execution.
PHYLOGENESIS AND DEVELOPMENT OF
THE MIRROR MECHANISM
The existence of a mirror mechanism has also
been demonstrated, with electrophysiological and
neuroimaging techniques, in children (Lepage &
Theoret, 2007; Nystrom, 2008; Nystrom et al.,
2011; Marshall et al., 2011) as early as six months
old (Shimada and Iraki, 2006). Thus, it is very
likely that this mechanism, as a product of primate
evolution, is already present at birth. An indirect
confirmation of this idea is provided by neonatal
imitation, a phenomenon initially demonstrated by
Meltzoff and Moore (1989) in human newborns a
few hours after birth and then found also in apes
(Myowa, 1996; Myowa-Yamakoshi et al., 2004)
and monkeys (Ferrari et al., 2006 ). It consists in
the replication, by the newborn, of the facial ges-
tures – mostly communicative – performed by an
adult in front of her/him. This phenomenon is very
likely related to a hard-wired mirror mechanism,
matching the observed gestures on their motor
representations. Interestingly, by recording EEG
activity from 1 to 7 day old infant macaques
during imitation of facial gestures performed by
the experimenter, Ferrari et al. (2012) could dem-
onstrate a desynchronization of the alpha rhythm
from central electrodes. Note that this desynchro-
nization typically occurs in adults and children
during action observation (Muthukumaraswamy
et al., 2004; Lepage and Theoret, 2007).
However, these data do not provide direct infor-
mation on the formation of the mirror mechanism
and whether this latter is influenced by experi-
ence. Some theoretical models tried to address
these issues. According to Keysers et al. (2014),
hebbian learning would allow, first of all, to cre-
ate, in the baby, a coupling between premotor and
STS neurons, thanks to the temporal contingency
between own action execution and the visual or
acoustic re-afference of the executed action. Then,
by means of generalization, the same visual/acous-
tic afference produced by another’s action would
activate the same STS-premotor potentiated con-
nection, thus originating the mirror function (cf.
Casile et al., 2011).
Associative sensorimotor learning is consid-
ered, by some researchers (Heyes et al., 2010), to
be fundamental for the creation of mirror neurons,
although they suggest that it is not necessary to
postulate that the mirror mechanism is genetically
coded. Another hypothesis, the epigenetic one
(Ferrari et al., 2013), proposes that the develop-
ment of mirror neurons may involve both genetic
and epigenetic factors. In this hypothesis, visual
stimuli provided by the behavior of others, i.e.
social stimuli, would activate a specific population
of visuomotor neurons. This specificity would
have been mediated by epigenetic mechanisms
giving advantages to the individuals possessing
them, and natural selection would have then led to
their stabilization.
Independently of which is the contribution of
phylogenetic and ontogenetic mechanism, it is
very clear, from both monkeys and humans stud-
ies, that the mirror neuron system, although keep-
ing its main properties, can be plastically modified
by experience, that allows an extension of the
individual’s motor repertoire (Calvo-Merino et al.,
2005; Umiltà et al., 2008).
ROLE OF SOMATOSENSORY CORTICES IN
MIRRORING SOMATOSENSATION
Beyond the classical activation of mirror neurons
during observation of others’ goal-directed motor
acts, there is also evidence of mirror activity when
individuals observe movements that produce, on
others, tactile sensation. On the side of single
neuron studies, Ishida et al. (2010), recording
from VIP, an area receiving both visual and soma-
tosensory input, recorded neurons responding
when a monkey was touched (e.g., on the arm)
and when it could see an experimenter stroking
the corresponding body part. They suggested that
these neurons could contribute to the perception
of others’ body parts using their own body as
reference.
In human studies, there is evidence of activa-
tion of somatosensory cortices during observation
of touch. For example, in an fMRI experiment
(Keysers et al., 2004), participants received a tac-
tile stimulus on the legs and observed the tactile
stimulation of others’ legs or, as control, of an
object. The tactile condition produced activation
of SI and SII, while the observation of touch pro-
duced activation of SII. In another experiment
(Ebish et al., 2008), observations of intentional
and accidental touch were compared. The study
confirmed an overlapping activation between the
experience of being touched and that of observing
 Mirror Mechanism in Cognition
others being touched, in bilateral SII. A difference
of activation between the intentional and acciden-
tal condition was found in SI, suggesting a higher
resonance of this latter cortical sector in the pres-
ence of an intentional agent. In order to determine
the differential processing during visual observa-
tion of tactile stimuli, Bolognini et al. (2011) used
repetitive TMS applied to SI or SII while partici-
pants looked a finger touching a hand, or a finger
moving in the same direction without touching.
The results showed that only the inactivation of SI
influences the subject’s interpretation of a tactile
event in the observed stimulus.
The differential contribution of somatosensory
cortices was also shown, in some studies, dur-
ing action observation. In particular, area 2 of SI
appears more activated than SII during observation
of manipulation, suggesting that beyond the motor
resonance, there is also an activation of the hap-
tic somatosensory input associated to the action
(Schaefer et al., 2009; cf. Keysers et al., 2010).
SUBCORTICAL STRUCTURES ACTIVATED
DURING ACTION OBSERVATION
In monkeys, there is no evidence, up to now, of
neurons with mirror properties in subcortical
structures. The two major candidates for the pos-
sibility to find neurons with these properties are
the basal ganglia and cerebellum, due to their
strong involvement in neuroanatomical loops with
agranular frontal and posterior parietal cortices.
Anatomical data show, in particular, that frontal
and parietal areas containing mirror neurons pro-
ject to specific sectors of the putamen, different
from the sector specifically connected with MI
(Gerbella et al., 2016).
In humans, a few studies reported the activa-
tion of cerebellum during action observation, but
this structure was not the main focus of the inves-
tigation (Calvo-Merino et al., 2005, 2006; Errante
and Fogassi, 2020; Frey and Gerry, 2006; Gazzola
and Keysers, 2009). A recent study (Abdelgabar
et al., 2019), in which participants had to observe
reaching-grasping actions, showed specific acti-
vation of cerebellar lobules VI, VIIb and VIIIa in
both hemispheres.
The existence of the mirror mechanism in cer-
ebellum was reported by a study (Gazzola and
Keysers, 2009) showing bilateral shared voxels
for observation and execution of hand, mouth, and
foot actions, with a higher percentage of hand-
related voxels, but the exact localization was not
reported. In a recent study by Errante et al. (2020),
291
participants were asked to observe and execute
manipulative actions, generally confirming the
subcortical activation reported in the literature.
The results of conjunction analysis between obser-
vation and execution conditions showed bilateral
shared activations in cerebellar lobules V, VI, crus
I, VIIIa, and VIIIb. These sectors are compatible
with those classically considered as part of the
motor loop. A shared activation was also observed
in the dentate nucleus, that constitutes the main
output channel of the cerebellum to the motor
thalamus (Strick, 1985).
Altogether, these data indicate that a mir-
ror mechanism is present also in the cerebel-
lar circuitry. What is its possible role within the
mirror system? Relevant theories proposed that
cerebellum, during movement execution, could
be involved in both forward and inverse models
(Caligiore et al., 2013; Callan et al., 2013; Frith,
2007; Ito, 2008; Kilner et al., 2003; Weeks et al.,
1999). Since during action observation cerebel-
lar activation appears to reproduce the processing
occurring during execution, this suggests that in
the former condition the motor system performs
an internal simulation of the action. The role of
cerebellum could be related, in particular, to pro-
cessing of sequential and temporal dynamics of
the action (Bijsterbosch et al., 2011; Caligiore
et al., 2013; de Solages et al., 2008).
Concerning the activation of basal ganglia dur-
ing action observation, the only electrophysiologi-
cal study (Alegre et al., 2010) during movement
observation and execution showed, in the subtha-
lamic nucleus (STN), an EEG beta-reduction. This
effect was stronger during the execution condition.
Ge and colleagues (2018), with fMRI, showed a
putamen activation during observation of grasp-
ing performed in first- or third-person perspective.
They suggested that, during reinforcement learn-
ing or imitation, this activation could be combined
with internal simulation of the same actions.
In the above reported study of Errante et al.
(2020) on observation/execution of object manip-
ulation, there was an activation of GP and STN.
The results of conjunction analysis between
observation and execution conditions showed sig-
nificant shared activations in both GP and STN,
while there was no shared activation of the motor
sector of the putamen. This could be explained by
a possible enhancement of activity of the so-called
hyper-direct pathway (linking directly motor cor-
tex with the STN) (Caligiore et al., 2013), instead
of the direct and indirect pathways, usually
involved during movement execution. This would
lead to an inhibition of the thalamic motor nuclei,
that could be explained by the need to block move-
ment during observation (Bonini, 2017).
292 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

MIRROR NEURONS AND INTENTION
UNDERSTANDING
The data discussed up to now, in both monkeys
and humans, mostly demonstrate that the mirror
mechanism allows the individual to automatically
understand the “what” of the action. However, it is
not clear whether this mechanism enables observ-
ers to also decode others’ motor intentions, mean-
ing with this term the final goal of an action. This
latter represents the behavioral outcome of an
action, for example grasping a cup of coffee and
bringing it to the mouth to drink from it. The issue
of intention decoding is very important, because it
is a basis of social interaction.
As a premise, we have widely described that
most neurons belonging to the parieto-premotor
system code the goal of motor acts. Is this type
of coding modulated by the intention underlying
the action? First of all, we carried out a series of
experiments in monkeys to assess the response of
grasping neurons during execution of two types of
actions- grasping for eating a piece of food and
grasping to place an object in a container – both
involving a grasping act (Bonini et al., 2010, 2011;
Fogassi et al., 2005). Grasping neurons were
recorded from areas PFG and F5, while a mon-
key performed the two actions. The results showed
that, although the grasping act was identical in the
eating and placing conditions, a high percentage
of PFG and F5 grasping neurons discharged dif-
ferently according to the final goal of the action
in which the grasping act was embedded, some
discharging stronger during grasping-to-eat, oth-
ers being more activated by grasping-to-place
(Figure 18.6). This modulation indicates that these
neurons are able to reflect the motor intention of
the agent. From these results, it has been proposed
that action organization is achieved through dif-
ferent chains of neurons, each chain encoding a
different intention (for example reach-grasp-bring
to the mouth-eat) (Fogassi et al., 2005; cf. Chersi
et al., 2011).
Subsequently, mirror neurons were recorded
from PFG and F5 while the monkey observed the
experimenter performing the same two actions.
Then, the monkey performed the same motor
task as described before. The results showed that,
during grasping observation, the visual discharge
of mirror neurons presents the same modulation
observed in grasping neurons during the motor
task (Figure 18.6). This means that during obser-
vation of the grasping act performed by the exper-
imenter, mirror neurons allow the observer to
predict agent’s intention. It has been hypothesized
that, in a given context, the observation of the
grasping acts retrieves the motor chain associated
to a specific intention, thus enabling the observer
to automatically understand the intention of the
observed agent. It is possible that this function,

Figure 18.6 Congruence of intentional coding between the visual and the motor response
of a PFG and an F5 mirror neuron. Rasters and histograms showing the motor and visual
responses are aligned with the moment in which the hand of the monkey or of the experi-
menter touched the target object.
 Mirror Mechanism in Cognition
demonstrated in monkeys, constitutes the basic
mechanism from which other more sophisticated
mechanisms of mindreading could have evolved
(Fogassi et al., 2005).
The presence of such a mechanism has also
been studied in humans (Iacoboni et al., 2005).
In this study participants had to observe three
different types of videoclips, corresponding to
three conditions: a video representing either a
breakfast to be started or ended (condition “con-
text”), a video showing a hand grasping a cup in
an empty background (condition “action”) and a
hand grasping a cup in one of the contexts of the
first condition (condition “intention”). The results
showed that the “intention” condition, as com-
pared to the sum of the other two conditions, pro-
duced a stronger activation in the right IFG. This
effect was independent of whether the participants
were asked to purely observe the three types of
videos or to observe them in order to explicitly
understand the intention.
MIRROR MECHANISMS AND EMOTIONS
The first evidence suggesting the existence of the
mirror mechanism for emotions has been pro-
vided by Dimberg et al. (1982). He investigated
whether the typical face and body configurations
of basic emotions that appear on the person expe-
riencing them were also present on an individual
observing that person. He recorded the EMG
activity of two facial muscles, the zygomaticus
major and upper corrugator, in volunteers observ-
ing static faces expressing happiness or anger.
The results showed that observation of happy
faces determined activation of the zygomaticus
major, while observing angry faces caused
increase of the EMG activity in the upper corru-
gator. In other words, the EMG pattern in the
observer mirrored that of the individual express-
ing a given emotion.
An early interpretation of these data proposed
that the mirror mechanism was located in the cor-
tical motor system and that the activation of the
emotional centers was a secondary consequence
of the motor activations. Although this is a pos-
sibility, there is convincing evidence that the emo-
tional responses during observation of emotion in
others are mostly due to a direct activation of cent-
ers encoding that emotion.
Strong evidence that emotional centers are
endowed with a mirror mechanism came from
fMRI and stereo-EEG studies. In the next sections
we will discuss the data for anterior insula, the
amygdala and the anterior cingulate cortex.
293
DISGUST AND THE ANTERIOR INSULA
Convincing evidence that disgust is encoded in the
anterior insula was provided at the end of nineties
by Phillips (1997, 1998) and Sprengelmeyer
(1998) and their coworkers. Both these groups
demonstrated, using fMRI, a selective activation
of the anterior insular (AI) cortex to presentation
of faces showing disgust relative to that elicited by
other emotional facial expressions.
An experiment that strongly contributed to prove
the existence of the mirror mechanism in AI was
carried out by (Wicker et al., 2003) in collabora-
tion with Keysers, Gallese, and Rizzolatti. This
study consisted of two distinct sessions: one olfac-
tory and one visual. In the former, participants were
administered pleasant (rose scent) and unpleasant
(rotten eggs) odorants. In the second one, partici-
pants observed videos where individuals sniffed at
glasses containing an unpleasant odorant, a pleas-
antly perfumed liquid, and a liquid with no smell
whatsoever, and reacted with the appropriate facial
expression. The results showed that, as expected,
disgusting odorants activated the AI, but, most
interestingly, this activation coincided, although
partially, with the insula activation induced by
personal experience of disgusting odorants (olfac-
tory condition). This experiment for the first time
showed an overlapping activation in the AI, induced
by first-hand experience of disgust and by observ-
ing grimaces of disgust on the faces of other people.
Besides fMRI studies, electrical stimulation
experiments in monkeys and humans established
a fundamental role of the AI in encoding dis-
gust. This had been shown already during the last
century by using macrostimulation. Much more
recently, researchers of the University of Parma
carried out an extensive exploration of the insula
using intracortical microstimulation (Caruana
et al., 2011; Jezzini et al., 2012). They found that,
in macaques, stimulation of the ventral sector of
the AI elicited disgust, sometimes accompanied
by bouts of retching.
Results congruent with those observed in the
monkey were found in drug-resistant epileptic
patients electrically stimulated during surgical
excision of an epileptic focus. Reaction of disgust
was reported in early studies as well as in more
recent research based on the stereo EEG technique.
Particularly interesting is the study by Krolak-
Salmon et al. (2003), who found ERP responses
in the ventral insula while the person was observ-
ing faces expressing disgust. The same authors
stimulated the active sites electrically, showing
that almost all patients complained of an unpleas-
ant disgust-like sensation. Thus, both vision of a
disgusted face and electrical stimulation of the
294 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
same site show that detection of disgust in others
and feeling disgust oneself are mediated by the
same part of the insula, indicating that this region
is endowed with the mirror mechanism.
FEAR AND THE AMYGDALA
Although amygdala is a complex subcortical
structure formed by about 12 different nuclei, for
the purpose of the present chapter we will describe
it as a single entity and will consider its main
function: encoding fear. In fact, albeit there is
little doubt that some of its nuclei may also have
other functions, the most consistent evidence on
its function concerns fear.
A selective activation of the amygdala for sight
of facial expressions of fear, relative to faces
showing happiness, was demonstrated in fMRI
studies carried out in the 1990s (Morris et al.,
1996; Phillips et al., 1997). Subsequently, it was
shown that amygdala is selectively activated by
vocal manifestation of fear (Phillips et al., 1998;
cf. Dolan et al., 2001). The relation between fear
and activation of amygdala was confirmed by Sato
(2004). Hadjikhani and de Gelder (2003) provided
evidence, also in an fMRI experiment, that the
amygdala was activated when participants saw
bodily postures communicating a sense of fear.
Whereas these brain imaging data demonstrate
a selective activation of amygdala to frightening
stimuli, there is now evidence that this structure
becomes also active when individuals experience
fear themselves. Meletti et al. (2006), in collabo-
ration with the surgeons of Niguarda Hospital in
Milan, stimulated the temporal lobe region, includ-
ing the amygdala, in over 70 patients with drug-
resistant epilepsy. The most important result was the
high frequency of responses with emotional content
almost all consisting in manifestation of fear as
well as in verbal report of fear and anxiety. Similar
results were found by Lanteaume et al. (2007).
Taken together, these findings indicate that the
amygdala is endowed with the mirror mechanism
for those processes that involve fear. As in the AI
for disgust, in the amygdala the mirror mechanism
transforms visual and auditory frightening stimuli in
fearful experiences as those we experience ourselves.
LAUGHING AND THE PREGENUAL
ANTERIOR CINGULATE CORTEX (pACC)
Classically, the cingulate cortex has been subdi-
vided into the anterior and posterior cingulate. A
more recent cingulate parcellation, which will be
adopted in this chapter, subdivides the cingulate
cortex into three major sectors: the anterior cingu-
late (subgenual, pregenual, and postgenual), the
middle cingulate (anterior middle and posterior
middle, both, in turn, subdivided into a dorsal and
ventral part) and the posterior cingulate
(Palomero-Gallagher, 2009, 2015; Vogt and Vogt,
2003; Vogt et al., 2005) (Figure 18.7).
ACC, unlike its caudal sectors, plays a role
in affect, with the pACC playing a role in posi-
tive affect and the subgenual ACC (sACC) being
involved in the negative ones (Vogt et al., 2005).
The most evident expression of positive affect
is laughter. Yet, until recently, a locus from
which laughter could be consistently elicited
was controversial, being laughter occasionally
evoked by several cortical sites, among which
the region that lies between the superior frontal
gyrus and the supplementary motor area (Fried
et al., 1998; Krolak-Salmon et al., 2006; Schmitt
et al., 2006).
A fundamental step in discovering the main
center for laughing was recently completed by
researchers at the University of Parma and the
Epilepsy Surgery Center of Milan’s Niguarda
Hospital (Caruana et al., 2015). By using intrac-
ranial electric stimulation, they examined the
responses of over fifty drug-resistant epileptic
patients. They found that the stimulation of pACC
induced laughter and hilarity.
Gibson et al. (2016) confirmed these results
using a more complex technique. These authors
combined deep brain stimulation of the internal
capsule and ventral striatum with fMRI. There
was previous evidence that this deep stimulation
procedure can modify the mood of patients with
compulsive-obsessive disorders, making them
more cheerful and eliciting smiles and even burst
of laughing. Gibson et al. (2016) found that this
deep brain stimulation activates the pACC and,
most interestingly, pACC activation was associ-
ated with laughter and hilarity. Along the same
lines, Matsunaga et al. (2016) reported that the
activation of the rostral cingulate cortex increases
with variations in the positive state of mind.
Taken together, these data support the notion
that pACC controls positive affect. Most impor-
tantly for the aim of this chapter, convincing
evidence shows that pACC is endowed with the
mirror mechanism. A meta-analysis by Fuser-
Poli et al. (2009) on the perception of emotional
faces confirmed this conclusion, showing that the
observation of faces expressing happiness, relative
to faces with neutral expressions, activates selec-
tively the pACC.
A strong proof that the pACC is endowed
with the mirror mechanism has been recently
 Mirror Mechanism in Cognition 295

Figure 18.7 Subdivision of human cingulate cortex. Top: mesial view showing eight cin-
gulate sectors. Bottom: Same subdivisions, shown in representative coronal sections. The
sectors are defined as follows: subgenual sector (sACC), that includes areas 25, s24, and s32
(Palomero-Gallagher et al. 2015); pregenual sector (pACC) and pregenual area 32 (Palomero-
Gallagher et al. 2008); rostrocaudal subdivisions of MCC (aMCC and pMCC) (Palomero-
Gallagher et al. 2009; Vogt and Vogt 2003; Vogt et al. 2005); PCC (Leech and Sharp 2014; Vogt
et al. 2003;). aMCC and pMCC were further subdivided in dorsal (aMCCd and pMCCd) and
ventral (aMCCv and pMCCv) (Palomero-Gallagher et al. 2009).
Source: From Caruana et al. 2018.

provided by Caruana et al. (2017) combining
intracranial electrical stimulation and intracranial
EEG recordings in a patient with drug-resistant
focal epilepsy. The authors presented the patient
with videos showing an actor laughing, crying or
expressing no emotion whatsoever. As expected,
smile was elicited when the pACC was stimulated.
The most interesting result was, however, that the
sites whose stimulation evoked laughter, showed
an increase of gamma activity (50–100 Hz). This
occurred exclusively while the patient was look-
ing at the video-clip showing laughing. No sig-
nificant activation was observed when the patient
was looking at the video-clips of an actor crying or
showing a neutral face.
Summing up, these data show that during the
observation of smiling faces, pACC is activated,
and triggers a complex pattern of motor processes
characterizing laughter and contributing to form-
ing the feeling of hilarity. In fact, the sensory
information arriving principally from the temporal
regions are transformed, in the pACC, into motor
representations, allowing the individual to recog-
nize other people’s expressions of laughter by acti-
vating the same cortical and subcortical circuits
activated by stimuli that induce laughter.
296 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
MOTOR REACTION AND THE ANTERIOR
MIDDLE CINGULATE CORTEX (aMCC)
The first evidence of the existence of the mirror
mechanism in human cingulate cortex was pro-
vided by Hutchinson et al. (1999). The activity of
single neurons was recorded from aMCC in
patients undergoing bilateral cingulotomy. Before
proceeding with the ablation, the surgeons tested
the responsiveness of aMCC neurons to different
types of nociceptive stimuli as well as to simple
touch. They found that a set of neurons that
responded selectively when a patient was pricked
with a needle, also activated when the patient saw
the experimenter being pricked with a needle.
Some years later, an apparent confirmation that
aMCC is a pain center and convincing evidence
that aMCC is endowed with mirror properties was
provided by Singer et al. (2004).
A clear proof that aMCC in not a pain center
was subsequently provided by an fMRI study by
Iannetti and coworkers (Mouraux et al., 2011),
who compared the activation of aMCC elicited
by nociceptive somatosensory, non-nociceptive
somatosensory, auditory, and visual stimuli. The
results showed similar aMCC activations elicited
by all four types of stimuli. In addition, the acti-
vations were stronger when the participants felt
the stimuli as salient. The authors concluded that
activation of the aMCC reflects processes that
are essential to orientate to salient stimuli, and to
assess the potential threat they pose and, where
necessary, to trigger the appropriate response.
Intracortical brain stimulation studies fully
confirmed this interpretation. In the early 1970s,
neurosurgeon Jean Talairach had observed how
electric stimulation of aMCC sites produced
complex motor behavior. These motor responses
could affect the whole body or the upper limbs.
Most importantly, none of the aMCC stimulation
produced pain or any form of emotional behav-
ior. The findings of Talairach were recently con-
firmed in a study conducted in collaboration with
the Epilepsy Surgery Center of Milan’s Niguarda
Hospital (Caruana et al., 2018). They found that
stimulation of the aMCC elicited complex motor
behaviors, but no actual feeling of pain. For
example, when stimulated, patients made postural
adjustments that clearly indicated an impellent
necessity to get out from the bed and even from
the room.
If we consider the data from the fMRI study
conducted by Iannetti (Mouraux et al., 2011)
together with the intracortical stimulation studies,
it emerges that aMCC plays a distinct role in trans-
forming a great variety of stimuli into specific
motor behavior that can subserve defensive or
aversive reactions.
MIRROR MECHANISMS AND VITALITY
FORMS
In all actions there are two components: the action
content (i.e., the action goal) and the action form
(i.e., how the goal is achieved). Whatever its con-
tent, actions may be energetic, gentle, abrupt, but
also hesitant, or effortless. Specifications of how
an action is performed do not refer only to “cold”
actions (i.e., those devoid of an emotional con-
tent), but also to “hot” actions involving emotions.
Thus, an individual can experience an irrepressi-
ble sense of disgust, or a spurt of explosive anger
that had been suppressed.
Stern called the forms of an action “vitality
forms.” Vitality forms express the agent’s attitudes
towards others. They describe the “How” of an
action, not its “What” or “Why” (Stern, 2010).
An important point worth mentioning (Stern,
1985; cf. Braten, 1998; Trevarthen, 1998) is that
“sharing vitality forms” is the “oldest, most direct
and immediate” way of interpersonal relations so
“deeply rooted” and “natural” as to pervade every
social interaction (Stern, 2010).
In the last few years, a series of experiments
tried to establish the brain region responsible for
vitality forms. The first experiment was an fMRI
study performed in Parma in collaboration with
Daniel Stern (Di Cesare et al., 2014). In this exper-
iment, participants were presented with video-
clips showing transitive actions (e.g., giving an
object) and four intransitive actions (e.g., stopping
gesture). All actions were performed with two dif-
ferent vitality forms (gentle or abrupt). The stimuli
were presented in pairs of consecutive video-clips,
where the “what” of the observed action, and the
“how” of it could be the same or change between
the video-clips pairs. There were two tasks (what
and how). In the what task, the participants were
required to pay attention to the goal of the actions
observed in the two consecutive videos and decide
whether the two actions were the same or differ-
ent, regardless of their vitality form. In the how
task the participants were required to focus their
attention on the vitality form of the two actions
and decide whether the vitality form was the same
or different in the two consecutive videos, in spite
of the fact the observed actions were different.
The results showed, in both tasks, activa-
tions of the parieto-frontal network known to
be involved in action execution and observation.
 Mirror Mechanism in Cognition 297

Most importantly, the contrast “how” vs. “what”
revealed a specific activation in the right dorso-
central insula (DCI), providing evidence that
central insula plays a specific role in processing
vitality forms.
In a subsequent fMRI study, Di Cesare et al.
(2015) tested whether DCI was also active dur-
ing the execution of actions endowed with vitality
forms (Figure 18.8. The experiment was carried
out on healthy right-handed individuals, asked to
perform three different tasks: observation (OBS),
imagination (IMA) and execution (EXE). In the
OBS task, the participants were shown video-
clips in which an actor was passing an object
to another one, either in a gentle or a rude way
(vitality condition) or in which an actor was
placing a small ball in a box (control condition).
In the EXE task, the participants were asked to
move an object in a rude or gentle way (execu-
tion task) or to place a small ball in a box in the
most neutral way as possible. Finally, in the IMA
task, participants were asked to imagine them-
selves passing an object towards the actor located
in front of them in a gentle or in a rude way or
to imagine themselves placing a small ball in the
box without any specific vitality form (control
imagination task).
In all three tasks there was a bilateral activation
of the premotor and parietal cortices, and a strong
activation of the left somatosensory cortex, motor
cortex, and of the cerebellum. Importantly, there
was also a strong activation of the DCI in all three
tasks showing that the mirror mechanism present
in the DCI transforms the visual representation of
vitality forms into their motor representation.
SUMMARY AND CONCLUSIONS
Mirror neurons are a specific class of neurons that
activate during both execution and observation of
the same motor acts. This mechanism enables the
observer to achieve an automatic understanding of
others’ behavior. This suggests a fundamental role
of this neural system in social cognition. The dis-
covery of mirror neurons was preceded by pro-
longed anatomical and functional investigation of
premotor and parietal areas, demonstrating the
cognitive function of these areas. The mirror
neuron mechanism has been shown to be present
also in the parietal and frontal cortex of the human
brain, and subsequently has also been demon-
strated in the basal ganglia and cerebellum. Recent
investigations have increased knowledge of the
functional role of the mirror mechanism, includ-
ing the decoding of others’ motor intentions, emo-
tions, and vitality forms.
The empirical evidence reviewed above indi-
cates that the DCI is a brain center controlling the
vitality forms for movements of the forelimb and
is endowed with the mirror mechanism for these
actions. We postulated that vitality forms exist
also for emotions. However, at present, there is no
evidence to localize the brain centers responsible

Figure 18.8 Cortical areas active during three different tasks (observation, imagination, and
execution) in the two experimental conditions (rude and gentle vs. control). The parasagittal
sections show the insular activations in two hemispheres.
LH, left hemisphere; RH, right hemisphere.
Source: From Di Cesare et al. 2015.
298 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
for giving form to the expression of emotion and
further studies are necessary to clarify this.
Note
1  In this chapter we use the term “motor act” to
indicate a synergy of movements aimed to attain
a goal (e.g., grasping an object), and the term
“action” to indicate a series of motor acts that
allow attaining a behavioral goal (e.g., grasping-
to-eat).
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Spatio-temporal Dynamics of
Brain Rhythms
M a r t i n S e e b e r, T h o m a s K o e n i g , a n d
INTRODUCTION
It is commonly understood that neuronal oscilla-
tions are not epiphenomena but are basic neuro-
physiological mechanisms that are essential for
information transmission and processing in the
brain (Buzsaki, 2006). Studies of local field
potentials (LFP) in animals and in the human
brain have repeatedly demonstrated that LFP
oscillations contribute to information coding in
the brain by adjusting the timing of neuronal
firing to the phase of a certain oscillation (Fries,
2005; Jensen and Lisman, 2000). Neurons thereby
form dynamical assemblies that work in syn-
chrony (Lopes da Silva, 1991), and multiple such
neuronal assemblies are usually simultaneously
active and constitute synchronized functional net-
works (Dehaene et al., 1998). Synchronization of
large-scale brain networks is thus a fundamental
mechanism in the coding of information with
respect to perception, memory, attention, cogni-
tion, and action (Fries, 2015).
Given that EEG signals reflect LFPs that are
transferred to the scalp by volume conduction,
they also convey information about neuronal syn-
chronization in the brain. It is therefore not sur-
prising that investigations of oscillations of the
spontaneous EEG and their relation to cognitive
19
Christoph M. Michel
processes has become an intense research topic in
human neuroscience (for a comprehensive review
see (Lopes da Silva, 2013).
EEG oscillations occur at different frequen-
cies. Traditionally, EEG signals are divided into
frequency bands from infraslow (<0.2 Hz), Delta
(from 0.2 to 3.5 Hz), Theta (from 4 to 7.5 Hz),
Alpha (from 8 to 13 Hz), Beta (from 14 to 30 Hz),
Gamma (from 30 to 90 Hz), to high-frequency
oscillations (HFO; >90 Hz). While the limits of
these bands are rather artificially defined and
the neurophysiological mechanisms underlying
these different rhythms is not yet well understood
(Buzsaki, 2006), it is generally agreed that slow
oscillations tend to spread across large cortical
areas, while higher frequency oscillations are
spatially more restricted. Low-frequency activ-
ity is related to neural mechanisms of inhibition
(Lundstrom, 2015). In non-REM sleep, low-
frequency synchronization with frequent appear-
ance of large oscillations (slow waves) reflects the
switch between up- and down-states, a bi-stability
that causes an impairment of causal interac-
tions among brain networks and loss of neuronal
integration and communication (Pigorini et al.,
2015; Sanchez-Vives and McCormick, 2000).
Oscillations in the theta and alpha range regu-
late information transfer between cortical areas
306 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
such as the hippocampus and the cortex for theta
(Mizuseki et al., 2009) and the thalamus and the
cortex for alpha (Lopes da Silva et al., 1980). High
frequency oscillations allow for binding informa-
tion among neuronal assemblies (Gray et al.,
1989). A comprehensive discussion of the func-
tional connotation of the different frequency bands
can be found in (Lopes da Silva, 2013).
SPATIO-TEMPORAL DYNAMICS OF
BRAIN RHYTHMS
The traditional analysis of oscillations in the
ongoing spontaneous EEG is the spectral analyses
of the signal at a given electrode using Fast
Fourier Transform and calculating the power of
the different frequency bands (Lopes da Silva and
Mars, 1987). In multichannel recordings, the
quantitative EEG (qEEG) approach consists of
calculating the power spectrum for each channel
and then constructing power maps averaged
within a given frequency band and comparing
them topographically between experimental or
pathological conditions (Duffy, 1985; John and
Prichep, 2006). While this analysis has undoubt-
edly led to a series of clinically relevant findings,
it contains numerous pitfalls that prevent non-
ambiguous conclusions about the neurophysiolog-
ical mechanisms underlying observed spectral
power changes.
First, the observation of oscillatory power is
dependent on the reference electrode because
the recorded voltages in EEG are always differ-
ences between two leads. Brain signals originat-
ing in specific locations are propagated to all scalp
electrodes mostly dependent on their distance and
source orientation because of volume conduction
(Fender, 1987). Given the reference dependence
and volume conduction, the spatial association of
oscillatory power at single electrodes is thus not
straightforward and experimental effects observed
at a single electrode may eventually have very dif-
ferent, and spatially remote origins in brain space
(Michel et al., 2009). This implies that the spatial
interpretation of oscillations (e.g., by frequency
analyses) should be handled with great care.
Second, the spectral analysis of single chan-
nel EEG implicitly assumes that the generators
of the oscillations remain the same across time
and between conditions and thus that differences
in spectral power between conditions are due to
differences in the oscillations of the same gen-
erators in the brain. This assumption also under-
lies the qEEG approach that considers the power
map averaged over time as spatially stable. This
assumption is not correct: the EEG exhibits not
only spectral, but also spatial signatures which
change dynamically over time in a sub-second
range (Michel, 2019). A simple examination of the
spati-temporal dynamic of a filtered EEG clearly
shows that the spatial configuration of the scalp
electric field is not stable over time. It changes
dynamically in the sub-second range (Figure 19.1).
Since different map configurations are by physical
laws due to differences in the underlying genera-
tors (Michel and Murray, 2012), the assumption of
spatial stationarity of the generators producing a
certain oscillation over longer time periods is inva-
lid. Therefore, changes of frequency power at one
specific electrode could be due to changes of the
oscillation of one specific brain network, or due to
changes of the network configuration that leads to
a different projection of the activity at the given
electrode.
However, assuming that there is a limited set
of brain functions that explain some interesting
psycho-physiological correlates and assuming
that these functions materialize as spatially and
temporally well-defined networks of brain electric
activity, it follows from the physics of EEG and
volume conduction that there must be an equally
limited set of spatially defined EEG components
that correspond, in their dynamics and in their
spatial distribution, to those functions and net-
works. Unfortunately, this inverse problem (i.e.,
decomposing the spatio-temporal components
of the EEG) generally has no unique solution.
Accordingly, much of the efforts in EEG analysis
has gone in the development and empirical evalu-
ation of priors that allow identifying these compo-
nents (Blankertz et al., 2007; Makeig et al., 1996;
Parra et al., 2005; Wu et al., 2020).
Many of the methods developed to tackle this
problem of meaningfully decompose an EEG sig-
nal can be framed as the identification and appli-
cation of particular spatial filters (Michel and
Pascual-Leone, 2020): Such spatial filters are ide-
ally designed to suitably compute signal dynamics
associated with some functional network. These
signal dynamics are computed as weighted sum of
the recorded voltages at a given time sample. The
spatial filters are composed of the weights for each
recording electrode. In other words, weights are
used to transform the data from recording space
into component space. However, weights of spatial
filters should not be physiologically interpreted.
For example, large positive and negative weights
at certain electrodes could only serve the cancel-
lation or suppression of unwanted signals such as
noise. The recorded signals can be described by
the summation of the signal components multi-
plied with their spatial patterns. Spatial patterns
(Figure 19.2) which are applied to back-project
 Spatio-temporal Dynamics of Brain Rhythms 307

Figure 19.1 Spatial non-stationarity of Alpha-EEG. Conventional frequency power analy-

sis assumes that the generators of the oscillatory activity remain the same over time. This
assumption is not valid as illustrated here: The top shows the spectral power of a 30-sec,
eyes-closed EEG calculated by a wavelet transformation and averaged over all channels. It
shows typical Alpha bursts at different time periods. Potential maps at some of the peaks of
Alpha activity are plotted below. Obviously, the topography of the maps at different time
points are very different, which signifies different networks generating the Alpha activity
at these time points. Even within a short period of 1-sec EEG, the topographies vary as illus-
trated on the bottom where all maps during a period of one Alpha burst are shown (high-
lighted in the time-frequency plot and on the EEG of one electrode during this period). This
example illustrates that even during an alpha burst, map topographies change, indicating
changes in the underlying generators.
Source: From Michel, 2019.

signal components into recording space can be
physiologically meaningful (Blankertz et al.,
2007; Cohen, 2021; Haufe et al., 2014; Parra et al.,
2005; Wu et al., 2020).
Yet, there are plural ways to determine spatial
filters and hence decompose recorded signals into
specific components. Any decomposition is based
on assumptions of the data and resulting decom-
posed components. Given the limited dimension-
ality of the data there is no unique solution without
introducing additional priors. Different decompo-
sition methods have different optimization criteria
determining the spatial filters and resulting sig-
nal components. Therefore, each decomposition
method and associated spatial filters are only as
appropriate as their optimization criterion is con-
sidering the experimental design and related data.
Two prominent families of spatial decomposi-
tions are Independent Component Analysis (ICA)
and Generalized Eigenvalue Decompositions
(GED). ICA aims for statistical independence
between the resulting components and therefore
is data-driven. ICA decomposition typically yields
to dipolar scalp maps and are thought to isolate
single brain sources while minimizing volume
conduction effects (Delorme et al., 2012).
GED is hypothesis-driven and optimizes signal
differences between separate sets of data (e.g.,
experimental conditions; Cohen, 2021; Parra et al.,
2005). So, the spatial patterns resulting from GED
308 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 19.2 Illustration of the spatial filtering of the EEG. The EEG is filtered in the Alpha
Band and the EEG microstates are defined using k-means cluster analysis. The Alpha-filtered
EEG is then spatially filtered for each microstate map. As can be seen, the Alpha power as
well as the temporal dynamics are distinctly different for the five spatially filtered signals.
Source localization of these spatially filtered signals allows to determine the networks
underlying these different oscillations.
Source: Adapted from Michel and Pascual-Leone, 2020.

can signify both single and distributed underlying
sources. In the case where multiple well-separate
cortical patches could be identified as sources of
GED patterns, that would indicate a distributed
functional network oscillating synchronously at
zero-phase lags.
In summary, diverse spatial decomposition
approaches have different inherent properties that
should be considered while interpreting their sig-
nal components and spatial patterns (Parra et al.,
2005). The main advantage of spatial filtering is
that resulting signal components are “unmixed”
following the criterion of the particular decompo-
sition method. Moreover, the spatial configuration
of these signals are well-defined and spatial pat-
terns can be used to estimate the underlying brain
structures generating these patterns and associated
signal components. Importantly, all of these spa-
tial filter approaches imply that the sources of the
putatively isolated processes are either spatially
compact (i.e. close to dipoles) or share a highly
correlated or anticorrelated time course (Michel
and Koenig, 2018). Thus, while recordings at
single electrodes contain the summation of many
signals with distinct spatial origin, frequency anal-
yses that are performed typically on time windows
of seconds could “wash out” the spatio-temporal
dynamics on the milliseconds level. However, suit-
ably unmixed signal components are associated
with well-defined spatial configurations and there-
fore are more appropriate to study oscillations on
a milliseconds level (e.g., by their instantaneous
amplitude or phase – see Figure 19.3).
Within this ongoing debate on suitable priors
for the decomposition of EEG signal, the con-
cept of so-called microstates has become increas-
ingly successful over the last two decades of EEG
research (Michel and Koenig, 2018). In brief, this
concept is driven by the point that at the level
where scalp EEG is recorded, the driving pro-
cesses that determine most of the data are func-
tional state dynamics that affect the brain on its
upmost, and therefore global scale. This implies
that any (sufficiently large) change in the overall
spatial configuration of brain electric activity and
thus any (sufficiently large) change in scalp field
configuration implies a change in the global func-
tional state of the brain. Framed otherwise, the
microstate approach postulates that there is, for
conceptual reasons, no overlap among the suitably
identifiable components of an EEG.
Starting from this a-priori rationale, it turns
out that empirically, these changes in global
functional state are discontinuous and separated
by transient periods of quasi stability (Lehmann
et al., 1987), which led to the term “microstates,”
and that in addition, there seems to be a relatively
low number of prototypical microstate configura-
tions that can be efficiently identified using spa-
tial clustering algorithms (Pascual-Marqui et al.,
1995). The approach to describe spontaneous EEG
as series of short-lasting periods of quasi-stable
 Spatio-temporal Dynamics of Brain Rhythms 309

Figure 19.3 Decomposition of two epochs of 30-sec multichannel EEG during eyes-closed
wakeful resting and during sleep onset into oscillatory events that are characterized as a
network of synchronously active sources (components) that produce prototypical scalp maps
(left row) and that are separated among themselves by time, frequency, or phase. The second
column shows the energy distribution of these classes of oscillatory EEG events as a function
of time and frequency. The third row shows the reconstructed time-course of these compo-
nents, and the last row their frequency distribution.

field configuration that can be assigned to one of
class of a low number of prototypical configu-
rations has, over the last two decades, lead to a
rapidly growing empirical body of findings on
the functional role of these prototypical states in
the context of brain development, neurological
and mental disorders and various cognitive states
(Bréchet et al., 2019; da Cruz et al., 2020; Khanna
et al., 2015; Michel and Koenig, 2018; Zanesco
et al., 2020).
On the other side, the microstate approach to
the EEG decomposition problem, as it is currently
310 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
implemented, can be criticized as it has been
applied almost exclusively to the time domain.
This implies that at any given moment in time,
there is only one, eventually broad frequency-
spectrum event that ought to account for the given
data. This clearly runs against the at least equally
successful strategy in EEG research to decom-
pose the data into a temporally overlapping set
of processes that are separated by frequency, as
it is frequently and very successfully done e.g. in
sleep research (Borbély, 1982), pharmaco-EEG
(Herrmann et al., 1989; Jobert et al., 2012), or
when analyzing event related spectral changes of
EEG (Makeig, 2002; Pfurtscheller and Lopes da
Silva, 1999). In other words, the assumption that
for the processes to be identified as not overlap-
ping, the claim that they must not overlap in time
may turn out to be overly strong and force what a
microstate must represent to include a package of
processes that certainly commonly form an overall
global state, but that may nevertheless also func-
tionally segregate in interesting ways, and that
may be separable by their spectral distribution.
Fortunately, this apparent dilemma between
two very successful, but seemingly incompatible
approaches to the problem of decomposing the
EEG can be avoided by relaxing the “no overlap”
priority of microstate analysis from the traditional
“no overlap in time of momentary maps”, to “no
overlap in time, frequency and phase of transient
oscillations” (Koenig et al., 2001; Studer et al.,
2006). As a result, this time-frequency approach
decomposes an ongoing EEG into a set of tran-
sient oscillations that are each uniquely defined by
their joint distribution in time and frequency, and
that again assumingly join all the EEG correlates
of the different elements of the brain networks that
produce each of these oscillations into a common
event (Figure 19.3). Combining resting state EEG
and fMRI data, Schwab et al could demonstrate
that the spontaneous fluctuations such synchro-
nized cortical oscillations seem to be associated
with the activity of particular thalamic subsystems
(Schwab et al., 2015).
CONNECTIVITY MEDIATED BY
BRAIN RHYTHMS
In the last decades, invasive multi-site recordings
are increasingly available along with non-invasive
high-density EEG. These developments open up
novel possibilities in studying long-range interac-
tions between different sites of the brain. Instead of
determining the frequency and power of a certain
brain rhythm at a single recording electrode,
multiple recording sites allows to study the relation
between them. Therefore, it is possible to investi-
gate the connectivity between sites in addition to
the local, frequency-specific power activity.
Despite these mere methodological considerations,
on a more conceptual level, connectivity metrics
are relevant to assess synchrony between sites,
which is thought as key-mechanism for grouping
neuronal populations into assemblies.
Gray et al. (1989) showed that neurons across
different columns of the cat visual cortex syn-
chronized their oscillatory responses specifically
to visual stimuli with matching features (i.e., ori-
entation and movement direction). In a follow-up
study, Engel et al. (1991) provided evidence that
neurons in the left and right hemisphere syn-
chronized and therefore bind features within and
between visual hemifields. Importantly, inter-
hemispheric synchronization was dependent on
corticocortical connections, because it became
absent after dissection of the corpus callosum. In
both of these seminal studies, synchronization was
present in the Gamma range with zero phase dif-
ferences between distant neuronal populations on
average.
More recently, oscillatory synchrony in the Beta
range differed for specific rules in the prefrontal
cortex in non-human primates (Buschman et al.,
2012). Furthermore, spike-field synchrony, a met-
ric for LFP phase-locked spiking of neurons for
a given frequency, revealed that Beta oscillations
selected neurons specifically for distinct rules.
Therefore, Beta oscillatory synchrony was sug-
gested to form rule-specific neural ensembles dur-
ing decision making. These results are moreover
in favor for the idea that oscillations contribute to
the grouping of spatially separated neurons into
ensembles selectively for distinct representations.
Given these seminal invasive studies in ani-
mals showing oscillatory synchrony between dis-
tant neurons and LFP oscillations contributing to
establish synchrony, it is of relevance to translate
these findings to the human brain. For example,
Beta band synchronization between distributed
cortical regions predicted the perception in sub-
jects responding to ambiguous audiovisual stimuli
in and MEG experiment (Hipp et al., 2011) and
attention modulated interregional synchronization
in a frequency-specific manner along the visual
pathway (Siegel et al., 2008).
Interregional co-activity was consistently
reported by another line of research studying
blood oxygen level dependent (BOLD) signals on
a much slower time scale in humans during rest,
periods of minimal sensory input without specific
task instructions (Biswal et al., 1995; Raichle,
2010; Smith et al., 2009). Intrinsic fluctuations
form meaningful, so-called resting-state networks
 Spatio-temporal Dynamics of Brain Rhythms
(RSN), between distant but functionally coupled
brain regions.
To investigate the electrophysiological basis of
RSN, several groups investigating the large-scale
networks derived either from EEG or MEG using
source reconstruction (Hipp et al., 2012; Mantini
et al., 2007; Samogin et al., 2019) or directly from
intracranial recordings (Hacker et al., 2017; He
et al., 2008; Kucyi et al., 2018). EEG/MEG source
reconstruction provides full coverage of the brain,
but the spatial resolution of these techniques is
moderate. Invasive recordings provide more direct
measures of local brain fluctuations but are limited
to the electrodes implantation sites.
These studies either confirmed or showed par-
allels between RSN and electrophysiological field
potentials. Based on the much slower time scale of
BOLD fluctuation, most studies either focused on
infraslow fluctuation or frequency-specific enve-
lopes to investigate the electrophysiological basis
of RSN. Although envelope correlation is capable
to quantify inter-regional functional coupling,
it does not necessarily express oscillatory phase
synchrony between these regions. Taken together,
phase synchrony and envelope correlation are two
distinct coupling modes in terms of their time
scale, neural mechanisms and putative functions
(Engel et al., 2013).
Motivated by invasive studies in animals show-
ing quasi zero-phase relations (Andreas et al.,
1991; Campo et al., 2019; Roelfsema et al., 1997)
between distant regions several groups investi-
gated synchrony in humans related to stimulus
perception and feature binding (Rodriguez et al.,
1999; Srinivasan et al., 1999; Tallon-Baudry et al.,
1996).
As with previous animal studies, increased
gamma coherence and power recorded by scalp
EEG was suggested to visual feature binding
and perception (Rodriguez et al., 1999; Tallon-
Baudry et al., 1996). However, Yuval-Greenberg
and Deouell (2009), as well as Yuval-Greenberg
et al. (2008), raised some awareness that minia-
ture saccadic eye movements result in transient
gamma band activity that overlap with genuine,
narrow-banded gamma responses in the scalp
EEG. Consequently, electrical activity produced
by microsaccades confound gamma band activity.
Following these concerns, (micro)saccadic
eye artifacts were thoroughly characterized.
The appearance of microsaccadic artifacts at
parietal and occipital electrodes can be caused
by an unfortunate choice of the reference elec-
trode at the nose or, more generally, electrodes
close to the eyes. Second, volume conduction
of the head’s biological tissues propagates elec-
trical signals to some extent to all electrodes on
311
the scalp. To distinguish saccadic artifacts from
genuine gamma band responses approaches such
as topographic and source analyses or ICA were
suggested (Carl et al., 2012; Keren et al., 2010).
Indeed, Hassler et al. (2011) showed induced
gamma band responses related to object recogni-
tion after controlling for microsaccadic artifacts.
Therefore, high-frequency oscillations in human
EEG are suitable for the investigation of cogni-
tive processes after appropriate control for artifact
contamination.
ZERO-PHASE SYNCHRONIZATION
BEYOND VOLUME CONDUCTION
Studies based on invasive recordings in humans
provided substantial insight into large-scale cou-
pling related to RSN recordings (Hacker et al.,
2017; He et al., 2008; Kucyi et al., 2018).
However, these studies investigated infraslow
dynamics or amplitude coupling. Interregional
phase synchrony is less studied in humans, mostly
because of spurious correlations confounding
genuine zero-phase relations in non-invasive
EEG/MEG recordings.
While volume conduction is generally the rea-
son why we can measure brain activities using
scalp EEG it inherently leads to spurious corre-
lations between scalp recordings. These spuri-
ous correlations impact scalp-based connectivity
estimates considerably (Brunner et al., 2016; Van
de Steen et al., 2017). Consequently, connectiv-
ity analyses following source estimation from
multi-channel EEG/MEG were proposed to pro-
vide more meaningful and spatially interpretable
results (He et al., 2019; Michel and He, 2018).
Although to a lesser extent, spurious correla-
tions are still present in source reconstructed sig-
nals, because of the limited spatial resolution of
EEG/MEG recording. When the number of sources
being estimated extents the number of recording
sensors, redundancy in source reconstructions is
inevitable. One approach to correct for spurious
correlation confounding connectivity estimates is
eliminating instantaneous phase relations between
signals investigated. Because volume conduction
is instantaneous, only signal components orthogo-
nal to each other could be investigated to dimin-
ish spurious effects (Colclough et al., 2015; Hipp
et al., 2012; Nolte et al., 2004).
However, this approach comes with the cost
of ignoring genuine zero-phase relations, which
previously were proposed as key-mechanism to
group distant neuronal populations. Phase-lagged
312 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
relations can be investigated after orthogonaliza-
tion while diminishing spurious relations. Yet,
phase-lagged metrics are sensitive to investigate
directional interactions (e.g., feedforward and
feedback interactions between different regions
along the visual hierarchy following a stimu-
lus). Meaning phase-lagged connectivity metrics
capture rather the transmission of information
between different processing stages than the dis-
tributed coherent representation of information
and global states of the brain (Ju and Bassett,
2020).
Moreover, if all zero-phase relations that are
present in multichannel recordings would result
from volume conduction, that would imply that
only one active source in the brain is active, which
is highly implausible from a physiological point
of view.
In addition to invasive animal literature, recent
studies indeed demonstrate inter-regional zero-
phase relation that cannot be explained by volume
conduction (O’Reilly and Elsabbagh, 2021; Seeber
and Michel, 2021). O’Reilly and Elsabbagh (2021)
used intracranial recordings to explicitly investi-
gate zero-lag connectivity between distant brain
regions. They found zero-phase relations between
homotopic brain areas but not between heterotopic
areas. Furthermore, zero-lag functional connec-
tion were found between distant regions that are
>100 mm apart. In intracranial recordings, volume
conduction does not confound signals on such
large distances. So, it is highly unlikely that these
results are an effect of residual volume conduc-
tion. In addition, recent findings combining EEG
and PET data in patients with dementia clearly
point at the beneficial functional role of zero-
phase, as opposed to lagged interactions among
brain regions (Smailovic et al., 2020).
Taken another angle on the same matter, we sys-
tematically compared simultaneous (i.e., zero-lag,
synchronization with the residual bias from spatial
smoothness of EEG source estimates). Based on
these analyses we indeed report simultaneous syn-
chronization exceeding confounds resulting from
volume conduction (Seeber and Michel, 2021). In
this study, we focused on the investigation of two
different networks spanning over frontal versus
parietal brain areas. We found simultaneous syn-
chronization between homologous brain areas of
the two different hemispheres. These functional
networks were not limited to two notes, but typi-
cally included at least one medial node (Figure
19.4). The finding of quasi zero-lags between
distant areas could signify the functional conver-
gence of involved regions during rest, where little
sensory input is perturbing intrinsic oscillations
minimally.
By investigating the instantaneous phase rela-
tion between the network nodes, we quantified the
time course of synchronization. These analyses
suggest that the manifestation of simultaneous
synchronous networks is briefly stable, not persis-
tently. Given the flexible spatial reconfiguration of
distinct networks, simultaneous synchronization
might be instrumental to the establishment of par-
ticular, re-occurring states. If a particular source
network configuration maintains quasi-zero phase
relations for a certain period, that necessarily
leads to a stable topography of the scalp potential
field. EEG microstates are defined as topographies
being briefly stable in time. Therefore, the brief
establishment of specific quasi zero-lag-related
network patterns can be seen as source dynam-
ics underlying the scalp-level observation of
microstates.
Based on simulated and real data, Sjogard et al.
(2019) demonstrated the relevance of quasi zero-
lag synchronization between posterior midline cor-
tices of the default-mode network. Interestingly,
posterior midline synchrony was only present
when using distributed source reconstruction, but
absent when using beamformers. Beamforming
minimizes linear correlation between source
reconstructions (Darvas et al., 2004; Van Veen
et al., 1997), which leads to underestimating of
the well-established coupling of posterior midline
areas. Furthermore, while comparing functional
MRI with source reconstructed EEG networks,
Rizkallah et al. (2020) showed that orthogonaliza-
tion is considerably reducing correlation between
these different modalities (Figure 19.4).
Taken together, zero-phase relations are physi-
ological meaningful and should not be ignored.
To date, to the best of our knowledge no appro-
priate leakage correction algorithm is existing.
Orthogonalization approaches do have limita-
tions (Palva et al., 2018) and do ignore all zero-
phase relations, which is not desirable for many
studies as outlined above. Therefore, we propose
either experimental or statistical assessment of
zero-phase interaction being beyond the level of
volume conduction in order to distinguish genuine
from spurious effects.
SUMMARY AND CONCLUSIONS
Multichannel scalp EEG recordings allow to
investigate neuronal oscillations at the whole brain
level and thus provide a window into the basic
neurophysiological mechanisms underlying com-
munication between remote brain areas. EEG
provides temporal, spectral and spatial information
 Spatio-temporal Dynamics of Brain Rhythms 313

Figure 19.4 Zero-phase synchronization beyond volume conduction. A: Simultaneous, i.e.,

zero-lag synchronization, between distant brain regions exceeds the residual bias from spa-
tial smoothness of EEG source estimates. B: Coupling of posterior midline areas that are pre-
sent in distributed source solutions (MNE) but are underestimated by beamformers (LCMV)
that minimize linear correlation between source reconstructions. C: Zero-phase relations are
present in intracranial recordings in homotopic, distant regions, as shown by introducing
an offset of 1 sample before computing phase lag index (PLI), which is insensitive to zero-
phase relations otherwise. D: Ignoring zero-phase relations significantly reduces the correla-
tion of functional networks derived from EEG and functional MRI. Functional EEG networks
were estimated using the Phase Locking Value (PLV), PLI, and multivariate orthogonalization
(PLVCol) and then compared to fMRI networks. Correlation between different modalities
(EEG and fMRI) is higher for PLV measures that are sensitive to zero-lag relations compared
to metrics ignoring zero-phase relations (i.e., PLI and PLVCol).
Source: Panels A–D adapted from (Seeber and Michel, 2021a), (Sjogard et al., 2019), (O’Reilly and Elsabbagh, 2021) and
(Rizkallah et al., 2020) respectively.

about the functioning of large-scale brain net-
works. While this makes EEG a potentially power-
ful technique to study brain neuronal dynamics,
the different dimensions lead to complex signals
on the scalp that need to be properly understood,
analyzed, and interpreted.
A first important fact to consider is that brain
network dynamics is extremely fast and network
configurations change in the sub-second time
scale. Assuming stationarity in time and in space,
as conventional frequency analysis methods do,
is not justified and leads to erroneous interpreta-
tion. Decomposing the signals using spatial filters
followed by time-resolved frequency analysis can
overcome this problem.
A second important point to consider is volume
conduction. A common pitfall in the interpreta-
tion of the results of scalp EEG analysis is the
assumption that the activity recorded at a certain
electrode is generated by the neuronal population
underlying this electrode. Due to volume conduc-
tion neuronal activity spreads to the scalp surface
in all directions and, consequently, activity of a
given brain area is captured by all electrodes to a
certain extent, depending on distance and orien-
tation. Interpretation of brain areas generating a
given scalp recording is only possible by solving
the so-called inverse problem (i.e., by converting
the signals from the sensor to the source-space).
Powerful distributed inverse solutions based on
314 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
realistic head-models provide reliable estimations
of the brain sources leading to the scalp recordings.
A third aspect concerns the study of functional
connectivity between brain areas using scalp
EEG measures. Obviously, due to the spread of
the neuronal activity to all scalp electrodes and
the reference-dependency, functional connectiv-
ity analysis on the scalp-level is difficult to inter-
pret. After converting the data to the source-space,
interpretation becomes more meaningful. Still,
volume conduction leads to spatial leakage. One
way to overcome this problem is to ignore simul-
taneous (zero-phase) synchronization when ana-
lyzing functional connectivity between different
nodes. This, however, ignores the well-known fact
that genuine zero-phase synchronization plays an
important functional role in information repre-
sentation, maintenance, and processing. Methods
that control for leakage are needed in order to
disentangle genuine from spurious simultaneous
synchronizations.
A fourth aspect concerns temporal coding of
information beyond frequency synchronization.
An interesting observation in broad-band EEG is
the fact that the spatial configuration of the scalp
potential fields remains stable for a few tenths
of milliseconds (80–120 ms) and then quickly
changes to a new configuration in which it remains
stable again. This empirical observation led to
the concept of EEG microstates as basic build-
ing blocks of conscious mentation. An increasing
number of studies have demonstrated the sensitiv-
ity of the temporal dynamics of specific micro-
states to the functional state of the brain, to the
content of the ongoing mental process, to the level
of consciousness, and, most importantly, to differ-
ent neuropsychiatric pathologies. EEG microstates
offer to study the syntax of flow of mental pro-
cesses that is not necessarily controlled by syn-
chronization in specific frequencies.
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Sleep and Circadian Rhythms:
Alpha Rhythm and
Alertness/Sleepiness
INTRODUCTION: SLEEP, ALERTNESS, AND
CIRCADIAN RHYTHMS
This chapter briefly describes the regulating pro-
cesses underlying two major human behaviour
rhythms, the 24-hour sleep–wake cycle, and cor-
responding alertness–sleepiness rhythm. In their
scientific elaboration, the chapter also provides an
illustration of the important role of brain waves,
including the alpha rhythm.
Circadian (∼one day) rhythms in human behav-
iour and physiology are regulated by a light sensi-
tive circadian pacemaker (i.e., master body clocks)
localized in the suprachiasmatic nuclei of the
hypothalamus (Pittendrigh and Daan, 1976). As
predicted by the general theory of oscillation and
confirmed by the empirical findings, the 24-hour
light-dark cycle is able to entrain this circadian
pacemaker. The entrainment results in matching a
period of the pacemaker to that of the environmen-
tal cycle, i.e., 24 hours. The circadian pacemaker,
in turn, entrains the behavioural, physiological
and hormonal rhythms, including the sleep–wake
cycle and daily fluctuations of alertness–sleepi-
ness level (Pittendrigh and Daan, 1976). Sleep–
wake cycle refers to the 24-hour daily sleep
pattern which usually consists of approximately
16 hours of daytime wakefulness and 8 hours of
20
Arcady A. Putilov
night-time sleep. Throughout each 24-hour period,
alertness–sleepiness level dips and rises, impact-
ing the amount of sleepy and alert substates of the
wakefulness state.
The basic properties of any biological time-
measuring system, including the circadian clocks,
have easily lent themselves to mathematical mod-
eling. Better understanding the rhythmic human
behaviours is provided by such modeling enriched
by model-based simulations of empirical data. The
best example is the two-process model of sleep–
wake regulation (Daan et al., 1984) that, for more
than three decades, has become the major con-
tributor to the current understanding of the mecha-
nisms underlying the human 24-hour sleep–wake
cycle (Borbély et al., 2016). In accord with this
model (Daan et al., 1984), two body processes
control sleep and wake states. These are the cir-
cadian process and sleep homeostatic process.
The circadian process represents the influence
of the circadian clocks on sleep timing, and the
sleep homeostatic process adjusts sleep intensity
and duration as a function of the duration of prior
wakefulness (Borbély et al., 2016; Daan et al.,
1984).
To examine human sleep and alertness/sleepi-
ness, electrodes are attached to the scalp and face
to allow measurement of electroencephalographic
 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness 319

(EEG) signal, eye movements, and muscle tone. SWA(t ) = [ XSWA l + C (t )] −

EEG recordings of brain waves derived from elec-
{SWA d − [SWA l + C (t )]}* e − ( t − t 2) /[ Td − k *C ( t )])   (20.1b)
trical activity in the brain are analysed for their
distribution and classified in accord with their
frequency, in cycles per second, or hertz (Hz). whereby C ( t ) = A * sin ( 2π * t / τ + )   (20.2)
0
Frequencies range from very slow to very fast
(labeled using Greek letters “delta” and “gamma,”
is a periodic function with a period τ assigned to
respectively). The frequency ranges are: delta (1
24 hours (i.e., this term represents the modulating
Hz–4 Hz), theta (5 Hz–8 Hz), beta (13 Hz–30 Hz),
action of the circadian process – body clocks – on
and gamma bandwaves (>30 Hz), respectively
the parameters of sleep homeostatic process in this
(Buzsaki, 2006). In addition, the sigma bandwave
version of two-process model).
(12–16 Hz) is especially important for sleep stud-
Figure 20.1a illustrates the results of apply-
ies due to the overlap with spindle activity (Holz
ing this model to simulate sleep times for several
et al., 2012). The two-process model of sleep–
days with the model’s parameters listed in Table
wake regulation (Daan et al., 1984) proposes that
20.1. Throughout a week, wake state is spontane-
sleep homeostatic process can be traced in experi-
ously terminated by this sleep–wake regulating
mental research by measuring brain activity thus
mechanism irrespective of whether sleep state was
allowing the simulations of the sleep–wake cycle
also spontaneously terminated (at free days) or
in terms of this model. From one approximately
terminated a bit earlier with alarm clocks on five
90-minute sleep cycle to the next, the amplitude
weekdays. An index of SWA is building up and
of waves in very slow (delta) range gradually
decaying during wake and sleep states within its
decreases exponentially. Delta activity is also
upper and lower thresholds, respectively.
found to be higher after sleep restriction/depriva-
Figure 20.1a also illustrates that, if wake state
tion, or lower after extended sleep duration or an
was not spontaneously terminated in the evening
afternoon nap. This pattern allows the utilization
(see the end of free day 1), “sleep debt” is accumu-
of the indexes of EEG Slow Wave Activity (SWA)
lated in the course of further (extended) wakeful-
as the conventional markers of the homeostatic
ness as indicated by a further buildup of the SWA
process (Borbély et al., 2016). SWA typically cor-
index above the upper threshold (Figure 20.1a).
responds to the signal power in the delta frequency
Consequently, this “debt” is expected to be “paid”
range (cf. Zielinski et al., 2019).
back during the following more intensive (recov-
In the Daan et al. (1984) model, SWA has been
ery) sleep.
proposed to decrease exponentially during the
One of the examples of application of the two-
sleep phase of the sleep–wake cycle, while its
process models is the result of evaluation of the
compensating rise during the wakefulness phase is
role of sleep homeostatic process in the well-
approximated by an inverse exponential function
documented ontogenetic changes in sleep timing
(it cannot be measured directly via EEG record-
and duration. The model-based simulations of
ing). The circadian process in the Daan et al.
experimental and epidemiological data pointed
(1984) model determines the circadian times for
at the kinetics of sleep homeostatic process as a
the spontaneous switches from the first to the sec-
cause of differences between mature and prepu-
ond phase (sleep offset) and back from the second
bescent adolescents in sleep timing and duration
to the first phase (sleep onset).
(Crowley et al., 2014; Hagenauer and Lee, 2013;
Putilov and Verevkin, 2018). Moreover, Skeldon
et al. (2016) demonstrated that changes in sleep
timing and duration occurring from adolescence
MODELING AND SIMULATION OF THE to old ages can be understood as a consequence of
SLEEP–WAKE CYCLE changes in the kinetics of this process. In contrast,
this process seems not to be involved in determi-
nation of the inter-individual differences in sleep
If t1 and t2 are the initial times for the buildup and associated with the phase of sleep–wake cycle.
decay phases of the 24-h sleep–wake cycle (i.e., the These differences exist in people who do not dif-
spontaneous sleep off- and on-set, respectively), the fer in sleep duration but differ in this phase (e.g.,
process of sleep–wake regulation, SWA(t), can be the so-called larks and owls with earlier and later
simulated (Figure 20.1a and Table 20.1) using the sleep timing, respectively).
following equations (Putilov, 1995): The predictive power of this version of two
process model (Putilov, 1995) is demonstrated by
SWA ( t ) = [SWA u + C (t )] − the experimental evidence supporting predictions
{[SWA u + C (t )] − SWA b }* e − ( t − t1) /[ Tb − k *C ( t )])    (20.1a) by the simulations’ modifying influence of the
320 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 20.1 Simulations of sleep times and sleepiness.

(a) Simulation of 10-day time course of SWA(t) associated with the 24-hour alternations of
wakefulness and sleep; throughout these days, the range of build-up and decay of SWA (1)
always remains to be limited by the upper and lower thresholds (SWAd and SWAb, respec-
tively); SD: Further build-up of SWA above the upper threshold, SWAd, is expected due to
prolongation of wakefulness beyond its normal everyday interval (i.e., sleep deprivation
associated with accumulation of “sleep debt”). (b) Simulation of 2.5-day time course of
sleepiness (3) indexed by the inverted score on the nine-step Karolinska Sleepiness Scale
(Åkerstedt and Gillberg, 1990), KSS(t) = 9-KSS score (see more details in Table 20.1).
 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness 321

Table 20.1 Model’s parameters in simulations of sleep times and sleepiness levels
Simulated sleep-wake cycle and alertness-sleepiness rhythm SWA Inverted KSS

Sine wave-form circadian modulation of the parameters of homeostatic processes (2):

A (circadian amplitude) 0.50 0.30
ΦMax (circadian phase for maximal rise of sine function), hours 15.0 5.0
τ (entrained circadian period), hours 24.0 24.0
Exponential buildup/decay of alertness/sleepiness, X(t) (1):
Xl(t) (lower asymptote for decay phase), see below
Xb (lowest decay of alertness during normal waking) 4.75
Xd (highest buildup of alertness during normal waking) 5.73
Xu(t) (upper asymptote for buildup phase), see below
Td (decay phase constant of the rhythm), hours 12.71
Tb (buildup phase constant of the rhythm), hours 19.23
Exponential buildup/decay of sleep/wakefulness that modulates SWAl(t) and SWAu(t) (3):
SWAl0 (lower asymptote for decay phase of the cycle) 0.70 4.50
SWAb0 (lowest decay during normal waking phase of the cycle) 0.76 5.93
SWAd0 (highest buildup during normal sleep phase of the 3.00 7.54
cycle)
SWAu0 (upper asymptote for buildup phase of the cycle) 5.50 7.60
Td (decay phase constant of the cycle), hours 26.63 20.57
Tb (buildup phase constant of the cycle), hours 2.75 2.24
Initial times for buildup/decay of sleep/wakefulness and alertness/sleepiness:
t2 (free day switch from buildup to decay phase), clock hours 23.4 21.0
t1 (free day switch from decay to buildup phase), clock hours 8.5 7.3

Note. For simulation of sleep process indexed by Slow-Wave Activity (SWA), SWA in the baseline night episode was set to 1.0
(see the simulation of the time courses of SWA in Figure 20.1a). For simulation of subjective alertness–sleepiness measure
(9-KSS score), sleep histories in the pre-experimental day self-reported by 48 study participants (Figure 20.2b) were used to
set mean initial times for going to bed (12.30 am) and waking up (8.48 am) in Figure 20.1b.

circadian process on the parameters of SWA with
the peak of such influence in the afternoon hours
(Lazar et al., 2015).
The utility of mathematical modeling pertains
to its ability to enable novel insights into human
rhythmic behaviour that are not simply intuitive.
Simulations of weekday and weekend sleep times
predict that sleep missed on weekdays are com-
pensated for by prolongation of weekend sleep
(Putilov and Verevkin, 2018). The simulations
suggested that, in any five work/school days, the
pressure for sleep (i.e., SWA level) builds up until
its expected upper threshold only (Figure 20.1a).
Indeed, when individuals try to sleep for longer
periods of time on weekends to make up for sleep
lost during the week, they fail to prolong their
sleep beyond its normal duration. By April 2020,
about half of the world’s population was under
some form of “lockdown” due to the COVID-19
pandemic. This “lockdown” provided a possibility
to demonstrate the predictive power of simulations
based on sleep–wake regulating models and their
ability to predict the counterintuitive findings.
Model-based predictions (Putilov and Verevkin,
2018) suggested that weekend sleep durations
reported before, during and after “lockdown”
would be practically identical despite a significant
increase in weekday sleep duration during “lock-
down” as compared with sleep duration before or
after “lockdown.” This counterintuitive predic-
tion was supported by empirical evidence based
on the analysis of sleep times before and during
“lockdown” (Putilov, 2021). In fact, it was demon-
strated that weekend times in bed before and dur-
ing “lockdown” were practically identical despite
the lockdown-associated shift of weekday wake-
ups on later hours that led to a longer weekday
time in bed (Putilov, 2021).
322 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
MODELING AND SIMULATION OF THE
ALERTNESS–SLEEPINESS RHYTHM
Despite a common-sense view that daily variation
in alertness–sleepiness level is simply a reflection
of human sleep–wake cycle, this variation can be
actually regarded as an example of a “strong”
(rigid) circadian rhythm, such as the daily varia-
tion in core body temperature and melatonin
secretion. A “strong” circadian rhythm is charac-
terized by a narrow range of entrainment that is
the range of synchronizer’s periods to which a
given rhythm is able to entrain. Unlike a weaker
(lax) rhythm, such as the sleep–wake cycle, a
“strong” rhythm cannot be entrained by a time
giver with a much longer or much shorter period
(Pittendrigh and Daan, 1976; Granada et al.,
2013). Experimental results indicate that the range
of entrainment of alertness–sleepiness rhythm is
even narrower than that of the core body tempera-
ture rhythm (Folkard et al., 1985). Therefore, the
simulations of the sleep–wake cycle and the simu-
lations of alertness–sleepiness rhythm can require
somewhat different models. At least one addi-
tional process is usually included in the model of
alertness–sleepiness fluctuations (Akerstedt and
Folkard, 1997).
Since in the course of prolonged wakeful-
ness, alertness demonstrates a gradual declining
trend from one day to another, this trend might be
accounted by postulating that the upper asymptote,
Xu, is not, as it is suggested in equation (20.1a),
a constant throughout the buildup (wake) phase
(Putilov et al., 2015). On the contrary, it can be
proposed to exponentially decline (as in equation
20.1b) to reflect the influence of the correspond-
ing phase of another homeostatic process, Xu(t):
X u (t ) = [ X lu + C (t )] −
{X u1 − [ X lu + C (t )]* e − ( t − t1) /[ Tdu − k *C ( t )]}   (20.3),
where Xu1 is a value at the initial time point t1,
whereas Xlu and Tdu are an asymptote and a time
constant, respectively, of the declining upper
asymptote Xu(t).
In such a bit more complicated variant of the
model (Putilov et al., 2014, 2015, 2019), the
process X(t) can be interpreted as the homeo-
static process representing a wake drive (i.e., a
wake-promoting process), whereas the process
Xu(t) can be suggested to be an opposing sleep
drive (i.e., a sleep-promoting process associated
with accumulation of “sleep debt” during wake-
fulness in the initial version of the two-process
model). This interpretation seems to resemble
the conceptualization of sleep–wake cycle in the
framework of so-called opponent process model
of sleep–wake regulation that postulates two
antagonistic drives – for wake and for sleep – that
oppose one another to regulate the cycle (Dijk and
Czeisler, 1995; Edgar et al., 1993).
Figure 20.1b illustrates the results of simula-
tion with this model the time course of subjectively
assessed sleepiness (KSS) during two-day sleep
deprivation experiment (see more details on the
model’s parameters in Table 20.1). Throughout
this experiment, a step-like, not gradual change in
sleepiness level occurred. It reflects the modulation
influence of the circadian clocks and sleep homeo-
static process on the wake homeostatic process.
This model of alertness–sleepiness rhythm was,
in particular, applied for simulating age-associated
changes in the 24-hour fluctuations of subjective
sleepiness. These simulations suggested that the
age-associated changes in the parameters of pro-
cesses regulating the fluctuations of sleepiness
seem to be rather small compared to the age-­
associated changes in the parameters of the processes
regulating the sleep–wake cycle (Putilov, 2016).
In sum, we have described the regulatory pro-
cesses underlying the 24-hour sleep–wake cycle
and alertness–sleepiness rhythm and the role of
brain waves in scientific research into the sleep–
wake cycle. Changes in EEG waves during sleep
and changes in subjective sleepiness during sleep
deprivation were found to relate to the compli-
mentary effect of the circadian, and homeostatic
regulatory processes impacting on the drive for
sleep. The results point to the prospect of using
changes in SWA and weekday–weekend shifts of
sleep times as markers of the mechanisms regulat-
ing rhythmicity of sleep and wakefulness.
ALPHA RHYTHM, SLEEPINESS, AND
ALERTNESS
Unfortunately, the changes in SWA levels fail to
reflect the changes in homeostatic sleep process
during wakefulness, but, fortunately, the changes
in some other frequency ranges of the EEG spec-
trum might help to differentiate between alert and
sleepy substates of wakefulness state. Most reports
have suggested the possibility of using changes in
oscillations in theta and alpha frequency ranges as
the spectral EEG indicators of sleepiness level
(Leproult et al., 2003; Lorenzo et al., 1995;
Marzano et al., 2007; Putilov and Donskaya, 2014;
Strijkstra et al., 2003).
 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness
Alpha waves fit in the middle of the brain
wave spectrum, between theta and beta frequency
ranges, 8 Hz–12 Hz. Despite falling in the mid-
dle of the EEG spectrum, the first letter of the
Greek alphabet was used for labelling alpha waves
because they were the first of the discovered pat-
terns of the EEG signal. In the early twentieth cen-
tury, Berger (1929) pioneered in observing these
waves by recording electrical activity from the
human scalp. This observation was the first of the
most important discoveries in the almost 100-year
history of the EEG research.
In healthy, awake adults, alpha waves occur
while resting with the eyes closed. They disappear
during sleep and vanish when there is concentra-
tion on a specific task or when eyes are opening
(Klimesch, 2012). Alpha waves are maximal over
the occipital (back) region of the brain (Barzegaran
et al., 2017; Hughes and Crunelli, 2005). Alpha
frequency and amplitude of alpha waves are
known to change systematically over the lifespan
(Anderson and Perone, 2018; Bell et al., 2012;
Bernhard and Skoglund, 1939; Campus et al.,
2021; Cellier et al., 2021; Chiang et al., 2011;
Clarke et al., 2001; Marshall et al., 2002).
Alpha waves were found to be the most salient
EEG event during wakefulness and may be funda-
mental for various cognitive processes (Ito et al.,
2005; Lustenberger et al., 2015; Samuel et al.,
2018; Von Stein and Sarnthein, 2000) includ-
ing attention (Boudewyn and Carter, 2018; Foxe
and Snyder, 2011; Saalmann et al., 2021), per-
ception (Arnal and Giraud, 2012; Capilla et al.,
2014; Samaha et al., 2015), working memory
(Hanslmayr et al., 2012; Jensen, 2002; Riddle
et al., 2020), inter alia.
The current EEG research suggested that brain
oscillations in the alpha frequency band not only
reflect an “idle” state of cortical activity, but also
take a more active role in the generation of com-
plex cognitive functions (Anokhin and Vogel,
1996; Grandy et al., 2013; Prent and Smit, 2020;
Sadaghiani and Kleinschmidt, 2016; Stevens and
Zabelina, 2019). For instance, more than 60% of
the observed inter-subject variability in perceptual
learning can be ascribed to ongoing alpha activity
(Freyer et al., 2013).
The circadian rhythm (period length around
24 hours) exerts the strongest influence on almost
all investigated characteristics of the EEG signal
(Croce et al., 2018; Dijk and Duffy, 1999; Gundel
et al., 1983; Lehnertz et al., 2021) and changes
in EEG waves are related to diurnal variation in
vigilance states and substates. In particular, alpha
waves can serve as indicators of the processes reg-
ulating circadian rhythmicity of sleep and wakeful-
ness states, substates of alertness and sleepiness,
323
daily variation in the levels of performance, atten-
tion, perception, etc. For instance, Aeschbach et al.
(1999) found that the circadian rhythm in alpha fre-
quency band exhibited a minimum near the body
temperature minimum. Moreover, alpha activity
has a potential as an index of homeostatically regu-
lated alternations between alertness and sleepiness
substates of wakefulness state. At least, it was
previously shown that this activity is attenuating
with increasing duration of wakefulness beyond
its normal interval in the 24-hour sleep–wake cycle
(Putilov and Donskaya, 2014; Putilov et al., 2021).
Thus, since their discovery (Berger, 1929),
and until recently, alpha waves have remained the
most salient EEG observation during wakefulness.
They may be fundamental for various cognitive
processes, might be associated with individual dif-
ferences in these processes, and have a potential
as a marker of regulatory mechanisms responsible
for the diurnal alternations between alertness and
sleepiness substates of wakefulness.
ALPHA WAVES AS AN OBJECTIVE
MARKER OF SLEEPINESS: DEPRIVATION
STUDIES
The studies of functional role of alpha oscillations
have usually focused on their relation with atten-
tion and perception. A less explored area for
application of the concept and measurement of
alpha waves is an objective evaluation of changes
in vigilant state. Below such kind of evaluation is
exemplified by the results of two sleep deprivation
experiments in which alpha activity was utilized
as an objective index of sleepiness level.
Subjective sensation of sleepiness prior to
habitual bedtime might have evolved to motivate
humans to switch from any kind of current day-
time activities to sleep-preparatory behaviours
(Axelsson et al., 2020; Shochat et al., 2021).
Such conceptualization of sleepiness motivated to
address the question of whether people, indepen-
dently of their age, are equipped with the ability
to become more and more sleepy due to prolonga-
tion of wakefulness beyond habitual bedtime hour
(i.e., as indicated by the time courses of both sub-
jective and objective measures of sleepiness). To
address this question, indexes of alpha and theta
activities were utilized for objective measurement
of sleepiness. It was hypothesized that an ability to
perceive sleepiness is preserved in people of older
age and that feeling sleepy is associated with the
specific pattern of spectral EEG signal (Putilov
and Donskaya, 2020).
324 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Methods of Deprivation Studies
The protocols of two experimental sleep depriva-
tion studies were approved by the ethics commit-
tee of the Institute for Molecular Biology and
Biophysics of the Federal Research Centre for
Fundamental and Translational Medicine
(Novosibirsk, Russia). The experiments were per-
formed in accordance with the ethical standards
laid down in the Declaration of Helsinki. Informed
written consents were obtained from all partici-
pants studied as paid volunteers. They were
recruited from the staff of the conglomeration of
medical research institutes and from the surround-
ing community. The participants did not undergo
a clinical evaluation, but, during a pre-experimen-
tal interview, they denied current health problems,
history of psychiatric or sleep disorders, and shift
work or trans-meridian flights in the preceding
month. For a week prior to the experiment, they
were asked to keep regular sleep–wake schedule
and to report history of their sleep for each of
these seven days.
Previously, the two analysed here EEG datasets
were used for introducing a single spectral EEG
measure of sleepiness calculated by summing 16
weighted single-Hz power densities of the EEG
spectrum (Putilov et al., 2019). The main EEG
dataset was collected from 48 participants (27
females) in two-day sleep deprivation experi-
ments. Ages ranged between 15 and 67 years with
mean age ± standard deviation of 36.6 ± 13.1
years. The participants were grouped into three
age groups of 15–18 participants each (younger:
15–26 years, intermediate: 30–40 years, and older:
46–67 years). They arrived in the research unit on
Friday before 18:30 hours and left on Sunday at
19:30 hours. It was expected that they would be
able to complete 25 or fewer sessions of resting
EEG recording separated by two-hour intervals
(2- and 5 minutes with eyes open and then closed,
respectively).
The additional EEG dataset from the experi-
ment on a shorter (one-night) sleep deprivation
was collected from a bigger number of volunteers
aged between 15 and 67 years with mean age ±
SD = 29.4 (± 12.2) years. The sample of 130 par-
ticipants (76 females) was divided into four age
groups (youngest: 15–21 years, younger: 22-24
years, intermediate: 25–39 years, and older: 40–67
years). They arrived in the research unit between
8:00 and 8:30 pm to leave it at 9:30 am next day
after completing nine sessions of resting EEG
recordings separated by 3-hour intervals (one
minute with open eyes of a study participant and
another with his/her eyes closed).
Subjective sleepiness was self-scored in each
EEG recording session using the nine-step KSS
(Åkerstedt and Gillberg, 1990). Each individual
KSS score obtained in any of the EEG recording
sessions was expressed as a deviation from the
initial score, at 19:00 hours for the two-day sleep
deprivation study, and at 21:00 hours for the one-
night sleep deprivation study.
Two electrodes, frontal (Fz–A2) and occipi-
tal (either Oz-A2 or O2-A2), were used for all
EEG recordings in accord with the International
10–20 system of electrode placement. For fixing
the electrodes, Ten20 conductive paste (Nicolet
Biomedical, Madison, WI, USA) was utilized. The
electrodes were removed after each EEG measure-
ment. Their exact positions were recorded using
a permanent ink marker. A 16-channel electroen-
cephalograph (Neuron-Spectrum-2, Neurosoft,
Ivanovo, Russia) was used to record EEG signals,
conditioned by the high-pass, low-pass and notch
filters (0.5 Hz, 35 Hz, and 50 Hz, respectively),
sampled and stored on a hard disc with a fre-
quency of 200 Hz. The EEG records were visually
inspected on two-second epochs for removing all
epochs containing artifacts from further analy-
sis. The FFTW (Fastest Fourier Transform in the
West) package (Frigo and Johnson, 2005) was
applied to compute power spectra densities for the
artifact-free epochs (see www.fftw.org for more
detail). Rectangular window taper was used on
one-second epochs without overlap for calculating
absolute spectral power densities (μV2) for each
of 16 first single-Hz frequency bandwidths (i.e.,
0.50–1.49 Hz, 1.50–2.49 Hz, 2.50–3.49 Hz, etc.).
These single-Hz power densities were aver-
aged across each of the 1-minute intervals of the
EEG record and ln-transformed. These power
densities were further averaged over derivations,
and further averaging was performed over 2-min-
ute intervals with eyes open and then closed, and
across 5-minute intervals with eyes closed, for
both the 4 4-Hz frequency range and the alpha
range (9 Hz-12 Hz). Each such value obtained in
the 13–25 EEG recording sessions of each of 48
participants during the two-day deprivation study
was subtracted from the first (evening) value
obtained at 19:00 hours. In the additional dataset
with 130 participants, each value was subtracted
from the value obtained at 21:00 hours on the
evening preceding the experimental prolongation
of wakefulness.
Participants were engaged in performance
measurements and questionnaire assessments.
During their free time they can surf the Internet,
watch TV, read, write, listen to music, play board,
and computer games. Participants can freely
 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness
move between several rooms of the research unit.
Throughout the experiment, they consumed at
self-chosen times light snacks and drinks (with
exception of alcohol and caffeinated beverages).
Taking any medications and heavy meals, smok-
ing, vigorous physical activity, and exposure to
light >500 lux were not allowed.
All calculations and all tests of significance
of the effects of age on subjective and objective
measures of sleepiness were performed using
the SPSS23.0 statistical software package (IBM,
Armonk, New York, USA). Pearson’s correlation
coefficient was calculated for the associations
between time courses of objective and subjective
sleepiness on the interval of 25 or 9 EEG recording
sessions and in order to relate age of participants
to sleepiness measures obtained for each EEG
recording session. Correlation analyses and one-
way ANOVAs with the independent factor “Age”
were performed to examine age-associated differ-
ences in pre-experimental sleep times and baseline
sleepiness measurements. In two-way ANOVAs,
the additional independent factor “Sex” was
added. Moreover, significance of main effect of
independent factor “Age” on a sequence of subjec-
tive and objective measurements of sleepiness was
tested with two-way repeated measure ANOVAs
(rANOVAs). The repeated measure was “Clock
hour” on day 1 and/or day 2 (between 21:00 hours
Friday or Saturday and 19:00 hours Saturday or
Sunday) and on night 1 (between 0:00 hours and
9:00 hours) in a two-day and one-night sleep dep-
rivation study, respectively. The independent fac-
tor “Sex” was added to “Age” “Clock hour” in
three-way rANOVAs. Finally, “Clock hour” and
“Single-Hz” powers from 1 Hz to 16 Hz, were
included in three-way rANOVAs to test signifi-
cance of interaction of these two repeated meas-
ures with the independent factor “Age.” Mauchly’s
test was conducted to assess the sphericity and, if
necessary, the Greenhouse–Geiser correction was
used to adjust the degrees of freedom, but the
original degrees of freedom are reported in Results
and Tables 20.2 and 20.3.
Results of Deprivation Studies
During a week preceding the experimental dep-
rivation studies, older study participants
reported earlier risetime than did younger par-
ticipants (F2,47 = 4.44, p = 0.017, and F3,128 =
14.27, p < 0.001 in two-day and one-night
experimental studies, respectively). Significantly
earlier bedtime was found in one of the studies
(although F2,47 = 2.38, p = 0.104 in a two-day
325
study, F3,128 = 11.74, p < 0.001 in one-night
study). However, there were not any significant
age-associated differences in self-reported nap
frequency and duration, night sleep onset
latency, and night sleep satisfaction. Moreover,
a significant association with age was found for
neither subjective nor objective evening sleepi-
ness measures prior to the experimental prolon-
gation of wakefulness (i.e., at 19:00 hours and
21:00 hours in the first and second studies,
respectively).
During the first day of sleep deprivation,
power in the alpha range (9 Hz–12 Hz) drastically
decreased in the young study participants, while
in the old participants they remained almost unaf-
fected by the moderate sleep loss (Figure 20.2).
However, the expected attenuation of the alpha
rhythm was found within any age group after fur-
ther extension of wakefulness to the second day
(Figure 20.2). The difference between age groups
during the first day of sleep deprivation was even
more profound in the response to sleep loss of the
slower frequency ranges including theta range (5
Hz-8 Hz). Power density increased in this range
in older participants but decreased in younger par-
ticipants (Figure 20.2a and 20.2b). In contrast, the
theta power only increased after prolongation of
wakefulness into the second day (Figure 20.2).
The significance of such differences between
the young and old participants in changes of
power densities throughout the first stage of
sleep deprivation was evident for the triple inter-
action between the independent factor “Age” and
repeated measures, “Clock hour” and “Single-Hz”
(F330,7425 = 1.55, p = 0.043, and F315,11340 = 1.27,
p = 0.049 in two-day and one-night experimental
studies, respectively). This interaction became
non-significant during the second day indicating
the increase of similarity of ages in their response
to further prolongation of wakefulness (F270,3630 =
1.16, p = 0.298, in two-day experimental study).
The dual interactions of “Age” with “Single-Hz”
(Figure 20.2a) was significant in each of two
days (F30,675 = 1.85, p = 0.007, and F30,330 = 3.03,
p = 0.006).
As illustrated in Figure 20.2b, the correlation
coefficient between time course of KSS score and
6-Hz power (i.e., within theta frequency range)
attained the value of 0.96 for the older partici-
pants on the first day of the two-day experiment,
while the correlation for this day was much lower
for younger aged participants, 0.56. The second
day correlations were 0.24 and 0.52, respectively
(Figure 20.2b). In contrast, the first day correla-
tions between time courses of KSS score and
10-Hz power (within alpha frequency range) were
weaker for the older participants, –0.67, and much
326 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
stronger for younger participants, –0.93 (Figure
20.2b). The coefficients were relatively similar
during the second day, –0.80 and –0.81 (first- and
second-day coefficients were –0.98 and –0.82 in
the whole sample).
Although the strong correlations with subjec-
tive sleepiness were not uncommon for both 6-Hz
and 10-Hz powers and for both younger and older
study participants, the patterns and strength of
correlation varied depending upon amount of
accumulated sleep debt, frequency, and age
(Figure 20.2).
For example, as suggested by results on the first
day of sleep deprivation in the two-day depriva-
tion study (Figure 20.2b) and by results of the one-
night study, the changes in theta frequency range
were strong predictors of the change in subjective
sleepiness score in older age participants while
the changes in alpha range were strong predictors
of self-reported sleepiness in the participants of
younger age. As illustrated in Figure 20.2a, dur-
ing the first day spectral powers in theta range
did not increase significantly in younger partici-
pants while spectral powers in alpha range did
not decrease significantly in older participants,
but more resembling one another changes in the
expected direction were shown by these ages dur-
ing the second day (Figure 20.2a, 20.2b).
On the two-day interval of sleep deprivation
study, the time course of KSS score strongly cor-
related with the majority of the 16 timecourses
of single-Hz spectral powers, but the strongest
(below –0.98) coefficient was shown by 10-Hz
power at the second minute with eyes closed.
Correlation coefficients of a similar strength were
also obtained after averaging over the first two or
all five minutes with eyes closed and over frequen-
cies in alpha frequency range, 9 Hz–12 Hz (Figure
20.2b and 20.2c). Therefore, alpha power for the
first two minutes and for the first minute of the
eyes closed section of the EEG record was chosen
for quantifying the strength of association between
objective sleepiness and age of participants of the
two-day and one-night study, respectively (Figure
20.2, and Tables 20.2 and 20.3).
Data for the first two minutes with eyes closed
(a–c) and for one minute with eyes closed (d) in
two-day and one-night sleep deprivation study,
respectively, for the whole sample (left graphs)
and separately for three or four ages (on the right
from these left graphs). (a) Power (density) spectra
on the interval of frequencies from 1 Hz to 16 Hz
expressed as deviation from the initial spectrum
at 19:00 hours; they were calculated separately
for the first and second day of two-day study (N =
48 and 25–42, respectively). (b) Time courses of
KSS score and two examples of time courses of
single-Hz powers (6 Hz and 10 Hz) related to the
initial score and initial powers at 19:00 hours; they
again were calculated separately on two 24-hour
intervals of two-day deprivation study (N = 48
and 25). (c) Two-day time courses of KSS score
and the example of time courses of Alpha power
(frequency range from 9 Hz to 12Hz) expressed
relative to the initial score and power at 19:00
hours; (d) One-night time courses of KSS score
and Alpha power related to the score and power at
21:00 hours (N = 130).
Alpha power was found to correlate signifi-
cantly with age in almost all EEG recording ses-
sions (Table 20.2). A weaker attenuation of alpha
rhythm in older participants was confirmed by sig-
nificant main effect of independent factor “Age”
in two-way and three-way rANOVAs (Table 20.3).
Thus, the associations with alpha range power
were the most reliable and persistent (over the
time of experiment) compared to all other possi-
ble objective sleepiness markers of sleepiness. The
association with sleepiness and age was the same
directional (Figure 20.2). In contrast, KSS score
did not show consistent significant relationship
with age in any of the studies (Figure 20.2b–20.2d
and Tables 20.2 and 20.3).
Discussion of Deprivation Studies
Analysis of the self-ratings of sleepiness failed to
reveal significant differences between ages in
strength of their ability to feel sleepy during sleep
deprivation. In contrast, the results also sug-
gested that, objectively, older adults had a
reduced vulnerability to sleep loss as indicated by
the decrease of alpha activity. However, the
changes of activity in lower frequency band asso-
ciated with increase of sleepiness appeared ear-
lier in the course of prolongation of wakefulness
by older adults. Consequently, the results revealed
that motivational action of subjective sleepiness
seemed to be age-independent. To some extent
this result contradicts with the age-associated
decline of objective sleepiness seen in the results
on responsiveness to sleep deprivation evaluated
with alpha waves or with theta waves. Alpha
waves showed low responsiveness in older adults,
and theta waves showed lower responsiveness in
younger adults. Therefore, the answer to such a
question as are younger adults become objec-
tively sleepier than older adults after sleep loss
depends upon the chosen measure (whether
sleepiness was evaluated using the alpha index or
with the lower frequency index or by
self-scoring).
 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness 327

Figure 20.2 Power spectra and time courses of sleepiness.

328 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Table 20.2 Objective and subjective sleepiness measures as the correlates of age
h n Whole n Male n Female n Whole n Male n Female

Alpha power, day 1 Alpha power, day 2

21 48 .37* 21 .28 27 .41* 42 .49*** 19 .53* 23 .47*
23 48 .28 21 .15 27 .35 42 .56*** 19 .57* 23 .61**
1 48 .34* 21 .32 27 .35 41 .42** 19 .54* 22 .35
3 48 .40** 21 .34 27 .47* 39 .43** 18 .52* 21 .38
5 48 .51*** 21 .48* 27 .57** 37 .35* 17 .45 20 .30
7 48 .39** 21 .37 27 .43* 36 .49** 17 .60* 19 .41
9 48 .33* 21 .32 27 .35 33 .36* 16 .50* 17 .25
11 48 .36* 21 .33 27 .39* 29 .50** 14 .63* 15 .42
13 48 .38** 21 .38 27 .39* 27 .49** 12 .52 15 .48
15 48 .32* 21 .35 27 .32 27 .39* 12 .35 15 .43
17 48 .31* 21 .31 27 .33 25 .22 11 .11 14 .29
19 48 .44** 21 .36 27 .49** 25 .48* 11 .43 14 .53
Alpha Rhythm power, night 1 KSS score, night 1
0 130 .03 54 –.12 76 .11 130 .07 54 .27* 76 –.08
3 130 .20* 54 .16 76 .20 130 –.15 54 –.16 76 -.18
6 130 .25** 54 .31* 76 .20 130 –.12 54 –.19 76 –.12
***
9 130 .32 54 .32* 76 .33** 130 –.19* 54 –.06 76 –.24*

Notes. Data on two first minutes with eyes closed in two-day sleep deprivation study and on one minute with eyes closed in
one-night sleep deprivation study. Pearson correlation coefficient between age of study participant and sleepiness measure.
The measure is either objective or subjective: either alpha power and KSS score related to 21:00 hours in one-night sleep
deprivation study or only alpha power related to 19:00 hours in two-day sleep deprivation study (for KSS score of two-day
study, none of the coefficients was found to be significant). Whole, Male and Female: Whole sample of study participants,
Male and Female study participants; h: Clock Hour; n: Number of study participants (it is gradually decreasing on day 2 of
two-day study due to dropouts occurring when desire to sleep becomes irresistible). Level of significance for Pearson correla-
tion coefficient: * p < 0.05, ** p < 0.01, ***p < 0.001.

Table 20.3 Main effects of the independent factors “Age” and “Sex” in rANOVAs
rANOVA Two-way Three-way
df Age df Age df Sex df Interaction

Day 1
Alpha power 2/45 5.32** 2/42 5.74** 1/42 2.34 2/42 0.16
KSS score 2/45 0.48 2/42 0.48 1/42 0.00 2/42 0.52
Day 2
Alpha power 2/22 4.96* 2/19 4.41* 1/19 0.24 2/19 0.41
KSS score 2/22 0.53 2/19 0.43 1/19 0.74 2/19 0.16
Night 1
Alpha power 3/126 3.15* 3/122 2.48 1/122 0.39 3/122 0.21
KSS score 3/126 0.77 3/122 1.11 1/122 4.60* 3/122 1.07

Notes. Data on the first two minutes with eyes closed collected during the first and second days of two-day sleep depriva-
tion study and data on one minute with eyes closed collected in one-night sleep deprivation study. “Clock hour” was the
repeated measure and either “Age” or “Age” and “Sex” were independent factors in two- and three-way rANOVAs, respec-
tively; objective and subjective sleepiness measures were alpha power (9 Hz–12 Hz) and KSS score, respectively. Interaction:
Interaction between independent factors. Estimates of sleepiness were related to either 19:00 hours or 21:00 hours in either
two-day or one-night sleep deprivation study, respectively. See Methods of deprivation studies and Figure 20.2c and 20.2d
for the division into either three or four age groups. Level of significance for F-ratio: * p < 0.05, ** p < 0.01.
 Sleep and Circadian Rhythms: Alpha Rhythm and Alertness/Sleepiness
Sleep deprivation experiments consistently
point at younger rather than older people as most
susceptible to impairment of alertness and perfor-
mance during extension of wakefulness beyond its
normal duration (Brendel et al., 1990; Cajochen
et al., 2006; Dijk et al., 2010; Duffy et al., 2009;
Landolt et al., 2012; Philip et al., 2004; Putilov
and Donskaya, 2016; Silva et al., 2010; Smulders
et al., 1997; Zitting et al., 2018). The results on
alpha index supported these findings. The fact
that lower frequency indexes responded earlier
to sleep deprivation in older adults might explain
identity of response of subjective sleepiness in
younger and older adults. Subjective sleepiness
might reflect an integrative response of different
brain functions to sleep loss, some of them decline
earlier in younger adults while other decline ear-
lier in older adults, and the sum of these responses
perceived as feeling sleepy might be identical in
younger and older people.
The results on the EEG response to sleep loss
are in agreement with the previous reports indi-
cating that, in eyes closed condition, sleepiness
is associated with a decrease of spectral power
density in the fast frequency rage and a change
in the opposite direction in slow frequency
range (i.e., alpha rhythm attenuates while theta
and delta waves increase in amplitude; Leproult
et al., 2003; Lorenzo et al., 1995; Marzano et al.,
2007; Putilov and Donskaya, 2014; Strijkstra
et al., 2003). As previously proposed (Putilov
and Donskaya, 2016), the brain response to sleep
loss might affect a wide range of frequencies of
the EEG signal rather than just one of the tradi-
tionally recognized frequency ranges. Such EEG
changes might represent the underlying influ-
ence of, at least, two antagonistic sleep–wake
regulating processes (i.e., the drives for wake
and sleep). The contribution of each of single-Hz
powers and each of the opposing drives might be
modified by age, duration of permanent wakeful-
ness, and so on (Dorokhov et al., 2021; Putilov
and Donskaya, 2016; Putilov et al., 2021).
Olbrich et al. (2009) proposed to determine the
1st of two stages of drowsiness as a change from
predominant frontal alpha activity to low volt-
age EEG without this activity, while an increase
of delta and theta power they recommended as
a marker of the next drowsiness stage preced-
ing sleep onset. However, the present results
suggested that such sequence of two-step spec-
tral EEG changes during transition from alert to
very sleep substate of wake state is typical only
for samples consisting of rather young study par-
ticipants (i.e., 15 people aged 19–35 years in the
report by Olbrich et al., 2009). The significant age
difference in the spectral EEG response to moder-
ate sleep loss votes for the necessity to identify
329
other spectral EEG indexes of sleepiness applica-
ble to old volunteers. Moreover, the results sug-
gesting the age independent response of subjective
sleepiness to sleep loss do not provide evidence
for such hypothetical age-associated sleep pathol-
ogies as a reduction in the neural mechanisms for
regulating sleep need and a desensitization to the
homeostatic sleep drive (Mander et al., 2017).
Thus, the diurnal variation in vigilance states
and sub-states can be linked to changes in EEG
waves in the eyes closed condition. Consequently,
these waves might serve as objective markers of
the mechanisms regulating the alertness–sleepi-
ness rhythm. One such marker (alpha waves in
the eyes closed condition), might provide a quan-
titative description of the processes regulating
alertness levels during extended periods of wake-
fulness. These prospects have been illustrated by
the results on evaluation of alpha waves as objec-
tive indexes of sleepiness in sleep deprivation
experiments. The tracing changes in these waves
in 130 and 48 participants of one- and two-day
sleep deprivation experiments, respectively, has
suggested that, similar to subjective measures
of sleepiness, alpha waves in the eyes closed
condition can quantitatively measure processes
regulating the alertness–sleepiness rhythm. This
objective index might be used instead of a subjec-
tive index (Figure 20.1b) in simulations of time
course of sleepiness in the two-day sleep depriva-
tion experiment.
SUMMARY AND CONCLUSIONS
The processes underlying two major human
behaviour rhythms, the 24-hour sleep–wake cycle,
and corresponding alertness–sleepiness rhythms
and the role of brain waves including the alpha
rhythm in their scientific research, have been
described. It has been demonstrated that the
changes in electroencephalographic waves can be
related to the diurnal variation in vigilance states
and substates. The results point to the prospect of
using these waves as markers of the mechanisms
regulating rhythmicity of sleep and wakefulness
states, alertness and sleepiness substates, levels of
performance, attention, perception, etc. One such
marker, slow waves during sleep episodes, tradi-
tionally have been utilized for simulation of the
kinetics of sleep homeostasis, and another marker,
alpha waves in an eyes closed condition, might
serve as a quantitative measure of the processes
regulating alertness level during extended wake-
fulness. The feasibility of such descriptors has
been illustrated by sleep deprivation experiments
330 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
evaluating alpha waves as objective indexes of
sleepiness. In addition to subjective measures of
sleepiness, alpha waves in an eyes closed condi-
tion can provide a quantitative description and
simulation of the processes regulating the alert-
ness–sleepiness rhythm.
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 PART V
Sensory-Perceptual
Systems and Cognition
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Auditory Processing
Erich Schröger and Alexandra Bendixen
INTRODUCTION
Auditory information processing is in the service
of gaining information about the physical, psy-
chological, and social world provided by the
acoustic environment. One important task is to
establish neural or mental representations of
sound sources (e.g., a particular speaker) and of
the auditory stimulus events they generate (e.g., a
spoken word). These events (i.e., discrete sounds)
are consciously perceived as auditory objects and
can be used by other processing modules of the
brain or mind. Following the definition of Bizley
and Cohen (2013), auditory objects are regarded
as perceptual constructs which correspond to
sound events that can be assigned to a particular
source. In order to accomplish this task, the sen-
sory stimulation caused by the arriving sound
waves has to be analyzed and related to our exist-
ing knowledge about the world. This includes
many subfunctions such as the identification of a
particular sound source (e.g., a human speaker),
the identification of the message conveyed by the
activity of that sound source (e.g., the understand-
ing of a spoken sentence), the separation of con-
currently active sound sources (also known as
cocktail-party problem; Cherry, 1953; Holmes
et al., 2021) and many others. This chapter will
21
introduce some important subfunctions that aid
our auditory system in this challenging task and
some models explaining how these functions are
achieved.
In addition to seeing, hearing is of high impor-
tance for human communication and other cog-
nitive functions. Analogous to electromagnetic
waves in vision, vibrations of a certain wavelength
are picked up in hearing and converted into sen-
sations. In the context of auditory processing, the
oscillations are air pressure fluctuations caused
by the sound source, that is, the sound-producing
entity such as a musical instrument, the human
vocal apparatus, or the collision of two enti-
ties. Often, the physical input parameters and
their psychophysical transformation are equated
between hearing and seeing: the amplitude of the
vibration is perceived as intensity (i.e., loudness
or brightness), the wavelength (frequency) of the
vibration corresponds psychologically to the pitch
or the experienced hue. But even for this simple
analogy one can already find counter-arguments.
One is that pitch is perceptually represented in
one dimension (i.e., all pitches can be arranged
next to each other on a scale), while colour space
is typically perceived as multidimensional – it is
not possible to sort all colours in order (Kavšek,
1996). Another counter-argument is the difference
338 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
in naming performance: while naming colours is
not a problem for most people, correctly naming
the pitch of a tone on a musical scale is a com-
paratively rare gift – so-called absolute pitch is
possessed by few people only (e.g., Elmer et al.,
2015). Such differences suggest that auditory pro-
cessing is organized by (partly) different princi-
ples than visual processing.
Possibly the most striking difference between
vision and audition is that the objects of the
respective sensory system are quite different with
respect to their ontological state. The objects of
seeing usually exist in ways that one can approach
them, can touch them, can determine their weight
and size; they are usually stable, that is, they are
there before one has seen them and continue to be
there after one has seen them. The objects of hear-
ing (the sounds) do not exist in the same sense.
Sounds are volatile, they often fade within a frac-
tion of a second, one usually cannot reinspect
them in the same way as a visual object. In other
words, sounds do not materialize similarly to the
objects of visual perception. Although generated
by an existing entity (i.e., the sound source such as
a human speaker), the perceived sound is phenom-
enologically not equivalent to this entity. Unlike
in vision, where the seen person is the person,
the heard word uttered by the speaker is not the
speaker. There are similar, but exceptional cases
in vision – for example, warning or signal lights
are usually not taken for the lamp or flashlight that
sends them, but for the message the signal com-
municates (e.g., SOS).
The information in the acoustic signal is distrib-
uted in time; for example, on a microscale the air
pressure fluctuations occurring a thousand times
per second at the eardrum results in the percep-
tion of a high-pitched tone; on a macroscale the
sequential presentation of tones with different
pitch may result in the perception of a familiar
melody. The exploitation of information contained
in sequences on different time scales and the con-
catenation of this information seems to be a char-
acteristic processing principle in audition. This
ability to recognize sequences and “sequences
of sequences” (Kiebel et al., 2009) is essential in
auditory information processing.
The auditory processing system interacts with
other information processing systems (e.g., vision,
action, memory, intention, emotion) as it provides
and receives information to and from these other
systems. For example, the perceived location of a
sound may be affected by the visual information
about the sound source (i.e., impact of vision for
audition), the quality of the representation of the
sound event may depend on the voluntary alloca-
tion of attention (i.e., impact of attention), the per-
ceived loudness may depend on whether the sound
was intentionally created by the listener of the
sound or by somebody else (i.e., impact of action).
And vice versa, a loud sound in the back could make
us turn (i.e., impact on motor behaviour / action)
and visually analyze the sound source (i.e., impact
on visual attention).
PHYSICAL, PHYSIOLOGICAL AND
PSYCHOPHYSICAL PRINCIPLES OF
HEARING
Mapping Physical to Perceptual
Dimensions (Psychophysics)
Pitch
Auditory stimulus events are (discrete) sounds
generated by an active sound source, that is, a
sound-producing entity such as a musical instru-
ment, the vocal apparatus of a bird, or the colli-
sion of a spoon with a plate. The sound-producing
entity moves quickly back and forth (i.e., vibrates)
so that fluctuations in air pressure are generated,
that is, alternating zones of compressed and
decompressed air, which propagate as longitudi-
nal waves. That is, in everyday life, acoustic infor-
mation is transmitted by changes in air pressure.
These changes (travelling sound waves) can often
be described as a superposition of different sinu-
soidal oscillations with a defined frequency. For
example, a human speaker emits signals of a cer-
tain fundamental frequency with several harmonic
overtones (integer multiples of the fundamental
frequency). The fundamental frequency depends
primarily on the speaker’s current vocal pitch, the
composition of the overtones on his breathing
technique as well as on anatomical parameters of
his vocal apparatus.
The frequency of a tone is expressed in Hertz
(Hz; number of oscillation cycles per second). Fast
vibrations are perceived as high-pitched tones,
slow vibrations as low-pitched tones. Humans can
hear frequencies with a lower limit of about 16 Hz
and an upper limit of about 20 kHz. This frequency
range declines significantly with age, especially
the upper limit. For that reason, elderly listen-
ers show difficulties in hearing high-­frequency
sounds, which impedes their ability to differen-
tiate certain speech sounds. Yet sounds with fre-
quencies outside the audible frequency range can,
to some extent, still be perceived. Intense low-
frequency infrasound (< 16 Hz) can cause soma-
tosensory feelings, and high-frequency ultrasound
(> 20 kHz) can lead to auditory percepts when it
reaches the cochlea via bone conduction.
 Auditory Processing
Loudness
The second important characteristic of a vibration
besides frequency is its amplitude. This physical
parameter translates into loudness perception at
the psychological level (although loudness is also
influenced by various other factors, such as sound
duration, complexity and distance of the sound
source). Natural sound waves typically do not
have a constant amplitude, but show amplitude
changes over time. These amplitude changes can
be described by the envelope of the sound. In
contrast, the temporal fine structure is determined
by the relative mixture of the frequency compo-
nents of the sound signal occurring at a particular
time. Surprisingly, complex signals such as speech
can be understood quite well based on the enve-
lope alone. However, in noisy environments, fine
structure becomes more important (Moon et al.,
2014; Moore, 2008).
The physical quantities of loudness are sound
intensity and sound pressure level (SPL). Sound
intensity is the energy of sound that passes
through a given area per second. Sound pressure
level is the more common term for the strength
of a sound. It is usually reported as a logarith-
mic quantity relative to a reference sound pres-
sure of 20Pa (2*10−5 N/m²), which is indicated
by SPL after the sound level value (e.g., 40 dB
SPL in a typical office environment). In terms of
audible sound intensities or sound pressures, the
human auditory system has a wide dynamic range,
extending from the absolute threshold of hearing
(which is at about 0 dB SPL for a 2000 Hz sound,
but can be very different for sounds of other fre-
quencies) to the threshold of pain (which is at
about 140 dB SPL, but again very much depend-
ent on the frequency composition). With a senso-
rineural hearing loss that often comes with age or
with a long history of noise exposure, the absolute
hearing thresholds increase – that is, sounds need
to be physically more intense for the listener to be
able to hear them. This threshold increase happens
in a frequency-specific manner. At the same time,
the threshold of pain does not increase, instead it
usually decreases with sensorineural hearing loss
as well. This convergence of the lower and upper
thresholds of hearing leads to a compression of the
dynamic range for loudness perception.
Timbre
A perceptually significant aspect of a sound is
timbre, which enables the listener to distinguish
similar sounds by the sources that produced them
(e.g., a musical note played by two different
instruments, or a word uttered by two different
speakers). Unlike frequency or amplitude, timbre
is a multidimensional quantity. Timbre is best
339
studied for the sound of musical instruments
(McAdams et al., 1995). However, it also plays an
important role in recognizing other sounds, espe-
cially in recognizing speakers by their voice. The
characteristic timbre of a sound source is deter-
mined by the envelope, especially the time course
at the onset of a sound (rise time), the temporal
development of harmonics over time, and the rela-
tive proportions of the energy of odd and even
overtones in the sound mixture. The importance of
timing in a sound can easily be demonstrated by
playing a short piano piece backwards, which
sounds as if played by an organ. Some sounds
increase in amplitude only gradually (e.g., an
organ sound), while others begin with a very
sudden increase in amplitude (e.g., a piano tone).
It is still investigated which other physical proper-
ties contribute to the psychological experience of
timbre and how timbre can be objectively meas-
ured (e.g., Rahne et al., 2010).
Location
In addition to pitch, timbre, and loudness, the
location from which the sensory information
originates is of importance, especially in contexts
in which the auditory system provides a warning
function for the organism. In order to be able to
react quickly to warning signals (the horn of a
vehicle, the roar of a lion), it is indispensable that
our auditory sense not only informs us that there
is danger “somewhere” in the environment, but
that it also immediately indicates the location (or
at least the direction) of the danger. Unlike in
vision (or somatosensation), the neural signal
generated by sound waves in the inner ear does
not contain direct information about the sound
location. In vision, the light (emitted or reflected
by the seen entity) hits a restricted area of the
retina, that is, the two-dimensional location infor-
mation is present at the respective sensory organ
and propagated to the corresponding areas in the
visual cortex (retinotopy). There is no such direct,
receptor-encoded location information in audi-
tion. Nevertheless, the location or direction of a
sound can be indirectly calculated by the auditory
system. The lateralization of sound sources is
largely based on binaural hearing, i.e., on an inte-
gration of information from the two ears. In this
integration process, interaural time differences
(ITDs) and interaural intensity differences (IIDs,
also: interaural level differences, ILDs) are evalu-
ated, which give information about the location of
the sound source. A sound signal coming from the
left reaches the left ear earlier (ITD) and with
higher intensity (ILD) than the right ear, the latter
due to energy losses over time and due to the
sound shadow caused by the intervening head.
340 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
ITD and ILD are not directly perceptual properties
of sound (i.e., one has no conscious access to the
information that the left ear was stimulated earlier
or more intensely, respectively), but they are auto-
matically recoded into directional information
(i.e., the conscious percept is that of a sound
source located to the left of the listener). The
resolvable travel time differences are far below
one millisecond – an amazingly precise comput-
ing power of the auditory system.
With these binaural cues, mainly the horizon-
tal localization of sound sources (left vs. right,
so-called azimuth) can be achieved. Vertical
localization estimation (above vs. below, so-called
elevation) is based on monaural cues (i.e., acces-
sible on the basis of information from only one
ear). These are generated by reflections and dif-
fractions of the sound wave in the outer ear, which
acts like a filter. Such a filter can be described by
the outer-ear- or head-related transfer function
(HRTF). However, in order to correctly interpret
this function, a certain knowledge of the physi-
cal composition of the original signal is required.
This – as well as the experiential knowledge of the
acoustic properties of one’s own outer ear – must
first be learned in the course of life.
By integrating monaural and binaural cues,
sound sources can be localized reasonably well
in two-dimensional space; nevertheless, some-
times ambiguities remain – that is, a certain acti-
vation pattern cannot be clearly assigned to a
specific sound direction. In these cases, listener
help themselves – often without noticing it – with
small head movements, which slightly change the
activation pattern and thus resolve the ambiguity.
This example illustrates that perception and motor
activity are closely linked in hearing – not only
in the sense that perception is the basis for motor
activity, but also in the opposite sense: “We must
perceive in order to move, but we must also move
in order to perceive” (Gibson, 1979).
In addition to the direction of sound (left/right,
up/down), the distance of the sound source from
the listener is also a relevant property in order to
be able to react adequately to a sensory stimulus
(the closer the honking car, the greater the need
to act). Distance information, in turn, can also
only be inferred indirectly; it is largely based on
the loudness of the signal, which is related to the
known or average loudness of the sound source
in question – similar to the way the visual sys-
tem includes the typical size of entities in the
distance calculation. However, it must be taken
into account that the visual system – in contrast
to the auditory system – usually has numerous
other cues available for spatial depth estimation,
for example, signals from the oculomotor system
(accommodation, convergence angle), binocular
matching (cross-disparity), and monocular cues
(occlusion, motion parallax, and the like). Despite
this limitation compared to visual perception, we
can find our way auditorily quite well in familiar
acoustic environments. Even in a new acoustic
environment, we quickly learn to orient ourselves
on the basis of acoustic information.
Together, information about azimuth, elevation,
and distance enables an approximate three-dimen-
sional perception of a sound’s location. Seemingly
even more complicated, but ecologically more
relevant, is the localization of a sound source that
is moving in space (e.g., a vehicle approaching or
moving away from us or the mosquito surround-
ing us at night), so that the location of the acoustic
stimulation is constantly changing relative to the
listener. Interestingly, this does not seem to pre-
sent any major difficulties for the auditory sys-
tem, since it is very well prepared to receive and
relate sequential input signals (i.e., sound events
stretched over time). The underlying ability to pro-
cess sequential information will be discussed later.
Neural Encoding of Sounds
(Physiology)
From sound waves to action potentials
The auditory sensory system converts vibrations
within the audible frequency range into neuronal
activation patterns. When arriving at the listener,
sound waves are first bundled and amplified by
the outer ear consisting of the pinna, the ear canal,
and the outer part of the eardrum. The sound
waves cause vibrations of the eardrum, which are
propagated and amplified by a chain of small
bones (hammer/malleus, anvil/incus, stirrup/
stapes) to the oval window enabling the transmis-
sion of vibration in air into vibration in liquid. The
oval window separates the middle (filled with air)
and the inner ear (filled with fluid). The deflec-
tions at the oval window move the fluid in the
inner ear; this is possible as the other window
separating the middle and the inner ear (the round
window) moves jointly with the oval window to
dissipate energy.
The actual translation into neural activity is
performed by a sensory organ in the inner ear, the
so-called organ of Corti on the basilar membrane
inside the cochlea. Here, the receptors of the audi-
tory system (the hair cells) are located. The cochlea
is a spiral-shaped cavity that is separated into three
chambers or ducts, the vestibular, the tympanic
and the cochlear duct. They are filled with two
different fluids (perilymph, endolymph) which
are similar to the fluid in which the brain floats.
The vibrations of a sound lead to corresponding
 Auditory Processing
movements of the endolymph in the cochlear
duct. When the basilar membrane vibrates, the
structures on the basilar membrane are shifted
against each other. This particularly affects the
tectorial membrane, where the outer hair cells,
topped with hair-like structures called stereocilia,
are attached. The back and forth of the tectorial
membrane in rhythm with the vibration bends the
stereocilia. When the stereocilia are deflected, a
sensing potential is generated at the hair cells that
initiates neural information processing (i.e., action
potentials in primary auditory neurons). About
3000 inner hair cells and 13000 outer hair cells
are located in the organ of Corti. Inner and outer
refers to the turn of the cochlea: the inner hair
cells are arranged in the inner turn. The inner hair
cells provide 95% of the output of the cochlea.
The outer hair cells, instead, mainly receive neural
input from the brain, which influences their motil-
ity as part of a special function of the cochlea as
a kind of mechanical pre-amplifier. This motility
increases the sensitivity to sounds considerably.
The motility expresses as evoked emissions, which
can be measured as an echo when a click is played
into the ear. The evoked emissions are louder and
longer in a well-functioning inner ear than to be
expected from a passive system. Measuring these
emissions is an important part of routine diagnosis
for possible hearing deficits in newborn infants.
Damage or deficiency of hair cells is the core
reason for elevated auditory thresholds that may
come with age or with prolonged noise exposure
(sensorineural hearing loss).
The location at which the hair cells are bent
maximally (i.e., the location at which the move-
ment of the basilar membrane is largest) directly
maps onto the frequency of the vibration. This
correspondence between frequency and coch-
lear location (called tonotopy) is realized by the
mechanical properties of the basilar membrane
(leading to different resonance frequencies in
different locations) and by the properties of the
inner ear fluid (leading to different propagation
depths of sound waves of different frequencies).
For frequencies below about 5000 Hz, there is
an additional time-based coding mechanism via
phase coupling of the activity of neuronal popu-
lations that “resonate” with the acoustic stimula-
tion. However, this mechanism reaches its limits
at higher frequencies.
Tonotopy is the most important organizing prin-
ciple in the auditory system. The frequency selec-
tivity is further enhanced by lateral inhibition,
where an activated neuron reduces the activity of
its neighbouring neurons. Tonotopy is found in all
temporally and anatomically downstream stages
of the auditory processing pathway in the brain.
341
In this respect, analogies exist between tonotopic
coding in the auditory system, retinotopic coding
in the visual system (i.e., coding according to the
location of activation on the retina), and somato-
topic coding in the somatosensory system (i.e.,
coding according to the location of activation on
the body). It is important to keep in mind that loca-
tion-based encoding in vision and touch (unlike
audition) directly reflects the actual location in the
world from which the activity originated because
of the physical relationships between sensory
stimulus and receptor.
Auditory pathway
Most properties of a sound must be extracted from
the neural signals along the auditory pathway
between the cochlea and the primary auditory
cortex. At the level of the hair cells, the mechani-
cal information is converted into neuronal excita-
tion at the axons of the auditory nerve. In addition
to hair cell deficiency, prolonged noise exposure
can also lead to damage in the synapses between
the hair cells and the auditory nerve, and in conse-
quence to a degeneration of auditory nerve fibers
(Kujawa and Liberman, 2009). This so-called
cochlear neuropathy leads to severe impairments
in understanding speech, but it does not come with
elevated auditory thresholds because it mainly
affects supra-threshold sound encoding
(Bharadwaj et al., 2014). The term hidden hearing
loss has been coined for this deficit (Liberman,
2015) since – unlike sensorineural hearing loss –
it is not revealed by conventional auditory thresh-
old testing.
The auditory processing pathway involves a
number of relay stations (nuclei, assemblies of
neuronal bodies) before the information arrives
at the cortex: the cochlear nucleus, the trapezoid
body, the superior olivary nucleus, the lateral lem-
niscus, the inferior colliculi, and the medial genic-
ulate body. The large number of relay stations
indicates a high degree of pre-processing, since at
the corresponding synapses – as everywhere in the
nervous system – information is not only passed
on one to one, but is accentuated and recombined.
The routing of signals in the auditory pro-
cessing pathway is hierarchical to a large extent.
Tonotopy as an organizing principle is maintained
in all core areas up to the auditory cortex, that is,
neighbouring populations of neurons respond to
similar frequencies. Unlike, for example, in the
somatosensory system, there is no uniquely lat-
eralized (i.e., ipsilateral or contralateral) trans-
mission of information in audition; instead,
processing pathways for signals from the left and
right ears converge in several nuclear areas. This
342 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
allows for an exchange of signals received by both
ears. The first core area for binaural integration is
the superior olive, where interaural time and level
differences (ITD, ILD) are computed as the basis
of sound localization.
Human auditory cortex is located bilaterally
in the superior temporal plane of the temporal
lobe and is largely “hidden” in the lateral sulcus
(Sylvian fissure). The auditory cortex is composed
of the primary auditory cortex, which extends over
the medial portion of the transverse temporal gyrus
(also known as Heschl’s gyrus), and several sec-
ondary and association areas located in adjacent
areas of the anterior and posterior superior tempo-
ral plane. The anatomical structure of the auditory
cortex shows major differences both between indi-
viduals and between the left and right hemispheres
of the same individual. Hemispheric differences
are partly associated with functional specializa-
tions related to speech and music processing.
In vision, two different processing routes were
distinguished, one mainly involved in the process-
ing of where information, the other in what infor-
mation. A similar distinction has been proposed
for the auditory system. Starting from the primary
auditory cortex, the ventral pathway, which con-
nects the auditory cortex to the frontal lobe via
the anterior temporal lobe, is assumed to play an
essential role in the detection and identification of
sound signals, whereas the dorsal pathway, which
connects the auditory cortex and the parietal
lobe, is associated with the localization of sound
sources (Wang et al., 2008). Overall, the auditory
cortex has numerous connections to frontal brain
areas (Plakke and Romanski, 2014).
It should be noted that at each intermediate pro-
cessing level of the auditory system, there are not
only ascending bottom-up connections but also
various feedback loops. Anatomically, there are
often even more top-down than bottom-up connec-
tions. The function of the top-down connections
are manifold. They are involved, for example, in
the initiation of reflexive muscle contraction in the
middle ear and in top-down modulation of neural
information. As a response to loud sounds, the
stapedius muscle and the tensor tympani muscle
in the middle ear are contracted (acoustic reflex).
This reduces transmission of mechanical energy to
the inner ear and thus protects the inner ear from
noise-induced damage. Neural processing at lower
levels can be modified by top-down effects caused
by implicit expectations, current perceptual inter-
ests, and action goals of the listener: For exam-
ple, certain acoustic information is prioritized in
processing to focus on single sound sources in the
environment (e.g., the interlocutor), while other
sound sources (e.g., street noise) are largely sup-
pressed from processing (see below).
SOUND SOURCE SEPARATION
The auditory system has to determine which
sound sources exist and which portions of the
complex sound signal belong to which source.
This is not a trivial task considering that the
acoustic waves generated by concurrently active
sound sources intermix with each other and with
their echoes (generated when the waves bounce
against a barrier, e.g., the walls in a classroom).
Moreover, the complex signals generated by a
sound source (such as a human speaker) vary con-
siderably over time. In addition, this extraction of
sound sources must happen quickly in order to be
able to monitor the occurrence of new (or the ter-
mination of active) sound sources in the dynamic
acoustic world. This process is called auditory
scene analysis (Bregman, 1990). Often, one of
these sources is then to be selected for further
(cognitive) processing. This is typically a function
of attention. Some theories conceptualize the for-
mation of sound sources and the selection of one
of those sound sources as one and the same pro-
cess (e.g., Shamma et al., 2011); others view the
two functions as sequential: Auditory scene analy-
sis comes first, followed by selection by the atten-
tional system (e.g., Bregman, 1990).
Bregman (1990) proposed that the auditory
system uses rules that apply in the majority of
cases and whose application massively simpli-
fies the problem of auditory scene analysis. Such
“simple” rules are called heuristics. One can
distinguish bottom-up and top-down heuristics.
Bottom-up heuristics are based on characteristics
of the signal and describe typical signs that sound
components belong together (i.e. were emitted by
the same source). They are better known under
the term auditory Gestalt laws. Top-down heu-
ristics describe prior assumptions of the listener,
for example, regarding the sound sources to be
expected in a particular listening environment.
The Gestalt laws formulate abstract principles
for whether certain components of the visual or
auditory input should be integrated (i.e. perceived
as belonging together or assigned to the same
source) or segregated (i.e. perceived as separate
or assigned to different sources). Both integration
and segregation can refer to a specific point in
time (instantaneous auditory scene analysis) or
unfold over time (sequential or temporal auditory
scene analysis). Instantaneous or simultaneous
integration or segregation helps in determining
how many sound sources are currently active and
which signal components belong to which one of
them. Integration or separation over time informs
whether the sound just heard belongs to the
same auditory source, for example, whether the
 Auditory Processing
same speaker who had already articulated sev-
eral words before continued to speak or whether
another speaker kicked in.
Instantaneous Auditory Scene
Analysis
The initial decision of whether parts of a signal
belong together is based on cues that are instanta-
neously available (i.e., they do not require taking
stimulus history into account), such as outstand-
ing spectral cues, onset relationship, harmonic
structure or location. The rationale of such an
instantaneous grouping rule is, for instance, that
parts of a sound coming from different directions
at the same time could hardly have been produced
by the same sound source and should therefore be
perceptually segregated. Similarly, natural sound
sources produce overtones whose frequencies are
integer multiples of the fundamental frequency.
When a single sound component falls out of such
a harmonic mixture, it is perceptually segregated
and assigned to a different source; this is called
inharmonicity-based sound source segregation.
Conversely, there is no good reason to assume that
a mixture of sounds in perfect harmonic relation
to each other happened to be produced by differ-
ent sound sources; perceptual integration there-
fore takes place. The fundamental frequency may
even be missing in the signal and still be heard
because it can be inferred from the other compo-
nents of the mixture. This so-called “missing
fundamental” effect is already found in four-
month-old infants (He and Trainor, 2009) as dem-
onstrated by recordings of their electrical brain
activity.
The recognition of sounds in a mixture of dif-
ferent sounds, that is, within a sound texture is
based on computations performed on the output of
the peripheral auditory system, which delivers the
sub-bands of the input signal and their envelopes.
These computations, as shown by McDermott and
Simoncelli (2011), yield the statistical moments
of the compressed envelopes and cross-band cor-
relations. Experiments with human participants
listening to synthetic sounds constructed accord-
ing to the model suggest that the auditory system
represents textures similarly to the principles of
this model.
The segregation of sources based on instanta-
neous cues such as harmonic structure has been
investigated with an event-related brain poten-
tial (ERP) component called the Object-Related
Negativity (ORN) (Alain et al., 2001; Kocsis
et al., 2016). The ORN occurs about 150–200 ms
after the onset of an instantaneous cue indicating
343
perceptual segregation of sound components and
is generated in the auditory cortex. The processing
of inharmonicity has also been traced further down
the auditory processing hierarchy, at the level of
scalp-recorded brainstem ERPs within tens of mil-
liseconds after the onset of a sound (Bidelman and
Alain, 2015).
Sequential Auditory Scene Analysis
Unlike in instantaneous grouping, the decision
whether successively (sequentially) occurring
sound parts should be perceptually integrated or
segregated requires taking stimulus history into
account. Sequential auditory scene analysis
assesses the similarity of the individual signals
over time: the more different the signals, the less
likely it is that they originate from the same sound
source. This is consistent with the Gestalt law of
similarity, with similarity referring to a variety of
dimensions such as frequency, location, loudness,
or timbre. The rationale of the law of similarity is
that a sound source can produce sounds only
within a well-defined range of characteristics
(e.g., timbre and frequency range of an instru-
ment) or that its location and loudness does not
vary too much within a short period of time. As a
sound source changes its characteristics after a
pause during which the sound source was inactive
or not audible, perception assesses the physical
similarity of the signals before and after the pause.
The longer the pause, the more dissimilar the sig-
nals can be in order to still be assigned to the same
sound source. With this temporal notion, the
Gestalt law of similarity changes into the Gestalt
law of good continuation: The smaller the extent
of feature value change per unit time, the greater
the tendency to perceptually integrate the signals.
The law of good continuation creates a strong
bias for a continuity of already known sound
sources. However, when plausible cues for contin-
uation are missing, the emergence of new sources is
considered. This so-called old-plus-new heuristic
(Bregman, 1990) can result in continuity illusions.
For example, if one intersperses a sound with regu-
lar gaps, that sound is correctly perceived as inter-
rupted; but if one fills the gaps with loud noise,
the sound is suddenly perceived as continuous
(Dannenbring, 1976; cf. http://webpages.mcgill.
ca/staff/Group2/abregm1/web/downloadstoc.
htm#29). Thus, the auditory system performs
sound source separation by segregating out of
the noise a sound that is not actually present but
could be contained in terms of physical inten-
sity ratios. This phenomenon is called conti-
nuity illusion. Interestingly, this also works
344 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
when speech is masked with noise at regular
intervals (Warren, 1970). One can follow the
speech signal interspersed with noise bursts bet-
ter than if it were interspersed with silent gaps
(for an auditory illustration of this picket-fence
effect with speech see http://webpages.mcgill.
ca/staff/Group2/abregm1/web/downloadstoc.
htm#31). At first glance, this is surprising. One
might think that the additional noise would rather
confuse the listener, because the acoustic signal
contains the same linguistic information in both
situations. On closer examination, such examples
impressively illustrate how auditory perception
uses heuristics and draws interpretations during
signal analysis.
Further grouping phenomena can be described
with the Gestalt law of common fate. In vision,
objects that move together are interpreted as
belonging together. In audition, the joint common
rise in amplitude at sound onset and the common
amplitude modulations (comodulation) while the
sound is played biases perception toward a com-
mon sound source (Bizley and Cohen, 2013).
Based on this principle, the influential theory of
temporal coherence has been formulated (Shamma
et al., 2011). Coherent changes can be found not
only in the amplitude but also in the frequency of
the signal components: As the frequency of the
fundamental changes (e.g., intonation at the end of
an interrogative sentence), so do all the overtones,
which in turn provides evidence for the common
origin of the signal components. The temporal
coherence of amplitude and frequency changes is
found on both short and longer time scales, plac-
ing it at the interface between instantaneous and
sequential auditory scene analysis. It is possible
that this forms the long-neglected link between
these two mechanisms of sound source attribution.
Sequential auditory scene analysis in humans
cannot be measured as directly from brain record-
ings as instantaneous auditory scene analysis,
since there is no direct electrophysiological marker
like the ORN. Yet auditory stimulus sequences
can be set up to obtain an indirect marker of
sequential auditory scene analysis, namely the
Mismatch Negativity (MMN) component of the
ERP (Näätänen et al., 1978; Sussman et al., 2014).
MMN is elicited when a sound is detected as vio-
lating a currently active (implicit) regularity of an
auditory stream. When using MMN as a measure
of sequential auditory scene analysis, one must
embed a regularity into an auditory scene that
can only be extracted if the sound sources in the
scene are segregated but not if they are integrated
(or vice versa; Spielmann et al., 2014). With such
specifically tailored paradigms, it has been shown
that newborn infants can already separate sound
sources in simplified auditory scenes (Winkler
et al., 2003a). It should be noticed that the elicita-
tion of MMN not only indicates the brain’s detec-
tion of a violation of an auditory regularity, but
also that the regularity must have been extracted
beforehand. Thus, MMN is a tool that taps into
auditory representations and expectations.
The auditory scene analysis mechanisms
described above happen to a large extent automati-
cally. That is, the listener does not need to intend
to segment the acoustic input – scene analysis
takes place during passive listening without the
need to allocate voluntary attention. This is evi-
denced by studies showing that ORN (Alain et al.,
2002) and MMN (Symonds et al., 2020; Winkler
et al., 2003b) can be elicited when participants
do not actively listen to the sounds. However,
this does not imply that ORN and MMN (and the
corresponding scene analysis processes) cannot
be modulated by attention. In fact, it seems that
attention can improve the establishment of percep-
tual representations underlying ORN (Zobel et al.,
2015) and MMN (Sussman, 2017). With age and
sensorineural hearing loss, the principal function
of auditory scene analysis should remain intact,
but its outcome suffers from reductions in fre-
quency resolution and in temporal precision that
are part of the many changes the auditory system
undergoes. Hence many elderly listeners experi-
ence difficulties in listening in noisy environ-
ments, part of which are probably due to reduced
precision of auditory scene analysis, while other
parts are due to changes of the attentional system
with age (e.g., Weeks and Hasher, 2018). Attention
plays a crucial role when trying to extract meaning
from one of the sound sources upon segregating
it out of the mixture. The influence of attention
on the processing of auditory information will be
discussed in the next section.
AUDITORY ATTENTION
Voluntary attention denotes the intended selection
of sounds or sound sources in order to focus
resources on relevant information – such as listen-
ing to a speaker against a mixture of background
noises in a cafeteria (or at a cocktail party, as the
early literature on auditory scene analysis and
attention liked to emphasize). Such resource allo-
cation can be achieved by attenuating the process-
ing of irrelevant, to-be-ignored information, or by
facilitating the processing of relevant information.
Voluntary attention must be distinguished from
involuntary attention, which comes into play
when something unexpected happens in the audi-
tory scene (put more formally, an implicit or
 Auditory Processing
explicit expectation generated on the basis of the
internal model of the auditory environment is
violated). For example, a wrongly played note in
a melody or a mobile phone ringing may call for
an attentional orienting toward the sound and
sound source. The sound or sound source can then
receive additional processing in order to check for
the relevance of the “new” information and to pos-
sibly initiate respective actions or to revise the
model about what to expect in the acoustic envi-
ronment. This call for attention by unexpected
stimulation may happen at the expense of costs in
the processing of information relevant for the task
at hand, and may result in behavioral distraction
(Parmentier, 2014). Voluntary and involuntary
attention complement each other, and are dis-
cussed below.
Voluntary Auditory Attention
Auditory attention research has classically dealt
with multi-talker scenarios: How can we recog-
nize what one speaker is saying in the presence of
other active speakers? This amazing capability of
the auditory attentional system was introduced
into the literature by Cherry (1953) as the “cock-
tail party problem” and is still intensively
researched today (Bronkhorst, 2015; Holmes
et al., 2021). Other research is concerned with the
allocation of attentional resources between modal-
ities, e.g., between hearing and vision (Zhang
et al., 2017). Effects of attention on the processing
of sounds can also be compared when attention is
directed to the external versus internal environ-
ment (Kam et al., 2021). In all three situations,
voluntary (top-down) attention is supposed to
cause a differential processing of attended and
unattended auditory information, by facilitating
the processing of to-be-attended information or by
suppressing the processing of to-be-ignored infor-
mation (Bidet-Caulet et al., 2010).
Attentional modulations along the auditory
pathway have been investigated in thousands of
studies in animal and human research. Effects
were reported all along the auditory pathway (Fritz
et al., 2007). Some studies reported effects of
attention already at the cochlear level in humans,
with attention modulating otoacoustic emissions
(Giard et al., 2000; Walsh et al., 2015; cf., Bell
and Jedrzejczak, 2021). Animal studies found
that spectro-temporal receptive fields (STRFs),
characterizing the selective responsiveness of
neurons to sounds, were larger when the sounds
were task-relevant (Kaya and Elhilali, 2017).
Human functional magnetic resonance imaging
(fMRI) research revealed increases in activation
345
by auditory attention in several auditory and non-
auditory cortical regions such as the superior tem-
poral, temporo-parietal, superior parietal, inferior
and middle frontal as well as supplementary motor
areas (Alho et al., 2015). The attentional selec-
tion of auditory information can be accomplished
within a single dimension such a lateralization of a
sound (e.g., “select left-side sounds, ignore right-
side sounds”) or pitch (e.g., “select high-pitch
sounds, ignore low-pitch sounds”), but also on
the basis of sound sources or streams (e.g., “lis-
ten to the female speaker, don’t listen to the male
speaker”), to some extent even with feature over-
lap (Woods and McDermott, 2015).
A newly emerging line of research attempts
to decode from listeners’ brain responses which
sound source they are paying attention to (Mirkovic
et al., 2016; O’Sullivan et al., 2015). Such attempts
exploit the fact that cortical processing “tracks”
(i.e., temporally aligns with) the envelope of the
sound that is currently being attended (Ahissar
et al., 2001). The attention-decoding research is
often motivated by the idea of using the informa-
tion about the currently attended sound source for
directional steering of a hearing aid, in order to
facilitate the difficult scene analysis task for those
listeners who are hard of hearing. One challenge
that remains to be solved is how such an attention-
steered hearing aid could still provide the listener
with information about unexpectedly occurring
sounds in the environment – in other words, how
to maintain the function of involuntary attention.
Involuntary Attention
Auditory involuntary attention comes into play
when something unexpected happens in the acous-
tic environment. We orient our attention toward
the unexpected event, an orienting response may
be elicited (Sokolov, 1990), phenomenologically a
feeling of surprise or alertness may occur. Two
types of phenomena can trigger involuntary audi-
tory attention: (1) a change or transient in an oth-
erwise stable acoustic environment, such as a
change in the loudness or pitch of a continuous
tone; (2) a deviation from a regularity in the
acoustic environment, such as repetition of a tone
in a series of otherwise alternating tones, or the
omission of a tone in an otherwise isochronous
sequence (note that the fact that attention can be
triggered by an absence of information alludes to
a non-trivial underlying mechanism). Two differ-
ent computational neural mechanisms were pro-
posed to be involved in these two forms of
involuntary attention. One consists in the release
of neural adaptation to a stable acoustic
346 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
environment (May et al., 2015), the other in a
mismatch between a prediction derived from a
detected regularity in the acoustic environment
and the actual sensory input (Wacongne et al.,
2012). Some neurocomputational models attempt
to integrate these seemingly different mechanisms
into a single mechanism (Chien et al., 2019).
In terms of the best possible adaptation to the
environment, an appropriate balance between
involuntary and voluntary attention must be
achieved. An imbalance toward voluntary atten-
tion can, for example, result in inattentional deaf-
ness, a failure to recognize important auditory
events such as alarms (Scheer et al., 2018). Vice
versa, an imbalance toward openness for new
information can, for example, lead to disruption
by unexpected sounds during reading (Vasilev
et al., 2021). The challenging task of the lis-
tener lies in paying attention to one sound source
while at the same time monitoring all other sound
sources in the auditory scene in order to be open
to relevant changes in their behaviour. To achieve
this, the listener needs a mental representation of
the whole auditory scene, in which the foreground
representation is processed in detail, and the back-
ground representation is continuously (and more
or less automatically) checked against the incom-
ing sensory information. Such auditory represen-
tations have long been postulated in the tradition
of cognitive psychology, and are now increasingly
being refined in neural terms.
AUDITORY REPRESENTATIONS
Auditory Event Representations and
Memory
Listeners establish and maintain internal represen-
tations of auditory stimulus events (i.e., of discrete
sounds) that are consciously perceived and that
can be used by other processing modules of the
brain or mind. One important characteristic of
auditory event representations is that they usually
remain active after the respective sound has faded.
Hence, they represent a form of memory. Keeping
information available for some time is important,
for example, in sentence comprehension or in
linking acoustic information across interruptions.
In fact, the current concept of auditory event rep-
resentation (Winkler and Schröger, 2015) corre-
sponds to the classic concept of auditory memory
from cognitive psychology (Cowan, 1984). For
auditory memory, two successive phases of stor-
age are distinguished. One is the short (pre-per-
ceptual) auditory memory, which has a storage
duration of about 200 ms, which enables integra-
tion and persistence phenomena. The other phase
is the long (synthesized) auditory memory (also
echoic memory), whose storage duration is about
10–30 secs. It represents a more static form of
storage that serves as a kind of database for fur-
ther processing.
Psychological concepts of memory trace for-
mation and memory fading have greatly influ-
enced research on auditory perception. Much of
this research has been in the tradition of unidi-
rectional bottom-up processing, where sensory
information is picked up, passed on, processed
and transformed into mental representations.
During the past ~15 years, research on auditory
perception has experienced a paradigm shift from
the prevailing framework of unidirectional infor-
mation processing toward a framework including
feedback loops and exchange of bottom-up infor-
mation with top-down expectations at all levels of
the auditory processing hierarchy. This develop-
ment has been strongly driven by the application
of predictive coding theory to auditory sensory
information processing (Friston, 2005).
Neural Representation and Predictive
Coding
The amazing skills of involuntary attention (notic-
ing energy decreases in sound sources that were
previously unattended) and of sequential auditory
scene analysis (assigning incoming signal parts to
sound sources to which they provide a good con-
tinuation) described above would be very cumber-
some to achieve in a purely bottom-up framework
of sensory information processing. The notion
that regularities are extracted from the auditory
surroundings and that incoming sounds are
checked against these regularities has been formu-
lated in the context of research on irregularity
detection (involving the MMN) and involuntary
attentional capture. Some early MMN research
has already expressed the idea that predictions are
derived from the regularities (Winkler et al.,
1996). This idea has gained momentum when
acoustic irregularities were discussed within pre-
dictive coding theory, a theoretical framework for
sensory processing (Friston, 2005). According to
this view, predictions are derived from the brain’s
generative model of the environment and com-
pared with the actual sensory input. This dynamic
system of feedback (predictions) and feedforward
(prediction error) recurrent loops aims at minimiz-
ing the prediction error. At each level of the corti-
cal hierarchy, the prediction error is passed on to
the higher levels. Thereby, the amount of sensory
 Auditory Processing
data that is fed forward and needs to be processed
further focuses on those parts that are not already
accounted for by the internal model. The predic-
tion error is in turn used to improve the model.
When the prediction error is minimized, that is,
when the prediction conforms to the input, the
internal model (i.e., the content specified by rep-
resentational neurons) is perceived. Predictive
coding theory has been instantiated in specific
neurocomputational and neurobiological models
that support and refine the mechanistic principles
underlying the sequential nature of auditory per-
ception (e.g., Spratling, 2017; Wacongne et al.,
2012).
Neurophysiological recordings show that irreg-
ularity detection happens at various levels of the
auditory pathway. Animal single-unit recordings
revealed effects in primary auditory cortex, the
medial geniculate body (MGB), and the inferior
colliculus (IC) (e.g., Valdés-Baizabal et al., 2021).
A recent study investigated the functional speciali-
zation of auditory areas in the rat for mere change
detection versus irregularity detection (Parras
et al., 2021). While the primary auditory cortex,
the anterior auditory field, the ventral auditory
field, and the suprarhinal auditory field are mainly
engaged in (release from) adaptation, irregularity
detection is processed preferentially in the non-
lemniscal, posterior auditory field. Research using
event-related fMRI revealed auditory irregularity
detection in the auditory cortex, the MGB and
the IC also in humans (Cacciaglia et al., 2015).
Altogether, a picture emerges that predictions are
locally instantiated and irregularities detected at
multiple different levels of the auditory pathway
(e.g., Tabas and von Kriegstein, 2021).
SUMMARY AND CONCLUSIONS
In this chapter we have discussed principles and
mechanisms of auditory processing from a cogni-
tive and neuroscientific view. By means of audi-
tory processing, we extract information from the
acoustic environment about the physical, psycho-
logical and social world we interact with. This
information describes the sound sources (e.g., a
particular speaker) and their behavior (e.g., the
message of a spoken sentence). We can, for exam-
ple, identify an instrument and enjoy a whole
melody played by it, perceive the trajectory of a
mosquito circling us, detect a familiar voice, rec-
ognize the mood of a speaker, understand the
content of a spoken message, and notice a car
approaching us from behind. This is achieved by
347
the interaction of bottom-up processing triggered
by the available sensory data and the top-down
processing triggered by our internal models. The
respective sensory data are based on excitation
patterns in the cochlea. The internal models host
our beliefs about the world, that is, the representa-
tions of our mental (memory) system. The result
of these interactive processing are auditory per-
ceptual representations of discrete sounds, which
are linked to and used for various cognitive pro-
cesses related to perception, attention, discrimina-
tion, evaluation, action planning, and the like.
Predictive coding theory is the currently prevail-
ing account for sequential auditory scene analysis,
background monitoring and involuntary attention
shifting. Temporal coherence theory is promising
for linking sequential auditory scene analysis with
instantaneous auditory scene analysis and with
mechanisms of voluntary attention. A theoretical
framework joining the underlying principles with
one another and with our knowledge on psycho-
physical and psychophysiological principles will
allow us to gain an even better understanding of
the fascinating properties of auditory perception.
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Vestibular Processing in Cognition
INTRODUCTION
Although parts of the vestibular peripheral organs
were described in the seventeenth century, Antonio
Scarpa provided the first detailed description of
the anatomy of the vestibular organs in 1789.
Subsequently, in 1842, Marie Jean Pierre Flourens
lesioned the semicircular canals of pigeons and
reported that movements became uncoordinated
in particular planes, but concluded that their role
was ultimately in audition. Jan Evangelista
Purkinje studied vertigo in 1820, noting like
others before him, that spinning people on rotat-
ing chairs lead to systematic eye movements, but
he concluded that it was predominantly cerebellar.
From the 1870s onward, researchers started to
suggest that the vestibular organs play a role in
balance. For example, Ernst Mach noticed that the
semicircular canals were insensitive to linear
forces, although he did not believe in a role for the
endolymph’s motion, but rather its pressure.
William James noted that out of over 500 deaf
mutes tested, more than one-third seemed immune
to dizziness after spinning, unlike all but one out
of 200 of his Harvard academic colleagues.
The anatomy of the vestibular sensory organs
provides important clues and constraints to vestib-
ular function – core to which is not balance per se,
22
P a u l C . J . Ta y l o r
but rather, detecting how the head is moving. The
structural blueprint of the vertebrate vestibular sys-
tem has been largely conserved across four hun-
dred million years of evolution (Straka and Baker,
2013). Within each inner ear are three semicircu-
lar canals and two other organs (otoliths), making
10 sensory organs, with five on each side. These
tiny bodies are all encapsulated within the floor
of the skull (Figure 22.1), reducing any timelag
between head movement and sensation.
The three semicircular canals are loops contain-
ing fluid, the endolymph, which moves relative to
the canal if three conditions are met. Firstly, the
head has to rotate. Secondly, this rotation has to
involve acceleration or deceleration. Canals are
blind to linear, constant velocity motion. Thirdly,
the rotation has to be in the right direction – the
canals are oriented at right angles to each other in
three-dimensional space so that all potential head
rotations can be detected. The horizontal canals
are oriented approximately horizontally, and so
are maximally sensitive to shaking the head from
side to side. Anterior and posterior canals are each
tipped by about 45 degrees from the vertical. Each
canal’s responses are increased by rotations in
one direction but inhibited in the opposite direc-
tion. The difference between responses between
“coplanar” members of each pair carries a rotation
352 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 22.1 The vestibular organs lie within the bone at the base of the skull (left). The
three semicircular canals are oriented at right angles to each other (middle) allowing detec-
tion of all types of head rotation (pitch, yaw, and tilt).
signal. The response of each canal is proportional
to the cosine of the angle between the canal plane
and the plane of motion (e.g., when the angle dif-
ference is low, the response is high). Fluid then
pushes against the end of the canal (the ampulla),
which contains a diaphragm (the cupula), stretch-
ing across the whole extent of the canal, receiv-
ing the full brunt of the shifting fluid. Within the
ampulla lie the sensory hair cells which transduce
mechanical movement into electrical impulses.
Hair cells extend into the cupula such that if the
cupula is displaced, the hair bundles are deflected.
If the hair bundle is shifted in one direction, it
depolarizes, and firing rate increases. A shift in the
opposite direction leads to hyperpolarization and a
reduced response.
Some sources still maintain that the cupula does
not reach the ceiling of the ampulla but acts as a
swinging gate, because the cupula would retract
and shrink back when prepared for histology. The
canal response was already well described in 1931
by Wilhelm Steinhausen as an “overdamped tor-
sion pendulum” (an analogy being a door handle
with a certain springiness to it, such that it snaps
back when pushed down). The biomechanics of
the canal response mean the response varies with
head velocity. Very slow rotations (below 0.1 Hz)
will not be detected because they do not produce
enough force to lead to relative motion of the
endolymph. For normal head movements, from
about 0.5 Hz up to about 10 Hz (Grossman et al.,
1988), there is no phase difference between head
movement and the bending of the cupula, and so
the fluid viscosity is the deciding factor. The gain
of response reduces as frequency increases.
It is left to the otolith organs (utricle and sac-
cule) to detect linear accelerations. Again, they are
blind to constant velocity stimulation. The ves-
tibular organs are then inertial sensors. The event
that is detected by the otolithic hair cells is pleas-
ingly mechanical (Figure 22.2). The hair cells
are physically weighed down by three layers of
material: a columnar layer of vertical filaments, a
dense gelatinous layer of randomly arranged fila-
ments, and the otoconial layer. This upper layer is
a loose fibrous network studded with crystals of
calcium carbonate in the form of calcite – a robust
but inert building material present throughout bio-
logical systems, for example in snail shells. If the
head moves in the right way, specifically a linear
acceleration, this material is moved. As it is denser
than the endolymph, it is carried by its own inertia,
bending the hair cells underneath (in the semicir-
cular canals, the cupula has a similar specific grav-
ity to the surrounding endolymphatic fluid and so
does not respond to linear forces). If movement
orientation is aligned with the hair cells, they bend
and trigger the sensory transduction cascade.
However, gravity is also a linear acceleration
(about 9.81 m/s2, or “g”). Otolithic hair cells
respond not only if the head moves linearly but
also if the head is tipped such that gravity bends
the hair cells, under the weight of the otoconia.
It is utterly ambiguous, from otolith responses
alone, whether a vestibular stimulus comprises a
linear acceleration or a tilt with respect to grav-
ity. Sudden accelerations during aviation can be
mistaken to indicate tilt of the aircraft (somato-
gravic illusion) or even of the visual horizon (the
oculogravic illusion). Canal input, together with
visual, somatosensory, proprioceptive, and cogni-
tive cues, can then resolve this.
Down the Vestibular Nerve
A vestibular hair cell only needs to be displaced by
a distance of the order of magnitude of a microme-
tre (depending on the frequency) to generate a
depolarizing current through the ion channels
within microseconds (Holt et al., 1998). These hair
cells synapse onto afferent neural fibres that form
a bundle, the vestibular or vestibulocochlear nerve,
 Vestibular Processing in Cognition
Figure 22.2 Schematic of otoconial hair cells and the layers of neuroepithelium
a branch of the VIII cranial nerve. Some hair cell
ion channels are open at rest, lending these affer-
ents a healthy baseline firing rate (e.g., higher than
retinal ganglion cells). These vestibular afferents
can then carry information by responding more
quickly or more slowly, and they have a smooth
response profile around the sensory threshold. Due
to the differing underlying sensory mechanics,
afferents from the semicircular canals and otoliths
encode velocity versus linear acceleration, respec-
tively. Afferent fibres can be classified according to
the regularity of their spontaneous action poten-
tials. Compared with more regular fibres, irregular
units are more sensitive, require less sensory input
to be activated, and have thicker axons (Goldberg,
2000). Irregular afferents can encode not only
acceleration, but also “jerk,” the change in accel-
eration. The two parallel information channels
however do not correspond to different central
vestibular pathways (Cullen, 2012).
Into the Subcortex
Only a fraction of the hundreds of human subcor-
tical regions has been mapped with MRI
(Forstmann et al., 2017), and in general, classical
connectomics has focused on cortex (Johansen-
Berg, 2013). Different nerve fibres project from
the canals, utricle or saccule and lead to intricate
connectivity patterns within the brain stem. This
complex of so-called vestibular nuclei consists of
353
four main nuclei and further subgroups, and many
nuclei have subdivisions and multiple names. The
vestibular nuclei also receive from other brain-
stem structures, cerebellum and cortex.
Additionally, efferent fibres project from the brain
stem back up to the hair cells, probably modulat-
ing hair cell excitability in a general and relatively
diffuse manner (Goldberg and Fernandez, 1980).
Neurons from this synapse onward show mixed
selectivities for velocity, acceleration, jerk, and
position (Laurens et al., 2017). Responses of the
vestibular sensory organs or the vestibular nerve
are independent of whether a head movement is
actively generated or passively applied (Cullen
and Minor, 2002). Yet in one class of vestibular
nuclei neurons of rhesus macaques, firing rates are
suppressed by more than half if monkeys actively
move their head relative to their trunk (Roy and
Cullen, 2001) and the vestibulo-spinal reflexes are
suppressed. The cerebellum is thought to predict
the sensory consequences of an action and to send
an (“efference”) copy of the motor command to
sensory areas. The sensation predicted to occur
with the action (for example, neck propriocep-
tive input) is then compared with what actually
happens. The neck proprioceptive input differs
according to whether the head moves on the trunk
or if the whole animal is moved passively, whereas
the vestibular input is the same. If there is no dif-
ference (and no prediction error) this indicates that
everything is going as expected, and the represen-
tation of the head turn in vestibular nuclei neurons
is inhibited. This means that the firing of these
354 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
neurons does not indicate head movement per se,
but rather selectively represents unintended, pas-
sive head-movements. An expected head motion
arising from an intended movements does not pro-
duce as much of a signal, and is prevented from
causing distraction.
Vestibular Reflexes for Movement
Control
Somatosensory and proprioceptive information
also converge on the vestibular nucleus, both from
the spinal cord, second-order neurons, cerebel-
lum, and cortex. Some (“vestibular-only”) neu-
rons in the vestibular nuclei project to the spinal
cord to mediate the vestibulo-spinal reflex, but
there are also projections to the thalamus and the
cerebellar nodulus and uvula, which are important
for postural control: vestibular cerebellar patients
do not show normal galvanically evoked body
sway responses (Kammermeier et al., 2009).
The vestibular system plays a crucial role in the
orienting of the eyes as well as the body. Separate
(“vestibulo-ocular reflex”) neurons are also visu-
ally sensitive and project to the motor neurons
for the eye muscles, to control gaze (Cullen and
Taube, 2017). One surprising aspect of subcorti-
cal circuitry is how separate structures are special-
ized not only for specific types of eye movements
but also within different planes and sometimes
in specific directions (e.g., upward versus down-
ward). Three separate reflex pathways function so
that the eyes can be kept fixating on an external
stimulus even if the head moves. Angular, trans-
lational and torsional vestibulo-ocular reflexes
(VORs) are each specialized to move the eyes in
the opposite direction to head movements occur-
ring due to turn, shift, or tilt of the head, respec-
tively. The direct VOR arc consists of only three
neurons after the hair cell: the primary vestibular
nerve leading away from the labyrinth, the sec-
ondary neuron leading away from the vestibular
nucleus, and the motor neurons themselves in the
oculomotor nuclei which directly innervate the
muscles around the eyeball. After monkey head-
rotation, some counter-rotation in the eye is appar-
ent within about 6ms (Huterer and Cullen, 2002).
Such speed is necessary, because if there were any
substantial lag between moving one’s head and
the eyes rotating in their socket to compensate
for this, the world would be perceived as moving
every time that the head is moved, before the eyes
have responded.
Additional pathways link the semicircular
canals to oculomotor neurons, modulating the
VOR, crossing the midline to co-ordinate binocular
movements, and using excitatory or inhibitory neu-
rotransmitters; the oculomotor nuclei also receive
input from vestibular neurons that lie outside of this
reflex arc and do not directly receive input from the
vestibular nerve; and in addition to these canal-
driven reflexes, there are also otolithic projec-
tions to oculomotor neurons mediating even more
intricate circuits and other oculomotor reflexes
(Goldberg et al., 2012). In order to move the eyes to
shift gaze, the VOR must logically be inhibited so
that gaze does not simply stay fixed. Reflex motor
control, although by definition automatic, is subtle
and can vary with the motor context (making crisp
delineations of what is “reflexive” difficult).
Before we turn to the contribution of vestibu-
lar cortical areas, one last impressive property is
known to arise in the subcortex and to contribute
to more abstract spatial cognition. The vestibular
signals indicating a change in head position have
clear relevance for the control of orchestrated
actions including multiple effectors. Accordingly,
studies have investigated how the egocentric ref-
erence frame for the head (both vestibular and
visual) is related to an absolute world-based
allocentric frame. A key element here is head-­
direction neurons, which fire as a function of
which direction an animal’s head is pointing inde-
pendently of where the animal is within a given
area (Taube et al., 1990). These neurons func-
tion like little compasses, and have been reported
throughout the mammal (and insect) brain. The
key role of vestibular processing can be demon-
strated by bilateral peripheral vestibular lesions
in the rat, which greatly disrupt the normal tun-
ing of head direction cells in the anterior thalamus
(Stackman and Taube, 1997). Head direction cells
form an important component building up to the
allocentric medial temporal system culminating
in hippocampal place cells, originally discovered
in the rat to fire not only when the rat was point-
ing in a particular direction but also in a particular
spatial area in the environment (and, interestingly,
also only if the animal was held down).
Cortical Processing of Visual and
Vestibular Heading in the Monkey
Given the sophisticated degree of processing
already occurring in the vestibular nuclei and asso-
ciated subcortical areas, one might be forgiven for
wondering what more processing could possibly
be necessary. A widespread network of cortical
areas has now been identified to show an associa-
tion with vestibular processing. This evidence
arises from integrating converging results from
different approaches that have used anatomical
 Vestibular Processing in Cognition
tracing, single-cell recording in monkeys being
moved around on motion platforms, or imaging in
humans while the vestibular periphery is in some
way stimulated artificially, as well as tasks simulat-
ing vestibular sensation.
Although the thalamus is clearly far from
simply being a relay of information, vestibular
thalamic neuronal responses often mimic the ves-
tibular nucleus, and a large thalamo-cortical net-
work responds to vestibular stimulation (Lopez
and Blanke, 2011). At least three distinct thalam-
ocortical pathways (Kotchabhakdi et al., 1980)
innervate the many areas referred to accordingly
as “vestibular cortex” (Guldin and Grüsser, 1998).
Unusually, there is no uncontested candidate for a
primary sensory cortex with as much support as
in other sensory systems, where one cortical area
receives by far the most input from the sensory
thalamus. One promising approach for dissociat-
ing nodes within the vestibular network has been
to measure how neurons respond to vestibular
stimulation, visual stimulation, and the combina-
tion of the two. In these experiments, the vestibular
stimulation is generated by actually moving mon-
keys on motion platforms while recording their
brain activity (note that the velocities and accelera-
tions that can be used with platforms is well below
the rapid speeds (up to 8G) at which monkeys can
move their heads voluntarily (Carriot et al., 2017)).
The visual stimulation used is optic flow, simulat-
ing what might be seen when moving through a
simple visual scene consisting of a cloud of dots.
This reveals a multimodal network of areas which
may function to determine the direction in which
motion is toward, referred to as “heading.” Areas
PIVC, VIP, and MSTd have received particular
scrutiny, and may follow a serial hierarchical rela-
tionship (Chen et al., 2016). In PIVC, vestibular
neuronal responses are most prominent, and this
area has therefore been highlighted as a key hub in
the monkey: PIVC shows strong connectivity with
vestibular subcortical nuclei. VIP shows an inter-
mediate mix of vestibular and visual responses,
and a closer association than MSTd with the
reported judgement of the monkey: including after
re-learning of visual-vestibular correspondences, if
a constant discrepancy is introduced between the
heading conveyed by vestibular and visual stimuli
(Zaidel et al., 2021). MSTd has the greatest degree
of visual responses (by contrast in MT vestibular
responses are absent). MSTd also shows a particu-
larly high proportion of neurons where the direc-
tion tuning for vestibular and visual tuning are
opposite, thereby representing the combination of
multimodal stimulation that would occur normally
(e.g., if the head tilts clockwise, the retinal image
tilts counter-clockwise; Takahashi et al., 2007).
355
The same serial order exists for which areas show
the earliest responses to vestibular translational
stimulation (Chen et al., 2011). Lesion studies indi-
cate that the cortical network for heading is distrib-
uted. Lesions in MSTd (Gu et al., 2012) alone do
not drastically impair vestibular heading percep-
tion, nor integrating visual and vestibular cues, but
do impair visual heading. VIP lesions affect nei-
ther visual nor vestibular heading, whereas PIVC
lesions affect both (Chen et al., 2016).
This corpus of work has also supported more
general models of how information is processed in
the brain. Studies of Bayes-optimal cue integration
test statistically optimal or ideal observer models:
the idea is that if information from one modal-
ity (say, vestibular) becomes more or less reli-
able during an experiment, its signal is weighted
accordingly (Fetsch et al., 2013). Human partici-
pants weight vestibular information more or less
during multisensory judgments depending on the
coherence of the visual motion (ter Horst et al.,
2015).
Imaging the Human Cortical
Vestibular Network During Vestibular
Stimulation
The spatial resolution and compatibility with
motion platforms make single-cell recordings
from monkeys an extremely important resource
for the student of the human vestibular system.
Some ingenious experiments have been devised to
be compatible with human participants. Various
methods allow stimulating the vestibular organs
peripherally while people are lying inside an MRI
scanner (Ertl and Boegle, 2019), and the mecha-
nism underlying each of these methods also illu-
minates our understanding of vestibular function.
In caloric irrigation a continuous stream of warm
or cold water is squirted into the left or right ear
(and caught below in a dish). This indirectly leads
to unilateral activation of the peripheral vestibular
system, and enables manipulating the left or right
inner ear independently of the other (unlike during
real motion). Robert Bárány in 1906 proposed the
underlying mechanism was that a change in tem-
perature across the labyrinth produced convection
currents in the endolymph. However, this cannot
explain why caloric irrigation still had effects on
two astronauts under the zero gravity of the
European Spacelab 1 mission (in 1983), and so
other non-convective explanations have been pro-
posed, such as changing the endolymph volume or
thermally activating the vestibular nerve (Scherer
and Clarke, 1985). In any case, caloric irrigation
356 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
can lead to a vestibular sensation as if rotating
(vertigo), and even nausea. Caloric irrigation is
also used clinically for testing the VOR which it
triggers, and the direction of the nystagmus it
causes flips direction depending on both the side
stimulated (left/ right) and the water temperature
(hot/cold).
The ability to use transcranial current stimula-
tion to stimulate the vestibular system was acci-
dentally discovered (although not understood) at
least by the nineteenth century (Purkinje, 1820).
Contemporary galvanic vestibular stimulation
(GVS) in the human passes a current through the
head between an anode and cathode, at least one
of which is placed over a mastoid. The clinical use
to diagnose which side is impaired (using unilat-
eral montages) is not routine, due to high interindi-
vidual variability and low selectivity (Dlugaiczyk
and Straka, 2019). In order to increase the effects,
smaller electrodes and higher intensities than in
conventional tCS are usually used (Nitsche and
Paulus, 2000), with settings of the order of 1–5 mA
(and 9 V). GVS likely directly activates both hair
cells and the vestibular nerve, on the basis of inva-
sive GVS in the tadpole (Gensberger et al., 2016).
As with tCS, different temporal profiles of stimu-
lation can easily be applied, and the precise sen-
sation of rotation, and pattern of eye movements
caused are variable not only with electrode loca-
tion but also across participants.
Brief and extremely loud sounds can also stim-
ulate the vestibular organs, as shown by measur-
ing the reflexive peripheral muscular contractions
brought out by the reflex arcs triggered (Halmagyi
et al., 2005). Note then that these three main meth-
ods for stimulating the vestibular system during
imaging vary in which of the vestibular organs are
stimulated. Nonetheless two main messages come
from meta-analyses of imaging studies using
these methods for vestibular stimulation (Lopez
et al., 2012). Firstly, there is a particularly promi-
nent activation in the deep areas within the lateral
fissure, where the temporal lobe meets the rest
of cortex (i.e., the territory of the insula and the
parietal and temporal opercula). Although some
descriptions tend to collapse across these, there is
clear heterogeneity and within these, OP2 may be
a key area (zu Eulenburg et al., 2012).
Converging evidence suggests that here or
within these deep regions may be a human homo-
logue of the monkey region PIVC, although con-
sensus is lacking in the field of exactly which
brain region in the human corresponds the best
(Pfeiffer et al., 2014). This area shows strong
functional connectivity with a core inner circle of
vestibular regions, including area 3a, other areas
around the lateral fissure, and an area near motion
visual cortex (zu Eulenburg et al., 2012): this is
similar to the PIVC connectivity reported origi-
nally in the monkey (Guldin and Grüsser, 1998).
Secondly, in addition to this region, a widespread
network is activated, including: on the midline a
medial part of posterior parietal cortex and of the
anterior cingulate, a ventral part of inferior pari-
etal cortex and the superior temporal gyrus; and
the frontal eye fields – and some of these activa-
tions are specific to particular forms of vestibular
stimulation (Lopez et al., 2012), and this remains
a conservative list to be combined with other
converging sources of data. In generative mod-
els such as predictive coding (Rao and Ballard,
1999) higher levels are considered to represent the
expected percept, and an error signal is sent up to
higher levels only in the event of a breach of that
expectation in comparison to the incoming sen-
sory signals from lower levels. According to this
interpretation, the neural activity caused by artifi-
cial vestibular stimulation includes the prediction
error caused by the absence of the other expected
sensory inputs (Klingner et al., 2016).
Newer methods for vestibular stimulation are
available. Strikingly, it has been demonstrated
that the static magnetic field of an MRI scanner
is capable of stimulating the vestibular system. A
nystagmus apparently caused by the magnetic field
is absent in patients with a bilateral labyrinthec-
tomy, and beats in different directions depending
on whether people are lying in the scanner head
first or feet first. The mechanism suggested is via
the static magnetic field interacting with the ion-
rich endolymphatic fluid to produce movement of
the fluid inside the canals through ionic currents
(“Lorentz forces”) (Roberts et al., 2011).
Vestibular Information for
Multisensory Guidance of Action
Some form of vestibular representation is then
combined with information arising from other
senses, often visual, for the control of movement,
whether of the eyes, limbs or body. If a constant
velocity rotation is suddenly braked, the mechan-
ics of the semicircular canals mean they continue
to send a signal indicating self-motion for some
time: this produces an illusory tilt and an altered
VOR, implying the presence of an internal model
of gravity (Merfeld et al., 1999). Patients with
vestibular sensory loss show problems with both
postural control and visual stability (Curthoys and
Halmagyi, 1995). Vestibular integration for the
sensorimotor control of action depends on the
context (Medendorp and Selen, 2017). For exam-
ple, to reach toward something while you are
moving requires incorporating vestibular signals
 Vestibular Processing in Cognition
to adjust and adapt to the various forces arising
(Lackner and DiZio, 2005). GVS that simulates
movement to one side also biases hand trajectories
to the other side during reaching (Bresciani et al.,
2002).
Visual and vestibular processing interact: per-
ception of self-motion relies above all on these
senses yet is impossible with either sense alone
(Noel and Angelaki, 2022). Being accelerated to
the left or right on a platform biases which of two
laterally presented visual stimuli are perceived to
have been presented first (Rincon-Gonzalez et al.,
2016). Although people can estimate distance
traveled from optic flow alone, the vestibular (plus
somatosensory) cues from real motion appear
to dominate when both are presented together
(Harris et al., 2000). Adaptation to optic flow
biases the reported vestibular perception when
moved on a moving platform afterward, as if ves-
tibular processing has been recalibrated (Cuturi
and MacNeilage, 2014).
Accordingly, acute vestibular loss is one cause
of oscillopsia, where the mechanisms for visual
stability via the VOR are compromised and so
the visual scene is seen to move when the eyes
do (Rinne et al., 1998). Such oscillopsia recovers
over time, and this may reflect central compensa-
tion: changes in downstream neural excitability in
such patients are also apparent as the raised thresh-
olds for inducing phosphenes with TMS (Ahmad
et al., 2017). Such patients show decreased rest-
ing-state functional connectivity in the insula/
opercular cortex, but interestingly those patients
whose VOR recovered the best showed increased
connectivity between cerebellum and part of the
posterior parietal cortex around the supramarginal
gyrus (Göttlich et al., 2014). FEF TMS improved
visual acuity in normals in a model of oscillopsia
using optokinetic nystagmus (Mastropasqua et al.,
2020). The unusual involvement of these more
dorsal areas is a theme that recurs below.
Multimodal Representation of
Verticality
A large network of areas has been associated with
pathological tilt when participants are asked to
gauge whether a line presented in front of them is
vertical or tilted to one side. Although areas
around the deep insular/opercular region do show
a correlation with the subjective visual vertical
(SVV), implicated lesions clearly extend frontally,
and parietally all the way up to the intraparietal
sulcus (Rousseaux et al., 2013). Transcranial
direct current stimulation to the posterior right
hemisphere shifts the SVV in normals (Santos
357
et al., 2018). TMS to the ventral parietal cortex
increases SVV errors (Fiori et al., 2015), and if the
head is tilted in one direction, errors are shifted in
the other (Kheradmand et al., 2015). TMS more
dorsally, to the intraparietal sulcus, improves SVV
performance in normals (Willacker et al., 2019).
Furthermore, through online ERP recording it
could be shown that TMS also reduced the normal
inter-individual variability in frontal neural pro-
cessing. In contrast, dorsal medial frontal TMS
reduces the intra-individual variability in the SVV
in normals, increasing precision of perceptual
decision making (Willacker et al., 2020). Within-
subject SVV variability is also increased in
patients with somatosensory loss (Barra et al.,
2010). The SVV is shifted if a visual background
rotates or if GVS is applied – and the effects of
these two summate linearly (Niehof et al., 2019).
The SVV then reflects how verticality per-
ception, and vestibular processing more widely,
employ a wide variety of areas and can use a
range of different modalities and types of infor-
mation. The network includes the “core” regions
around the insula, but converging data implicates
other areas including members of the dorsal vis-
ual attentional network (Corbetta and Shulman,
2011), such as the intraparietal sulcus, frontal eye
field, and dorsomedial frontal cortex. For example,
the potential human VIP homologue also shows
responses in fMRI to vision, touch, and audition
(Bremmer et al., 2001). TMS to similar regions
also affects other types of multimodal judgments
(Konen and Haggard, 2014) and postural control
(Kaulmann et al., 2017). Human VIP is activated
in tasks requiring dissociating between simulated
self- and object-motion (Field et al., 2020). More
generally, parietal cortex can represent posture in
freely foraging rats (Mimica et al., 2018) and may
integrate self-motion and visual input to form an
input to the hippocampal formation for naviga-
tion (Nau et al., 2018). The frontal eye fields also
contain neurons in the macaque with a functional
profile supporting visual-vestibular integration
(Gu et al., 2016). FEF TMS not only affects neu-
ral activity during visual attentional tasks (Taylor
et al., 2007) but can also elicit neck muscle activa-
tions as if triggering an orienting response via a
head movement (Goonetilleke et al., 2011).
Representation of the Body in Space
Vestibular processing then has a role in the transfor-
mation of information between reference frames,
the prediction of the sensory consequences of
movement, and incorporation of intentional signals:
these are also considered fundamental components
358 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
of attentional selection, spatial cognition, and the
control of voluntary movement. Contrary to subjec-
tive experience, it has been hard to find a consensus
definition of attention (Nobre and Kastner, 2014):
although some abandon it as a useful concept
(Hommel et al., 2019), another approach is to con-
sider the prioritization of particular information
processing as a function that only seems bafflingly
general because it can apply to many stages of pro-
cessing, from perception to action (Luo and
Maunsell, 2019). Disrupting vestibular processing
can affect an egocentric representation used to
guide action. Three neglect patients showed judg-
ments of straight-ahead that were skewed abnor-
mally to the right, consistent with their neglect, but
this was transiently restored after (cold) caloric
irrigation of the left ear (Karnath, 1994). GVS dis-
torts the reported perception of straight-ahead in
normals, an effect that still occurs with crossed
hands, and could not be attributed to effects of GVS
on gaze direction (Abekawa et al., 2018). Voxel-
based lesion symptom mapping in stroke patients
correlates a deviation in straight-ahead with damage
to a large strip of anterior parietal cortex running
from dorsal to ventral, whereas postural problems
were associated with the tissue around the insula
and parietal operculum (Rousseaux et al., 2013).
Recent work is exploring the role of vestibular
processing in other forms of body representation
(Ferrè et al., 2013). One patient suffering acute
vestibular loss, John Crawford (Harvard biolo-
gist and physician), wrote an evocative account
in 1952 of his own subjective experience. In addi-
tion to impaired balance, nausea, and oscillopsia,
he reported that if when moving in bed he closed
his eyes (to prevent dizziness), he would have the
bizarre illusion that the bed itself was flipping
over on its side around him (cf. Memorial, 2005).
Caloric irrigation increased the perceived size
of participants’ own hands, or of objects touch-
ing their hands (Lopez et al., 2012). Deep brain
stimulation around the ventral part of the pari-
etal produced interesting reported experiences in
a patient: weak stimulation produced vestibular
sensation (as had been reported in various areas
by Wilder Penfield in 1957), but high intensity
stimulation lead to an out-of-body experience
where the patient reported seeing part of her body
from above (Blanke et al., 2002). Although such
experiences also have been reported in the normal
population, they are nearly three times as likely
in patients suffering from dizziness (Lopez and
Elzière, 2018).
Effects of GVS are increasingly being tested for
in other domains. Performance at a visual spatial
memory task is improved if the targets were previ-
ously presented during GVS (Smith et al., 2020).
The classification of whether a participant is thinking
“yes” or “no” on the basis of EEG is improved if
those thoughts were previously conditioned with
GVS (Yoshimura et al., 2021). Establishing how
vestibular stimulation, including GVS, may have
effects will require future studies to control for
the accompanying non-specific sensations arising
directly from stimulation (Lopez, 2016) as well as
any indirect effects via eye movements or dizziness
and, as with tCS, demonstrating statistical differ-
ences from direct comparison to identical stimula-
tion of a control site (Parkin et al., 2015).
Visually Induced Vestibular Subjective
Experiences
It is possible to elicit a strong vestibular percept of
self-motion by looking at a visual stimulus simu-
lating what one would see if one was moving, even
with simple rotating patterns (reported by Ernst
Mach in 1875). Such “vection” is sometimes per-
ceived by rail passengers who may feel the illusion
that their stationary train is moving, if they see a
neighbouring train pulling away. In one extreme
case, participants sat still in a small furnished
room, which could rotate fully around them, and
perceived themselves to be performing full 360-
degree flipping (Allison et al., 1999): vection was
much weaker if the field of view was restricted
(a potential limitation for some fMRI and virtual
reality setups). Vection is if anything increased
during microgravity (Cheung et al., 1990) or while
underwater (Fauville et al., 2021), when there are
fewer other somatosensory and proprioceptive cues
available to signify that the visual stimulation is
incorrect. Vection can arise from other modalities
and is sensitive to a wide range of stimulus proper-
ties and cognitive factors (Palmisano et al., 2015).
fMRI studies presenting participants with rela-
tively large-field optic flow report BOLD changes
in several areas (Berti and Keshavarz, 2020),
including not only potential human homologues of
the vestibular areas mentioned above, MST, VIP
and PIVC, but also V6 and CSv. Neural correlates
of vection have been reported in the alpha band
with EEG, for example by using sophisticated
measures such as event-related spectral perturba-
tions (Palmisano et al., 2016) or steady-state
evoked potentials (Dowsett et al., 2020). A similar
EEG signature has been found during studies of
real motion to reflect the remapping of visual space
(Gutteling et al., 2015), or to be inhibited in
patients with vestibular loss (Gale et al., 2016).
The alpha band event-related desynchronization
evoked by optic flow, and that is related to postural
sway and vection, can be reduced by top-down
expectation (Obereisenbuchner et al., 2021).
 Vestibular Processing in Cognition
Dizziness and sickness can of course be evoked
by stimulating the vestibular system (e.g. spinning
with eyes closed). There is also a class of visual
stimuli beyond optic flow which make viewers
feel unwell, such as intense dazzling light, or some
flicker (Morgan et al., 2020). However, a feeling
of nausea is precipitated if visual and vestibular
inputs conflict e.g. visually induced motion sick-
ness (VIMS). This can of course be one compo-
nent of the sickness felt during vehicular transport,
but is also reported during computer games, flight
simulators or virtual reality (“gaming sickness,
“simulator sickness,” “cybersickness”), or many
of the situations in which vection can be triggered.
The evolutionary function and neural mechanisms
underlying motion sickness and VIMS are unclear
(Lackner, 2014). In the study of nausea and vom-
iting, lesion studies in anaesthetized cats suggest
causal roles for the cerebellum and its interac-
tions with the vestibular nucleus plus other brain
stem nuclei, the area postrema, lateral tegmental
field, medial medullary reticular formation, and
nucleus tractus solitarius (NTS), parabrachial
nuclei, and the ventral respiratory group. Some of
these areas project onto respiratory motor neurons
(co-contraction of which produces emesis), others
to the hypothalamus and limbic system, others to
the cerebellum. Importantly for clinical models,
the lab rat and mouse cannot vomit, which may
be a feature of all rodents, who lack not only some
brainstem structures but also bear important dif-
ferences in the musculature of the abdomen (Horn
et al., 2013). In general, cross-species comparisons
can delineate general principles underlying ves-
tibular processing, both when convergent mecha-
nisms arise, and if they differ due to a species’
particular lifestyle and niche (Straka et al., 2016).
Although visually induced motion sickness is
reduced in patients with bilateral labyrinthecto-
mies, it is in some cases not abolished (Johnson
et al., 1999). Congenitally blind individuals can
get motion sickness, just as the sighted can.
Skylab astronauts in zero gravity no longer felt
sick during a complex rotation paradigm, as they
did on Earth. They were tested several days into
the mission, after which any initial space-sick-
ness symptoms had improved through adaptation
or pharmacological treatment. Motion sickness
is blocked with lesions encompassing both area
postrema and NTS (Borison and Borison, 1986).
Activity in many of the brain stem nuclei for
vomiting also correlate with motion sickness:
nausea and vomiting may then be functions
of the same pathways, although the role of the
many other neural areas responding to vestibular-
vestibular integration in triggering these is under-
explored (Yates et al., 2014).
359
The literature is mixed as to whether there is
a correlation between these two subjective flow-
induced phenomena, vection, and VIMS (Nooij
et al., 2017), or not (Golding et al., 2021). This
may depend greatly on factors such as the precise
stimuli used, type of response, and sample size.
In one study (Obereisenbuchner et al., 2021),
the degree of vection correlated with the VIMS.
However, there was also clear heterogeneity
within the group whereby many people reported
vection without any VIMS, although no-one felt
sick without reporting vection.
Moving the immediate visual surroundings
forward or backward induces postural sway. The
visual stimulation indicates to participants that
they are falling over, triggering compensation
for the (erroneously) expected shift in momen-
tum. Visually evoked sway can be reduced by
top-down control, if the optic flow is self-initi-
ated (Obereisenbuchner et al., 2021). Vestibular
patients are abnormally sensitive to sway-induc-
ing optic flow, showing higher magnitude sway
(Redfern and Furman, 1994). Such visual depend-
ency may lead to visually induced sensations of
sway or dizziness in busy visual environments
after other aspects of the vestibular disorder have
recovered (visual vertigo), associated with devia-
tions of the reported vertical (Guerraz et al., 2001).
A functional (i.e., “psychogenic”) vestibular syn-
drome is now called persistent postural perceptual
dizziness (PPPD), encompassing previously used
terminology (Staab et al., 2017).
Treatments for dizziness depend on the specific
causal disorder. During episodes of benign parox-
ysmal positioning vertigo (BPPV), for example,
particles of otoconia become detached, and floating
freely, lead to vestibular stimulation. Consequent
bouts of dizziness can be exceptionally strong,
but in some cases are resolved by performing a
sequence of whole-body jerks to physically shake
the otolithic material away (Mandala et al., 2019).
There are several types of physical vestibular reha-
bilitation which are robust treatments for several
causes of dizziness. Nevertheless, future strate-
gies for treating vestibular disorders will need to
be geared toward the individual patient (Pavlou,
2017), and there is a need to develop other treat-
ment approaches involving pharmacology, genetic
screening, vestibular implants, and the use of vir-
tual reality.
SUMMARY AND CONCLUSIONS
Within the walls of the skull lie the vestibular
organs, mechanically tuned to detect specific head
360 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
movements. Although omitted from Aristotle’s list
of five classic senses, there is a now extensive lit-
erature on the functions of the vestibular system.
This chapter focuses on aspects of vestibular pro-
cessing relevant to cognitive neuroscience. Many
fundamental principles delineating vestibular cog-
nition are inherited from the make-up of sensory
transduction onward. A full account of the pro-
cesses underlying how vestibular cognition
occurs, and how this relates to initial vestibular
processing stages, requires synthesizing the key
principles of early vestibular processing. Even the
simplest reflex-like vestibular functions, such as
compensatory eye movements or postural correc-
tion, are relevant for cognition. Vestibular sensory
processing is deeply intertwined with the motor
system. Furthermore, throughout the vestibular
network and from the earliest stages there is an
extraordinary degree of multisensory interaction
(to the extent that stimuli in other modalities can
elicit vestibular sensations). Incorporating these
three principles of vestibular function – reflex,
motor, multisensory – sets the stage for the contri-
bution of this system to more abstract functions
such as the representation of egocentric space,
navigation, and the bodily self. In this way
research into the role of vestibular processing in
cognition spans fields ranging from sport science
to space science, and from the clinical to the
philosophical.
Every sense has its own peculiar proper-
ties and phenomena. What principles dictate the
functioning of the vestibular system? First is the
direct relationship to action, including both rapid
reflexes and voluntary motor control. Second is
the segregation into four main separable ascend-
ing systems for i) postural stabilization; ii) gaze
stabilization; iii) an anterior thalamo-cortical path-
way leading to the head cell network and medial
temporal structures; and iv) a posterior thalamo-
cortical pathway leading to vestibular cortical
areas and which is itself further divisible (Cullen,
2019; Noel and Angelaki, 2022). Third is the high
and early degree of integration with other senses,
indicating how these different paths may modu-
late one another and have widespread feedforward
feedback effects (Brooks and Cullen, 2019), and
meaning that vestibular perception can be modu-
lated or even triggered by stimulation in other
modalities. Integration of different types of infor-
mation beyond the purely vestibular is required to
appreciate at least some crucial aspects of vestibu-
lar function. This leads us to the fourth principle,
the profound relationship between supposedly
non-cognitive and cognitive processes (Firestone
and Scholl, 2016). The best way to frame the dif-
ferent types of more or less cognitive vestibular
processing has also not yet reached a consensus,
with some highlighting the differences between
more reflexive processing versus more abstract
spatial cognition (Ferrè and Haggard, 2020), and
others emphasizing how cognition can modulate
the earliest stages of processing (Cullen and Wang,
2020). Vestibular cognition needs to be considered
conceptually (Garzorz and Deroy, 2020) and in
the context of many other systems, functions, and
principles mentioned in this book.
ACKNOWLEDGMENTS
The author is grateful to Madeleine Seitz for the
illustrations.
Funded by the DFG (TA 857/3-2).
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Somatosensory Processing
J o n H . K a a s , L e a h A . K r u b i t z e r, H u i - X i n Q i ,
INTRODUCTION
This review focuses on somatosensory processing
of tactile information from the hand in primates.
Much of this review is based on studies in mon-
keys, and to some extent humans (Figure 23.1).
Most of the sensory information from the gla-
brous hand, which is an especially important
tactile organ, comes from two classes of affer-
ents and their receptors, the rapidly adapting
type 1 (RA1) and the slowly adapting type 1
(SA1) afferents. Other afferents and their recep-
tors, RA2 and SA2, also subserve the glabrous
hand, and receptors around the base of hairs in
the hairy skin provide additional tactile infor-
mation. These afferents from the hand branch as
they enter the spinal cord to travel in the dorsal
column pathway to the cuneate nucleus or ter-
minate on neurons in the dorsal horn of the
spinal cord that provide second-order input to
the cuneate nucleus at the brainstem-spinal cord
junction. Neurons in the cuneate nucleus have
axons that cross to the contralateral side of the
brainstem, where they terminate in the ven-
troposterior nucleus (VP) of the somatosensory
thalamus. Neurons in VP then project to the
hand representation of the primary somatosen-
sory cortex (S1, Brodmann’s Area 3b; see
23
and Jamie L. Reed
Garey, 1994) and also project to layer 3 of the
hand representation of adjoining Area 1. These
two cortical areas then contribute tactile infor-
mation to an array of higher-order somatosen-
sory areas, including Brodmann’s Area 2, the
second somatosensory area (S2), the parietal
ventral area (PV), and the ventral somatosen-
sory areas (VSr and VSc). This network expands
to include areas of insular cortex, posterior
parietal cortex, and premotor and motor cortex.
Feedback connections at all levels add to this
complex network of interconnections.
While tactile afferents from the hand are
very important in humans and other primates
(Mountcastle, 2005), tactile afferents from other
parts of the body form similar projection pat-
terns in parallel with those for the hand to com-
plete the representation of the body surface in
multiple subcortical and cortical representations
of receptors from the skin of the contralateral
body. In addition, at least some of these nuclei
and areas contain representations of both the
contralateral and ipsilateral tongue and teeth.
The pathways from face and oral structures
are somewhat different than those described
for the body. The processed information from
peripheral receptors allows humans and other
primates to identify objects by touch and use
366 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
this information to guide and control sensori-
motor behavior. Other mammals have similar
somatosensory systems, but often with some-
what different specializations related to spe-
cific behaviors and peripheral morphologies. In
addition, the number of cortical areas and the
complexity of cortical networks is often less
elaborate compared to primates. Our review
also briefly considers the systems for other
types of receptor-afferent inputs, such as those
for proprioception, pain, and temperature.
TACTILE RECEPTORS AND AFFERENTS
FROM THE GLABROUS SKIN AND
HAIRY SKIN
For all mammals, sensory inputs from the face,
lips, tongue, and teeth are highly important as
most mammals grasp food and prey directly with
the mouth and pre-process food by chewing.
Primates also use their hands to explore the envi-
ronment, and grasp food and bring it directly to
the mouth. Sensory hairs around the mouth are
less important in primates, and missing in humans.
Early studies of afferents from the hand in pri-
mates and humans have identified four types of
low-threshold mechanosensory receptors and
afferents (Johansson and Flannagan, 2008;
Johnson, 2001). The slowly adapting type I sen-
sory afferents (SA1) are activated by a number of
closely spaced Merkel cell receptors located in the
superficial skin. These afferents are responsive to
light touch on the skin, and continue to respond
during a maintained contact or skin indentation.
Merkel cells are most dense in the glabrous skin
of the fingertips. Thus, SA1 afferents are impor-
tant for identifying object form and texture.
The rapidly adapting type I (RA1) afferents
rapidly adapt to light touch and skin indentation,
and are most important for signaling change as a
result of stimulus movement, as well as signaling a
series of repeated taps in the low frequency range
of flutter. RA1 afferents have the smallest recep-
tive fields, and can signal the details of stimulus
form. The receptors of RA1 afferents are Meissner
corpuscles, which are most densely packed in the
skin of the finger tips. Most Meissner corpuscles
are innervated by more than one axon, and each
axon innervates a tight group of corpuscles. The
SA1 and RA1 afferents make up the vast majority
of tactile afferents from the hands.
The slowly adapting type 2 afferents from the
hand innervate encapsulated Ruffini-like cor-
puscles that are deeper in the skin, and are also
found in ligaments and tendons of the hand and
elsewhere. Movement of the skin stretches the
corpuscles and activates the SA2 afferents. The
afferents have large receptive fields with uncer-
tain borders. SA2 afferents signal the direction of
strain and stress of the skin, and likely have a role
in proprioception and motor control. Contributions
to tactile sensations, if any, are unknown.
The rapidly adapting type 2 afferents (RA2)
innervate Pacinian corpuscles deeper in the skin.
The layers of the Pacinian corpuscles filter out
slow changes in pressure on the corpuscle, while
the corpuscle transmits rapid compressions pro-
duced by high frequency vibrations to the axon in
the core of the corpuscle. The Pacinian corpuscles
are found elsewhere on the body, and in deep tis-
sue. Distant vibrations conducted via a hard sur-
face such as a table or floor to the hand or foot can
be detected, and provide useful information. The
receptive fields of Pacinian corpuscle afferents are
hard to define, as vibrations may extend through
body tissue, and the sources of vibrations may be
distant from of the body.
Other somatosensory afferents stem from the
base of sensory hairs, and from receptors near
hairs (Bolanowski et al., 1994). Merkel cell slowly
adapting receptors are found both in hair folli-
cles and touch domes on the hairy skin. Rapidly
adapting afferents also innervate hair follicles
and adjoining skin. The long sensory vibrissae
or whiskers found on the face of mice and rats,
as well as many other mammals, can be actively
moved to explore and detect objects near the face.
For example, rats can use their extra-large macro
vibrissae to discriminate shapes, texture and the
locations of objects near their face (Diamond and
Arabzadeh, 2013; Diamond et al., 2008). The pri-
mary afferents for touch on the face and mouth
form the trigeminal nerve which enters the pons
of the brainstem where the afferents branch and
terminate in the nuclei of the trigeminal complex.
The principal nucleus of this complex receives
RA1 and SA1 afferent inputs, and neurons in the
principal nucleus project to the contralateral ven-
troposterior medial nucleus to join those from the
dorsal column nuclei from the lower body (Ebner
and Kaas, 2015). The neurons in VP project
densely to primary somatosensory cortex (S1),
which corresponds to Area 3b of Brodmann in
primates (Kaas, 1983). Other terminations of VP
are in the second somatosensory area, S2, of most
mammals, and in Area 1 of primates.
Other afferents that have been related to touch
are the wide-dynamic range afferents that respond
to increasing pressure on the skin into the range
of pain. These afferents terminate on neurons in
the dorsal horn of the spinal cord and axons from
these neurons project contralaterally to form the
spinothalamic pathway that terminates in the
ventroposterior inferior nucleus (VPI). The VPI
 Somatosensory Processing
neurons project to the superficial layers of primary
somatosensory cortex (S1) or Area 3b, and in some
mammals, other cortical areas including S2 and PV.
Proprioceptive afferents from muscle spin-
dles, which signal muscle length, provide criti-
cally important proprioceptive inputs through the
dorsal column-medial lemniscal pathway to the
ventroposterior superior nucleus, VPS. Thus,
the ability to perceive joint position survives
after joint removal and replacement in humans.
However, Ruffini type receptors in joints and
other deep tissues also contribute to the sense of
joint position. Unmyelinated, slowly conducting
afferents and thinly myelinated, moderately con-
ducting afferents signal slow and fast pain, and
other afferents signal temperature (Craig, 2015).
Thin, slowly conducting afferents from the hairy
skin appear to signal pleasant (affiliative) touch
(Keysers et al., 2010), and project to dorsal horn
neurons that in turn project to the contralateral
somatosensory thalamus via the spinothalamic
tract. Thalamic projections are to the insular
cortex (Olausson et al., 2002).
AFFERENT PATHWAYS AND
TARGET NUCLEI
Peripheral nerves contain a mixture of several
afferents of different types, and motor axons that
travel to the muscles. The cell bodies of sensory
afferents are in the dorsal root ganglia. The inputs
to each of the dorsal roots are from receptors in
strips of skin, the dermatomes, that form the rough
somatotopic sequence from tail to face (e.g.,
Pubols and Pubols, 1969). The tactile afferents
from the arm and hand enter at the cervical level
of the spinal cord and branch to ascend in the
dorsal columns to terminate in the cuneate nucleus
near the spinal cord – brainstem junction
(Figure 23.1). The other branches terminate on
second-order sensory neurons in the dorsal horn
of the spinal cord at the same level. The axons
from the second-order tactile neurons of the spinal
cord mainly join the cuneate fasciculus, but some
travel to the cuneate nucleus via a lateral fascicu-
lus (Liao et al., 2015). Thus, the cuneate nucleus
gets primary afferents from the arm and hand, and
much of the same information from secondary
neurons in the dorsal horn of the spinal cord. The
primary afferents terminate in a very precise
somatotopic pattern in the cuneate nucleus so that
the digits and pads of the hand are represented
separately in somewhat reliable species specific
somatotopic patterns (Florence et al., 1989). The
inputs from the dorsal horn neurons appear to
conform to this somatotopic pattern, with perhaps
367
less precision. Surprisingly, some of these second-
ary dorsal horn neurons project to the contralateral
cuneate nucleus (Liao et al., 2015), possibly con-
tributing to the inhibitory receptive field sur-
rounds of relay neurons in the cuneate nucleus.
Overall, the contributions of the second-order
afferents to the receptive fields of cuneate neurons
are not well understood, but such inputs are
thought to modulate the responses of cuneate
relay neurons to the driving inputs of the primary
afferents (Liao et al., 2018).
The main activating inputs to the central core of
the cuneate nucleus in primates are from the RA1
and SA1 afferents from the glabrous hand. Recent
electrophysiological recordings indicate that the
responding neurons typically receive activating
inputs from both RA1 and SA1 afferents (Suresh
et al., 2021), although one type or the other may
dominate. The cuneate nucleus also receives
feedback connections mainly from the hand rep-
resentations in S1 (Area 3b) and other areas of
somatosensory cortex (Liao et al., 2021). These
inputs also seem to be mainly suppressive by acti-
vating inhibitory neurons (Conner et al., 2021).
Tactile afferents from the lower trunk and leg
enter the spinal cord at lower levels, and join the
dorsal column pathway and synapse in the grac-
ile nucleus, medial and adjacent to the cuneate
nucleus (Qi and Kaas, 2006). These axons also
have a branch that terminates on dorsal horn neu-
rons that provide a secondary input to the gracile
nucleus. Primary afferents for touch on the face
travel in the trigeminal nerve to enter the brain-
stem and branch to terminate in the principal divi-
sion of the trigeminal nucleus, analogous to the
gracile and cuneate nuclei, and in the spinal divi-
sion of the trigeminal nucleus, analogous in part to
the dorsal horn of the spinal cord. Relay neurons
in the gracile, cuneate, and principal trigeminal
nuclei project contralaterally to the ventropos-
terior nucleus, which contains a detailed repre-
sentation of the contralateral body surface and
projects densely to the primary somatosensory
area (Area 3b) and less so to Area 1.
Damage to the primary afferents in the cune-
ate dorsal columns at a high cervical level greatly
impairs the use of the ipsilateral hand to the extent
that touch on the hand is not felt. However, if a
few primary afferents from the hand survive, hand
use and the sense of touch on the hand recovers
to the extent that nearly normal hand use returns
(Qi et al., 2021).
Inputs from proprioceptive afferents, such as
muscle spindle, tendon, and joint afferents form
pathways to higher centers that are separate from
those for tactile afferents. The cuneate dorsal col-
umn complex has separate nuclei for muscle spin-
dle and other proprioceptive afferents. Those for
the arm terminate in the external cuneate nucleus,
368 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 23.1 Levels of processing in the somatosensory systems of anthropoid primates

Tactile afferents from the hands project to the ipsilateral cuneate nucleus (Cu) at the junction
of the spinal cord and brainstem (arrows). These direct projections are joined by those from
second-order neurons in the dorsal horn of the spinal cord. The cuneate nucleus neurons
then project to the contralateral ventroposterior nucleus (VP) of the thalamus. VP projects to
layer 4 of cortical Area 3b (S1 of somatosensory cortex), and less densely to layer 3 of Area 1.
Area 3b projects to Areas 3a, 1, 2, the second somatosensory area (S2), and the parietal ventral
area PV. These areas provide feedback connections to Area 3b (S1). The hand representation in
Area 3b has few callosal connections, but such connections exist between 3a, 1, 2, S2, and PV.
The cortical connections of areas S2 and PV include posterior parietal cortex and frontal motor
cortex. Somatosensory cortex also projects back to VP and Cu. See text for details.

travel in the gracile dorsal columns at lower lev-
els, but then leave to terminate in Clarke’s nucleus
in the intermediate zone of the spinal cord. Many
of the neurons in Clarke’s nucleus project to the
cerebellum or project directly to the contralateral
thalamus, where they terminate dorsal to the ven-
troposterior nucleus. While these projections are
often described as in a dorsorostral part of the
ventroposterior nucleus, in primates this target
is widely recognized as a separate ventroposte-
rior superior nucleus (VPS) that caps the tactile
ventroposterior nucleus (VP). VPS projects to
Area 3a and Area 2 of the anterior parietal cor-
tex, and the somatotopy of VPS mirrors that of VP
(Cusick et al., 1985; Padberg et al., 2009). Area
3a represents body muscles and other propriocep-
tive inputs in parallel to the tactile representation
in Area 3b. Area 2 combines tactile and proprio-
ceptive inputs in a representation that is in parallel
with the Area 1 representation.
SPINOTHALAMIC PATHWAYS
Other sensory inputs related to touch, pain, and
temperature enter the spinal cord or brainstem to
activate neurons in the dorsal horn or in brainstem
 Somatosensory Processing
nuclei that have axons that cross to the contralat-
eral side to join the lateral spinothalamic tract that
terminates in parts of the somatosensory thalamus
near and in the ventroposterior nucleus. In pri-
mates, one of the targets is identified as the ven-
troposterior inferior nucleus (VPI; Craig, 2006).
Some neurons in VPI and the septal regions of VP
are responsive to “wide-dynamic range,” tactile to
noxious stimuli. Neurons in VPI project to S1 and
more densely to higher-order somatosensory areas
such as S2, PV, and Area 1 (Coq et al., 2004;
Disbrow et al., 2002; Padberg et al., 2009;
Qi et al., 2002).
SOMATOSENSORY MIDBRAIN
For most vertebrates, the midbrain is the major
sensorimotor center for controlling behavior. The
visual midbrain, the superior colliculus (SC) of
mammals receives direct input from the retina,
and the inferior colliculus (IC) is a major auditory
relay center. Yet, the deeper layers of the SC and
the external nucleus of the IC receive ascending
somatosensory inputs from the trigeminal nuclei,
dorsal column nuclei, and somatosensory cortex
(see Kaas and Huerta (1988)), and these inputs are
likely important in the multisensory motor func-
tions of the midbrain. The deeper layers of the SC
are divided histologically into modular compart-
ments that express acetylcholinesterase (AChE) or
receive somatosensory inputs and express
parvalbumin (Illing, 1992).
SOMATOSENSORY THALAMUS
The most obvious somatosensory nucleus of the
thalamus is the ventroposterior nucleus (VP),
which traditionally has been divided into the ven-
troposterior lateral sub-nucleus (VPL) represent-
ing the body, and the ventroposterior medial
sub-nucleus (VPM) representing the face, mouth,
and head (Figure 23.2). Together, they form the
ventroposterior nucleus, VP. The activating inputs
are rapidly adapting and slowly adapting afferents
from the contralateral dorsal column nuclei, and
the trigeminal principal nucleus, respectively
(Kaas, 2008). VP represents tactile inputs from
the tail to the tongue in a lateromedial sequence.
Narrow cell poor septal bands separate the more
lateral representation of the foot from that of the
hand, and narrower septal areas separate represen-
tations of the toes and fingers from each other. A
wider septal band separates VPL from VPM.
Thus, much of the somatotopy of VP is obvious in
369
histological preparations. Somewhat surprisingly,
the tongue and teeth are represented twice in
VPM, one for inputs from the contralateral teeth
and tongue, as for the rest of the body, and again
for the ipsilateral teeth and tongue (Rausell and
Jones, 1991). These representations of the ipsilat-
eral mouth depend on ipsilateral projections from
the brainstem trigeminal nuclei. Neurons in VP
largely reflect a mixture of the RA1 and SA1
afferent inputs to the spinal cord and brainstem.
Individual neurons and clusters of neurons are
likely to reflect more or less of these two main
classes of peripheral afferents (Sur et al., 1984).
In all mammals, VP projects to primary soma-
tosensory cortex (S1 or Area 3b). In most studied
mammals, VP also projects to other areas such as
S2 and PV (Krubitzer and Kaas, 1987). In mon-
keys, and likely humans, VP projections to S2 and
PV are greatly reduced or absent (Krubitzer and
Kaas, 1992), while other projections include the
representations in Area 1, Area 2, and even most of
Area 5 (Padberg et al., 2009), areas not generally
recognized in non-primate mammals. VP receives
feedback connections from primary somatosen-
sory cortex, Area 3b, and from other somatosen-
sory areas (Area 1, Area 2, S2, PV).
Architectonically, the ventroposterior superior
nucleus, VPS, resembles VP in histological stains
for neurons, while VPI is quite distinct from VP as
a cell sparse region that is contiguous with the cell
sparse septa that separate the major body parts in
VP, which in primates are considered part of VPI,
rather than part of VP. However, both VPI and
VPS are histologically distinct from VP by having
less expression of cytochrome oxidase and more
expression of calbindin (Kaas et al., 2006). Unlike
neurons in VP which have extremely small recep-
tive fields, neurons in VPS and VPI have much
larger receptive fields and a less precise topography.
Two other somatosensory nuclei are important
parts of the somatosensory thalamus in primates
and other mammals. A nucleus on the medial mar-
gin of VPM, the parvocellular nucleus of VPM
(VPMpc, also called the basal ventral medial
nucleus, VMb), receives taste inputs, as well as
tactile inputs from the tongue, and projects to the
representation of the tongue in primary soma-
tosensory cortex as well as to gustatory cortex
(Iyengar et al., 2007; Kaas et al., 2006). In mon-
keys, Craig et al. (1984) identified a posterior ven-
tral medial nucleus (VMpo) just caudal to VPMpc
that receives nociceptive inputs from the spinotha-
lamic and trigeminothalamic ascending pathways
(Craig, 2006, 2015). VMpo is not distinct in non-
primates, and may be included in parts of VPI
and VP. Other relevant nuclei have not been well
established as “somatosensory” nuclei. The ante-
rior pulvinar (PLa), proposed for only primates, is
370 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 23.2 The three main somatosensory nuclei of thalamus in primates

The ventroposterior (VP) nucleus, shown here for its two subnuclei, VPL (ventroposterior
lateral) for the limbs, trunk and tail body, and VPM (ventral posterior medial) for the head,
face, and mouth. VP represents tactile inputs relayed from spinal cord and brainstem nuclei.
The ventroposterior inferior nucleus (VPI) receives a mixture of somatosensory inputs
from the second-order neurons in the contralateral spinal cord and brainstem. The ventral
posterior superior nucleus (VPS) receives inputs from contralateral neurons in the spinal
cord and brainstem nuclei that are activated by movement sensitive receptors and afferents
from muscles and joints that provide proprioceptive information. Both brain sections are in
the frontal (coronal) plane and are processed for the glutamate transporter type 2 (VGLUT2),
which is highly expressed in somatosensory nuclei and S1. A brain section is shown for a
squirrel monkey (A) and a macaque monkey (B). Notice that VP is darkly stained for both
primates. Unstained septal regions separate VPL from VPM, and further divide the two
subnuclei. In addition, VPS expresses less VGLUT2 than VP, and VPI expresses much less than
VP. The scale bar = 1 mm. Dorsal (D) is up, and lateral (L) is left. Rt is reticular nucleus of the
ventral thalamus.

a region of the thalamus with broad connections
with areas of somatosensory cortex. Neurons in
the PLa respond to cutaneous stimulation of the
contralateral body (Padberg et al., 2009; Sherman
and Guillery, 2006). The anterior pulvinar projects
to cortical regions of posterior parietal cortex that
have multisensory or somatosensory functions
(Gharbawie et al., 2010). In primates, the lateral
posterior nucleus, LP, has connections with pos-
terior parietal cortex (Jones, 2007; Padberg et al.,
2009), and thus is involved in somatosensory pro-
cessing. In non-primate mammals, LP is often
identified as the pulvinar or part of the pulvinar,
confusing comparisons with primates. In some
rodents and other mammals, part of the thalamus
just caudal to VP has been identified as the poste-
rior medial nucleus (POm; cf. Audette et al., 2018;
Ebner and Kaas, 2015), adding confusion by using
different terminologies for rodents and primates.
Somatosensory areas of cortex also project
back to somatosensory nuclei. These projections
are mainly from layer 6 neurons, but some layer
5 projections exist (Kaas, 2008). The cortical
projections from layer 6 largely appear to modu-
late thalamic neuron activity by activating local
thalamic inhibitory interneurons (Ergenzinger
et al., 1998), while layer 5 inputs are activating
excitatory neurons (Sherman and Guillery, 2006).
Cortical areas also project to brainstem and dorsal
column relay nuclei (Liao et al., 2021), where they
appear to activate local inhibitory neurons that
constrain receptive field sizes.
SOMATOSENSORY CORTEX
All mammals have cortex in which neurons
respond to somatosensory stimuli, and these
regions are divided into several cortical areas on
the basis of having separate representations of
 Somatosensory Processing 371

tactile and proprioceptive inputs from the contralat-
eral body surface. These separate representations
differ in their patterns of connections, and to vary-
ing extents in their cortical architecture. A primary
Area, S1, is basic to all mammals, but has been
modified in separate lines of mammalian evolu-
tion in various ways, most often in relation to
changes in peripheral morphology and sensory
receptor arrays on specialized body parts associ-
ated with ethologically relevant behaviors. Inputs
from the face and mouth are extremely important
relays in all mammals, and these inputs are repre-
sented by more cortical territory and more neu-
rons (cortical magnification). In highly dexterous
primates, there is also magnification of the inputs
from the glabrous hands. The primary cortical
area, Area 3b in primates, is most distinct in archi-
tecture, including a well-developed layer 4 with
small, closely packed neurons (Qi et al., 2008).
The S1 representation tends to proceed from tail
to tongue in a mediolateral sequence across pari-
etal cortex, with representations of the tongue and
teeth located most laterally. Most mammals also
have two additional somatosensory cortical areas
that are well developed; the classical second
somatosensory area, S2, and the later discovered
parietal ventral area, PV (Krubitzer et al., 1986).
Primates have additional areas that are responsive
to touch and some may be unique to this order
(Figure 23.3).

Figure 23.3 Somatosensory areas of the cortex of an owl monkey

This New World monkey does not have a central sulcus, and thus more somatosensory cortex
is on the exposed cortical surface. Primary somatosensory cortex, Area 3b, and adjoining
Areas 3a, 1, and 2 all contain parallel representations of the contralateral body from foot
to mouth in a mediolateral sequence. Areas 3b, 3a, and 1 have representations of both the
contralateral (C) and ipsilateral (I) teeth and tongue. Smaller somatosensory representations
include the second somatosensory area (S2), the parietal ventral area (PV), the rostroventral
parietal area (PR), which may have gustatory functions (G), and rostral (VSr) and caudal (VSc)
divisions of the ventral somatosensory areas. The lateral sulcus has been opened to show
these areas. Primary motor cortex (M1) has a crude somatotopic representation of move-
ments and somatosensory responses. The supplementary motor area (SMA), dorsal premotor
area (PMd), ventral premotor area (PMv) all have somatosensory inputs. The frontal eye field
(FEF), auditory areas, and visual areas 1 and 2 are shown for reference. The anterior part of
posterior parietal cortex is highly involved in somatosensory-motor functions. Auditory areas
include primary auditory cortex (A1), rostral (R) and rostral temporal (RT) areas, and the
caudal medial (CM) area.
372 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Some of the somatosensory areas in primates
correspond to architectonic divisions that were
recognized by Brodmann, and are now known as
Brodmann’s areas (3b for primary somatosensory
cortex, Area 3a for a rostrally adjoining strip of
cortex, Area 1 for a caudally adjoining strip of
cortex, and Area 2 for a more caudally adjoining
strip of cortex adjacent to area 1; Figure 23.3).
These areas form adjoining representations of
the contralateral body from toes most medially to
tongue and teeth most laterally. These somatosen-
sory areas occupy mediolateral strips of cortex in
anterior parietal cortex, including the caudal wall
of the deep central sulcus of those primates where
such a sulcus is present. Early studies in humans
and monkeys confounded most or all of these four
representations as parts of S1, as recordings and
somatotopic maps were largely based on areas
most accessible on the brain surface, area 1 and
most of Area 2. While the Area 3b representation
has long been known to correspond to the repre-
sentation of S1 in other mammals (Kaas, 1983),
some current researchers still confound the con-
cept of S1 by including representations in Areas
3a, 1, and 2. Areas 3a, 3b, 1, and 2 have been
architectonically compared in macaques, chim-
panzees, and humans (Qi et al., 2008), and have
been described in many other primates.
PRIMARY SOMATOSENSORY CORTEX,
AREA 3B
Primary somatosensory cortex, S1 or Area 3b, is
present in the neocortex of all mammals, although
not always identified as Area 3b. The somatotopic
representations across studied mammals are simi-
lar, but differ in the proportional representations
as some skin surfaces are variably important
across taxa (Krubitzer and Stolzenberg, 2014).
Thus, most of S1 and other somatosensory areas
represent the highly sensitive bill in the duck-
billed platypus, the hand and mouth in primates,
the glabrous skin of the tail in spider and cebus
monkeys, the hand of raccoons, the nose of the
star-nosed mole, the wing of bats, and facial
vibrissa of rats and mice (Kaas, 2021). The impor-
tant sensory surfaces have more receptors, and
occupy more of subcortical as well as cortical
representations, thus providing proportionally
more neurons for processing sensory information
at every level.
Neurons in Area 3b have the smallest recep-
tive field with excitatory receptive field centers
where light touch evokes a large response, while
also having receptive field surrounds where touch
suppresses the center response. The response to
small receptive field centers on the hand in mon-
keys are suppressed by touch on other parts of the
hand (Reed et al., 2008, 2010), and even by touch
on the other hand (Reed et al., 2011), although
this likely requires indirect pathways, as the hand
representation of Area 3b has few callosal con-
nections (Killackey et al., 1983). Neurons in Area
1 have converging inputs from Area 3b, and thus
have larger receptive fields. Area 2 has inputs from
3b and 1, as well as from the thalamic nucleus
VPS, so Area 2 neurons are activated by proprio-
ceptive and tactile inputs. Area 3a neurons are
most strongly activated by proprioceptive inputs
from VPS. Areas S2, PV, and VS are smaller rep-
resentations with inputs from Areas 3b, 1, and 2,
and have large receptive fields. These higher-order
somatosensory areas relate to sensorimotor, action
specific domains in posterior parietal cortex that
project to matching action specific domains in pre-
motor and motor cortex (Kaas et al., 2018). These
actions are guided by inputs from higher-order
somatosensory and visual areas.
Early microelectrode recordings from hundreds
of recording sites in anterior parietal cortex in
macaque monkeys first established the existence
of multiple, separate somatotopic representations
corresponding to Brodmann’s Areas 3a, 3b, 1, and
2 (Brodmann, 1909; Kaas, 1983; Krubitzer et al.,
2004). Important features of Area 3b include rep-
resentations of the glabrous surface of digits 1-5
in a lateromedial sequence, with digit tips repre-
sented rostrally (deep in the central sulcus) and
digit representations separated by narrow, cell
poor septa (Qi and Kaas, 2004). The histologi-
cal characteristics of Area 3b are so clear it was
possible to relate a complete representation of the
contralateral body surface to a single architec-
tonic area in early studies using myelin stained
or Nissl-stained brain sections. The innovation
of manually flattening the folded cortex after
separating it from the underlying fibers and cut-
ting this flattened cortex parallel to the surface,
meant that large portions of the Area 3b borders
with adjoining Area 3a and Area 1 could be visu-
alized in single sections. This was even easier to
do in rodents with a smooth cortex without any
fissures, so that histological preparations, includ-
ing stains such as cytochrome oxidase, allowed all
of S1 (3b) to be viewed in a single section. These
preparations revealed the somatotopy of the rodent
S1 in such detail that it was possible to determine
the sex of the animal from the surface view of
the representation (Lenschow and Brecht, 2018).
Such preparations also reveal the differences in
S1 representation across mammalian taxa. For
small mammals with no or few cortical fissures,
parts of the tactile representations in S1 have large
 Somatosensory Processing
separations between the representations of the
hindlimb, forelimb, lower face, and upper face,
containing neurons that respond to stimulation
of proprioceptors. In primates, these interdigita-
tions of proprioceptive cortex have been pushed
out as S1 (3b) compressed and elongated. Thus,
cortex adjoining Area 3b (Area 3a) has become
more strip like, much like Area 3b. Although not
widely recognized as such, the proprioceptive cor-
tex along the anterior border of, and interdigitated
with Area 3b in non-primate mammals is the hom-
ologue of Area 3a in primates (Ebner and Kaas,
2015; Krubitzer et al., 2011; Slutsky et al., 2000).
As a further point on the somatotopy of area 3b of
primates, the most lateral part of the representa-
tion includes, in sequence, the contralateral face,
teeth, and tongue, followed by a representation of
the ipsilateral teeth and tongue (Kaas et al., 2006).
Thus, the sensory inputs from the teeth and tongue
are so important that both the ipsilateral and con-
tralateral teeth and tongue are represented in both
hemispheres. This depends on both the contralat-
eral and ipsilateral teeth and tongue being repre-
sented in the ventroposterior nucleus.
Neurons in Area 3b reflect the relay of SA1,
RA1 and RA2 classes of tactile afferents (Carter
et al., 2014; Lieber and Bensmaia, 2019). While
cortical neurons have responses to tactile stimu-
lation that reflect both SA1 and RA1 afferents,
layer 4 neurons are grouped in modules that are
more dominated by either SA1 and RA1 classes of
afferents (Sur et al., 1984). However, more super-
ficial neurons in S1 lose the slowly adapting com-
ponent, perhaps as a result of local inputs from
inhibitory neurons. The receptive fields of neurons
activated by touch on the hand, for example, have
an excitatory center for specific locations on the
glabrous hand, with an inhibitory surround, so that
the response to touch in the center is reduced by
touch elsewhere on the hand, and the magnitude
of the inhibition decreases with distance from
the excitatory center (Qi et al., 2016; Reed et al.,
2008). The suppressive surround does not extend
beyond the hand to parts of the arm. Surprisingly,
a weaker suppressive surround includes the gla-
brous skin of the opposite hand (Reed et al., 2011).
Thus, these neurons in the hand representation in
primate S1 have excitatory receptive fields with
bilateral inhibitory surrounds. The widespread
intrinsic connections within Area 3b likely con-
tribute to these widespread inhibitory surrounds
(Liao et al., 2013). The pathways mediating the
bilateral effects are not yet known.
The cortical connections of S1 include includes
cortex along the anterior and posterior borders
of S1, which in primates is Area 3a and area 1
(or Area 1/2 in some New World monkeys and
prosimians). Other connections are to areas S2
373
and PV (Burton et al., 1995; Disbrow et al., 2003;
Krubitzer and Kaas, 1990; Liao et al., 2013; Pons
et al., 1985). Subcortical connections include
those to VP of the thalamus, the superior col-
liculus, and trigeminal and dorsal column nuclei
(Liao et al., 2021).
AREA 1
Area 1 of primates contains a somatotopic repre-
sentation of the contralateral body surface, that
closely mirrors that in Area 3b (Kaas, 1983).
Thus, representations of the palm adjoin at the
3b/1border, and the representation of the digits
point in opposite directions. The less distinct rep-
resentation along the posterior border of S1 in
some rodents and other mammals contains what
may be a homolog of Area 1 (or Area 1/2) of pri-
mates (Ebner and Kaas, 2015; Krubitzer et al.,
2011; Slutsky et al., 2000). Area 1 receives its
driving input from Area 3b, while also receiving
direct inputs from VP, which are thought to have
modulatory functions (Garraghty et al., 1990).
Other connections of Area 1 include soma-
totopic interconnections with areas 3a and 2,
regions of the posterior parietal cortex, S2 and PV
(Cerkevich and Kaas, 2019; Disbrow et al., 2003;
Krubitzer and Kaas, 1990), and a less widely
recognized area of the lateral sulcus, the ventral
somatosensory area (VS), and the rostroventral
parietal area (PR) (Cerkevich and Kaas, 2019;
Disbrow et al., 2003; Krubitzer and Kaas, 1990;
Padberg et al., 2019). Other connections are with
motor and premotor cortex. The response prop-
erties of neurons in Area 1 largely reflect those
of the activating neurons in Area 3b, with some
convergence resulting in larger receptive fields
(Rossi-Pool et al., 2021).
AREAS 3A AND 2
Just rostral to Area 3b, area 3a is largely activated
by proprioceptive inputs (Krubitzer et al., 2004;
Krubitzer and Kaas, 1990). Projections from VP
and VPS activate neurons in area 3a (Padberg
et al., 2009), and some from the same neurons
activate neurons in Area 2 (Cusick et al., 1985).
Area 3a can be regarded as a primary area for
proprioceptive inputs, mainly from muscle spindle
afferents. Area 2 is more responsive to tactile
inputs, although neurons also respond to stimula-
tion of proprioceptors (Pons et al., 1985).
374 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
While Area 3a is widely recognized in the primate
taxa, homologs appear to exist in non-primate
mammals (Krubitzer et al., 2004). Area 2 is not
distinguished from Area 1 in all primates, and the
region caudal to Area 3b is designated as Area 1/2
in some primates (Padberg et al., 2005); however,
see Cerkevich and Kaas (2019). Area 2 receives
much of its input from VPS of the thalamus, and
moderate inputs from other thalamic nuclei such
as VP and PLa (Padberg et al., 2009; Pons and
Kaas, 1986). Cortical connections of Area 2
include those with Areas 3a, 3b, 1, S2, and regions
of posterior parietal cortex (Padberg et al., 2009;
Pons and Kaas, 1986). Neurons in Areas 3a and 2
respond to manipulating joints and muscles, and
movements of hands and digits (Krubitzer et al.,
2004; Krubitzer and Kaas, 1990; Pons et al.,
1985). Especially in Area 2, the proprioceptive
signals interact with tactile signals (Kim et al.,
2015). Some neurons in Area 2 have matching
excitatory receptive fields on both hands (Iwamura
et al., 2001). Area 3a contains a somatotopic rep-
resentation of the contralateral body that is paral-
lel to that in area 3b (Huffman & Krubitzer, 2001;
Krubitzer et al., 2004), while Area 2 has a repre-
sentation in parallel with Area 1 (Padberg et al.,
2007; Pons et al., 1985).
AREAS S2, PV, AND VS
Areas S2, PV, and VS constitute a region of
higher-order somatosensory processing located
on the upper bank of the lateral sulcus
(Figure 23.3). Areas S2 and PV appear to directly
border S1 (area 3b) in some primates such as
marmosets (Krubitzer and Kaas, 1990). In other
primates, such as titi monkeys, PV directly abuts
area 3b, and S2 abuts area 3b and area 1 (Coq
et al., 2004); and in macaques and squirrel mon-
keys, S2 adjoins area 1, and PV adjoins areas 3b
and 1 along the representation of the face and
mouth (Cerkevich and Kaas, 2019; Krubitzer
et al., 1995). Representations of the face and
mouth in PV and S2 are followed by that of the
arm and forearm, and the leg somewhat deeper in
the lateral sulcus. The representations of PV and
S2 are mirror images of each other. Deeper in the
sulcus, PV and S2 are joined by additional repre-
sentations, the rostral (VSr) and caudal (VSc)
divisions of the ventral somatosensory area VS
(Coq et al., 2004; Cusick et al., 1989; Krubitzer
et al., 1995). These areas get thalamic inputs
mainly from the ventroposterior inferior nucleus
(VPI), but also from the anterior pulvinar
(Disbrow et al., 2002; Krubitzer and Kaas, 1992;
Qi et al., 2002). In addition to connections with
each other, and areas 3a, 3b, and 1, PV and S2
have connections with sensorimotor modules of
posterior parietal cortex (Padberg et al., 2019;
Stepniewska et al., 2009; Wang et al., 2021).
Neurons in these areas have large receptive fields
and appear to have both tactile and propriocep-
tive components (Coq et al., 2004). S2 and PV
are somatosensory areas that have been described
in humans (Disbrow et al., 2000) as well as in a
range of non-primate mammals (Beck et al.,
1996; Catania and Kaas, 2001; Ebner and Kaas,
2015; Krubitzer and Calford, 1992; Krubitzer
et al., 2011). In humans, bilateral stimulation of
the hands activates S2 and PV regions more than
stimulation of the contralateral hand alone
(Disbrow et al., 2001).
SUMMARY AND CONCLUSIONS
All primates appear to have expanded somatosen-
sory networks at the cortical level. These include
the traditional areas numbered after Brodmann
(Brodmann, 1909), Areas 3a, 3b, 1, and 2; more
recently defined areas S2, PV, VSr, and VSc; an
array of multisensory domains in posterior parietal
cortex; and tactile and proprioceptive components
of domains in premotor and motor cortex. The
main peripheral afferents that provide information
to the vast network include the four members of
rapidly and slowly adaptive classes 1 and 2.
Afferents related to hair movements, muscle spin-
dles, tendon stretch, nociception, and temperature
add to this mixture. Tactile afferents terminate in
brainstem and spinal cord nuclei, where neurons
have small receptive fields for locations on the
body with antagonistic receptive field surrounds.
Neurons in the ventroposterior nucleus of the thala-
mus and primary somatosensory cortex have simi-
lar receptive field sizes, while neurons in
higher-order areas have larger receptive fields,
more extensive antagonistic surrounds, and more
sources of influences on response properties,
including those from roughly matching inputs
stemming from both sides of the body. In posterior
parietal cortex and frontal motor areas, multisen-
sory neurons are often sensitive to visual and audi-
tory signals. Non-primate mammals often have less
complex somatosensory systems, but like primates,
they are specialized in various ways for specific
adaptations. However, at the cortical level, the
presence of S1 is universal and S1 is commonly
bordered by an anterior zone for proprioception
much like Area 3a, a posterior zone suggestive of
Area 1/2 in primates, and Areas S2 and PV.
 Somatosensory Processing
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Motor Control: Response
Preparation, Initiation,
and Inhibition
Vishal Rawji, John C. Rothwell,
and Marjan Jahanshahi
INTRODUCTION: WHAT IS THE ROLE OF
THE MOTOR SYSTEM?
Take the example of writing one’s name on a
whiteboard versus writing on a piece of paper.
Writing on a whiteboard is predominantly executed
by proximal musculature, whereas writing one’s
name on paper involves small muscles of the hand
with stability of the shoulder. Hence despite the
same motor goal (i.e., writing one’s name), the
muscles involved, and movements required differ
greatly. This simple example emphasizes some of
the intricacies that the motor system must
implement to make an appropriate movement: the
correct dynamic and stabilizing forces must be
applied at specific muscles and around joints, with
muscle contractions which must be performed
smoothly and be of appropriate size and duration.
Simultaneously, the motor system must keep track
of and account for the quality of the unfolding
movement, such that subsequent actions can be
adjusted accordingly. Thus, the idea of a motor
system reiterates that it takes a series of intercon-
nected brain regions to produce efficient and
appropriate movements given a particular context.
More formally, the motor system describes the
central and peripheral components of the nerv-
ous system that generate and support movement.
24
It provides the means to navigate and interact
successfully in the world; in fact, there is a view
that the principal function of the human brain is to
produce movement.
From the motor chauvinist’s point of view the
entire purpose of the human brain is to produce
movement. Movement is the only way we have of
interacting with the world. All communication,
including speech, sign language, gestures and
writing, is mediated via the motor system. All
sensory and cognitive processes may be viewed as
inputs that determine future motor outputs.
(Wolpert et al., 2001)
While the motor chauvinist’s perspective is rather
polarizing, it nevertheless highlights that human
control of voluntary movement is a fundamental
and impressive feature of brain function, gen-
erating, and controlling a range of motor behav-
iors including speech, gestures, writing, walking,
reaching, grasping, and an extensive motor reper-
toire (e.g., dancing, playing musical instruments,
playing tennis, skiing, etc.) some of which set us
apart from other animals. Additionally, movement
also has relevance to social cognition: commu-
nicating with others and inferring the intentions
of others from their verbal (tone of speech) and
380 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
subtle non-verbal motor behavior (facial expres-
sion, gaze, and eye focusing, gestures).
As with most things, we come to appreciate
our motor systems when we recognize what it
means not to have a fully functioning one (e.g.,
after leg amputation or hemiplegia secondary to
stroke), or to have one which does not function
properly (as in motor neuron disease, cerebellar
ataxias, or parkinsonism). In a more light-hearted
manner, our intact motor system is sorely missed
after the temporary state of alcohol-induced cer-
ebellar dysfunction that results in uncoordinated
walking and slurred speech. Furthermore, in the
field of artificial intelligence, while building com-
puters with higher “cognitive” capacity, faster
processing speed and ability for deep learning is
now a reality, building robots with the fine motor
skills of a human musician or the subtle motor
coordination of a ballerina has proven to be a
greater challenge. The excerpt above still runs true
20 years after it was published, with smartphones
and computers becoming a norm of communica-
tion and a means of interacting with the world;
after all, these devices and methods of commu-
nication still require an intact motor system, that
may actually require a more sophisticated motor
system and dextrous control of hand muscles than
has previously been required.
In the sections that follow, we aim to outline the
structure and function of the human motor system
that allows such a wide repertoire of movement.
We discuss models of movement that highlight that
rather than being driven in a top-down manner by
a “movement centre,” effective movement unfolds
due to a constant interplay between several brain
regions and with the extensive use of feedforward
and feedback-driven control. We then consider
how movements are prepared and initiated and
how they may be inhibited when necessary.
BUILDING BLOCKS OF
THE MOTOR SYSTEM
Several interconnected structures make up the
human motor system in a hierarchical manner.
Broadly speaking, the motor system is divided
into its central (brain and spinal cord) and periph-
eral (ventral nerve roots, peripheral nerves, neuro-
muscular junction, and muscle) parts. The
corticospinal (or pyramidal) tract represents the
main pathway used to generate voluntary move-
ment, starting in the brain and flowing via the
spinal cord to muscles. The central component of
the motor system is further subdivided into the
pyramidal (corticospinal) and extrapyramidal
(basal ganglia and cerebellum) systems; the
extrapyramidal system supports higher-order fea-
tures of motor control such as appropriate effector
selection and error-mediated adjustment of
movements. In essence, the pyramidal system acts
to generate movements, whereas the extrapyrami-
dal system acts to optimize movement and
behavior. The motor system also receives exten-
sive afferent input from other cortical areas that
further facilitate the selection and execution of
appropriate movement, as will be discussed in
further sections. Dividing the motor system in this
manner has functional value to clinicians, given
that distinct clinical syndromes are observed in
patients with lesions of central vs. peripheral and
pyramidal vs. extrapyramidal systems.
A major output of the motor system is the
pyramidal/corticospinal tract, formed from
layer V of several cortical regions, including the
primary motor cortex, supplementary motor area
and premotor cortex (Figure 24.1a). The larg-
est contribution comes from the motor cortex,
defined based on the cytoarchitectural subdivi-
sion proposed by Brodmann (1909; cf. Elston
and Garey, 2013). Betz cells originating in layer
V of the motor cortex terminate on interneurons
and anterior horn cells located in the spinal cord.
From there, spinal motor neurons fire to generate
forces via their corresponding muscles. It is inter-
esting to note that there is a sense of decreasing
dimensionality as one progresses from the motor
cortex to muscle; cortical motor neurons vastly
outnumber lower motor neurons, which outnum-
ber the number of muscle fibres and muscles.
This arrangement likely affords the motor system
with a great deal of flexibility and resistance to
neuronal loss (e.g., during ageing or after brain
injury) such that a number of different combina-
tions of cortical neural activity can result in the
same movement. The imbalance in dimensionality
between components of the corticospinal tract has
placed attention on how neurons work together to
produce movement.
Much of the early work on the motor cortex
focused on how individual cortical motor neu-
rons generated movements, showing that the fir-
ing of individual motor neurons preceded EMG
and closely correlated with force generated by
corresponding muscles (Evarts and Tanji, 1976;
Tanji and Evarts, 1976). However, not all neurons
in a patch of motor cortex will respond similarly
preceding movement: more specifically, whilst
some motor neurons increase their activity, oth-
ers decrease theirs and some show no change
at all. This discrepancy has been reconciled by
considering that neurons work together to per-
form computations necessary for generating and
supporting movement (rather than all neurons in
 Motor Control: Response Preparation, Initiation, and Inhibition 381

Figure 24.1 Building blocks of the motor system.

Panel a: the corticospinal tract originates from a somatotopically organized motor “Homunculus.”
At the spinal cord level, descending corticospinal efferents terminate on anterior horn cells and
interneurons. Spinal reflexes are mediated by sensory afferents from muscle spindles making a
monosynaptic connection with alpha motor neurons.
Panel b: direct and indirect pathways via the basal ganglia allow appropriate response selection.
Panel c: proprioceptive inputs from spinal circuits (via the spinocerebellar tract), head posi-
tion sense inputs from vestibular nuclei and descending motor commands constitute affer-
ents to the cerebellar cortex. Efferents from the cerebellar cortex travel to the motor cortex
via the thalamus. (Created with BioRender.com, adapted from templates: “Direct and Indirect
Pathways of the Basal Ganglia” and “Brainstem and Diencephalon Structures Related to the
Cerebellum”)

an area responding in the same way). It is this
fundamental shift in thinking that has resulted
in improved decoding of brain activity that may
pioneer advances in brain–machine interfaces
(Willett et al., 2021).
As illustrated above, the human motor sys-
tem can execute movements with huge degrees
of freedom. But how does one decide which
movement to make from all the possibilities that
its motor system affords? A set of subcortical
nuclei comprises the basal ganglia, which help
select actions based on the internal state, context/
task rules and prior experiences (Figure 24.1b).
Dopamine transients are used to reinforce cer-
tain actions that are deemed advantageous, such
that these actions can be called upon appropri-
ately when the context arises again. Conversely,
withholding dopamine transients after an action
is made does not reinforce those actions, which
result in them not being selected in future itera-
tions of the scenario (Redgrave et al., 2016). In
doing so, the basal ganglia act as a hub for learning
what action is best suited for a given situation and
offers a powerful way to optimize ongoing action
selection. A dichotomy has been classically drawn
between two streams that act via the basal ganglia:
the direct and indirect pathways, which have been
purported to be pro- and anti-kinetic, respectively.
While compelling evidence for this dichotomy
has come from optogenetic stimulation of these
382 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
pathways in mice (Kravitz et al., 2010), this model
of separable pathways has been refined over time
given that activity in both pathways is increased
during movement and decreased during periods
of immobility (Jin et al., 2014). Instead, the latter
study supports a model whereby activities in the
direct and indirect pathways carefully sculpt basal
ganglia outflow to select optimal actions.
Once an action has been selected, it is imple-
mented via the pyramidal tracts, predominantly
via the motor cortex. However, there are ancil-
lary structures that help facilitate the smooth
execution of movement. One such complex of
structures are the supplementary motor areas
(SMA) that are located anterior to the motor cor-
tex and serve to facilitate complex components
of motor behavior such as sequence generation,
task switching, and response preparation and
inhibition. Support for the role of the SMA in the
aforementioned behaviors comes predominantly
from imaging studies. Stimulation studies of the
SMA, on the other hand, have shown that this can
result in complex movements (such as stepping),
the urge to move and even arrest of ongoing
action. It is improbable that the SMA is called
upon or its functions are restricted to those speci-
fied above; indeed, some authors have noted that
the plurality of functions of the SMA is unified
by an association between conditions and action
(Nachev et al., 2008).
The cerebellum is another structure support-
ing smooth movement control that contains more
neurons than the rest of the brain (Figure 24.1c).
It integrates sensory information from proprio-
ceptors, vestibular inputs from the otoliths and
descending motor commands from the motor
cortex. In doing so, the cerebellum can compare
information about descending motor commands
and their sensory consequences to help modulate
ongoing movement (discussed below). The signif-
icance of the cerebellum’s role in motor control is
probably most notable during lesions, which result
in poor timing of muscular contractions eventually
producing loss of co-ordination (i.e., ataxia) and
dysdiadochokinesia. Less obvious from lesion
studies is that the cerebellum also plays a role in
the learning of motor skills and motor adaptation.
While we have emphasized the role of the cor-
ticospinal tract in dextrous hand and arm move-
ments, we must not forget how the remainder of
human motor control is mediated. For example,
the reticulospinal and vestibulospinal tracts origi-
nate in the reticular formations and vestibular
nuclei, respectively. They then descend via the
spinal cord to bilaterally innervate neck, proximal,
and axial muscles. In all, these tracts are used to
maintain posture and balance.
INTERNAL FORWARD AND INVERSE
MODELS OF MOVEMENT
Equipped with the architecture required for move-
ment, a human must decide how to select a move-
ment, given all the possibilities that its motor
system afford it; just think of the vast degrees of
freedom conferred by the brain’s many motor
neurons and motor units. One option might be to
have a sort of look-up table, containing all possi-
ble movements that the body can make. Such a
system, however, is intractable and would struggle
to keep up with the flexibility of movements
required by an ever-changing environment. An
alternative solution would be to have a motor
system that calculates the muscle forces required
for successful movement, that is based on prior
experience. Importantly, the calculation requires
specification of a movement goal – that is, what
the motor system is trying to achieve.
Key to the above idea is that the brain holds a
model of the environment in which the movement
is performed, and of the how the motor system
itself is organized. Take the example of picking up
a cup of tea. There is a model of the cup in its envi-
ronment (if it’s on a table or the amount of tea in
the cup) and a model of the human in that environ-
ment (where the arms are relative to the cup or any
preferences such as handedness). One example of
internal models used by the brain are inverse mod-
els (Figure 24.2), which incorporate the current
state of the body (joint positions, velocities, accel-
erations) and future desired state (motor goal) to
generate motor commands (activation of motor
neurons that lead to muscle activation and motor
torque) that are used by the motor system to bring
the body closer to the desired state (Kawato et al.,
1987). The final state can be specified as a number
of smaller states and as such, many inverse mod-
els accumulate to result in the movement; in this
instantiation, forward models are continuously
used to update the state of the body and error sig-
nals are used to modify the ongoing movement.
Generation of effective motor commands by
the inverse model arises during motor learning.
In particular, the feedback-error learning model
posits that the discrepancy between the desired
state and estimated state for a given action is used
as an error signal to generate a feedback motor
command, which goes on to modify the feedfor-
ward motor command generated by the inverse
model (Kawato et al., 1987). Consequently, the
signal generated by the feedback controller is
used to train the inverse model and if there is no
discrepancy between the desired and estimated
states, there will be no error signal as the inverse
 Motor Control: Response Preparation, Initiation, and Inhibition 383

Figure 24.2 Internal forward and inverse models during movement.

The desired movement is first specified, and an inverse model is used to generate the rele-
vant motor commands. These motor commands are passed to a motor system to be executed
and a copy is sent to be used by a forward model, which estimates the corresponding future
state and sensory feedback. The sensory system (peripheral sensory receptors such as muscle
spindles) conveys the sensory consequences of the actual movement, which is then com-
pared with the estimated state and sensory feedback generated by the forward model. Any
discrepancy between the actual and estimated state and sensory feedback is then used as an
error signal to modify subsequent motor commands. (Created with BioRender.com)

model is performing optimally. Explicit error
signals are also used to train the inverse model
(Albert and Shadmehr, 2016) and it is likely that
a number of learning mechanisms, such as basal
ganglia-mediated reinforcement learning, are used
to refine the inverse model.
Human movement is commonly made in an
ever-changing environment, requiring a motor
system that is adaptable and that can make con-
text-dependent adjustments depending on chang-
ing movement goals. The changes in environment
are conveyed via sensory information (visual,
proprioceptive, task-based signals), which is inter-
preted by sensory cortices and incorporated into
the evolving movement, thereby creating a senso-
rimotor loop. However, there is a significant delay
between the generation of sensory information
and incorporation into the movement that makes
a sense-plan-act approach to motor control unvi-
able; by the time sensory information is received
by the brain, it represents an outdated version of
the environment that may no longer be of value
(and may even be deleterious).
Control theory has been used to inspire mod-
els which reconcile the human ability to make
efficient movements despite sensory conduction
delays (McNamee and Wolpert, 2019; Wolpert
and Ghahramani, 2000). Internal feedforward
models (Figure 24.2) state that the brain predicts
the future state (forward dynamics model) and
sensory consequences of the future state (forward
sensory model – joint positions, velocities, accel-
erations) for a given action using an efference
copy of the action and uses these predictions to
optimize movement. In essence, the motor system
sends one copy of the motor command through
its output structures and another (efference copy)
to a dynamics predictor. The dynamics predictor
uses the previous state of the human body and
the efference copy to predict what the next state
of the body and its sensory consequences will be,
given the motor command (efference copy). The
predicted sensory consequences and real sensory
feedback are then compared, with any discrepancy
between the two acting as an error signal. The
error signal is used by the motor system to enact
online adjustments to movements so that they are
made accurately. Importantly, online adjustments
to movement in response to forward model error
signals are specific to goals of the movement –
adjustments to movement are not made if the per-
turbation/error signal does not interfere with the
success of the movement (Nashed et al., 2012).
A distinction must be made by the term error
signal: in the context of forward models, error
signals, and their consequences for voluntary
384 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
movement are generated continuously, throughout
the movement, as opposed to error signals gener-
ated after movement (such as those used in rein-
forcement learning literature). Therefore, feedback
control in this instance is a continuous process
throughout movement. The automaticity of online
adjustments to movement is made possible by
the spinal motor system. Short and long-latency
stretch reflexes are tuned to movement goals such
that deviations from movement path may be cor-
rected quickly and specifically (Doemges and
Rack, 1992; Pruszynski et al., 2011). There are,
however, some movements (such as golf swings
or tennis serves) that unfold too quickly to benefit
from corrections via spinal circuits. Instead, these
movements are likely controlled predominantly by
internal models.
Sensory inputs can be divided into afferents that
occur as a consequence of the environment and
reafferent (or efference copy) inputs, which arise
as a consequence of the body’s own actions. These
two sources of sensory input cannot be distin-
guished from each other using the body’s sensory
receptors. The forward model helps to differenti-
ate the two sources of sensory input by subtracting
the predicted sensory consequences (efference)
from the incoming sensory input, thereby leaving
the signals generated by the environment. This is
perhaps best appreciated as visual stability despite
quick saccadic eye movements – an efference
copy of the saccade is sent from the thalamus to
the frontal eye fields to shift the neuron’s visual
receptive field spatially (Haarmeier et al., 2001).
This shift in receptive field accounts for the dis-
placement due to the upcoming saccade (Sommer
and Wurtz, 2006). Without forward models, the
environment (as opposed to the eyes) may be
perceived to move during saccades.
Forward models are also hypothesized to allow
for the next movement in a sequence to be planned
without waiting for sensory feedback from the
first movement, which is especially useful in
speeded motor sequences such as piano playing
and for anticipatory changes requiring pre-emp-
tive movement. For example, consider a pianist
that is sight-playing, that plans the next sequence
of keys as they are executing the current note. A
third use of feedforward models is in action selec-
tion: movements can be “trialed” internally with
the predicted sensory consequences being used as
a dummy outcome. The action which is hypoth-
esized to minimize this sensory prediction error
can then be chosen and acted out, which is cru-
cial for context-dependent modulation of move-
ment. Central to this idea is Bayesian modeling,
which combines prior information about the state
of a system with the likelihood that sensory data
is produced by a given state to update estimations
of the prior to result in a more accurate estima-
tion of the state (van de Schoot et al., 2021).
Take the example of picking up an empty bottle
from the kitchen counter – visual information may
set the prior belief that the bottle is more likely
to be full. Motor commands will be produced for
each alternative (empty, full, and other intermedi-
ate states), along with efference copies and their
corresponding sensory consequences. Note that
each motor command will require different forces
to be produced by the effectors. As the grasping
movement begins and the bottle is lifted, affer-
ent sensory information is received and compared
with the internal forward model sensory predic-
tions for the full bottle and empty bottle scenarios
(likelihoods). The forward model that minimizes
the prediction-afferent error is chosen as the most
probable state of the bottle; the corresponding
motor commands for this option are chosen and
combined with the prior to change the forces
applied during ongoing movement to appropri-
ately pick up an empty bottle. The idea is that mul-
tiple inverse and forward models run in parallel
and operate in a modular fashion to continuously
optimize movement (Wolpert and Kawato, 1998).
The use of afferent sensory information to
update forward and inverse models is an important
facet of control theory. This is emphasized by an
elegant study whereby participants were asked to
either drink from a cup of water using their hands
or with a straw. Importantly, self-generated weight
changes were experienced when the cup was lifted
and not when participants drank using a straw;
they did have visual feedback that there was less
water in the cup. Interestingly, the authors found
that subsequent forces generated to lift the cup
were suboptimal when people first drank from a
straw vs. when they lifted the cup (Nowak and
Hermsdorfer, 2003). The idea was that cutaneous
and proprioceptive information were required to
effectively update the internal model of the cup
and its state. The significance of afferent pro-
prioceptive information is further highlighted by
considering that deafferentation can result in dif-
ficulty with complex voluntary movements, espe-
cially apparent when constant forces over longer
(than one or two seconds) periods of time are
required (Rothwell et al., 1982).
The cerebellum and parietal cortex have been
proposed as candidate neural substrates to repre-
sent internal models as described above. Much
evidence for the cerebellum’s role in holding inter-
nal forward models comes from studies of motor
learning and adaptation in patients with cerebel-
lar lesions (Morton, 2006; Tseng et al., 2007).
More specifically, whilst patients with cerebellar
lesions are able to make on-line corrections to
ongoing reaches (Smith et al., 2000), their motor
 Motor Control: Response Preparation, Initiation, and Inhibition
adaptations following error trials are random and
uninformed by the error (Smith and Shadmehr,
2005). Non-invasive stimulation of the ipsilateral
cerebellum with transcranial magnetic stimulation
causes directional errors when suddenly reach-
ing toward a visual target (Miall et al., 2007). The
cellular architecture of the cerebellum also lends
itself to acting as a hub for internal models, with
extensive feedforward circuitry from mossy fibres
to dentate nucleus cells representing an internal
forward model, and cerebellar output via Purkinje
cells representing a time-delayed version of the
current state (Tanaka et al., 2020). The parietal
cortex has similarly been suggested to hold inter-
nal models. In non-human primates performing
a joystick reaching task, neurons in the posterior
parietal cortex collectively encode the dynamic
movement angle of the cursor, reflecting a forward
estimate of the state of the cursor (Mulliken et al.,
2008). As with studies in the cerebellum, lesion-
ing studies using cooling (Takei et al., 2021) or
non-invasive brain stimulation (Desmurget et al.,
1999) result in an impairment of error-based cor-
rections and state estimation during reaching
movements. Thus, there is converging evidence
that the cerebellum and parietal cortex hold inter-
nal copies of the motor command that have a role
in adapting subsequent motor actions.
An alternative perspective of motor control
is active inference. This proposes that instead of
being generated by descending motor commands
from the motor cortex (as with inverse mod-
els), muscle forces are generated by spinal alpha
motor neurons, the activity and gain of which is
calibrated by the discrepancies between incoming
proprioceptive information and the predictions of
sensory consequences of movements sent down by
the motor cortex. Understood in this way, move-
ment serves to minimize proprioceptive predic-
tion errors. A simple example would equate to
the “follow-up servo” model of Merton (1953). In
this model, the CNS activates intrafusal fibres of
muscle spindles, which stretch the sensory end-
ings and cause an afferent discharge in muscle
spindle afferents. This results in reflex contrac-
tion of the extrafusal muscle in order to return
the spindle discharge to zero. The “prediction”
in this case is expressed as the desired length of
the muscle spindle; reflexes serve to minimize
the difference between the desired muscle length
and the current length. However, in this case, fur-
ther studies showed that the gain of the feedback
was too small for reflexes to produce the desired
change in length (Marsden et al., 1983) and the
theory was abandoned. Furthermore, muscle
spindle discharge starts after the onset of muscle
activity, contrary to a model whereby spindle dis-
charge results in motor activity (Vallbo, 1970).
385
The modern prediction error theories overcome
this problem by having multiple feedback loops at
many levels of the CNS. Active inference models
notably get rid of the inverse model and are based
purely on forward modeling. Furthermore, they
pose an alternative account of the role of the motor
cortex – that integrates inputs from other brain
regions (such as premotor and parietal cortices) to
output predictions about the sensory consequences
of an intended movement. Active inference mod-
eling with prior knowledge of neuroanatomy and
functional connectivity has been used to gener-
ate synthetic motor behavior that resembles that
of humans, and even recapitulates the types of
clinical syndromes seen during lesioning (e.g.,
hyperreflexia after upper motor neuron lesions –
Parr et al., 2021).
RESPONSE PREPARATION AND
INITIATION
Consider a tennis player hitting an approaching
tennis ball. The brain must attend to and predict
where the ball will end up at each time-step, there-
fore establishing the future trajectory of the ball as
it approaches. Given that the aim of the game is to
win the point, relevant environmental features
must be considered, such as the location of the
player and the opponent on the court. With this
information, the motor goal may be specified as
returning the ball over the net, within the bound-
ary lines at a location far from the opposite player,
in order to maximize the likelihood of winning the
point. Herein forms the motor goal or the “what”
of movement planning. Once specified, the player
must decide upon which shot (from all the shots
that can conceivably be played) is most appropri-
ate (or most likely to win the point), given the
trajectory of the ball–action selection. With speci-
fication of the desired action, the motor system
must plan how corresponding muscular contrac-
tions and forces will be generated by the motor
cortex and other downstream effectors. Finally,
the motor system uses this template to perform the
desired action. As we have appreciated from for-
ward and inverse models, whilst the whole motor
plan for the shot may be specified beforehand, it’s
subsequent planning and execution unfolds with
feedback from the sensorium so that movement
can be adapted online.
The example above highlights that move-
ment generation has classically been parsed
into preparation (the what and how of move-
ment (Wong et al., 2015)) and initiation and
execution (generation of the appropriate forces
386 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 24.3 The use of various types of reaction time (RT) tasks for behavioral assessment
of response preparation, initiation and execution.
Several behavioral tasks can be used to study movement preparation, initiation, and
execution.
Panel a: Simple reaction time task (SRT) – participants respond to a single go stimulus with
the same response.
Panel b: Choice reaction time task (CRT) with multiple response alternatives.
Panel c: Pre-cued choice reaction time task: Movement preparation and execution can be
parsed by introduction of delays: A pre-cue (left or right arrow) indicates the response to
be prepared. This is followed by a second, go cue, which signals the participant to make the
prepared response. Activity before and after the go cue represent activity during movement
preparation and execution, respectively. By changing the interval between the go cue and
the pre-cue arrow, the time allowed for movement preparation can be altered – the shorter
the interval, the less time allowed for movement preparation. Darker hands underneath each
task represent the correct/chosen responses. (Created with BioRender.com)

via muscular contractions). The neuroscience
of movement is studied using behavioral para-
digms that separate planning from execution
phases of movement (Figures 24.3 and 24.4).
Employing mechanical or electronic devices,
these RT paradigms allow measurement of RT:
the interval between the presentation of a stimu-
lus and initiation of a response, and movement
time: the time taken for execution of a move-
ment from its initiation. In its simplest form,
the simple reaction time task (SRT), partici-
pants are presented with a single go stimulus,
instructing them to initiate and execute the
same prepared response, with the correspond-
ing RT serving to represent a behavioral index
of movement preparation, initiation, and execu-
tion (Jahanshahi, 2003).
In the choice reaction time task (CRT), partici-
pants are presented with one target stimulus of sev-
eral possible alternatives, each requiring a specific
response. Importantly, in each trial of the CRT, the
specific target stimulus is unknown until its pres-
entation. Additionally, the CRT requires selection
of the appropriate response once the stimulus has
been presented. This is in contrast to the SRT,
where participants are aware of the response that
is to be performed prior to presentation of the
stimulus and can have it preprogramed and pre-
pared, only waiting for the go stimulus before it is
initiated and executed. This difference in response
 Motor Control: Response Preparation, Initiation, and Inhibition 387

Figure 24.4 The putative stages of processing in simple, un-cued and pre-cued choice
reaction time tasks.
Source: Adapted from Jahanshahi, 2003.
*S-R mapping is required only when the compatibility between stimuli and responses is low.

selection and extent of motor preparation between
the SRT and CRT manifests as longer RTs in
the latter. This observation points toward move-
ment preparation as conferring a RT advantage.
The CRT can be modified further to distinguish
movement preparation and execution – namely
by inserting a delay between presentation of the
target stimulus and the imperative or go stimulus.
In this pre-cued CRT, the delay between the pre-
cue and the go stimulus presentation allows for
movement preparation. Indeed, with sufficiently
long pre-cue intervals, reaction times are similar
in pre-cued CRT and SRT, owing to the affordance
conferred by movement preparation.
A notable benefit of these task manipulations is
that different phases of movement (and their cor-
responding neural activity) can be clearly deline-
ated by varying and time-locking to pre-cue and
go cues. By changing the time between the pre-
cue and go-cue, the experimenter can change the
time allowed for movement preparation (shorter
pre-cue – go-cue interval results in less time for
preparation) and hence investigate the interaction
between movement preparation and execution.
Haith et al. (2016) used this method and com-
pared a Free RT condition (participants instructed
to respond as quickly as possible to the target
presentation after a predictable sequence of audi-
tory tones spaced 500 ms apart) and a Forced RT
(participants were trained to initiate their reach-
ing movement synchronously with the onset of the
fourth tone). They showed that in the Forced RT
task participants could make accurate responses
approximately 80 ms faster than their fastest
responses in the Free RT condition. The occur-
rence of errors was also greater when the amount
388 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
of time allowed for preparation was reduced. The
authors reasoned that movement preparation and
initiation are independent from one another (Haith
et al., 2016). In fact, population-level recordings
from macaque M1 and dorsal premotor cortex
show that sequences of movements are performed
according to a model of independent movement
preparation and execution and occur simultane-
ously; movement preparation for the subsequent
movement in a sequence occurs at the same time
as movement execution for the prior movement
(Zimnik and Churchland, 2021).
While the assumption of serial and independ-
ent stages of processing in SRT and CRT tasks as
illustrated in Figure 24.4, has been widely criti-
cized (see Jahanshahi, 2003), reaction time para-
digms have nevertheless been used extensively to
study speed of movement initiation, preparation,
and execution. Reaction time tasks have also lent
themselves to be paired with electrophysiological
markers of motor preparation such as the contin-
gent negative variation (CNV), the negative EEG
potential which is recorded in the interval between
a warning stimulus and an imperative go stimulus.
The CNV represents the neural activity related to
preparation and execution of externally-triggered,
voluntary movements. Another neural marker of
movement preparation is the bereitschaftspotential
(BP), a negative cortical potential measured using
EEG over central regions, which is associated
with the preparation of a self-generated movement
(Kornhuber and Deecke, 2016). The BP begins to
rise in both hemispheres approximately 1–1.5 sec-
onds preceding EMG onset and is characterized
by an early, late, and peak component. Whereas
the early part of the BP is measured in electrodes
overlying the supplementary motor area (SMA),
late and peak components become maximal in
amplitude when measured over the hemisphere
contralateral to the effector that moves, suggesting
that the locus of these components is the motor cor-
tex (Jahanshahi and Hallett, 2003). In fact, when
a pre-cue is used to signal an upcoming move-
ment (such as a right-hand movement), a lateral-
izing potential develops in the contralateral (left)
hemisphere. This lateralized readiness potential
(LRP), calculated as the difference in EEG voltage
between contralateral electrodes (e.g., C3 and C4
for hand movements), is proposed to represent the
preparation for the forthcoming movement (Kutas
and Donchin, 1980) given that it appears well
before the EMG response. Furthermore, LRPs are
present even in the absence of movement but when
a movement is prepared: LRPs have been recorded
in the context of a stop-signal task whereby par-
ticipants make responses to a go stimulus but must
abort their developing response on a minority of
stop trials. LRPs are still seen in successful stop
trials, where participants prepared a go response
but did not end up making a response (Jong et al.,
1990). This finding provides further evidence that
the LRP is a distinct cortical response related to
the preparation of movement.
Preparation of a movement necessitates the
specification of what movement must be made
(given the state of the body, environment and
movement goals) and how the said movement
must be executed. Recordings from monkeys per-
forming a pre-cued CRT show increases in neural
activity in the delay period (reflecting a movement
preparation period) distributed across the pre-
motor, parietal and motor cortices. Interestingly,
activity during movement execution is also meas-
ured from these same regions, implying that,
despite being conceptually distinct, movement
preparation and execution are not clearly neuro-
anatomically separable. Nevertheless, some brain
regions hold greater weighting during specific
aspects of movement preparation, such as the role
of the parietal cortex in holding internal models
and in state estimation described above (Mulliken
et al., 2008). Premotor cortices are involved in
movement planning processes such as motor ini-
tiation, suppression and selection. Lesions of the
SMA lead to a variety of higher-order movement
deficits such as unconscious, disinhibited limb
movements to grasp objects (as in alien-limb phe-
nomenon), impairments in motor selection and the
loss of reaction time affordances provided by pre-
cues in a pre-cued CRT. Furthermore, electrical
stimulation of the SMA in humans evokes an urge
to move without resulting in overt motor activity
whereas stimulation in monkeys (with different
pulse parameters to those in humans) results in the
adoption of postures and complex movements.
An important distinction is between self-gener-
ated and externally triggered movements. There is
now a body of evidence from imaging and lesion-
ing studies that self-generated and externally-
triggered movements are mediated by different
brain networks (Deiber et al., 1991; Playford
et al., 1992; Jahanshahi et al., 1995). Neurons
in the SMA fire earlier during self-initiated than
externally generated movements and non-human
primates with lesions of the SMA make fewer
self-initiated movements, but retain the ability to
respond to external cues (Thaler and Passingham,
1995). In a study by Jahanshahi et al. (1995), par-
ticipants were asked to make finger movements
approximately every three seconds or the same
movement was externally triggered by an auditory
tone, while the BP was measured from scalp EEG
recordings. The amplitude of the late and peak
components of the BP were found to be greater
when movements were self-initiated than when
they were predictably externally triggered, but the
 Motor Control: Response Preparation, Initiation, and Inhibition
amplitude of the early BP did not differ between
the two conditions, suggestive of similar extents of
motor preparation (Jahanshahi et al., 1995). More
specifically, the BP seems related to the predict-
ability of the forthcoming movement, given that
the BP was either absent or reduced in amplitude
during unpredictably cued movements relative
to self-initiated movements (Jahanshahi et. al.,
1995). Measurements of regional cerebral blood
flow clarified that this difference in BP amplitude
may be related to activation of the rostral SMA,
anterior cingulate cortex and dorsolateral prefron-
tal cortex during self-initiated movements that is
not present during movements triggered by unpre-
dictable cues (Jenkins et al., 2000).
Once preparation specifies what the appropri-
ate movement is and how it is to be achieved, it
needs to be executed via the pyramidal tract – the
bulk of which is derived from the motor cortex
(although other cortical areas also contribute).
Using its extensive efference connections with
spinal interneurons and motor neurons, the corti-
cospinal tract generates the muscle activations and
forces required for successful movement initiation
and execution. Indeed, the firing patterns of corti-
cal motor neurons are closely related to the cor-
responding EMG output (Cheney and Fetz, 1980)
and display maximal firing to a preferred direction
of limb movement.
There have been recent developments in the
understanding of how motor cortical neurons gen-
erate the patterns required to generate complex
movements. As mentioned earlier, the responses of
motor cortical neurons preceding movement vary
greatly, with some increasing and others decreas-
ing firing rates before EMG onset. This oddity has
been reconciled by considering that the output of
the motor cortex is a combination of the activity of
the neurons that make it, and that the various dif-
ferent responses of neurons result in a pattern of
activity being generated by the motor cortex (Vyas
et al., 2020). Effectively, the motor cortex utilizes
its many motor cortical neurons to flexibly gener-
ate patterns of neural activity that drive EMG. The
ability to record multiple neurons simultaneously,
along with dimensionality reduction methods has
revealed that movement execution is marked by
motor neurons conforming to a particular “rota-
tional” pattern of dynamics (Churchland et al.,
2012). These findings are based on the dynamical
systems perspective of motor control, which pro-
poses that, instead of representing explicit features
of the movement (such as direction or velocity),
activity during motor preparation sets the initial
state of a dynamical system, that evolves into the
desired movement (Churchland et al., 2010) upon
the receipt of some trigger to move (Kaufman
et al., 2016; Nashef et al., 2021). Consequently,
389
neural activity during movement preparation and
execution reflects the transition from one state to
the next under some dynamical rule, and hence not
all M1 activity need represent movement-related
activity. Notably, the dynamical system arises as
an interplay between populations of neurons dur-
ing motor preparation and execution and is not
appreciated from the single-neuron perspective,
which has traditionally driven theories of motor
control. The same methods have been applied to
the understanding of how single neurons work
together during movement preparation. A key
feature of the dynamical systems perspective is
that, during motor preparation, population activity
evolves along a “null space” where the activity of
individual neurons on corticospinal outputs sums
to zero through varying degrees of excitation and
inhibition; this results in a new state primed for
motor execution but in which there is no change
in corticospinal output (Kaufman et al., 2014;
Stavisky et al., 2017).
RESPONSE INHIBITION
Effective motor behavior relies on the ability to
flexibly modulate movement depending on ever-
changing motor goals. One example of this flexi-
ble modulation of movement includes behavioral
inhibition, a key component of normal human
functioning, serving to suppress inappropriate or
unwanted actions (Hannah and Aron, 2021).
Accordingly, motor inhibition pertains to how
motor actions are restricted or aborted. Motor
inhibition can be selective (a musician that stops
singing but continues to play the piano) or global
(freezing when faced with a bear in a forest). Most
typically, motor inhibition is dichotomized into
reactive and proactive sub-types, each of which is
used depending on the behavioral demands/task
goals. Reactive inhibition is used when sudden
stopping of a response is required and is cued by
external events that require rapid cancellation of
ongoing motor activity. For example, reactive
inhibition is called upon when a cyclist suddenly
stops in response to a wayward pedestrian coming
into their path. Indeed, the cyclist might expect
that a pedestrian could walk out onto the road
without first looking and use this prior knowledge
to appropriately modulate the cycle speed when
approaching busy areas. In anticipation of carefree
pedestrians, the cyclist could cycle more slowly in
central London as compared with in a quiet
­country lane. This use of prior information about
the environment or task to modulate speed and
inhibit movement if deemed necessary is termed
390 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
proactive inhibition, a prospective and goal orien-
tated type of behavioral inhibition, concerned
with responding under restraint. Thus, rather than
operating independently, proactive and reactive
inhibition act synergistically to enhance behavio-
ral inhibition, wherein engagement of proactive
inhibition enhances the efficacy of reactive inhibi-
tion (Schall et al., 2017).
In everyday life, various sensory cues from the
environment have the potential to trigger relevant
motor actions. This activation of a movement
triggered by simple external cues is an automatic
mechanism, which prompts motor preparation
in order to facilitate motor execution (Sumner
and Husain, 2008). Whilst these prompts afford
certain motor advantages, they require a mecha-
nism to prevent us from responding to every cue
in our environment. This introduces automatic
inhibition which is used to avoid automatic cou-
pling of sensory cues to motor actions. It was
initially identified when a patient with a visual
cortex lesion could still differentiate between two
visual stimuli, despite not consciously perceiving
them (Weiskrantz et al., 1974). Following this, it
has been found that subliminal, sensory cues can
modulate motor actions (Eimer and Schlaghecken,
2003; Obhi, 2007). Whilst reactive inhibition can
become automatic and habitual through learning
and repetition, automatic inhibition differs in that
its effects are derived subliminally. Simply put,
the sensory cues which evoke automatic inhibi-
tion are not perceived, whereas they are in reactive
inhibition.
As with response initiation, reaction time para-
digms form the mainstay of laboratory investiga-
tion of behavioral motor inhibition. Two popular
tasks to probe action restraint and reactive inhibi-
tion are the go/no-go task and the stop-signal task
(SST), both of which require participants to with-
hold or suddenly abort prepotent motor responses.
In the go/no-go task, participants are asked to
respond as quickly as possible to either a go cue
(e.g., a green circle) but to withhold responding to
a stop cue (e.g., red cross, Figure 24.5). On an SST,
participants are instructed to respond quickly to a
go stimulus but to stop themselves from making
a response when a stop signal (e.g., red cross or
tone) is presented shortly after the go stimulus on
a percentage of trials.
The ability to enact reactive inhibition can be
made more or less difficult by changing the ratio
of go and stop trials; the greater the proportion
of go trials, the greater the chance of participants
responding on a stop trial (making a stop failure
commission error), thereby making the response
more prepotent and reactive inhibition more dif-
ficult. The time delay between the go and stop
cues is made shorter or longer to make reactive
inhibition more or less difficult, respectively. In
addition to the adjustment in the stop signal delay
(interval between go and stop signals), as noted
above, the ratio of go and stop trials can be adjusted
to change the difficulty of reactive inhibition.
An important feature of the SST is that the time
delay between the go and stop cues is dynamically
adjusted based on the participant’s performance,
which normalizes the proportion of successfully
stopped trials between participants. The efficacy
of reactive inhibition must be inferred in the SST,
given that successful reactive inhibition is achieved
by the absence of a response. The inferred meas-
ure is termed the stop signal reaction time (SSRT),
which gives an indication of how well a partici-
pant can stop reactively (Figure 24.5). Whilst both
the SST and go/no-go tasks are both used to meas-
ure reactive inhibition, they require inhibition of
movements at different phases of movement: in
the go/no-go task reactive inhibition involves inhi-
bition of movement initiation, whereas in the SST,
reactive inhibition requires cancelling a movement
that has already been initiated (see Verbruggen
et al., 2019, for consensus view on the measure-
ment of response inhibition).
Proactive inhibition can be assessed by com-
paring reaction times on go trials between tasks
with and without stop trials. The assumption is
that on tasks with no stop trials, no or little proac-
tive control is exerted whereas reaction time tasks
with stop trials involve proactive inhibition, since
individuals slow their responses to the go signal
in anticipation of a stop signal, despite instruc-
tions not to do so. Hence the difference in reaction
time on go trials between tasks with and without
stop trials gives an index of proactive control.
More specifically, participants have faster reaction
times on go trials when they are performed in a
task with no stop signals than in a task with stop
signals due to the anticipation of potentially stop-
ping in the latter. One caveat to measuring pro-
active inhibition in this manner is the difference
in attentional demands between tasks, which may
confound measures of proactive control (Dimoska
and Johnstone, 2008; Elchlepp et al., 2016; Jahfari
et al., 2015; Liebrand et al., 2017; Verbruggen
et al., 2014). A variant of the SST, the conditional
stop-signal task (CSST), addresses this caveat by
simultaneously probing reactive and proactive
inhibition in the same task (Obeso et al., 2014;
Rawji et al., 2020). Participants make responses
to one of two go stimuli (e.g., right or left pointing
arrows) and stop signals are presented after the go
stimuli, as in the SST. At the beginning of the task,
participants are instructed that they must follow
the stopping rule if the stop signal appears after
one of the go stimuli only (right OR left point-
ing arrow). In doing so, participants slow their
 Motor Control: Response Preparation, Initiation, and Inhibition 391

Figure 24.5 The behavioral assessment of response inhibition.

Reactive inhibition is typically studied using the go/no-go or stop-signal task.
Panel a: In the go/no-go task, one of two signals can appear after the fixation cross – a go
(green circle) or no-go (red cross) signal.
Panel b: The stop-signal task asks participants to respond to a go cue on all trials (right
arrow). On a minority of trials, a stop signal (red cross) is shown after the go cue, instructing
participants to abort the ongoing response. Whilst both tasks measure reactive inhibition, an
important difference is that successful reactive inhibition in the go/no-go task is achieved
by inhibition of response initiation, whereas it is achieved by inhibition on an already initi-
ated response in the stop-signal task. Proactive inhibition can be measured by measuring the
reaction time difference between go reaction times in tasks with and without no-go/stop
signals, or by use of the conditional stop-signal task (see text).
Panel c: Automatic inhibition is measured using masked priming tasks. Primes are only shown
for short times (approximately 17 ms) and are then obscured by masks. Following the mask,
the target cue appears, which is shown for longer. Importantly, the prime is not consciously
perceived, yet its identity affects reaction times to targets such that if a prime and target
are the same, there is a reaction time shortening relative to a condition without priming or
if the prime and target are opposite. A reversal of this normal priming effect is seen when
the delay between prime and target reaches approximately 150 ms, believed to reflect auto-
matic motor inhibition. Darker hands underneath each task represent the correct/chosen
responses. Created with BioRender.com.

responses on go trials to the direction that they
might have to stop, thereby exerting proactive
control; the reaction time difference on go trials
between the two conditions is the objective meas-
ure of proactive inhibition.
Automatic motor inhibition is assessed using the
masked priming task (Eimer and Schlaghecken,
2003; Rawji et al., 2020). Participants are asked to
make responses to one of two directions (left cue or
right cue) following a go cue (baseline condition).
392 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Preceding this go cue, a prime (left cue or right
cue) is presented for a short time (17 ms) followed
by a non-sensical mask (randomly orientated
lines), which occludes the prime. Importantly, the
prime is presented for such a short time that it is
not consciously perceived. Despite this, the iden-
tity of the prime confers differential effects on the
reaction time to the go cue such that if the prime
and go cue are the same, responses are made faster
than the baseline reaction time. Conversely, if the
prime and go cue are different from each other, the
reaction time is longer than baseline.
Given that the prime is not consciously per-
ceived, its effects are deemed as being automatic.
Indeed, the lack of generalization provides evi-
dence of its automaticity; primes only modulate
performance if they are of the same kind as go
cues. For example, prime-cue effects are seen if
the combinations are both left/rightward facing
arrows, but not if the prime is an arrow and the
target is a letter (L or R) denoting the effector to
be used (left or right, respectively). Interestingly,
reversal of the priming effect is seen as the time
interval between prime and go cue is increased
above 150 ms, such that incompatible prime-cue
pairs now result in faster reaction times than com-
patible prime-cue pairs. The magnitude of the
reaction time reversal above 150 ms is deemed to
be the objective readout of automatic motor inhibi-
tion (Aron et al., 2003; Eimer and Schlaghecken,
1998, 2003; Lleras and Enns, 2004; Sohrabi and
West, 2009; Wilson et al., 2011).
The proposed mechanism for automatic inhibi-
tion is as follows: the subliminal prime causes an
automatic, initial motor facilitation correspond-
ing to the prime choice alternative. The prime is
then replaced by the mask, which decreases motor
activity for the prime and causes motor inhi-
bition. If the go cue is presented early after the
prime, when motor facilitation is still active, then
responses are faster during compatible trials. If the
go cue is presented late after the prime (interval
above 150 ms), when motor inhibition has now
occurred, then responses on compatible trials are
now slower (Eimer and Schlaghecken, 1998). This
model of how the prime and go cue interact is
supported by LRPs measured during the masked
priming task, which show a tri-phasic waveform.
The first two peaks are thought to form the exci-
tation-then-inhibition induced by the prime-mask
combination, with the final peak corresponding to
motor execution (Seiss et al., 2014).
Neuroimaging studies in humans have shown
that the neuroanatomical substrates mediating
different forms of behavioral inhibition are ana-
tomically distinct, although they all operate via the
basal ganglia to exert their influences on behavior
(Jahanshahi and Rothwell, 2017; Jahanshahi et al.,
2015). Indeed, pathologies of the basal ganglia
such as Parkinson’s disease (Obeso et al., 2011)
and Huntington’s disease (Rao et al., 2014) have
shown deficits in response inhibition.
Functional neuroimaging studies have shown
that reactive inhibition is implemented using
a circuit incorporating the right inferior fron-
tal gyrus (rIFG), pre-SMA (Simmonds et al.,
2008), and subthalamic nucleus (STN) via a
cortico-subthalamic hyperdirect pathway (Frank
et al., 2007; Nambu et al., 2002). In particular, the
STN is an important node in the inhibitory control
network, given that its activity correlates with that
of the rIFG and is negatively correlated with the
SSRT (Aron et al., 2007). In addition, the strength
of activity in these nodes is greater during suc-
cessful than unsuccessful stop trials (Aron, 2006).
Patients with Parkinson’s disease who undergo
deep brain stimulation have electrodes implanted
in their STN, which can be recorded from during
tasks of response inhibition. Patients with deep
brain stimulation of the STN show impaired per-
formance on motor tasks involving inhibitory con-
trol relative to patients without DBS and healthy,
age-matched controls (Hershey et al., 2004; Obeso
et al., 2013; Georgiev et al, 2016). Notably, the
impairments in both reactive and proactive inhibi-
tion are observed in patients who have undergone
a right-sided subthalamotomy only (Obeso et al.,
2014) a finding that is consistent with the right lat-
eralization of the stopping network (Aron, 2006).
Electrophysiological recordings of the STN in
patients with Parkinson’s disease who have had
DBS surgery show an increase in beta-band power
during successful action restraint in a go/no-go task
(Kühn et al., 2004). Transcranial magnetic stimu-
lation (TMS) of the motor cortex has been applied
during tasks of reactive inhibition to provide an
insight into the cortical dynamics of reactive
inhibition, finding that motor cortex excitability
is suppressed in response to stop signal presenta-
tion (MacDonald et al., 2014; Sohn et al., 2002;
Van Den Wildenberg et al., 2010). This decrement
in excitability is not only limited to the effector
that is to stop but also produces global influences
on motor system output. For example, suddenly
aborting speech decreases motor cortex activity in
hand muscles, too (Badry et al., 2009; Greenhouse
et al., 2012; Majid et al., 2012; Pouget et al., 2017;
Wessel et al., 2013). Of note, successful stopping
results in motor cortical excitability reducing to a
level lower than that at baseline, suggesting that
successful stopping is due to an active inhibitory
process (Coxon, 2006; Sohn et al., 2002).
Proactive inhibition is implemented through
the cortico-striatal-thalamo-cortical indirect path-
way of the basal ganglia (Aron, 2006; Jahanshahi
et al., 2015). As with tasks of reactive inhibition,
 Motor Control: Response Preparation, Initiation, and Inhibition
functional neuroimaging has shown greater activa-
tion of the striatum (Vink et al., 2005; Zandbelt
and Vink, 2010) and dorsolateral prefrontal cor-
tex (DLPFC) (Chikazoe et al., 2009; Jahfari et al.,
2010; Smittenaar et al., 2013) when a stop signal is
anticipated. Proactive inhibition measured during
the CSST is impaired in patients with Parkinson’s
disease who have undergone a right-sided sub-
thalamotomy and as with reactive inhibition, this
effect seems to lateralize to the right hemisphere
given that there was no differential effect on pro-
active inhibition in patients with left-sided sub-
thalamotomies (Obeso et al., 2014). The STN may
be perfectly suited to implementing proactive inhi-
bition given that it acts as a “hold-your-horses”
signal, which pauses movement until conflict can
be resolved (Frank et al., 2007). Proactive inhibi-
tion usually necessitates the inhibition of a spe-
cific response, as in the CSST. In these tasks of
selective stopping that employ proactive inhibi-
tion, motor cortex excitability is held lower than
the baseline value, again suggesting an active sup-
pression as the movement is being prepared (Cai
et al., 2011; Claffey et al., 2010). Contrary to the
global suppression during reactive stopping, pro-
active inhibition is focal and specific to the effec-
tor that might need to stop (Cai et al., 2011).
Patients with lesions have provided a rich
source to study the neuroanatomical basis of auto-
matic inhibition. Two such patients with small,
focal lesions of the SMA and supplementary eye
field (SEF) display impaired automatic inhibition
specific to the effector supplied by the SMA/SEF.
That is, the patient with the SMA lesion showed
impaired automatic inhibition if the task involved
responding with the contralateral limb but normal
automatic inhibition when the task was performed
with eye movements. The reverse was observed
in the patient with the SEF lesion (Sumner et al.,
2007). Functional neuroimaging during the
masked priming task has highlighted the basal
ganglia (striatum) (D’Ostilio et al., 2012) and
thalamus (Aron et al., 2003) although both studies
were performed in patients with neurological dis-
ease. Furthermore, patients with primary tic disor-
ders (believed to be due to pathologies of the basal
ganglia striatum) and SMA show impairments in
automatic inhibition (Rawji et al., 2020).
SUMMARY AND CONCLUSIONS
Human voluntary movement is co-ordinated by a
network of interconnected brain regions, each of
which plays a particular role. The main outflow
of the motor system operates through the
393
corticospinal tract, which has varied inputs from
across the cortex. The basal ganglia help select
an optimal motor programme given a particular
situation, and the execution of the ensuing move-
ment is made smooth by the cerebellum. The
sensory consequences of ongoing movements are
used to update subsequent motor plans, such that
movement goals are met in an ever-changing
environment. The stages of voluntary movement
have been parsed into preparation, initiation and
execution, and reaction time paradigms have
been developed in an attempt to understand how
these processes are enacted by the brain.
Neuroimaging and neurophysiology have shown
a particular role of the SMA during movement
preparation, with its engagement depending on
whether movement is internally generated or
externally triggered, and the predictability of
movement initiation. Finally, movements are
executed via the corticospinal tract, following a
“motor command” issued by the motor cortex.
Changes in the environment may necessitate ces-
sation of ongoing motor output, requiring motor
inhibition. Conceptually, behavioral inhibition is
subdivided depending on the type of inhibition
required and the circuits mediating each type of
response inhibition have been shown to be neuro-
anatomically distinct. The motor system has the
degrees of freedom and flexibility to generate the
multitude and range of gross (e.g., gait) and fine
movements (e.g., playing the violin) that are
necessary for us to move, act and interact with
our environment and other people.
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 25
Olfactory and Gustatory
Sensation-Perception
Anna Kristina Hernandez, Laiquan Zou,
and Thomas Hummel

INTRODUCTION older people as it is also an expression of over-

Unlike vision and audition, the value of olfaction
and gustation is often neglected, and only recog-
nized when these senses are lost. Then it becomes
clear that olfaction and gustation play an impor-
tant role in our daily life, including detection of
environmental dangers (i.e., fire, toxic fumes,
spoiled food, etc.), enjoyment of food, social com-
munication, and the overall quality of life (Schäfer
et al., 2021).
Among many other factors, olfactory sensi-
tivity depends on age and gender. Women are
superior to men in virtually all aspects of olfac-
tory function (Sorokowski et al. 2019), although
the effect sizes are not very large. The exact rea-
son for this is unclear. Hormonal effect has been
discussed but remains a matter of debate (Doty
and Cameron, 2009); possibly the higher social
awareness of women also plays a role, in so far
that women, more than men, show interest in
odours as social signals (e.g., body odors, food
odors). Accordingly, women on average suffer
more than men from loss of smell (Frasnelli and
Hummel, 2005). The reduced ability to smell with
increasing age is long known (Doty et al., 1984)
and is also partly due to the decrease in receptor
expression patterns (Verbeurgt et al., 2014). The
degree of presbyosmia can, however, vary among
all health (Mackay-Sim et al., 2006). People who
have “aged well” and do not take any medication
seem to have essentially normal smell thresholds
(Almkvist et al., 1992). The slow, age-related loss
of smell is however not always noticed or com-
plained about; and the loss of “fine taste” is appar-
ently partly offset by gustatory and trigeminal
sensations (Shu et al., 2009).
In the general population, complete or partial
loss of olfactory function have been reported in
3.6 to 5.8%, and 13 to 18% respectively (Hummel
et al., 2017), while gustatory dysfuction is less
frequent and occurs with an estimated preva-
lence of 5% (Welge-Luessen et al., 2011) to 20%
(Vennemann et al., 2008), depending on defini-
tions or assessment tools used for smell or taste
loss. Previous studies showed that, apart from
aging, olfactory dysfunction can have various
causes, including head trauma, infections of the
upper respiratory tract, sinonasal diseases, drugs
or toxins, or neurological disease (Hummel et al.,
2017; Whitcroft and Hummel, 2019). In addi-
tion, it is estimated that approximately 1 of 8000
individuals have congenital anosmia (Abolmaali
et al., 2002). As for gustatory dysfunction, the
main causes, apart from idiopathic gustatory dys-
function, are as follows: direct nerve injuries (i.e.,
after dental/oral/ear surgery, neurologic diseases,
 Olfactory and Gustatory Sensation-Perception
stroke, head trauma, etc.), vitamin and mineral
deficiencies, systemic diseases (i.e., cancer, dia-
betes, sarcoidosis, etc.), side effects from drugs
(i.e., chemotherapy), post-infectious (i.e., Bell’s
palsy), and idiopathic or psychologic causes (i.e.,
Burning mouth syndrome) (Hsieh et al., 2022;
Bromley and Doty, 2015; Zhu and Hummel,
2021; Fark et al., 2013). In recent years, olfactory
and gustatory dysfunction have been considered
as dominant symptoms of the coronavirus dis-
ease 2019 (COVID-19) infection (Parma et al.,
2020; Saniasiaya et al., 2022; Trecca et al., 2022;
Whitcroft and Hummel, 2020).
Over the past decades, many different
approaches have been available to evaluate olfac-
tory and gustatory function, including subjective,
self-reported questionnaires or scales, psycho-
physical tests, electrophysiological tests and neu-
roimaging (Hummel et al., 2017; Han et al., 2020).
To provide a better understanding of the olfactory
and gustatory sensation, this chapter contains a
summary of various testing options used to evalu-
ate olfactory and gustatory function in humans
and an overview on the description, epidemiol-
ogy, assessment, and treatment of olfactory and
gustatory disorders.
OLFACTORY SENSATION
Anatomy and Physiology
The perception of odor requires the activation of
the olfactory nerve (Cranial Nerve I), and also the
trigeminal nerve (Cranial Nerve V) especially in
higher concentrations (Frasnelli and Manescu,
2017), by volatile chemicals through the
nasal cavity. Somatosensory and chemesthetic
sensations of the nose (i.e., burning, warmth, cold-
ness, and pain) may accompany odor perception
(Frasnelli and Manescu, 2017; Whitcroft and
Hummel, 2019). The presence of adequate nasal
airflow and an intact peripheral and central olfac-
tory system are, likewise, important in this process.
Olfactory Neuroepithelium
The olfactory neuroepithelium, composed of
pseudostratified columnar epithelium (Young and
Heath, 2000), is a small (∼2 to 5cm2) area of nasal
mucosa located inferior to the cribriform plate, on
the upper nasal septum, the dorsal superior turbi-
nate, and the middle turbinate, with approximately
5 to 15% of incoming airstream passing near it.
(Zhao and Frye, 2015). Alterations in the nasal
anatomy (i.e., septal deviation, fractures, tumors,
399
etc.) may affect the flow of air to the olfactory
neuroepithelium. In particular, certain areas in the
nasal cavity, namely: the area of the olfactory cleft
and the nasal valve, were found to be important
for individual variation of odor thresholds among
healthy individuals (Damm et al., 2002).
In the human genome, there are approximately
1000 olfactory receptors encoded, of which
approximately 380 are functionally expressed in
the human olfactory epithelium (Buck and Axel,
1991; Firestein, 2001). Each olfactory receptor
neuron (ORN) expresses a specific receptor type.
A single odorant typically binds to different recep-
tor types, which ultimately leads to different acti-
vation patterns in the olfactory bulb. The axonal
projections are then conveyed with the relay in the
olfactory bulb via the olfactory tract to the primary
and secondary olfactory cortices, including the
piriform cortex, the amygdala, the rostral entorhi-
nal cortex, orbitofrontal cortex (OFC), hippocam-
pus, parahippocampal gyrus, cingulate cortex,
insula, striatum hypothalamus, and the mediodor-
sal thalamus (Zhou et al., 2019; Gottfried, 2010).
Orthonasal and Retronasal Olfaction
There are two different pathways for odor mole-
cules to reach the olfactory epithelium in the
human olfactory system (i.e., orthonasal and ret-
ronasal olfaction (Rozin, 1982)). In orthonasal
olfaction, odors are perceived during breathing
and sniffing through the nostrils; whereas in retro-
nasal olfaction, odors reach the olfactory mucosa
via the nasopharynx during eating or drinking.
OLFACTORY ASSESSMENT
Different approaches can be used to evaluate
olfactory function: (1) Subjective, self-reported
olfactory questionnaires or scales (Han et al.,
2020); (2) Psychophysical olfactory tests;
(3) Olfactory measures using electrophysiology
studies or magnetic resonance imaging. In the fol-
lowing sections, various methods of olfactory
assessment are described in detail.
Psychometric Questionnaires
Frasnelli and Hummel (2005) developed the most
widely used self-report olfactory dysfunction
questionnaire (i.e., Questionnaire of Olfactory
Disorders; QOD). The QOD is divided into four
subscales: four items on parosmia, 19 items on
quality of life, four items on socially desired
400 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
responses, and five items on visual analogue scale
ratings on problems arising from olfactory dys-
function related to work, to the family, and to
one’s social life. Due to the questionnaire’s good
reliability and validity, it has been increasingly
used by clinicians and researchers, and multi-lan-
guage versions have been validated, such as
Chinese, English, Persian, and Korean (Choi
et al., 2018; Jalessi et al., 2017; Langstaff et al.,
2019; Shu et al., 2011; Yang et al., 2016).
In order to have a broader clinical and research
utility, Mattos et al. (2019) developed a brief ver-
sion of the QOD-NS, which only includes seven
items and maintains consistency with the 17-item
QOD-NS. Zou et al. (2022) further evaluated
the reliability and validity of the brief QOD,
including seven items concerning quality of life
(QOD-QOL), four items concerning parosmia
(QOD-P), and three visual analogue scales con-
cerning disease burden, awareness of the disorder,
and issues related to professional life (QOD-VAS).
The brief QOD showed suitable reliability and
validity for assessing the subjective severity of
olfactory dysfunction.
The QOD is widely used in both clinical and
research settings. It provides insight regard-
ing both qualitative olfactory dysfunction (i.e.,
parosmia) and olfactory-related quality of life.
However, there is a need for shorter screening ver-
sions of these established psychometric measures
for easier use in a clinical context. Zou et al. (2020)
developed the Self-Reported Mini Olfactory
Questionnaire (Self-MOQ) to screen for quan-
titative olfactory dysfunction (i.e., anosmia and
hyposmia). It includes only five items, but these
items describe situations that are very common
and usually experienced in daily life, for example:
“I do not perceive the smell of coffee and fresh
bread.” The Self-MOQ has good internal reliability
and validity. The receiver operating characteristic
(ROC) analyses indicated that the Self-MOQ is an
effective measure for discriminating normosmic
from hyposmic and anosmic patients. In China,
Liu et al. (2021) developed the Self-reported
Olfactory Dysfunction Questionnaire (SODQ) for
screening quantitative olfactory dysfunction. The
SODQ consists of 10 items with excellent reli-
ability and high validity. Using the Self-MOQ or
SODQ, the optimal cut-off scores are 3.5 or 22,
respectively, for distinguishing normosmic indi-
viduals from olfactory dysfunction patients (Liu
et al., 2021; Zou et al., 2020).
Apart from the above-mentioned questionnaires
for qualitative or quantitative olfactory dysfunc-
tion, a questionnaire to measure hedonic capac-
ity for experiencing olfactory pleasure, namely,
the Chemosensory Pleasure Scale (CPS), has also
been developed (CPS; Qiu et al., 2021; Zhao et al.,
2019). It consists of 12 items divided into three
factors: food, imagination, and nature, which rep-
resent the ability to experience pleasure while eat-
ing, anticipating food, and smelling natural scents,
respectively. The CPS has good validity and high
test-retest reliability in various versions for adults
and adolescents/children (Qiu et al., 2021, 2022;
Zhao et al., 2019).
PSYCHOPHYSICAL TESTS
Orthonasal Olfactory Function
A variety of olfactory tests have been developed to
assess orthonasal olfactory function for clinical
and research purposes (Hummel and Podlesek
2021). In this part, we focus on the two most
widely used tests (i.e., the “Sniffin’ Sticks” test
(Hummel et al., 1997) and the University of
Pennsylvania Smell Identification Test [SIT-40]
(Doty et al., 1984)).
The “Sniffin’ Sticks” test battery is com-
prised of reusable felt-tip pens that are used to
test for odor threshold (T), discrimination (D),
and identification (I) (Hummel et al., 1997;
see Figure 25.1). For odor threshold and dis-
crimination tests, a three-alternative forced-
choice paradigm is used. The tests include
16 triplets of pens that are presented at a distance
of about 2 cm from the nostrils. Scores for odor
threshold and discrimination ranges from 1 or
0, respectively, to 16. For odor identification, a
four-alternative forced-choice method is used.
Sixteen (16) pens containing suprathreshold
concentrations of common odors are presented
and participants are tasked to select among four
(4) alternative descriptors (including both words
and pictures), the one that best corresponds to
their perceived odor. Scores for odor identifica-
tion ranges from 0 to 16. A composite TDI score,
composed of odor threshold, discrimination, and
identification scores, ranges from 1 to 48, with
higher scores indicating better olfactory ability.
The “Sniffin’ Sticks” Test has good reliability
and validity, and normative data from a wide
age range (from children to elderly population)
are available (Hummel et al., 2007; Kobal et al.,
2000; Oleszkiewicz et al., 2019). It has also been
adapted and validated in a number of different
countries (Catana et al., 2012; Dalton et al., 2013;
Delgado-Losada et al., 2020; Fjaeldstad et al.,
2015; Konstantinidis et al., 2008; Langstaff et al.,
2021; Neumann et al., 2012; Oleszkiewicz et al.,
2016; Ribeiro et al., 2016; Sai-Guan et al., 2020;
Tekeli et al., 2013).
 Olfactory and Gustatory Sensation-Perception 401

Figure 25.1 Various psychophysical olfactory and gustatory tests.

A. The “Sniffin’ Sticks” test battery (Hummel et al., 1997): Odor identification test in
foreground. Olfactory threshold test in the middle. Olfactory discrimination test in the back.
B & C. The retronasal test battery. B. Odor delivery container for retronasal olfactory threshold.
C. Tasteless powders for retronasal olfactory identification.
D. The Taste Strips test (Landis et al., 2009): Filter paper strips are infiltrated with four con-
centrations each of sucrose, citric acid, sodium chloride, and quinine hydrochloride. It can
test the taste function of the whole or only the left or right side of the tongue.
Sources: Yoshino et al., 2021; Zhu & Hummel, 2022.

The SIT-40 includes 40 “scratch and sniff”
microencapsulated odors and is a reliable, stand-
ardized, forced-choice identification test (Doty
et al., 1984). The total SIT-40 score ranges from
0 to 40, with higher scores indicating better olfac-
tory identification ability and extremely low
scores indicating possible malingering. Similar to
other olfactory tests, it allows the categorization of
olfactory function into normosmia, “microsmia”,
and anosmia. Normative data from children to the
elderly population are also available. It has been
adapted and validated for use in a number of dif-
ferent countries, such as China, Iran, Brazil, and
Portugal (Fornazieri et al., 2013, 2015; Jiang et al.,
2014; Kamrava et al., 2014).
Retronasal olfactory function
In contrast to orthonasal olfaction, there are lim-
ited methods for assessing retronasal olfaction
(i.e., flavor perception). Several established tools
used to assess retronasal flavor identification
function include the taste powders test (Heilmann
et al., 2002), Candy Smell Test (Renner et al.,
2009), and tasteless powders test (Pieniak et al.,
2021; Yoshino et al., 2021).
The taste powders test contains 20 grocery-
available food powders (Heilmann et al., 2002).
It is a four-alternative forced-choice identification
test where powders are placed on the center of
the tongue inside the oral cavity, and subjects are
asked to identify the taste based on a list of four
verbal descriptors. Similarly, the Candy Smell
Test (CST) consists of 23 different aromatized
smell candies using four-alternative forced-choice
procedure (Renner et al., 2009). The CST is suit-
able for both children and adults. Furthermore, a
shortened self-administered version of the CST
consisting of seven items (7-CST) was developed
by Besser et al. (2020).
However, both the taste powders and CST
are limited when assessing retronasal olfactory
402 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
identification function, in that they have both
taste and/or texture components, which is espe-
cially true for the taste powders, and are not pure
tests of retronasal olfaction alone (Yoshino et al.,
2021),. Therefore, to overcome the issue, a new
test for assessing retronasal identification with
tasteless powders was developed (Yoshino et al.,
2021). The tasteless powder test is comprised of
20 aroma powders which are selected to minimize
stimulation of taste. Based on the tasteless powder
test, Pieniak et al. (2021) developed the Q-Powers,
a 3-item version of the tasteless powders test used
for quick retronasal screening purposes.
The above-mentioned retronasal olfactory
tests can only assess odor identification function.
To assess retronasal function more completely,
Yoshino et al. (2021) developed a retronasal test
battery comprised of the retronasal olfactory
threshold and identification function (Figure 25.1)
which has been examined for validity and reli-
ability. The retronasal olfactory threshold was
assessed using a modified odor delivery container
procedure, whilst identification function was eval-
uated using 16 tasteless powders.
OLFACTORY TESTING IN CHILDREN
Although the “Sniffin’ Sticks” test and SIT-40 are
widely used in both clinical and research contexts,
these tests may not accurately measure children’s
olfactory ability due, in part, to children’s limited
attention span and unfamiliarity with the odors
(Zou et al., 2020). Several odor-identification tests
have been developed for children, such as, the
Sydney Children’s Hospital Odor Identification
Test (SCHOT; Jiang et al., 2014), the Lyon
Clinical Olfactory Test (LCOT; Monnery-Patris
et al., 2009), the NIH Toolbox Odor Identification
Test (Dalton et al., 2013), the Smell Wheel
(Cameron and Doty, 2013), and the “Sniffin’
Kids” Test (Schriever et al., 2014). However, these
tests for children have not been validated in a
cross-cultural context. Hence, Schriever and col-
leagues developed the U-Sniff test as an interna-
tional 12-item odor identification test for children
(Schriever et al., 2018). Similar to the “Sniffin’
Sticks” Test, it is based on reusable felt-tip pen-
like devices. The U-Sniff Test for children shows
a high test-retest reliability on a global scale,
normative data of the U-Sniff test has been estab-
lished for 27 countries (Gellrich et al., 2019; Zou
et al., 2020). While the above olfactory tests for
children are used to assess orthonasal olfaction,
no methods have been developed to specifically
assess retronasal olfaction in children. The CST
may be suitable for children (Renner et al., 2009).
However, the reliability and validity of the other
above-mentioned retronasal tests remain to be
investigated.
ELECTROPHYSIOLOGY AND FUNCTIONAL
BRAIN IMAGING
Subjective questionnaires/scales and psychophys-
ical measures are widely used in clinical practice
and research. However, these tests may be
influenced by patients’ response bias.
Electrophysiological (including electroencepha-
lography and electro-olfactogram) and imaging
techniques provide non-invasive tools to assess
olfaction in a more objective way (Hummel et al.,
2017). Electroencephalography (EEG) and EEG-
derived event-related potentials (ERP) are directly
related to neuronal activation, have high temporal
resolution but low spatial resolution. Several stud-
ies showed that this technique produces reliable
and valid results (Grosser et al., 2000; Hummel
and Heilmann, 2008; Hummel et al., 2007; Lötsch
and Hummel, 2006; Pause and Krauel, 2000;
Rombaux et al., 2010). Localization analysis iden-
tified sources of olfactory ERP in mesial tempo-
ral, lateral temporal, and frontal structures
(Lascano et al., 2010). Electro-olfactograms
(EOG) allow the recording of the olfactory
mucosal potential though an electrode in contact
with the olfactory neuroepithelium (Hummel
et al., 1996; Lapid and Hummel 2013). A non-
invasive method of signal recording from the
olfactory bulb through probes over the nasal
dorsum have been previously reported also
(Iravani et al., 2020). However, the utility of EEG
and EOG is limited to specific centers due to their
dependence on high-precision olfactometry to
deliver precisely known concentrations of odor
(Lundström et al., 2010).
Functional imaging based on positron emis-
sion tomography (PET) and magnetic resonance
imaging (fMRI) map the brain activity via the
cerebral blood flow changes (Savic, 2002). These
techniques have a high spatial resolution and have
significantly contributed to investigate the brain
activity in the processing of olfactory stimuli (Han
et al., 2019). Similar to electrophysiological tech-
niques, an olfactometer is needed to deliver the
relevant odorants when investigating brain activ-
ity. Previous studies showed that odor-induced brain
activation was decreased in patients with olfactory
dysfunction compared to healthy controls in olfac-
tory related regions, including the piriform cor-
tex, amygdala, OFC, insula, and anterior cingulate
 Olfactory and Gustatory Sensation-Perception
cortex (Han et al. 2018; Moon et al. 2018; Pellegrino
et al. 2016). In addition, functional connectivity of
the olfactory related regions including the ante-
rior prefrontal cortex, anterior cingulate cortex, the
entorhinal cortex and the cerebellum was reduced
in patients with olfactory dysfunction (Kollndorfer
et al., 2015a,b). Still, as of today, olfactory FMRI
recordings cannot be used on an individual basis,
for example— to support diagnostical decisions
(Zang et al., 2021).
STRUCTURAL BRAIN IMAGING
The MRI technique can be used to measure the
olfactory bulb volume and olfactory sulcus depth.
As the most important relay station in olfactory
processing, a large number of studies have dem-
onstrated that the OB volume is related to olfac-
tory function and the prognosis of olfactory loss
(Buschhüter et al., 2008; Lu et al., 2021; Mazal
et al., 2016; Rombaux et al., 2012; Seubert et al.,
2013; Yousem et al., 1998). Furthermore, a recent
systematic review showed that strong associations
between OB volume and olfactory function were
consistently found across various etiologies of
olfactory disorders in previous studies
(Manan et al., 2022).
The olfactory sulcus receives indirect projec-
tions from the olfactory bulb and the depth of the
sulcus can be used in evaluating olfactory function
(Abolmaali et al., 2002; Huart et al., 2011). It has
been shown that there is a relationship between
olfactory sulcus depth and olfactory function in
healthy subjects (Hummel et al., 2003) and in
olfactory dysfunction patients (Abolmaali et al.,
2002; Huart et al., 2011; Hummel et al., 2015;
Karstensen et al., 2018; Miao et al., 2015); there-
fore, it appears helpful to measure these routinely
in clinical settings.
Apart from its relation to the olfactory bulb
and sulcus, olfactory dysfunction also results in
structural changes in higher-order brain regions.
Manan et al. (2022) conducted a systematic
review on the morphological variations in gray
matter and white matter volume in both congenital
and acquired anosmia. Individuals with acquired
anosmia were found to have reduced gray matter
in the gyrus rectus, medial orbitofrontal cortex,
anterior cingulate cortex, and cerebellum, whereas
those with congenital anosmia had larger volume
and greater thickness in parts of the olfactory net-
work, including the piriform cortex, orbitofrontal
cortex, and insula. In addition, previous diffusion
tensor imaging (DTI) studies showed that olfac-
tory function is positively correlated with white
403
matter integrity (Gullmar et al. 2017; Segura et al.
2013; Woodward et al. 2017). Chen et al. (2020)
further found that patients with olfactory dysfunc-
tion demonstrated relevant white matter network
dysfunction, although their structural integrity
remained intact.
OLFACTORY DYSFUNCTION
Description and Epidemiology
Olfactory dysfunction can be distinguished as
quantitative and qualitative impairment.
Quantitative olfactory dysfunction may be classi-
fied into two: hyposmia and anosmia. Hyposmia
is defined as a reduced perception of odors, while
anosmia is the inability to perceive odors (Hummel
et al., 2017, Hernandez et al., 2023). On the other
hand, qualitative olfactory dysfunction can be
further classified as either parosmia or phantos-
mia. Parosmia is defined as distorted perception of
an odor, while phantosmia refers to a perception
of an odor in the absence of an odor stimulus
(Hummel et al., 2017; Leopold, 2002; Hernandez
et al., 2023).
Prevalence of olfactory dysfunction can greatly
vary depending on the demographic characteris-
tics of the study population. In a review by Desiato
et al. (2022), the prevalence of olfactory dysfunc-
tion in the general population is as high as 22%.
In addition, some studies report the prevalence of
anosmia and hyposmia in the general population
to be 3.6 to 5.8% anosmia and 13 to 18%, respec-
tively (Hummel et al., 2017). Quantitative olfac-
tory disorders can also be congenital, and may
occur as part of a genetic condition, prenatally
acquired diseases or syndromes, or as an isolated,
idiopathic, non-syndromic olfactory loss with-
out a known genetic cause (Schäfer et al., 2021;
Whitcroft and Hummel, 2021). As for qualitative
impairment (e.g., parosmia), the prevalence is
estimated at around 3.9% in the general popula-
tion (Nordin et al., 2007), although these estimates
greatly depend on how “parosmia” is defined.
OLFACTORY CLINICAL EXAMINATIONS
AND TREATMENTS
Accurate assessment and diagnosis of patients
with olfactory disorders is very important.
Through measurement of olfactory function, clini-
cians are better able to counsel patients on the
404 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
prognosis of their condition and provide guidance
on treatment and other management approaches.
A thorough and systematic clinical history taking
and a full ENT examination should be done
(Hummel et al., 2014, 2017). Questions related to
the nature of the impairment, onset, duration, fre-
quency, severity may already provide insight as to
a probable cause. Other symptoms (both sinonasal
and non-sinonasal), past medical and family med-
ical history, medications or previous treatments,
may help narrow down the list further (Hummel
et al., 2017). As mentioned above, different
approaches can be used to comprehensively evalu-
ate olfactory function. Psychometric question-
naires and scales, such as Self-MOQ and SODQ
can be performed to screen for the presence of
olfactory disorders. These questionnaires have
been shown to be simple, reliable, and valid
screening tools for olfactory dysfunction in clini-
cal practice. However, one should keep in mind
that it is best for questionnaires and scales to be
validated for the target population. Although these
measures may help to screen for olfactory dys-
function, olfactory testing is considered an essen-
tial aspect of olfactory assessment.
Standardized psychophysical orthonasal and
retronasal tests can be easily implemented in clini-
cal practice as less-biased diagnostic tools – in
comparison to ratings – to detect olfactory disor-
ders. The delineation for anosmia, hyposmia, and
normosmia depends on which psychophysical test
is used, and is often based on the performance of
a sample of normal individuals in a particular age
group. For example, in the “Sniffin’ Sticks” test, a
composite TDI score was used to define anosmia
(TDI ≤16), hyposmia (16 < TDI < 30.75), or nor-
mosmia (TDI ≥30.75) (Oleszkiewicz et al., 2019).
The composite score below 17 in the retronasal
test battery (Yoshino et al., 2021b) was the cut-off
value for olfactory disorders.
In contrast to olfactory questionnaires and
psychophysical olfactory tests, electrophysiologi-
cal tools, like olfactory ERP, are less dependent
on subjective response bias and can detect subtle
changes of olfactory function (Peters et al., 2003).
It has clinical value and is feasible for clinical
practice (Güdücü et al., 2019), although the setup
requires expertise in terms of both handling of
dynamic continuous air-flow oflactometry and the
analysis and interpretation of the results.
Structural MRI is the gold standard for the
diagnosis of congenital olfactory dysfunction
which is typically, but not always, associated with
olfactory bulb aplasia or hypoplasia. Previous
studies showed that the depth of the olfactory
sulcus was significantly shorter in patients with
congenital anosmia (Abolmaali et al., 2002; Huart
et al., 2011). Structural alterations in higher-order
olfactory related regions are also affected in the
olfactory disorders secondary to traumatic brain
injury, post-infectious olfactory loss, neurodegen-
erative diseases, and following exposure to toxins
(Han et al., 2019). Moreover, a number of stud-
ies have shown abnormal brain responses to odors
in patients with olfactory disorders (Han et al.,
2019). Currently, structural and functional MRI
may help in investigating the underlying cause of
olfactory disorders. However, it is not common
practice to use structural and functional MRI of
higher-order olfactory-related regions to diagnose
olfactory disorders (Zang et al., 2021).
Patients with smell dysfunction should be
counselled on general safety and may benefit from
installation of smoke/gas alarms and adherence
to use-by dates on food products (Hummel et al.,
2017). Depending on the underlying etiology,
there are several interventions in the treatment of
olfactory disorders. Olfactory training remains to
have the strongest evidence for the treatment of
olfactory loss, with 30% of individuals reporting
improvement in olfactory function after 12 weeks
(Hummel et al., 2009; Patel et al. 2022). Varying
degrees of effect have been reported depending
on the duration of training and etiology of olfac-
tory dysfunction (Oleszkiewicz et al., 2018).
Olfactory training has also been widely studied
in relation to various etiologies of olfactory loss,
including post-infectious (including COVID-19),
post-traumatic, and even in neurodegenerative
diseases (Pieniak et al., 2022). Other treatment
interventions include: corticosteroids (i.e., sys-
temic and topical), intranasal vitamin A, sodium
citrate, phosphodiesterase inhibitors, monoclonal
antibodies, omega-3, platelet rich plasma, palmi-
toyl ethanolamide/luteolin, or surgery (Hernandez
et al., 2022; Hummel et al., 2017; Pieniak et al.,
2022; Whitcroft and Hummel 2019; Yan et al.,
2023). Patients who may experience anxiety or
depression, as well as those who have other sys-
temic or neurologic symptoms should be referred
to specialists as appropriate. (Hummel et al., 2017)
Gustatory sensation
Anatomy and Physiology
The sense of taste is based on the detection of chemi-
cals by specialized taste cells in the mouth. Taste
receptor cells are located within taste buds, which
again are contained in the visible papillae. Fungiform,
circumvallate, and foliate papillae contain taste buds,
while filiform papillae contain only keratinocytes.
Fungiform papillae are scattered across the tip and
middle of the tongue, and usually each papilla con-
tains only one taste bud. The human tongue has
between 2,000 and 8,000 taste pores, each packed
with approximately 50 to 100 taste cells (Chaudhari
 Olfactory and Gustatory Sensation-Perception
and Roper, 2010; Witt et al., 2003). Taste cells have
regenerative capabilities with an approximate life
span of 10 to 20 days.
Taste cells are classified based on their taste
receptor expression profiles. Type I cells are most
abundant, comprising about 50% of cells in taste
buds. These cells provide support and protection
for other taste cells, and are often referred to as
“glia-like cells.” Type I cells may also be respon-
sible for the transduction of salty taste via ionic
currents. Type II cells contain receptors for sweet,
bitter, umami and possibly salty tastes. Type III
cells may respond directly to sour taste stimuli.
Each taste bud also contains 7 to 13 Type IV cells,
which are located at the basement membrane or on
the outside the taste buds. These Type IV cells are
thought to be pluripotent stem cells for regenera-
tion of taste cells every 10 to 14 days (Chaudhari
and Roper, 2010; Witt et al., 2003).
Type II cells in the taste bud express G-protein
coupled receptor proteins (GCRPs) for sweet, bitter
and umami (Chandrashekar et al., 2014). Type III
cells express ionic taste receptors for salty or sour
tastants but the exact receptors have not been fully
elucidated (Kobayakawa and Ogawa, 2014; Niki
et al., 2010). Afferent nerves make contact with the
receptor cells at the base of the taste bud. A single
taste bud may be innervated by several afferents,
while a single fiber may innervate several taste
buds. There is not always a correlation between
chemical stimulant and perceived taste quality;
in turn, different types of chemicals can evoke
similar taste sensations (Smith, 1997; Smith and
St John, 1999).
Information is mainly carried by specific
branches of three cranial nerves (CN). The facial
nerve (CN VII) innervates the anterior two-thirds
of the tongue, the glossopharyngeal nerve (CN
IX) innervates the posterior one-third of the
tongue, and the vagal nerve (CN X) carries taste
information from the back part of the mouth
including the upper third of the esophagus. The
tongue is also innervated by the trigeminal nerve
(CN V), which is involved in tasting through the
perception of touch, pressure, temperature, and
pain (e.g., spicy foods). The first nuclear region
in the brainstem is the nucleus of the solitary
tract of the medulla from which the information
runs to the posteromedial ventral nucleus of the
thalamus, and then to the cortex, where taste
information is integrated with other sensory
information to form a “flavor” (Rolls, 2019).
GUSTATORY DYSFUNCTION
Taste dysfunction can greatly affect an individual’s
safety, quality of life (e.g., increasing risk of
405
ingesting rotten or poisonous foods, devastating the
enjoyment of eating, resulting in changes in eating
habits (Clark, 1998), and mental health (e.g.,
depression and anxiety; Han et al., 2018; Hur et al.,
2018). Malnutrition (Malaty and Malaty, 2013),
metabolic, and cardiovascular disease (Sergi et al.,
2017; Xue et al., 2020) and obesity (Nasser, 2001)
have been reported to follow taste dysfunction.
Taste dysfunction (dysgeusia) can be clinically
categorized as quantitative and qualitative taste
disorders (Landis et al., 2004). Quantitative taste
disorders include ageusia (a complete loss of taste),
hypogeusia (diminished sense of taste), and hyper-
geusia (enhanced taste sensitivity). Qualitative
taste disorders include parageusia and phantogeu-
sia. Parageusia is described as a taste distortion
where gustatory stimuli are reported to be differ-
ent from what they used to be. They are perceived
as bitter, sour, or metallic (e.g., metallic taste when
eating). Phantogeusia relates to a persistent taste
sensation in the absence of stimulation (Boesveldt
et al., 2011). Taste phantoms (phantogeusia) have
been reported in both epilepsy and schizophrenia
(Hausser-Hauw and Bancaud, 1987). In clinical
practice, many patients are found to suffer from
both quantitative and qualitative taste disorders
(Fark et al., 2013).
The three most frequent causes of taste dysfunc-
tion depend on the investigated samples. A study
(Ikeda et al., 2008) based on 408 patients with taste
loss showed that the most frequent causative fac-
tor was the administration of drugs (32%), followed
by idiopathic factors (28%) and systemic disease
(13%). Another study reviewing 491 patients
with quantitative and/or qualitative taste disorders
showed that the three most frequent causes were
idiopathic (34%), head trauma (24%), and surgery
(e.g., tonsillectomy, 15%), with a much lower per-
centage of patients with dysgeusia following admin-
istration of drugs or contact with toxic substances
(4%) (Fark et al., 2013).
GUSTATORY CLINICAL EXAMINATIONS
AND TREATMENTS
Many individuals do not spontaneously report
their taste disorder, particularly if other symptoms
are present (Soter et al., 2008; Welge-Lüssen
et al., 2011). Thus, it appears extremely important
to ask “effective” questions. For example, the
question “Do you have difficulties in recognizing
food or beverages as sweet, sour, bitter, or salty?”
is evidenced to be more effective than the simple
question “Do you have a taste problem?” in
detecting real taste problems and rule out non-
taste problems (Gent et al., 1987).
406 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
However, asking about taste function is unreli-
able and becomes meaningful only with concurrent
testing (Landis et al., 2004). Clinically, psychophys-
ical tests are most commonly used, which involve
different subtypes. For example, based on different
aims, there are taste threshold tests, taste identifi-
cation tests (e.g., Taste strips; Landis et al., 2009,
Zhu & Hummel, 2022; see Figure 25.1) and taste
intensity tests. Based on the use of either chemical
stimuli or electric stimuli, there are chemogustom-
etry and electrogustometry. Based on different test-
ing regions, there could be whole-mouth testing and
regional testing (Zhu and Hummel, 2021).
Taking clinical history from patients is important
(Gent et al., 1987). The history should focus on prob-
able causes and accompanying diseases (e.g., diabe-
tes mellitus, hypothyroidism, or cancer; Malaty and
Malaty, 2013). For example, if abnormalities in the
nervous pathways or lesions of brain are suspected,
electrophysiological tests (Jääskeläinen et al., 1997)
or structural imaging (e.g., MRI) can be employed
(Heckmann et al., 2003). In addition, analysis of
saliva (Bradley and Beidler, 2003), and assessment
of morphological changes of the tongue tissues are
also available if necessary (Hummel et al., 2004).
Blood tests to screen for systemic diseases or defi-
ciency states may be warranted in selected patients
(Hsieh et al., 2022).
Counseling on food safety should be routine,
also possibly referring to other specialists (i.e.,
psychologists, psychiatrist, neurologist, dentist,
etc.) as appropriate (Hummel et al., 2017). Patients
should be warned against overseasoning with salt
or sugar, and instead may be taught to accentu-
ate other sensory experiences of meals (texture,
temperature, color, aroma, spicyness; Bromley
& Doty, 2015). Supplementations with zinc glu-
conate and alpha lipoic acid for several months
have been reported to help restore taste in a subset
of patients (Femiano and Scully, 2002; Takaoka
et al., 2010). In addition, both corticosteroids and
vitamin A have been used to treat taste disorders,
despite the lack of convincing clinical studies.
Thus, in gustatory disorders, the focus is on the
search for, and therapy of, possible underlying
diseases. This approach also includes the thorough
review of drugs taken by the patient (Naik et al.,
2010). If there is no specific treatment option, par-
ticularly in the case of idiopathic dysgeusia, zinc
may be promising according to preliminary data
(Heckmann et al., 2005; Stoll and Oepen, 1994).
SUMMARY AND CONCLUSIONS
The chemical olfactory and gustatory senses are
important in one’s daily life. Generally, three func-
tions are assigned to the sense of smell, namely:
warning us of potential danger, allowing social com-
munication, and facilitating the appreciation of food
and drinks. These functions are also reflected in some
complaints of patients with smell disorders: occur-
rence of accidents related to foods, inability to smell
other people like family members, and the loss of
flavour perception. Still, approximately 5% of the
general population live without the sense of smell
(with “old age” being a major factor in smell loss).
Other causes of olfactory loss include: acute infec-
tions of the upper respiratory tract (like COVID-19),
sinonasal diseases (including chronic rhinosinusitis
or allergies), or head trauma. Of course, people can
live without their sense of smell, but their quality of
life diminishes, with a proportion of them showing
signs of depression.
The discrimination of odor qualities originates
from the olfactory mucosa with olfactory recep-
tor neurons (which can regenerate) expressing
one specific olfactory receptor from a variety of
approximately 400 of them. Odorants typically
activate not just one, but several types of recep-
tors, which then leads to a specific pattern of acti-
vation in the olfactory bulb ultimately resulting
in an olfactory percept. Apart from the olfactory
bulb, numerous other brain structures are involved
in processing of odor-related information (i.e., the
primary olfactory cortex including the entorhinal
and the piriform cortex, the amygdala, and the sec-
ondary olfactory cortex including the hippocam-
pus and the orbitofrontal cortex. In the gustatory
system, with taste cells on the tongue, few recep-
tors are involved in the mediation of sensations
like sweet, umami, sour, and salty, while approxi-
mately 25 receptors detect bitterness. Information
from the mouth is then mediated to the brainstem
through the chorda tympani, the glossopharyngeal
nerve, and the vagus nerve, and is finally received
at the insula, also the primary gustatory cortex.
Being highly interactive, taste, smell, and the
trigeminal system (burning, stinging, or tickling)
are typically integrated within the central nervous
system (CNS) in order to form holistic percepts.
In recent years, there have been major improve-
ments in the assessment of olfactory and gus-
tatory abilities in chemosensory dysfunction,
which is important in the development of treat-
ment options. We discussed the various tests used
to evaluate olfactory and gustatory function in
humans, including questionnaires, psychophysical
tests, as well as electrophysiological and imaging
techniques. Most questionnaires and psychophysi-
cal tests are used for evaluation of adults, while a
few standardized (especially gustatory) tests have
been developed for children. Numerous child-
hood disorders are associated with olfactory and
gustatory dysfunction, so further development and
implementation of simple, useful tools for chil-
dren is necessary.
 Olfactory and Gustatory Sensation-Perception
In contrast to questionnaires and psychophysi-
cal tests, electrophysiological and imaging tech-
niques are objective measuring techniques that can
detect subtle neurological changes of olfactory
and gustatory function. Structural and functional
MRI help us understand olfactory and gustatory
disorders. However, it is far from clinical practice
to investigate higher-order brain regions using
functional MRI as individual markers for diagno-
sis of olfactory and gustatory disorders.
Overall, the chemical senses contribute greatly
to one’s social life, enjoyment of eating and drink-
ing, and quality of life. They are different from
other senses in many aspects, one of them being
that they exhibit strong regenerative capacities.
Based on the evolution of knowledge regarding the
biology of chemical senses over the last 20 years,
there remains more to discover and develop in this
constantly evolving field.
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Interoception and
H u g o D . C r i t c h l e y , Yo k o N a g a i , a n d L i s a Q u a d t
INTRODUCTION
Functions
Interoception is the sense that concerns the inter-
nal physiological state of the body, and encapsu-
lates the afferent signaling, sensing, transmission,
and perceptual representation of internal bodily
signals, transmitted via neural and humoral path-
ways (Cameron, 2002; Craig, 2014; Khalsa et al.,
2018). Interoception drives simple homeostatic
(autonomic and neuroendocrine) reflexes, and
more complex allostatic responses, including
adaptive behavior. In part through the experience
of motivational and emotional feelings, interocep-
tion coordinates physiological changes across
organ systems, and higher-level motivational and
emotional behaviors. By extension, interoception
shapes longer-term behavioral repertoires, to
ensure health and welfare by guiding the selection
and timing of action policies that help maintain
stable access to resources (in, for example, the
planning of routine meals including what to eat,
when to eat, and with whom).
Interoception is distinct from the exteroceptive
senses that sample and describe the external envi-
ronment. Interoception is also conceptually dis-
tinguishable from proprioception, which encodes
26
Thermoreception
the position of the body within the external world.
However, boundaries between interoception and
these other senses are blurred: For example, sens-
ing the environment through tactile, thermal, and
chemoreceptive channels “internalizes” informa-
tion salient to physiological health (Craig, 2014).
Moreover, acting on the environment changes
one’s internal state, since proprioceptive and ves-
tibular feedback of skeletomotor activity is tightly
coupled to efferent autonomic responses, ena-
bling the fine dynamic cardiovascular support of
movement (Yates et al., 2014).
PERCEPTION
Although interoception includes the conscious
perception and appraisal of inner bodily sensa-
tions, for the most part, we are unaware of the
majority of interoceptive signals, when perceived
consciously (e.g., when feeling the need to void
bladder or bowel), visceromotor sensations are
mostly rather diffuse, and lack the perceptual
clarity of exteroceptive senses. When we do
become consciously aware of our internal bodily
signals, this often means that we need to select a
behavior to help maintain homeostatic state
 Interoception and Thermoreception
(i.e., the internal changes of a magnitude that
exceeds the potential for autonomic reflexes to
sustain homeostasis on their own) (Critchley and
Garfinkel, 2017). Perhaps one exception is the
good conscious access we have to respiratory
sensations. Speculatively, this ability to perceptu-
ally track and volitionally regulate breathing may
be tied to the evolutionary development of human
speech. The perception of interoceptive respira-
tory sensations is also closely coupled to more
accessible somatosensory signals of pharyngeal
airflow (Sozansky and Houser, 2014) and chest
wall motion. When internal changes are intense
enough to generate viscerosensory pain, soma-
tosensory pathways are also often recruited. This
can amplify the perceptual precision of the
strength and attributed location of that pain
(Gebhart and Bielefeldt, 2016).
EMOTION
In modern Western psychological thought, interest
in interoception has flourished within the context
of emotion. Physiological sensations, notably of
strong fast heartbeats, have been associated with
passions since at least the time of Aristotle. James
(1884) and Lange (1907) proposed a “peripheral
theory” of emotion that encouraged people to
consider the perception of physiological sensa-
tions as the fundamental basis to emotional feel-
ings, while James highlighted the link between
somatomotor feedback and fear in his suggestion
that “fear is running from the bear.” Lange
emphasized more the relationship between vascu-
lar responses and diffuse emotional feeling states.
Exploration of, and challenges to, this reductionist
model ensued: Evidence against it included
Sherrington’s (1900) observation that emotional/
affective reactivity remained in dogs after the
brain had been (partially) isolated from the physi-
ological state of the body by spinal transection.
Cannon (1927) and Bard (1934) also argued
against James and Lange’s theory by focusing on
the lack of strong emotion-specific patterning to
peripheral bodily responses. However, evidence in
support of the James–Lange therapy included
masking studies that showed physiological reac-
tions to emotive stimuli can be evoked automati-
cally with minimal conscious appraisal (Dimberg
et al., 2000). The issue of lack of specificity of
emotion-related physiological responses was
partly resolved by “two-factor” models. These
were backed by studies showing that the emo-
tional reaction to heightened states of physiologi-
cal arousal in the body (adrenalin-induced) were
415
determined by context (Cantrill and Hunt, 1932;
Schachter and Singer, 1962). Happiness is
reported when arousal is experienced in a happy
emotional context, and anger is reported when
arousal is experienced in an angry emotional
context.
Thus, an emotion may be triggered and inten-
sified by interoceptive signaling of physiological
arousal, yet the explanatory (psychosocial) context
in which the arousal occurs allows the emotion to
be specifically defined and labelled. A related con-
structionist account of human emotion from Lisa
Feldman Barrett (Barrett, 2017), still grounded
on the primacy of interoception, has emerged as a
powerful riposte to the competing idea that there
are individual “basic” emotions (such as fear, dis-
gust, sadness, anger, and happiness) that are deter-
mined by evolution for specific functions. Such
emotions are typically viewed as fundamental
“natural kinds” that have their own specific neu-
ral-circuity and labelled-line responses (Darwin,
1872; Ekman et al., 1983; Panksepp, 2011). The
clinical, experimental and theoretical work of
Antonio Damasio (Damasio, 1999, 2010) revived
an interest in body–brain interaction, placing it
once more toward the foreground of human neu-
ropsychological thinking. Their studies, compar-
ing people with and without specific brain lesions
as they performed gambling tasks, showed that
implicit physiological arousal responses (somatic
markers) can predict and guide adaptive motiva-
tional (“microeconomic”) decisions even before
an individual can consciously describe why they
made a particular decision (Bechara et al., 1997,
2005). This work highlighted the influence of
physiological state and bodily feelings on both
cognition and emotion, and thus reinvigorated the
field of interoception.
BROADER ASPECTS OF INTEROCEPTION
Psychology has weighted interoceptive science
toward the study of how body-to-brain signals
are perceived consciously; with perhaps undue
emphasis on individual differences in people’s
ability to perceive their heart beating at rest. This
continues as a topic of rich debate. In parallel,
other areas of interoceptive science have devel-
oped independently: Advances in the understand-
ing of the gut–brain axis (including microbiome;
Dinan and Cryan, 2017; Meyer 2011), humoral
signaling from tissues (e.g., in energy storage
and metabolism; Sun et al., 2014), and immune-
brain signaling (Dantzer et al., 2008) are influen-
tial fields that carry their own momentum.
416 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
These channels of interoceptive information flow
typically operate on slower timescales than the
neural signaling of autonomically controlled
visceromotor responses. They nonetheless illus-
trate the powerful expression of interoceptive
influences on brain and behavior (Critchley and
Harrison 2013).
INTEROCEPTORS
Charles Sherrington (1906) first proposed the
notion of interoceptors, referring to sensors detect-
ing changes in internal states of the body.
He implied that this concept largely referred to
chemoreception (e.g., from gut) and encompassed
taste responses (now not generally considered
interoceptive). Present conceptualizations of inter-
oception recognize multiple sensors (tuned to
mechanical, chemical, osmotic, and thermal
changes) and a range of transduction mechanisms
(that include free nerve endings, general and spe-
cialized chemoreception, PEIZO mechanosensi-
tive channels, thermal sensing).
Visceromotor signals pertaining to mechani-
cal function (stretch and compression) of visceral
organs (including vessels) are conveyed along
neural pathways (Bernston and Khalsa, 2021),
which also convey peripheral chemosensory infor-
mation about luminal contents and tissue integrity.
The carotid bodies represent one specialist site
of chemosensation. Chemoreceptive signals are
also sampled directly from circulating blood by
the brain itself, via specialized circumventricular
organs and by specific populations of neuroglia
and neurons (Critchley and Harrison, 2013).
MECHANORECEPTION
Many interoceptive sensations have unique quali-
ties, distinct from non-visceral somatosensory
sensations: Feelings of bloating, organ distension,
breathlessness, and nausea are “visceral” (typi-
cally dull or spasmodic and poorly localized).
Even when such sensations intensify to the point
of pain, their origin can remain difficult to localize,
with the exception of referred pain, i.e., where pain
is perceived at a different location than its origin
and radiating into adjacent regions. Thus, cardiac
angina is felt in the left anterior shoulder, medial
upper arm, and throat; pancreatic or renal pain is
felt in the back. These referred locations reflect the
recruitment of more localizable somatosensory
pathways at the same spinal level/dorsal
horn (somatotome) as the strong viscerosensory
input. Intraspinal sensitization also contributes to
the cross-processing of such sensations.
Characteristically, internal organs do not carry the
variety and density of receptor nerve terminals
when compared to the skin surface or specialist
sensory organs. Within the smooth muscle of the
gastrointestinal tract, there are broadly two types
of receptor terminal; intramuscular laminar arrays
(IMAs) and intraganglionic laminar endings
(IGLEs). Both terminal types respond to tissue
stretch and also have chemoreceptive properties
(Bethoud and Neuhuber, 2000). Other visceral
organs possess similar afferent terminals, the car-
diac sensory endings showing greater complexity
(Marron et al., 1995).
Overall, visceral afferent sensors (visceros-
ensory terminals) appear less specialized and
more “primitive” when compared to soma-
tosensory and kinaesthetic receptors in skin,
muscle, tendons, and joints (e.g., Ruffini end-
ings, Merkel cells, and Paccinian corpuscles)
and generally cannot convey perceptions of
nuanced touch, pinch, cutting, tickle, or vibra-
tion. Viscerosensory terminals are innervated
by thin myelinated (A delta) and unmyelinated
(C) nerve fibres that relay information to brain-
stem via prevertebral plexuses and paravertebral
ganglia projections into ascending spinal cord
tracts (Craig, 2004), or more directly via cranial
nerves, most importantly though the vagus nerve
(Berthoud and Neuhuber, 2000; Jaenig, 2008).
CHEMORECEPTION IN THE PERIPHERY
Specialist organs such as the carotid bodies
(innervated by a branch of the glossopharyngeal
cranial nerve) show chemoreceptive sensitivity to
CO2, O2 and pH levels (e.g., through TWIK-
related acid-sensitive K+ channels; Fagerlund
et al., 2010) and provide strong interoceptive
drive for cardiorespiratory reflex control.
Chemoreceptors are also widely distributed across
bodily organs, expressed often on specialized
cells (e.g., neuropods projecting into the gut
lumen) that sample the local chemical environ-
ment. Such sensory cells are innervated by vis-
ceral afferents ultimately entering the vagus nerve
or spinal cord. Viscerosensory nerves themselves,
through “free nerve endings,” can also directly
respond to specific (e.g., glucose, immune, and
hormone receptors) and non-specific (pH, osmo-
larity, cytokine) changes in peripheral chemical
environment.
 Interoception and Thermoreception
CENTRAL CHEMORECEPTION
The brain directly samples internal states via the
circulation: changes in the constitution of the
blood, including the presence of nutrients, hor-
mones, immune modulators, and inflammatory
proteins are detected directly by the brain at the
level of the sensory circumventricular organs:
The area postrema (AP), organum vasculosum of
the lamina terminalae (OVLT), and subfornical
organ (SFO) are located in the walls of the third
and fourth cerebral ventricles and consist of per-
meable fenestrated capillary tissue within perivas-
cular spaces. The tissue surfaces express multiple
chemoreceptor types, sensitive to systemic
osmotic, metabolic, and inflammatory status.
There is a degree of specialization: The AP is
linked to feeding behavior (including vomiting),
satiety and hunger (Hindmarch et al., 2011)
though reciprocal connections with the Nucleus of
the Solitary Tract (NTS) and hypothalamus. The
OVLT has intrinsic osmosensory properties (Ciura
et al., 2011) and corresponding coupling to hypo-
thalamic supraoptic nucleus (SON) vasopressin
release. The SFO appears to have a broader role in
viscerosensing (reviewed by Critchley and
Harrison, 2013).
Many circulating molecules also cross the blood
brain barrier (either actively or passively) to stimu-
late chemoreceptors on neurons and glia. NTS neu-
rons express receptors for Angiotensin II and the
satiety factor GLP-1, while neurons in hypothalamic
nuclei respond to hormones, vascular and immune
mediators, and to glucose levels. Glucose-sensing
in hypothalamus is linked to feeding (lateral arcu-
ate nucleus) and satiety (ventromedial hypothala-
mus) (Oomura et al., 1969). Glucose sensing also
occurs in other brain regions, e.g., medial amyg-
dala nucleus and in monoaminergic (dopamine and
noradrenaline) neurons expressing ATP-sensitive
potassium channels (Dunn-Meynell et al., 1998). In
fact, glucose sensing may be an intrinsic feature of
the brain reward system (Koekkoek et al., 2017),
wherein motivational learning is grounded on
metabolic homeostatic foundations. Interoceptive
signaling regarding the availability and allocation
of energy resources is fundamental to shaping moti-
vational behavior, in part through feeling of need,
want, and pleasure. This is expressed at multiple
levels in the relationship between interoceptive
signaling pathways and the brain circuitry encod-
ing reward and punishment, motivation drive and
satiety and the selection of behaviors through rein-
forcement learning.
Microglia are also important to immune aspects
of interoception, continuously sampling the
brain’s extracellular space. Circulating cytokines
417
or prostaglandin E2 activate microglia through
Toll-like receptors and tumour necrosis factor
release to initiate a cascade of immune reactions in
brain (Nadeau and Rivest, 2000; cf. Critchley and
Harrison, 2013). This central response to bodily
infection and inflammation is associated with the
triggering of sickness behaviors, a constellation
of adaptive allostatic responses affecting moti-
vational and emotional state, attenuating social
engagement and reallocating the energy utilization
across the body in a sustained reaction to internal
interoceptive threat.
DETECTING TEMPERATURE
The regulation of bodily temperature is crucial to
health and wellbeing, ensuring efficient skeletomo-
tor, neural, and organ function. Core body tempera-
ture is tightly controlled within a narrow range
through homeostatic reflexes and behaviors.
Elevated temperature does occur in allostatic sick-
ness states but arguably as a compromise that car-
ries significant risk. Temperature sensing is thus a
particular important form of interoception
(Crucanelli et al., 2022). Both peripheral and
central temperature sensing occur and are linked to
local and systemic physiological reflex mecha-
nisms for temperature regulation (increasing or
decreasing skin blood flow, sweat production, and
thermogenic shivering or metabolism). In addition,
temperature sensing drives adaptive behavioral
responses. Temperature in the periphery fluctuates
more directly with the environment, and changes
are sensed by hot and cold sensitive neurons
located mainly in the skin with cell bodies in the
spinal dorsal root ganglia (body) or trigeminal gan-
glion (head, face). Cold neurons respond to cooling
through activation of the Transient Receptor
Potential Melastantin 8 channel (TRPM8; also
sensitive to menthol). Warmth sensitivity is medi-
ated by neurons expressing Transient Receptor
Potential Vanilloid 1 (TRPV1), TRPM2 and per-
haps other related TRPV and TRPM receptors.
While the bare skin of face, hands, and feet enables
tactile discrimination of the temperature of external
objects, hairy skin elsewhere is important for
interoceptive thermoregulatory control. There is
also some peripheral temperature sensing that
occurs in visceral organs and within the spinal cord
itself (Ran et al. 2016). Thermosensory input from
the periphery terminates in the brain, at the level of
the preoptic area (POA) of the hypothalamus.
Importantly, this region also contains neurons that
are directly sensitive to brain (hence systemic
bodily) temperature (Tan and Knight, 2018).
418 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
INTEROCEPTIVE ANATOMY
Pathways to Brain
The unmyelinated (C fibre) or thin (Að fibre)
sensory neurons that innervate the vasculature and
viscera travel to the brain via cranial nerves
(mostly via vagus and glossopharyngeal nerves)
and via afferents that ascend the spinal cord
(Jaenig, 2008) The latter track back in
post-ganglionic sympathetic nerves to preverte-
bral plexuses and paravertebral ganglia projec-
tions into the spinal cord. Autonomic spinal
reflexes provide some proximate homeostatic
control; yet, the consequences of such reflexes
may also be systemic, for example in dysreflexic
responses to tissue injury or bladder filling in
patients with spinal cord transection (Rabchevsky,
2006). Voiding and sexual functions also depend
on visceral afferent feedback into spinal reflexes,
processes that are under descending control.
Within the spinal cord, cell bodies lie in dorsal
root ganglia and axons ascend both ipsilaterally
and contralaterally spinothalamic tracts. Spinal
Lamina 1, inputting into the dorsal spinothalamic
tract, conveys temperature and pain sensations.
This is argued to be a specialized channel dedicated
to carrying motivationally salient viscerosensory
information that ultimately give rise to affectively
laden sensations (Craig, 2004, 2014). Slow, light,
repeated mechanical tactile stimulation and warm
skin sensations, ultimately giving rise to positive
feelings (e.g., “sensual touch”) also are carried
by unmyelinated fibres originating within cuta-
neous and mucosal epithelia. This information
is purportedly also relayed via spinal Laminar 1
(Craig, 2004, 2014), though ablation of this tract
does not necessarily dispute affective aspects of
touch (Marshall et al., 2019). Information about
bodily temperature, from both skin and internal
organs, also reaches Laminar 1. This tract projects
strongly into “homeostatic” brainstem centres in
the medulla, notably the Nucleus of the Solitary
Tract (NTS) and onto parabrachial nucleus and
thalamus. The vagus (in which over 80% of fibres
are afferent) and glossopharyngeal (innervating
the carotid sinus and body) nerves also project into
the NTS, the “classical visceral receiving area”
of the brainstem (Bethoud and Neuhuber, 2000;
Jaenig, 2008).
While much of interoceptive signaling is covert,
a number of interoceptive sensations (e.g., those
relating to voiding and breathing) are commonly
perceived. Feelings of bloating, organ distension,
breathlessness, and nausea are also uniquely vis-
ceral, hence are poorly localized. Such sensations
are likely to be conveyed via the spinal route along
with correlated “quasi-interoceptive” somatosen-
sory information e.g., regarding chest movement,
pharyngeal airflow, cardiac percussion of chest, or
skin pulsation. Such sensations may be appraised
consciously with greater spatial and temporal pre-
cision. Moreover, when spinal interoceptive sign-
aling intensifies (e.g., when organs are damaged,
visceral pain may be referred, or perceived as an
exteroceptive somatosensory sensation at a loca-
tion different to its origin): Thus, pain around the
left neck, anterior shoulder, and medial upper arm
may signal cardiac angina; pain in the back may
signal pancreatic and renal damage (Gebhart and
Bielefeld, 2016).
BRAIN ANATOMY OF INTEROCEPTION
AND THERMORECEPTION
Within the medulla, the Nucleus of the Solitary
Tract (NTS) receives ascending visceral afferent
inputs form spinal neurons with cell bodies in the
dorsal root ganglion and from cranial nerves,
notably the vagus and glossopharyngeal nerves.
The NTS is a primary site of anatomical conver-
gence of gustatory, gastrointestinal, cardiovascu-
lar, hepatic, renal, respiratory, and immune system
and is critically important to homeostasis; its
destruction is lethal (Doba and Reis, 1973). The
NTS supports specific functions dependent upon
this primary viscerosensory role. These include
the coordination of simple autonomic reflexes
generating respiratory and cardiovascular rhythms
and peristalsis of the upper gastrointestinal tract.
In addition, it relays signals of taste, satiety, and
visceral pain (Boscan et al., 2001; Cutsforth-
Gregory and Bennarroch 2017). The NTS also
contributes to the coordination of stress responses,
via inputs that modulate the homeostatic auto-
nomic rhythms (e.g., generating a state of cardio-
vascular arousal through baroreflex suppression
allowing blood pressure and heart rate to rise
together to facilitate action-related behaviors), and
through efferent modulation of hypothalamic-
pituitary-adrenal (HPA) axis activity (correspond-
ingly NTS neurons express glucocorticoid
receptors) (Gosal et al., 2014).
There is broad rostrocaudal viscerotopic
organization, yet NTS neurons with distinct vis-
ceroceptor input (e.g., arterial baroreceptors or
gastrointestinal chemoreceptors) often lie in close
proximity (Paton et al., 1999) whereby crossmodal
integration may occur. Interoceptive information
from the NTS projects through ventroposterior
medial thalamus to cortex, branching to synapse
 Interoception and Thermoreception
within pons and midbrain (e.g., parabrachial
nucleus, locus coeruleus, hypothalamus) to influ-
ence ascending and descending neuromodulatory
pathways and subcortical substrates of motiva-
tional behavior. At this level also, humoral infor-
mation, sampled from the systemic circulation by
the brain, is integrated with other viscerosensory
signals to influence the neurosecretory regulation
of fluid balance and hormonal status, and shape
descending autonomic control of the cardiovas-
cular system, digestive tract, and genitourinary
organs.
The NTS proximally supports autonomic
reflexes through output to brainstem centres con-
trolling autonomic function. In the baroreflex, for
example, the phasic input from arterial (aortic
arch, carotid body) baroreceptors enhances para-
sympathetic output to the heart via stimulation of
the dorsal motor nucleus of the vagus to reduce
heartrate (Benarroch, 2008). These baroreceptor
signals also inhibit efferent sympathetic outflow
at the level of the rostral ventrolateral medulla
(RVLM) reducing vasoconstriction within mus-
cle vascular beds. This mechanism permits blood
pressure regulation at a beat-by-beat level, yet is
further modulated by multiple other viscerosen-
sory inputs (nociceptors, pH, CO2, O2, lactate,
hormones, prostaglandins, cytokines, and temper-
ature) via GABAergic action on the second order
NTS neurons that project to the rostral ventrolat-
eral medulla.
The NTS has close bidirectional connections
with the parabrachial nucleus, periaqueductal gray
matter, hypothalamus, and bed nucleus of the stria
terminalis. These centers, in turn, link function-
ally to forebrain regions, notably amygdala, adja-
cent basal ganglia, and insula cortex, cingulate,
hippocampus, and prefrontal cortices (Benarroch,
1993; Blessing, 1997). The flow of interoceptive
information to these regions is paralleled by neu-
romodulator projections (notably cholinergic and
monoaminergic) originating in adjacent brainstem
and midbrain nuclei (Bernston et al., 2003) the
likely means by which arousal, attention, and moti-
vation are coupled to internal state. The Lamina 1
spinothalamic tract, along with the cranial nerve
visceral afferent input into NTS, projects via the
ventroposterior thalamus into posterior and dorsal
mid insular cortices. The dorsal insula is viewed
as the primary viscerosensory cortex; represent-
ing internal bodily sensations (Craig, 2002, 2014).
The re-representation of interoceptive information
in more anterior insular regions, and its integration
with contextual information from exteroceptive
perceptions, mnemonic and contextual informa-
tion is linked to conscious awareness of internal
physiological state, and associated interoceptive
motivational and emotional feelings (Craig, 2002;
419
Critchley et al., 2004). Orbitofrontal and anterior
cingulate cortices, amygdala and hippocampus
receive viscerosensory information both directly
(mostly from insular projections) and indirectly
(e.g., via subcortical and alternative dorsome-
dial thalamic branch and via the subcortical and
neuromodulatory pathways).
HUMORAL AND THERMOSENSORY
INFORMATION
Wide-reaching connections from the circumven-
tricular organs enable information concerning
humoral physiology (i.e., systemic metabolic
inflammatory or osmotic status) to integrate with
other interoceptive representations). Much of this
is achieved at the level of the hypothalamus,
which, as noted, also contains the brain’s “ther-
mometer” (POA). The contribution of the AP to
cardiovascular regulation and immune reactivity
is also achieved through close reciprocal connec-
tions with the NTS, parabrachial nucleus, sympa-
thetic medullary nuclei, and the parasympathetic
dorsal motor nucleus and nucleus ambiguus of the
vagus (van der Kooy and Koda 1983). The OVLT
projects to the supraoptic nucleus of the hypo-
thalamus to support osmoregulation, yet it also
projects to NTS, parabrachial nucleus and other
regions of hypothalamus. Moreover, its projection
to midline thalamus, and onto insula and cingulate
cortices, is proposed to underpin the motivational
feeling of thirst.
Thermal information about body tempera-
ture from peripheral tissues (notably the skin,
Crucianelli et al., 2022) projects from both lami-
nar 1 and classical somatosensory spinothalamic
tract into the NTS, lateral parabrachial and thal-
amus. Parabrachial lesions abolish autonomic
responses to skin warming and cooling. Thus, the
parabrachial nucleus is important for thermoregu-
latory responses to environmental temperature
(Nakamura and Morrison, 2008). At the cortical
level, peripheral temperature is represented in
posterior insular (Craig et al., 2000) and soma-
tosensory cortices. Interestingly, lesions to this cor-
ticothalamic pathway have only a limited impact
on thermoregulatory responses. The projection of
temperature information from lateral parabrachial
nucleus to the POA in midline hypothalamus is
more salient: The intrinsically thermosensitive
neurons in POA, when heated, initiate reflexes
and behaviors to promote heat loss. Conversely,
cooling the POA triggers systemic physiological
and behavioral responses to preserve and gener-
ate body heat. Thus, POA appears to be critical to
420 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
integrating central and peripheral thermosensory
information for temperature regulation (Tan and
Knight, 2016).
Human neuroimaging studies, together with
lesion studies and stimulation studies, have
mapped neural correlates of peripheral arousal
and interoceptive processing, often coupled to
autonomic control, to brain regions throughout the
neuraxis (Beissner et al., 2013). These findings are
consistent with information from animal physiol-
ogy, identifying brainstem, midbrain, and thalamic
relays of detailed viscerosensory/interoceptive
information to insular cortex and related regions,
including forebrain components of the reward sys-
tem including amygdala and anterior hippocam-
pus, orbitofrontal cortices, and both dorsal and
subgenual anterior cingulate cortex. Co-activation
of, and interaction between, visceromotor dorsal
anterior cingulate cortex and viscerosensory insula
have been framed in terms of the detection of
“interoceptive surprise.” Here, insula is proposed
to compare the afferent (interoceptive) informa-
tion about current bodily states with the efference
copies of descending visceromotor signals from
anterior cingulate cortex (predictions). The latter
typically drive sympathetically dominant allo-
static states of cardiorespiratory arousal, linked to
the facilitation of motor action (Critchley, 2005,
2009). Neuroimaging and lesions studies further
support the role of insular cortex as a basis for
conscious viscerosensory representations that are
elaborated as motivational and emotional feelings
(Craig, 2004, 2014; Critchley, 2005; Critchley
et al., 2004).
Brain-wise associations between interregional
functional connectivity, inferred from enhanced
correlations in haemodynamic signatures of neu-
ral activity (and also electrocortical or magnetoen-
cephalographic neurophysiological measures)
indicate distribution of interoceptive informa-
tion across brain networks (Jarrahi and Kollias,
2020). Some, for example related to electrogas-
tric activity (Rebollo et al., 2018), may represent
independent functional brain networks that can
be distinct from the acknowledged association
between salience/executive attentional networks
or the default mode network and states of high
and low peripheral arousal. Electrocortical and
magnetocortical correlates of heartbeats (heart-
beat evoked potential, HEP, and heartbeat evoked
response; HER ) present specific challenges with
respect to artefact removal and interpretation.
Nevertheless, these indices similarly suggest that
interoceptive information concerning heartbeats
(potentially driven by the activation of fast arterial
baroreceptors) has a broad reach over frontotem-
poral and insular cortices (Luft and Battacharya,
2015; Park et al., 2018).
PSYCHOLOGICAL REPRESENTATIONS OF
INTEROCEPTIVE INFORMATION
Interoceptive information is fundamental for life,
driving organ- and system-level homeostatic
reflexes and organism-level coordination of
allostatic responses. The latter encompasses moti-
vational behaviors through to relatively simple
affective feelings and primordial emotional states
such as hunger, thirst, warmth- or cold-seeking to
more elaborate levels of emotional affiliative,
social, emotional, and cognitive experiences that
are coupled to action decisions and adaptive behav-
ioral policies. Thus, at multiple levels, mental pro-
cesses are influenced by interoceptive signals
representing physiological integrity and need.
Perhaps interoception’s biggest influence on
psychological processes occur implicitly, without
the need for conscious appraisal: Fluctuating inter-
oceptive states (e.g., changing blood glucose level,
osmolality, bodily temperature) re-orientate moti-
vations and entrain behavioral routines (including
food-seeking and voiding) before even sensations
of early hunger, thirst, satiety, and arousal are per-
ceived. These preconscious signals also dictate
dominant sensory and behavioral interests (e.g.,
in food, action, seeking shelter, clothing, or hugs)
and set the state of self-efficacy, motivational drive
and capacity to learn. There are multiple examples
of this, but rarely confined to discrete organ spe-
cific level. Blood pressure fluctuations can gate
pain processing (Gray et al., 2009), the signaling
of cardiovascular arousal enhances threat percep-
tion (Garfinkel and Critchley, 2016; Garfinkel
et al., 2001). Psychological “repertoires,” includ-
ing the drop in mood, decreased social interest,
and anorexia can be elicited by low-grade inter-
oceptive immune challenges, (Harrison et al.,
2009) influence and bias foreground sensorimotor
functions. Physiological arousal states influence
cognitive alertness and performance. Such pre-
perceptual interoceptive influences are revealed
experimentally in the interaction between pha-
sic physiology signals (e.g., heartbeats, respira-
tion, gastric motility) or more tonic physiological
states (glycaemia, cytokine response) and/or their
neural representation (e.g., as heartbeat evoked
potentials) and with perceptual sensitivity to
exteroceptive stimuli or changing cognitive or
emotional responses (Garfinkel and Critchley,
2016; Garfinkel et al., 2014; Saloman et al., 2018).
Such theoretical notions were earlier formalized
in the somatic marker hypothesis (Bechara et al.,
2005). More broadly, the continuous background
hum of interoceptive activity interacts with senso-
rimotor functions across all domains. Whether or
not this is definitively or explicitly perceived as
 Interoception and Thermoreception
an internal bodily sensation, the implicit impact
of interoceptive signaling and the relentlessness
of dynamic interoceptive control is proposed to
be fundamental to the sense of “self” as a unitary
actor and observer navigating and interacting with
the external world (Craig, 2014; Critchley, 2005;
Damasio, 1999, 2010; Seth et al., 2012; Tallon-
Baudry et al., 2018).
Clearly, however, many interoceptive sensa-
tions are consciously perceived, but usually with-
out fine spatiotemporal precision. The role of these
sensations as the basis for motivational behaviors
often conflates afferent representation with affec-
tive drive. Patterns of interoceptive response are
important; the sensation of hunger goes beyond
feelings of stomach emptiness. In their influential
theory of emotion, James (1884) and (especially)
Lange (1907) proposed the perception of bod-
ily changes, often triggered automatically by the
“emotive stimulus,” is the basis of emotional feel-
ings that “color” the otherwise cold perception
of the stimulus with a value-laden sensation. The
conscious experience of interoceptive sensations
as emotional feelings is commonly enhanced by
correlated somatosensory signals (e.g., the feel
of the skin’s piloerection, shivering or sweating
accompanies interoceptive signaling of tempera-
ture regulation and fear) including more obvious
feedback from emotion-triggered behaviors (like
running from a bear).
LEVELS OF INTEROCEPTIVE PERCEPTION
The proposal that interoceptive signaling may be
an important component of emotional processing
found some qualified support in the observed
effects of adrenaline injections (Cantril and Hunt,
1932; Marañon, 1924). The proposal also moti-
vated research to quantify individual differences
in sensitivity to internal bodily changes. If people
vary in the degree to which they are more or less
sensitive to internal bodily changes, they may
consequently feel emotion with lesser or greater
intensity. By extension, this may have clinical
relevance in that they may be more prone to anxi-
ety and panic, may somatize emotional experi-
ences more, or conversely may be better at
self-regulating their state of emotional arousal.
Approaches to quantify individual differences in
interoceptive sensitivity have centered on:
(1) performance measures in tasks that ask people
to judge “objectively” measured changes in their
body; (2) self-ratings (e.g., questionnaires) of
judged sensitivity or confidence in their experi-
ence of bodily sensations; (3) examination of
421
people’s insight (“metacognitive” awareness) into
their own interoceptive ability (Garfinkel and
Critchley, 2013, Garfinkel et al., 2015; Quadt
et al., 2018). These approaches were formulated
into a three-level categorization of psychological
aspects of interoception that attempted to over-
come previous discrepancies in this research field
that clouded inference about interoception’s
impact on emotion and cognition (although note
novel iterations of this approach, e.g., Suksasilp
and Garfinkel, 2022).
As an easily identifiable interoceptive stimulus,
the heartbeat has been the mainstay of “objec-
tive” tasks of interoceptive sensitivity. Heartbeat
detection tasks seek to quantify an individual’s
ability to perceive of their own heartbeats at rest,
by counting, tapping, or by judging heartbeat tim-
ing relative to an external stimulus. Many of these
tasks have long-recognized psychometric limita-
tions, particularly where prior knowledge influ-
ences the performance of the “heartbeat counting
task” (Ring and Brener, 1996). Concerns about
the “two-interval heartbeat discrimination task”
are more about task difficulty (most people expe-
rience heartbeats at around the same time within
the cardiac cycle, Betka et al., 2021; Wiens and
Palmer, 2001) (see Figure 26.1). Although they
may often conflate interoceptive beliefs with
interoceptive perception, heartbeat detection tasks
remain widely used for reasons of practicality,
and inferences are necessarily constrained and
contextualized. Newer related heartbeat tasks are
emerging that attempt to improve on the objec-
tive validity of the measure of interoceptive per-
formance accuracy (Betka et al., 2021, Larsson
et al., 2021), and beliefs (Legrand et al., 2021).
There are similar tests for gastrointestinal and res-
piratory interoceptive sensitivity (Garfinkel et al.,
2016), but there is a dearth of methods to measure
objectively other aspects of interoceptive percep-
tion, including thermal sensitivity.
The partitioning of interoception along three
psychological dimensions, as described above,
represented a leap forward for interoception
research (Garfinkel and Critchley, 2013; Garfinkel
et al., 2015; Quadt et al., 2018; see also Table 26.1).
This framework distinguished between: (1) objec-
tive measures of interoception (i.e. interoceptive
performance (e.g., behavioral score on a heartbeat
detection task); (2) subjective measures of intero-
ception (how well a person thinks they perceive
interoceptive signals (e.g., self-rated confidence
on heartbeat detection, or score on self-reported
questionnaires); and (3) metacognitive intero-
ceptive awareness insight (e.g., correspondence
between actual objective performance and subjec-
tive sense of interoceptive ability). These psycho-
logical dimensions of interoception are typically
422 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 26.1 When and where people perceive heartbeats

A multi-interval heartbeat task is a proposed alternative means of measuring interoceptive
performance accuracy (sensitivity to feeling one’s heart beating at rest) that overcomes
psychometric limitations of heartbeat counting and 2-interval heartbeat discrimination task
(Ring and Brener 1996; Wiens and Palmer 2001). Here, Betka et al. (2021) asked healthy par-
ticipants to match the timing of when they felt their heartbeat to external tones presented
at different time intervals relative to the electrocardiogram (ECG) R-wave (measuring the
myoelectric trigger of ventricular contraction). Participants then indicated where on their
body they felt their heart beating.
A. There was consistency in the timing of heartbeat perception; most heartbeats were per-
ceived between 150 and 350 ms (peak approximately 250ms after the ECG R-wave) by the
majority of participants.
B. There was less consistency in the reported site of heartbeat perception; nevertheless,
the most common location endorsed by participants was the left side front of the chest.
Interestingly there was no systematic correspondence between when and where people
reported heartbeat sensations.
Source: From data published in Betka et al., 2021.

dissociable from each other. Moreover, the degree
to which subjective and objective dimensions align
can predict emotion states and affective psycho-
pathology (Garfinkel et al., 2015). An extended
dimensional model of interoception incorporates
lower-level measures of visceral afferent neural
traffic (to quantify afferent signal strength objec-
tively (e.g., through heartbeat evoked potentials
(Gray et al., 2007), and the preconscious impact
of interoceptive signals on sensory processing
(e.g., modification of startle response (Schulz
et al., 2017) or augmentation of threat processing
(Critchley et al., 2002; Garfinkel and Critchley,
2016; Garfinkel et al., 2014, 2020). The model
also can be extended beyond metacognition, to
encompass executive processes, including flexible
switching of interoceptive attention (Table 26.1).
The impact of phasic interoceptive signals on
emotional processes is perhaps best described
for the cardiovascular channel, though, as noted
above, respiratory and gastric signals modulate
brain responses and associated cognition and
perception. Cardiovascular arousal is signaled by
arterial baroreceptors in aorta and carotids that
fire with each heartbeat as ventricular contraction
pumps blood out of the heart. Thus, baroreceptors
 Interoception and Thermoreception
Table 26.1 Dimensions of interoception
Dimension Level
Metacognition Execution/Attribution Metacognitive
execution/
attribution
Interoceptive Metacognitive
awareness accuracy
Behaviour Interoceptive Subjective belief
sensibility
Interoceptive accuracy Behavioral
performance
Brain/Body Preconscious impact Brain-body interaction Degree of impact of
of afferent signal
Afferent signal Interoceptive signal
signal the timing and strength of each heartbeat
to brainstem via the vagus and glossopharyngeal
nerves and inform the reflexive control of blood
pressure through the baroreflex. In states of car-
diovascular arousal (including emotional stress),
the baroreflex is suppressed, allowing heart rate
and blood pressure to rise together. The impact
of this channel of interoceptive information on
brain processes can be assessed by exploiting the
phasic nature of baroreceptor firing. Responses to
brief stimuli presented around systole, when the
baroreceptors are active, can be contrasted with
responses to stimuli presented at diastole, when
the baroreceptors are quiescent. Differences are
thus attributable to the presence, versus absence,
of cardiac interoceptive signals. Historically,
such experiments highlight the inhibitory nature
of cardiac afferent signals. Interoceptive inhi-
bition is also apparent in suppression of startle
responses and attenuation of memory for words
encoded at systole (Garfinkel et al., 2013; Schulz
et al., 2009). However, these baroreceptor signals
amplify threat processing, enhancing the detec-
tion and perception of fear and threat (Garfinkel
and Critchley, 2016; Garfinkel et al., 2014,
2020). Importantly also, when it comes to the
learning and recollection of bodily threat, signals
pertaining to cardiovascular arousal can act both
as an amplifier of the threat (that may general-
ize to related stimuli), and as a context, such that
threats learned in a state of high or low cardio-
vascular arousal will be preferentially evoked
in the same physiological context (Garfinkel
et al., 2020). This dual interoceptive influence
may have relevance in the expression of clinical
symptoms and the shaping of perceptions that
underpin “better safe than sorry” behavioral pat-
terns (Van den Bergh et al., 2021).
423
Measurement Example
Attention modulation/ Attributing aversive
attribution of outcomes to heart
bodily signals pounding
Insight into Confidence-accuracy
performance correspondence
aptitude
Self-report Questionnaires
Performance on Heartbeat detection
behavioural tasks tasks
Cardiac modulation
signal of fear
Strength of signal Heartbeat evoked
potentials
INTEROCEPTIVE DIMENSIONS AND
CLINICAL SYMPTOMS
Different aspects of interoception interact in how
they shape emotional states and behaviors. The
impact of phasic cardiac signals may be tempered
by interoceptive accuracy (i.e., the degree to
which an individual can perform a heartbeat
detection task), mitigating the deleterious impact
of bodily arousal signals on memory (Pfeifer
et al., 2017) and enhancing the processing of self-
related signals (Seth and Tsakiris, 2018). Good
interoceptive accuracy is also generally associated
with better affective regulation. Positive shifts in
interoceptive accuracy induced by contemplative
training are associated with improved capacity to
verbalize emotional states (decreased alexithy-
mia). Disruption of interoceptive signaling, accu-
racy, and subjective sensibility are observed in
clinical disorders that affect self-focused emo-
tional control (Bonaz et al., 2018; Khalsa et al.,
2018). Moreover, the alignment of subjective and
subjective components of emotion appears to pre-
dict emergence of affective symptoms. For exam-
ple, in autistic people, the degree of “mismatch”
between perceived sensitivity to interoceptive
state and observed accuracy in performing an
interoceptive task (heartbeat detection) predicts
anxiety symptoms and deficits in interpersonal
emotional interaction (Garfinkel et al., 2016).
Beyond anxiety, interoceptive dysfunction
expressed differentially across different interocep-
tive levels (and organ systems) is implicated in the
expression of a wider range of clinical disorders,
from dysregulation of metabolism, immune
responses or respiration, dysautonomia, to func-
tional neurological symptoms (see below).
424 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
COMPUTATIONAL MODELING IN
INTEROCEPTIVE SCIENCE
The control of the internal physiological state of
the body is achieved through the regulation of
interoception. Organ-level homeostatic reflexes
are enacted through sensory control loops, and
coordinated across organs at a system level. This
higher-order coordination is shaped and allo-
statically adjusted by purposeful action-selection
and the pursuit of longer-term behavioral strate-
gies. Fundamental homeostatic processes, such
as the baroreflex, cardiorespiratory control, and
the regulation of bodily temperature, are inher-
ently complex, even before one considers how
physiology might anticipate prospective internal
and external challenges. Computational mode-
ling seeks to provide deeper insight into the
observable data relating to interoceptive signal-
ing and its influence upon motivational, behav-
ioral, psychological, and physical processes and
their dysfunction (Allen et al., 2019; Petzschner
et al., 2021; Smith et al., 2017). Complementing
experimental and clinical observations, compu-
tational modeling is useful in systematically
organizing and testing the feasibility of differ-
ent, and potentially competing, mechanistic
hypotheses and making predictions about
responses at multiple levels. There is the poten-
tial for model parameters (which may otherwise
not be measurable) to reveal hidden or emergent
mechanisms and “computational biomarkers” to
support diagnosis or treatment represents one
aim of computational models of interoception.
The mathematical modeling of physiological
processes has a rich history. Interoceptive relevant
examples include detailed simulation of cardiopul-
monary interaction bringing together biophysical
aspects of respiration with those of blood circu-
lation, the modeling of the baroreflex as a func-
tional arc or broken down into the afferent control
system interacting with the pulsating heart allows
for modeling of complex processes at different
levels of description while always providing a
simplification to retain and highlight fundamental
mechanistic insight. Assumptions, conditions and
constraints need to be broadly correct at a work-
able level of complexity for the question in hand.
These can range from simplified models of neural
firing such as “leaky integrate and fire” (Mahdi
et al., 2019), vascular viscoelasticity (Raghu
et al., 2011), or the passive thermal properties
of cylindrical body segments in heat convection
and conduction (Katic et al., 2016). The accu-
rate simulation of physiological control process
may valuably be used to understand higher-order
mind–body interaction (Van Roon et al., 2004).
Recent computational models of interoception
extend more general principles of computational
neuroscience applied to sensation and perception,
motivational learning and sensorimotor control,
albeit within the unique and varied properties
of interoceptive signaling. An early assumption
is the hierarchical nature of interoception and
its control: Afferent (sensory) signals from vis-
ceral organs support local and spinal autonomic
reflexes and hypothalamus/brainstem-level
autonomic and neuroendocrine reactions within
“hard-wired” negative neural and humoral feed-
back loops. The set-points of these are neverthe-
less subject to top-down modulation to engage
these dynamic adjustments in support of allo-
static policies that ensure future stability through
change. These polices (sequences of responses or
actions) take place at a higher, more integrated,
level of representation, for example representing
the organism as a whole, rather than a single organ
system. Here, both the reflex set-point and the
higher-order policy reveal an internal (generative
or inverse) model, i.e., a representation of what
the internal state ought to be. More generally, it is
proposed that the brain makes sense of (typically
noisy) sensory information by comparison with an
internal model that can be viewed as an expecta-
tion or prediction of the source of the sensation.
As applied to interoception, this is a prediction
of the desired internal physiological state. Many
current computational neuroscience approaches
to perception and sensorimotor control imple-
ment Bayesian statistical principles of inference
as predictive coding: Here, afferent information
is evaluated against a priori sensory predictions
(expectation or beliefs) to generate prediction
errors (sensory surprise). The system as a whole
is conceptualized as a hierarchically, with predic-
tion errors (initially from low-level reflex loops)
ascending against descending higher-level pre-
dictions) primed to diminish prediction errors
by either adjusting the prediction itself (through
learning) or changing the sensory signal (through
action) (Petzschner et al., 2017; Pezzulo et al.,
2015; Seth and Critchley, 2013).
Physiological control through interoception
is fundamental to survival, hence the updat-
ing of interoceptive predictions often equates to
reinforcement learning of reward/punishment.
Alongside internal efferent autonomic responses,
actions that change interoceptive predictions
include appetitive and aversive motivational
behaviors (e.g., feeding, warmth-seeking, social
affiliation) behaviors. Both can be viewed as
interoceptive active inference; a process that sup-
ports allostatic adaptation: Allostatic (autonomic,
behavioral) policies enable short-term adjust-
ment of homeostatic reflex set-points in order to
 Interoception and Thermoreception 425

Figure 26.2 Interoceptive inference

A. This panel shows a model of the dynamics of active interoceptive inference in health.
Predictions (“P”) about interoceptive states are passed down via backward connections and
compared against actual interoceptive input. Mismatches between predicted and actual
states lead to the generation of prediction errors (“PE”). In order to inhibit autonomic
control, ascending error signals are attenuated so not to change predictions. When, in turn,
prediction errors are quashed by autonomic control, changed interoceptive input if fed
forward to inform future predictions.
B. A model depicting the dynamics of faulty interoceptive inference in the case of depression
or chronic fatigue. The over-prediction of metabolic energy demands leads to a downregu-
lation of noisy error signals, thus inhibiting the possibility of correcting these faulty
predictions, and resulting in a “locked-in” state that perpetuates this cycle.
Source: Adapted from Quadt et al., 2019.

permit longer-term maintenance of integrity of the computational neuroscience methods to intero-

whole organism. This survival-related primacy of ception can help advance clinical understanding
interoception means that interoceptive prediction and design of interventions relevant to biopsycho-
likely underpins cognition, emotion and even the social determinants of physical and mental health
conscious continuity and unitary sense of self- outcomes (Petzschner et al., 2017).
hood. A higher-level interoceptive representation
can also support an integrated prediction about the
effectiveness of coordinated interoceptive control,
and, correspondingly, self-efficacy (i.e., the capac-
ity to engage in physiological and behavioral acts
DISORDERS OF INTEROCEPTION AND
of self-regulation). This metacognitive index of THERMOREGULATION
allostatic self-efficacy is a proposed basis to trig-
gered states of fatigue and depression (Stephan While basic interoceptive functioning is essential
et al., 2016), illustrating how the application of for homeostasis (and is hence a prerequisite for
426 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
life), the abnormal integration and control of
interoceptive processes can manifest clinically
across psychological and physical conditions.
Disordered interoception is increasingly impli-
cated in the pathophysiology and expression of
symptoms of psychiatric, neurodegenerative,
developmental, and neurological conditions
(Bonaz et al., 2021). Problems may arise at dis-
tinct levels of interoceptive processing, for exam-
ple in peripheral signaling (e.g., neuropathies;
following vagotomy; spinal cord transection), in
the central discriminative representation, sensory
gating and impact on other sensory processes
(e.g., pain), and in the prediction, interpretation,
and general awareness of sensations from the
internal body. Fundamental problems with intero-
ception may give rise to metabolic disturbances
and dysautonomia control of the body, often
co-occuring and interacting.
Reflecting core contributions to motivation
and emotion, interoceptive dysfunction is increas-
ingly considered in relation to psychological and
psychiatric disorders, particularly where there is
disruption in motivated behavior, often accom-
panied by affective symptoms (Khalsa et al.,
2018, Critchley et al., 2023). Eating disorders
(Jenkinson et al., 2018) and drug addiction (Paulus
and Stewart, 2014) are representative expressions
of aberrant processing of embodied motivational
signals (e.g., hunger, satiety, craving, withdrawal).
Interoceptive signaling of exaggerated states of
physiological arousal is a prominent feature of
anxiety disorders, including Panic Disorder, and
Post Traumatic Stress Disorder (PTSD), and often
there is a more general and over-focusing on such
signals (Adams et al., 2022). Depression is often
accompanied by a flattening of interoceptive
processing (e.g., Eggart et al., 2019) (potentially
leading to feelings of emptiness and hollowness)
while dissociative states (e.g., depersonalization
and derealization, often arising clinically as a con-
sequence of extreme anxiety, suggest perturbation
in interoceptive coherence, such that the under-
lying “biological” self-representation diverges
from metacognitive appraisal (Khalsa et al., 2018;
Table 26.2). Interoceptive perceptual deficits are
reported in the context of schizophrenia (Ardizzi
et al., 2016) yet metacognitive interoceptive defi-
cits appear better able to explain perturbations
of self-representation intrinsic to the dissociative
symptoms of psychosis (Garfinkel et al., 2018).
The dysregulation of interoceptive control
features in stress-sensitive medical conditions,
including irritable bowel syndrome, fibromy-
algia, chronic pelvic pain, and ME/CFS that are
often accompanied by dysautonomia symptoms
(Csecs et al., 2022). Misattribution and/or gener-
alization of interoceptive sensations similarly may
account for non-cardiac chest pains and symptom
maintenance in other chronic medical conditions.
A structural framework to consider how differ-
ent levels of interoceptive processing contrib-
ute to symptom-expression across mental health
and related disorders is needed. Computational
approaches may be usefully leveraged to param-
eterize, and hence quantify, such contributions in
order to plan and tailor specific interventions, and
also to gain a richer insight into how psychoso-
cial factors influence physical and mental health
outcomes.
While interoceptive influences are brain-wide,
central neurological brain disorders may specifi-
cally impact interoceptive pathways or hubs. For
example, epilepsies involving insular cortex may
give rise to interoceptive sensations and feelings
(including ecstatic experiences (Picard and Craig,
2009)) and compromise allostatic control of car-
diac function to jeopardize health through arrhyth-
mia and/or sudden death (Cheung and Hachinski,
2000). Neurodegenerative disorders can also
impact the central processing and representation
of interoceptive information. In so doing, these
may shed a light more generally on interoceptive
mechanism in pathology (Garcia-Cordero et al.,
2016). Amotivational and fatigue states, flattened
affective reactivity, and reduction in drug-crav-
ing are reported alongside reduced interoceptive
sensitivity to bodily signals following lesions to
insula, ventral prefrontal, and cingulate cortices
(Darby et al., 2018; Fuchs et al., 2019). Such
symptoms occur also in dementia, where loss of
self-awareness may be prominent in later stages
(Mograbi et al., 2021).
Thermoregulatory disorders represent an inter-
esting expression of interoceptive dysfunction.
Mostly, thermoregulatory problems arise from the
inability to lose or retain heat as an expression of
autonomic problems and/or extreme behavioral
and environmental challenges, rather than from
primary deficits in the interoceptive sensing of
temperature (Cheshire, 2016). Nevertheless, small
fibre neuropathies (e.g., with diabetes) may not
only impact (efferent) sweat gland function but
lead to abnormal temperature signaling (including
sensations of burning) through compromised vis-
cerosensory and cutaneous sensory fibres (Flores
et al., 2015). Central neurological disorders may
also impair thermosensation: Examples include
demyelination in multiple sclerosis (fatigue in
multiple sclerosis is associated with raised central/
brain temperature) and dementias. Both cold and
heat insensitivity are reported. Certain drugs, not
least monoaminergic-acting psychomotor stimu-
lants such as cocaine and amphetamines, perturb
central thermosensation, while increasing activ-
ity levels. The pyrexia associated with immune
 Interoception and Thermoreception 427

Table 26.2 Illustrative disorders of interoception

Disorder Interoceptive signature Bodily/affective expression

Eating disorders
Panic and anxiety disorders
Depression
Dissociative disorders
Substance abuse disorders
Multiple sclerosis
Diabetes
Epilepsy
Aberrant processing of motivational signals Insensitivity to hunger signals, food anxiety
and compulsions
Over-focus on / misinterpretation of Exaggerated physiological states, fear
internal signals
Flattening of interoceptive signals Feelings of hollowness/emptiness,
exhaustion, psychomotor slowing
Perturbation in interoceptive coherence Feelings of detachment, tingling sensations
Aberrant processing of motivational signals Exaggerated physiological states,
withdrawal, craving
Impaired thermosensation Increased heat/cold sensitivity, fatigue
Abnormal temperature signaling Sensations of burning, tingling sensations
Compromised central allostatic control / Seizure propagation
afferent gating of cortical arousal Pro-ictal states; evocation of bodily
sensations and emotional states

responses to inflammatory interoceptive chal- symptoms, opportunities arise to improve physical

lenges, mediated by prostaglandin E2 acting on
POA neurons, also reflects a down-regulation of
thermostatic reflex function that is typically adap-
tive within the constellation of sickness behaviors
yet may be as life threatening as externally induced
causes of hyperthermia leaning to heat exhaustion,
organ/tissue damage, and death (Cheshire, 2016;
Skok et al., 2020).
As noted, certain areas of interoceptive science
(not least interactions between the immune system
and brain, and the gut and brain) are developing
rapidly, often ahead of general understanding and
appreciation of viscerosensory aspects of intero-
ception. Topic areas including immunopsychiatry
and “the microbiota and behavior” have emerged.
These are consequently finding independent appli-
cation to understanding and treatment of clinical
disorders. Overall, interoceptive mechanisms are
increasingly considered within mechanistic refor-
mulations of clinical conditions, particularly those
disorders at the interface between mental and
physical health, and where chronicity and com-
plexity limit quick-fix interventions that target spe-
cific organ systems in isolation. Emergent models
of interoception are providing fresh insights into
established therapeutic approaches and leading to
new treatments.
THERAPEUTIC TARGETING OF
INTEROCEPTION
As we learn more about interoceptive processes
and their role in the expression of (often interact-
ing) physical, motivational, and emotional
and psychological wellbeing and function through
interventions that act upon the representation and
control of internal bodily states. There are some
noteworthy established examples: Implanted vagus
nerve stimulation is presumed to reduce seizure
frequency in (treatment resistant) epilepsy through
action on ascending interoceptive influences on
thalamocortical excitability (Henry, 2002). The
impact of this interoceptive therapy on treatment
resistant depression indicates an effect on mood
stability, arousal, and positive affect attributable to
ascending monoaminegic neuromodulatory
systems (Sackheim et al., 2001). Exercise interven-
tions, breath training, biofeedback approaches, and
even evoking the diving reflex by immersing one’s
head in cold water, a recommended strategy in
dialectical behavioral therapy (Lineman et al.,
2007), have a long history of use to enhance mood
and emotional regulation. Each of these techniques
are associated with enhanced engagements of
vagus afferents and vagally mediated parasympa-
thetic cardiac outflow.
Treatments directed at interoceptive processing
may target distinct levels of this sensing hierarchy,
targeting in the periphery the signaling of pain,
inflammatory status, visceromotor activity, ther-
mal change, and humoral contents or modifying
the function of pathways communicating intero-
ceptive information to the brain. Interventions can
target neural brain systems, while both behav-
ioral and psychological interventions can focus
on changing the perception and interpretation of
interoceptive signals. The purpose of the interven-
tion is also important to consider: An intervention
may seek to decrease or increase the symptoms
arising as direct consequences of the interoceptive
sensation or to modify the impact of interoceptive
428 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
sensation on other functions or symptoms (includ-
ing somatic, neural, psychological, or behavioral
processes). Many interventions modify autonomic
(re)activity in order to evoke the therapeutic
benefits of effects of an altered (attenuated or
amplified) interoceptive state.
Pharmacological treatments can target periph-
eral aspects of interoception via autonomic
responses (e.g., smooth muscle relaxants, beta-
blockers), or afferent signaling (e.g., pain killers,
and antinflammatory drugs, local anaesthetics,
antacids, intravesical capsaicin, and Botulinus
toxin). Surgical approaches extend beyond neu-
rodestructive vagotomy (for gastric and cardiac
symptoms) to neuromodulatory approaches
including sacral nerve stimulation (Dasgupta
et al., 2005) and vagus nerve stimulation that also
interrupt visceral afferent signaling (Sackheim
et al., 2001). However, the impact may extend
beyond proximate interoceptive symptoms to
affect neurological function and mood state.
Neurostimulatory approaches to brain, neverthe-
less, become more removed from clear interocep-
tive targets. However, such mechanisms are likely
to play a part in, for example, the improvement in
neurovegetative symptoms of psychomotor slow-
ing in depression following deep brain stimulation
applied to subgenual cingulate cortex and associ-
ated regions (Sankar et al., 2020).
Biobehavioral approaches including biofeed-
back and cognitive behavioral strategies have
found particular use: Biofeedback, by “closing
the interoceptive loop” on typically covert auto-
nomic control signals and associated interocep-
tive responses, can be used to train the control
of internal state and its integration with psycho-
logical and behavioral processes. In this con-
text, electrodermal biofeedback has been used to
diminish sympathetic activity in stress states, e.g.,
anxiety, panic, conditions such as irritable bowel
syndrome and may be useful in managing tic dis-
order (Gilbert, 1986; Leahy et al., 1988; Nagai
et al., 2014). Training the capacity to volition-
ally increase sympathetic arousal can empower
patients with epilepsy to employ effective coun-
termeasures to mitigate seizures in pro-ictal states,
leveraging apparent inverse coupling of interocep-
tive coupling of bodily arousal states to thalamo-
cotical excitability (Nagai et al., 2018). Heart rate
variability biofeedback, aiming to amplify para-
sympathetic “neurovisceral integration,” has been
applied to enhance the management of affective
symptoms (Goessl et al., 2013; Schumann et al.,
2019) and sport performance (Jiminez-Morgan
and Molina-Mora, 2017). There is much prom-
ise in the application of “proxy” somatosensory
stimulation that can compete with or entrain
central interoceptive representation to attenuate
unhelpful feedback contributions of arousal on
behavior (Azevedo et al., 2017; Morera Maiquez
et al., 2020; Ventureya, 2000). Thermal biofeed-
back is typically used for clinical conditions such
as migraine, hypertension, and Raynaud’s syn-
drome (Blanchard et al., 1984; Karavidas et al.,
2006; Nakao et al., 2003; Sharff et al., 2002).
Hand warming biofeedback demonstrated clinical
improvement of migraine in paediatric popula-
tion in a controlled trial. Biofeedback to increase
temperature is also effective for hypertension and
Raynaud’s syndrome, increasing the circulation of
peripheral blood flow.
The identified association of symptoms, such
as anxiety, with discrepancies in objective and
subjective axes (Garfinkel et al., 2015, 2016)
(and interoceptive metacognitive insight) has ena-
bled development of cognitive and biobehavioral
remediating strategies that specifically target the
mismatch across interoceptive dimensions (opera-
tionalized for example in heartbeat detection per-
formances accuracy versus subjective confidence
or questionnaire self-rating of interoceptive sensi-
tivity) (Quadt et al., 2021). This focused approach
likely targets mechanisms that are also implicit in
the beneficial consequences of exercise, “breath-
work” and interoceptive exposure therapies.
There, the conceptual framework is consistent
with computational notions of interoceptive pre-
dictive control in which subjective report may be
viewed as expressing top-down predictions tested
against ascending objective interoceptive signals
(see earlier). A large clinical trial for anxiety, in
an adult autistic population, attests to the value
and acceptability of interoceptive training of this
nature (Quadt et al., 2021).
SUMMARY AND CONCLUSIONS
The representation of the internal physiological
state of the body is fundamental to the processes
through which an individual senses, interprets,
integrates, and regulates informative signals from
within itself and applies this representation to navi-
gating and adapting to an uncertain external world.
A maturing framework for understanding intero-
ception includes the signaling and processing
through the neuraxis including expression at dis-
tinct levels of perception and cognition.
Interoception is an important component of
somatic, neurological, psychiatric, and behavioral
disorders and the expression of symptoms in
chronic and complex conditions that span physical
and mental health. Better understanding of the
neural basis of interoception may refine existing
 Interoception and Thermoreception
treatments offer new focused therapeutic targets for
somatic, psychological and neurological disorders.
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Peripersonal Space
Representation:
Neural Bases, Properties, and
Functional Significance
Claudio Brozzoli, Nadia Bolognini,
Alessandro Zanini, and Alessandro Farnè
INTRODUCTION
The brain creates multiple representations of
space, which encode sensory information in a
diversity of frames of references centered on the
body or on the environment, depending on the
source of sensory stimulation and the nature of
interaction between the individual and the objects
it contains. The body constitutes the origin of
most of spatial representations, with different
neuronal populations representing two main sec-
tors of space in terms of distance from the body:
the peripersonal space, which is the space imme-
diately surrounding our bodies and the extra-­
personal space, which is far from our body. Such
dichotomy dates back to the last century, when
Brain (1941) proposed to distinguish between a
“grasping” space from a “walking” space, an idea
that followed his investigation of selective impair-
ments of these two spatial representations in
brain-damaged patients. Since then, almost a cen-
tury of interdisciplinary neuroscientific research
has developed such intuition, yielding insights on
the neural foundations and psychological mecha-
nisms unique to the representation of the space
close to the body.
The goal of this chapter is to provide an over-
view of modern conceptions of the peripersonal
27
space that span from the seminal discovery of
multisensory neurons with specific spatial proper-
ties in monkey models to neuroimaging evidence
of the existence of a peripersonal space system in
the human brain. Starting from neurophysiology,
new theoretical frameworks have been developed
to define the functional and dynamic features
of the human peripersonal space in relation to
perception, action, and social cognition.
NEURAL BASES OF PERIPERSONAL
SPACE REPRESENTATION IN
MONKEY MODELS
The definition of peripersonal space originates
from single-unit electrophysiological studies in
macaque monkeys that have provided an influential
framework for the demonstration of the existence
of a selective specific system to represent the space
closely surrounding the human body. Single-unit
electrophysiological studies in macaque monkeys
revealed the existence of a class of multisensory
neurons suggested to represent the neural basis of
peripersonal space representations (Graziano,
2001; Rizzolatti et al., 1981a). Their most relevant
436 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
feature is to respond both to visual and tactile
stimuli, showing visually evoked responses modu-
lated by the distance between the object and the
tactile receptive field (RF). Some of these neurons
also respond to auditory stimuli (Graziano, 2001).
The visual RFs are usually, though not always,
confined to the space near the body, and they are
better represented like bubbles of space anchored
to the body surface (Figure 27.1). This allows for
the coding of visual information that is dependent
(centered) on the body part that contains the tac-
tile RF. These body-centered RFs of visuo-tactile
neurons likely form the neural mechanism for the
psychological concept of peripersonal space.
Visuo-tactile neurons with body-centered
RFs have been reported in several regions of the
monkey brain (Figure 27.2), including the premo-
tor Area 6, parietal areas (Broadmann’s Area 7b
and the ventral intraparietal area, VIP) and the
putamen (Fogassi et al., 1999; Graziano, 2001;
Rizzolatti et al., 1997).
Peripersonal visuo-tactile neurons in the F4 sub-
region of ventral premotor cortex (Matelli et al.,
1985) present with large tactile RFs located primar-
ily on the monkey’s face, neck, arm, hand, or both
hands and face (Gentilucci et al., 1989; Rizzolatti
et al., 1981a). A large proportion (85%) of these
neurons also respond to visual stimuli according
to their distance from the body because their vis-
ual RFs are limited in depth (from ∼5 to ∼50 cm).
Figure 27.1 Schematic illustration of the
peripersonal space (dark gray area; the light
gray area depicts the extrapersonal-far -
space) surrounding the monkey’s body.
Darkest circles depict body-part-centered
(hand- and face-centered) peripersonal
space representations.
Figure 27.2 Neural bases of peripersonal
space in the macaque brain.
Lateral view of a macaque’s brain showing
the parietal area VIP (the ventral sec-
tion of the intraparietal sulcus) and
7b (in inferior posterior parietal lobe), the
polysensory zone in the posterior half of F4
(a subregion of inferior Area 6 in the ventral
premotor cortex) and the putamen (dotted
line). Single-cell recordings highlighted the
presence, in all these areas, of visuo-tactile
neurons with body-part-centered RFs.
(from Graziano, 2001).
About half of these visuo-tactile neurons are
named pericutaneous (54%) since they respond
to visual stimuli presented in the close proxim-
ity (a few centimeters, 10 cm or less) to the skin,
while the so-called distant peripersonal neurons
(46%) responds to visual stimuli within the mon-
key’ reaching distance (Rizzolatti et al., 1981b,c).
Another key property of the visual RFs of premo-
tor neurons is their independence from the posi-
tion of the eyes, being anchored to the tactile
RFs (Fogassi et al., 1992; Gentilucci et al., 1983;
Graziano et al., 1994, 1997). For instance, in a
neuron with a tactile RF on the arm, the corre-
sponding visual RF shifts along with the arm if it
is moved (Figure 27.3), while remaining relatively
fixed near the arm if only the eyes are moved.
Visuo-tactile neurons are also present in the
adjacent area F5, along the inferior branch of the
arcuate sulcus. They have smaller tactile RFs (than
that of F4 neurons) located on the face, the hand,
or both, and respond stronger to visual stimuli
close to the body but the type of the stimuli is a
critical factor in driving the activity of F5 neurons.
Indeed, the visual response of F5 neurons mostly
relies on whether the viewed object is graspable
or not, rather than on their distance from the body
(Bonini et al., 2014).
 PERIPERSONAL SPACE REPRESENTATION 437

Figure 27.3 Schematic of receptive fields (RFs) of visuo-tactile neuron.

(A) The tactile RF is centered on the hand and the visual RF (red area) on the area surround-
ing the hand. (B) When the monkey’s limb is passively moved over the midline, the visual RF
shifts accordingly. (C) Graphic representation of the responses of a premotor bimodal neuron
to four trajectories of an approaching visual stimulus (arrows 1–4); The arm is visible to the
monkey. When the left hand is on the left (dark gray line), neuron’s response (spike/second)
is maximal for trajectory “3,” which is approaching the neuron’s tactile RF. When the left
hand is on the right (light gray line), the response is maximal for trajectory “2,” which is now
approaching the tactile RF (from Brozzoli et al., 2012a).

The posterior parietal lobe of the macaque brain
contains two regions involved in peripersonal space
representations: Area 7b of the inferior posterior
parietal lobe and the ventral section of the intrapari-
etal sulcus (VIP). Area 7b contains a coarse soma-
totopic organization, with separate face, arm, and
hand representations: the face map lies on the upper
inferior parietal convexity, at the border with area
7a; adjacent to the face area, along the inferior pari-
etal convexity, there are arm and hand representa-
tions, followed by the foot ones (Hyvarinen, 1981;
Hyvarinen and Shelepin, 1979). In the face and
arm region of Area 7b, about 33% of the cells have
visual RFs spatially aligned with their tactile RFs
(Hyvarinen, 1981; Hyvarinen and Shelepin, 1979;
Leinonen, 1980; Leinonen and Nyman, 1979). The
visual responses of 7b neurons emerge prior to the
neuron’s tactile RF is touched, suggesting a sort
of “anticipatory” function of these bimodal cells
(Hyvarinen and Poranen, 1974). Most of these neu-
rons respond to visual stimuli moving toward the
tactile RF, if within a reachable distance (about 10
cm), while the 20% of them are active only during
the monkey’s own movements (in particular, grasp-
ing, and manipulation with fingers) (Leinonen and
Nyman, 1979).
Multisensory neurons have also been found in
the monkey area VIP, an audio-visuo-tactile con-
vergence site in the fundus of the intraparietal
sulcus (Avillac et al., 2005; Colby et al., 1993;
Duhamel et al., 1998). VIP neurons respond to
tactile and visual stimulation presented within a
few centimeters of the tactile RF. Unlike area 7b
neurons, tactile RFs in VIP are primarily located
on the face and head, and visual RFs are anchored
to a region of space around the face. Moreover,
VIP neurons encode visual information in a gradi-
ent of eye- to head-frame of reference, while tac-
tile stimuli are encoded in a head-centered frame
of reference. Consequently, while for some VIP
neurons the visual and tactile RFs are spatially
aligned irrespectively of eye position, for others
their alignment depends on gaze direction.
Notably, visuo-tactile neurons within area 7b
and VIP not only respond to objects close to the
body, but even when another individual (a human
experimenter) body part is approached by a vis-
ual stimulus: Ishida and colleagues (Ishida et al.,
2009) found that some visuo-tactile neurons with
RFs anchored on the monkey’s body showed
visual responses matched to corresponding body
parts of the experimenter observed by the monkey,
438 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
regardless (at least for some of these neurons) of
the position of the experimenter with respect to
the monkey.
In the putamen, visuo-tactile neurons are soma-
totopically organized and present with tactile RFs
on the arm, hand, and face to which the visual ones
are anchored. A large portion (82%) of face neu-
rons responds best to visual stimuli presented in a
region of space within 10–20 cm from the tactile
RF, whereas neurons with tactile RFs on the arm
and hand present even more shallow (up to 5 cm)
visual RFs (Graziano and Gross, 1993).
An important characteristic of some visuo-
tactile cells is the plastic feature of their visual
RFs. For instance, the extent in depth of the visual
RFs of F4 visuo-tactile neurons increases with the
velocity (20–80 cm/s) of an approaching visual
stimulus (Fogassi et al., 1996). Iriki and col-
leagues revealed that, after training monkeys to
use a rake as a tool to reach food pellets placed
outside their reaching space, some neurons start
to respond to stimuli near the far end of the tool,
a sector of the space unreachable without it (Iriki
et al., 1996). These and other dynamic properties
of the visual RFs seem to depend on the execution
of specific motor actions (Rizzolatti et al., 1998).
The above-mentioned regions form a densely
interconnected cortical and subcortical network
supporting various body-part-centered representa-
tions of the near space, which relies on the neural
integration of the tactile stimuli on a given body
part with visual information related to external
objects close to the body.
Human Peripersonal Space and
its Neural Bases
The initial studies aimed to identify a peripersonal
space representation in humans, functionally
homologous to that described in non-human pri-
mates, were carried out on stroke patients suffering
from “spatial extinction” after unilateral cortical or
subcortical brain injury, typically affecting the right
cerebral hemisphere (Ladavas and Farne, 2004).
Patients showing spatial extinction can typically
detect a single sensory stimulus regardless of
whether it is presented in the ipsilesional or contral-
esional hemispace. However, when presented with
two stimuli concurrently, the contralesional stimu-
lus is “extinguished” from awareness. This phe-
nomenon can arise within each sensory modality
and crossmodally, so that an ipsilesional visual or
auditory event may extinguish awareness of a touch
on the contralesional hand that would otherwise
have been felt (Mattingley et al., 1997). The extent
of crossmodal extinction depends on the proximity
of the extinguishing stimulus to the relevant body
part in external space, suggesting that extinction
arises in a spatial reference frame that is anchored
to the hand and it can even remap when the hand
moves. This neuropsychological evidence demon-
strates that crossmodal extinction takes place
within a limited sector of space closely surrounding
the body surface, namely the peripersonal space.
Moreover, the investigation of crossmodal extinc-
tion demonstrated the plastic nature of the human
peripersonal space, which can extend after tool use
similarly to what had been shown in monkeys
(Ladavas and Farne, 2004). Overall, the findings on
crossmodal extinction are entirely consistent with
the functional properties of the monkey multisen-
sory neuronal cells.
The neuropsychological investigation of unilat-
eral spatial neglect syndrome further showed the
modularity of spatial representations, document-
ing double dissociations between peripersonal and
extrapersonal, farther space. The basic defining
feature of this syndrome is a deficit in the abil-
ity to orient attention toward the contralesional
(usually the left) side of space, that manifest as
inability to report sensory events occurring in that
side of space and to perform actions in that portion
of space (Vallar and Bolognini, 2014). Of inter-
est, some individuals present with neglect that is
restricted to near space, whilst others show the
reverse pattern (Berti and Frassinetti 2000; Berti
et al. 2001; Bisiach et al., 1989; Cowey et al. 1994;
Halligan and Marshall, 1991; Vuilleumier et al.,
1998; cf. Halligan et al., 2003).
A large body of evidence in healthy humans
confirmed the neuropsychological findings
(Maravita et al., 2003). In healthy humans, the
peripersonal space may be assessed with various
multisensory behavioral paradigms (Figure 27.4),
as the crossmodal congruency task (Spence
et al., 2004a,b). The crossmodal congruency task
requires to discriminate, as quickly as possible,
the elevation (up or down) of a tactile stimulus
applied to the thumb or the index fingers while a
synchronous visual stimulus appears near either
finger. Participants discriminate faster the tactile
elevation when visuo-tactile stimuli are congruent,
rather than incongruent. This strength of this effect,
which decays with the increased distance of visual
stimuli from the fingers, is considered a proxy of
the extent of space where visuo-tactile integration
occurs and this of the peripersonal space. Indeed,
if the hand is moved to a different location, as
whit hand crossed, the crossmodal congruency
effects swaps accordingly. Crossmodal ­congruency
effects can also be elicited by far visual distractors
after tool-use (Maravita et al., 2003).
The behavioral findings on brain-damaged
and healthy subjects have led to hypothesize that
 PERIPERSONAL SPACE REPRESENTATION 439

Figure 27.4 Example of tasks to measure peripersonal space in humans.

(A) Some paradigms assess crossmodal facilitation. In this case, a visual stimulus (yellow star)
is randomly presented at different distances from the body (e.g., participant’s hand). The
visual stimulus may be static or moving (approaching to or receding from the body). Tactile
targets (red circles) are applied to the participant’s hand. Participants have to respond to
the tactile target as quickly as possible. Auditory, instead of visual, stimuli may be also used.
Typically, participants respond faster to touches when the visual/auditory stimulus is near the
hand, as compared to when it is far away from it. (B) The crossmodal congruency task instead
assesses the crossmodal interference between visual and tactile stimuli delivered in the
proximity of the body. In the original design, participants hold a sponge cube in either hand,
in which two vibrotactile stimulators (red circles) and two visual distractors (red circles) are
embedded. Participants have to discriminate the elevation of vibrotactile targets presented
unpredictably to the thumb or index finger (lower versus upper elevation, respectively) of
either hand. A visual distractor is presented randomly from one of the four possible loca-
tions from which a vibrotactile stimulus can be delivered. Thus, the visual distractor can be
congruent or incongruent in elevation (e.g., a “congruent” upper light together with upper
touch, versus an “incongruent” lower light together with the same upper touch). Incongruent
visual distractors delay tactile elevation judgments and produce more errors. This interfer-
ence effect (crossmodal congruency effect) is larger for a visual distractor near the tactually
stimulated hand than for one near the opposite, unstimulated, hand.

the neural underpinnings of peripersonal space
could involve a similar network across species.
In a seminal human fMRI study, Bremmer et al.
(2001) investigated the pattern of neural responses
to tactile stimulations applied to the face and vis-
ual and auditory stimulations moving toward the
face. They observed an overlap of the responses
elicited by the three sensory stimuli in the deeper
part of the intraparietal sulcus (IPS), in the ven-
tral premotor cortex (PMv), and in the lateral part
of the postcentral gyrus (Bremmer et al., 2001).
Subsequent studies have confirmed the existence
of a somatotopic mapping of close visual stimuli
within the inferior parietal cortex, with the face
represented at the level of the IPS, the lower part
of the body more medially and the upper limbs in
the lateral-anterior portion of IPS (Huang et al.,
2012). Furthermore, the level of activation of the
peripersonal space network, and in particular of
the premotor cortex, can predict and explain inter-
individual differences in the extent of the periper-
sonal space boundary. In particular, an increased
variability of BOLD responses in the premotor
cortex to far – rather than near – approaching
(auditory) stimuli predicts the individual extent of
peripersonal space (Ferri et al., 2015).
Considering the primary role of hands in eve-
ryday actions, a large amount of neuroimaging
research in humans focused on the study of the
peripersonal space centered on the hands, the so-
called “peri-hand” space. Such peri-hand space
is encoded in the human IPS and lateral occipital
440 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

complex (LOC), with a sort of transition from a
strictly visual representation of the hand in the
posterior IPS (adjoining the transverse occipital
sulcus) and in LOC regions to a representation
based on both visual and proprioceptive informa-
tion in the anterior IPS. Indeed, the anterior IPS is
featured by a proprioceptive representation of the
hand, as well as by a tactile hand-specific activa-
tion, suggesting a homology with monkey parietal
hand-centered areas (Bolognini and Maravita,
2007; Makin et al., 2007). By taking advantage of
the neuronal adaptation phenomenon in fMRI,1 a
better characterization of the human brain network
selectively activated by objects in the peri-hand
space has been reached, showing that the perip-
ersonal space network includes not only IPS, but
also the supramarginal gyrus (SMG), dorsal and
ventral premotor cortices, cerebellum and puta-
men (Brozzoli et al., 2011).
The increased sensitivity of the fMRI adap-
tion method also highlighted the hand-centered
nature of the visual processing occurring in these
areas (Figure 27.5): maintaining the same fixa-
tion point and the same absolute position of the
external stimulus (a 3D object), the proximity of
the hand to the object induces adaptation within
the peripersonal space network, while its displace-
ment in a position far away does not generate such
a response. By moving the object closer to the
new hand position, the peripersonal space network
response reappears (Brozzoli et al., 2012b). These
results indicate that an object presented within the
reachable space elicits – or not – adaptation within
the peripersonal space network as a function of its
proximity to the hand.
Crucially, the brain regions identified to
respond to a visual object in the peri-hand space
also integrate multisensory signals (Gentile et al.,
2011), as shown by the presence of super- and sub-
additive responses to the combination of stimuli
of different sensory modalities, as compared to
their responses to unisensory stimuli (Stein and
Standord, 2008), again in line with findings in ani-
mals (Avillac et al., 2005). Indeed, the concurrent
presentation of visual and tactile stimuli increases
the activity of peripersonal space network, while
introducing temporal and/or spatial mismatch
between modalities disrupts its response (Gentile
et al., 2013).
Even within the human visual cortex preferen-
tial responses to near vs. far stimuli were found
(Previc, 1990). Indeed, already in low-level visual
cortical areas such as V2 and V3 it is possible to
observe the presence of distinct neural populations
representing the lower and upper visual field that
respond selectively to stimuli presented in the near
or far space respectively (Nasr and Tootell, 2018,
2020).
Thus, in humans, neuroimaging studies have
revealed a peripersonal space network including
bilateral fronto-parietal regions and the putamen,
which is thought to represent a putative homo-
logue of the premotor-parietal network described
in monkeys, sharing similar functional proper-
ties. The areas forming the human peripersonal
space network are densely interconnected and are

Figure 27.5. Neural bases of the human peripersonal space.

(A) Experimental conditions: The participant’s right hand was placed on the table, on either
the left or the right of a central fixation point (black cross). A 3D object was presented to
either the left or the right of the fixation point. (B) Blood oxygen level–dependent (BOLD)
adaptation to the 3D visual stimulus moving near the hand, using a gradient indexing the
degree of hand-centered encoding (0 = absence of hand-centered responses, 5 = stronger
hand-centered encoding). The posterior parietal and premotor cortices showed a high
degree of hand-centered encoding. IPS = intraparietal sulcus; SMG = supramarginal gyrus;
PMv = ventral premotor cortex; PMd = dorsal premotor cortex.
Source: Modified from Brozzoli and others (2012b).
 PERIPERSONAL SPACE REPRESENTATION
usually activated during sensory-motor tasks, sug-
gesting that the peripersonal space could act as a
sensory-motor interface. By contrast, a distinct
ventral network is dedicated to far space process-
ing, which includes occipital, temporal, parietal,
posterior cingulate as well as orbitofrontal regions
not activated by near space, likely subserving the
processing of the shape and identity of objects and
visually guided action in the far space (Aimola
et al., 2012; Cléry et al. 2015, 2018; Lane et al.
2013; Weiss et al., 2000).
Functional Significance of the
Peripersonal Space
Why does our brain need to represent the periper-
sonal space, distinct from the extrapersonal space?
Most likely because many benefits derive from the
availability of a brain system specifically dedi-
cated to peripersonal space coding and monitor-
ing. The space around us is indeed the arena of our
interactions with the external world, whether we
want to reach a glass of wine or avoid an unidenti-
fied insect flying toward our hand, or pass the
glass we grabbed over to our dear friend. Hence,
the peripersonal space has an inherent “appeti-
tive” function, being involved in the execution of
actions toward entities in the proximity of the
body, but also a “defensive” function, dealing with
avoidance or protective actions meant to preserve
the integrity of our body. Furthermore, the perip-
ersonal space representation entails also a poten-
tial “social” function and may be linked to the
representation of the self.
Appetitive Function of the
Peripersonal Space
Thanks to its functional properties and its ana-
tomical position at the interface with motor
regions, the peripersonal space may serve many
motor functions related to body–objects interac-
tions. The visuo-tactile neurons of the parietal
Area 7b, the premotor Area 6 and putamen are
activated not only when a visual or tactile stimula-
tion is passively perceived, but also when a motor
response is implemented (Brozzoli et al., 2014).
Furthermore, both the sensory and motor activities
are expressed in a system of common spatial coor-
dinates, which places in a common spatial repre-
sentation the position of the body-parts, the target
to be reached and the movement necessary to
reach it (Caminiti et al., 1991). To underline that
the cerebral network involved in peripersonal
441
space representation is also implicated in the guid-
ance of voluntary, object-oriented actions, the
peripersonal space has been also called “action
space.” Objects in the vicinity of the body are
indeed more relevant by virtue of the possible
interactions our body can establish with them, as
compared to distant objects. Body-centered repre-
sentations of the space around us allow to access
to accurate information regarding the spatial posi-
tion of objects with respect to our body-parts, in
turn facilitating and fastening our actions toward
objects within reaching distance. By acting as an
anticipatory sensory-motor interface, by which
our brain can successfully predict the arrival of
environmental stimuli, the peripersonal space also
allows an early and fast detection of objects
approaching the body, assisting automatic reac-
tions (Fogassi and Luppino, 2005; Graziano and
Cooke, 2006).
The same anticipatory mechanism supports
also voluntary object-oriented actions (Rizzolatti
et al., 1997). In everyday life, the location of
external objects as inside or outside the periper-
sonal space depends not only on objects dynam-
ics, but also on the movements of the body and
its parts. This requires an online remapping of
the peripersonal space as a function of voluntary
goal-directed actions. This has been shown behav-
iorally in healthy humans by using a modified,
dynamic, version of the crossmodal congruency
task (Spence et al., 2004a,b), which included a
reaching-to-grasp movement toward an object.
The strength of visuo-tactile interaction increases
during, and even immediately before, the hand
movement, meaning that a far object affects tactile
processing at the hand whenever a hand move-
ment is executed, or even just planned, toward
it (Brozzoli et al., 2009). It follows that the spa-
tial constraints of multisensory interactions are
recoded in an anticipatory fashion. This is the case
not only for hand movements, but also for whole
body movements (Noel et al., 2015). Moreover,
the visuo-tactile effect is influenced by the spe-
cificities of the sensorimotor demands (Brozzoli
et al., 2010) and the goal of the action sequence
(Senna et al., 2019), thus adjusting peripersonal
space processing to include the target of goal-
directed actions.
The involvement of the peripersonal space in
action planning and execution would also predict
it plays a role in situations where, instead of mov-
ing the hand toward an object, the object moves
toward the hand. An object approaching the hand
might thus interfere with an ongoing manual motor
program. This was shown by assessing the “readi-
ness” of the motor cortical hand representation to
an approaching object by means of Transcranial
Magnetic Stimulation (TMS) and the recording
442 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
of Motor Evoked Potentials (MEPs): an object
falling near the hand suppresses the ongoing
hand motor plan a few milliseconds after object
vision (Makin et al., 2009). This indicates that the
peripersonal space not only serves goal-directed
actions, but also updates quickly our motor system
about the relevant events arising in surrounding
space. Despite the peripersonal space may share
some characteristics with the arm-reaching space,
which is the space reachable by extending the arm
without moving the trunk, the two representations
are not equivalent. Indeed, the peripersonal space
(as measured with a visuo-tactile detection task) is
smaller and codes for the target of our actions in
a hand-centered reference frame, while the arm-
reaching space (as measured with a reachability
judgment task) is larger and not hand-centered
(Zanini et al., 2021a).
The plasticity of the peripersonal space for
action has been extensively studied with respect
to the use of mechanical tools, and more recently
even with the use of technological devices, to
reach targets outside the physical limits of their
body (Serino, 2019). Different lines of behavioral
investigations in humans showed an extension of
the extent of multisensory interactions to include
the tool’s action space, hence demonstrating a
dynamical shaping of the extension of the periper-
sonal space (Maravita and Iriki, 2004). Critically,
the extension of peripersonal space representation
is determined by where and how the tool is func-
tionally used, not by its physical length or structure
(Farne et al., 2005). The plasticity of the periper-
sonal space is bidirectional, since it can expand
or contract depending on the motor effort/ability
and on the degree of limb use (Bassolino et al.,
2015; Lourenco and Longo, 2009). Peripersonal
space changes after tool-use emerge quickly, after
few seconds of use (Holmes et al., 2007), but also
reverse quickly, disappearing after a few minutes
of no tool-use (Farne et al., 2007), a finding fur-
ther stressing the role of motor experience. On
the other hand, extensive (daily use for long time
periods) and functionally relevant tool-use could
promote a much longer lasting expansion of the
peripersonal space, as found in the case of blind
cane users (Serino et al., 2007).
DEFENSIVE FUNCTION OF PERIPERSONAL
SPACE
The mechanism that quickly informs our motor
system about the presence of an object in the near
space is also useful when a potential threat
approaches our body. Indeed, another main motor
function of the peripersonal space is related to
defensive (reactions, dealing with the protection
of our body.
Studies in non-human primates had shown that
electrical stimulation of the VIP area in the intrapa-
rietal sulcus and of the “polysensory zone” within
the premotor cortex causes movement patterns
that are compatible with defensive, or avoidance
responses (Graziano and Cooke, 2006). By chemi-
cally modulating the activity of these regions, it is
possible to provoke a consequent modulation of
the defensive behavior, inhibiting or enhancing it
(Cooke and Graziano, 2004b). Defensive reactions
include movements of the eyes, face, shoulders,
head and arms aimed at protecting the body part
where the sensory RFs of the neurons are located
(Cooke and Graziano, 2003, 2004a). Similar
response patterns have also been reproduced in the
presence of real external threatening stimuli, such
as sudden air puffs on the surface of the body, with
peripersonal space neurons showing a strong pref-
erence for moving stimuli (Cooke and Graziano,
2003; Fogassi et al., 1996). These properties led
some authors to describe the neurons coding the
surrounding space as “looming detectors” and the
peripersonal space as a “bubble” around our body
that creates a margin of safety from approaching
dangers (Graziano and Cooke, 2006).
Evidence in humans supporting the defensive
function of the peripersonal space comes from
investigations of the hand blink reflex (HBR), a
contraction of the orbicularis oculi muscle elicited
by a threatening touch to the hand (i.e., electrical
stimulation of the median nerve). The magnitude
of the HBR increases in a non-linear fashion with
the reduction of the distance between the hand and
the face, as if, beyond a certain distance from the
face, the stimulus applied to the hand suddenly
becomes threatening (Sambo and Iannetti, 2013),
unless there is a protection between the hand and
the face (Sambo et al., 2012). Modeling the mag-
nitude of the HBR as a function of the position of
the hand in the space around the head shows that
the representation of the head-centered peripersonal
space is symmetrical on the horizontal axis, but not
on the vertical one, resulting in a half-ellipsoidal
shape toward the top (Bufacchi et al., 2016). This
configuration is likely due to the fact that our inter-
actions with the world are shaped by physical laws,
including that of gravity. If we throw something, or
if something is thrown toward us, its trajectory will
tend downward. It is therefore conceivable that even
a mechanism designed to protect our body takes
this property into consideration. In accordance with
this, by changing the posture of the participants, for
example by making them lie down on their back,
the peripersonal space reshapes, extending upward
(Bufacchi and Iannetti, 2016).
 PERIPERSONAL SPACE REPRESENTATION 443

Figure 27.6 (A) The hand blink reflex (HBR) with the hand far from (on the left) or near
(on the right) the face. (B) Half-ellipsoidal shape of the peripersonal space centered on
the head, as evidenced by the gradual reduction in magnitude of the HBR elicited by the
electrical stimulation of the hand as function of the proximity of the hand to the face. Note
the dramatic increase of the HBR when the hand is inside the peripersonal space surrounding
the face (closest dark areas).
Source: Modified from Bufacchi et al., 2016.

The extent of the peripersonal space is also
influenced by the identity of the approaching
stimulus, namely its valence and in particular its
threatening value, as well as by the characteristic
of the observer, such as the level of fear or anxi-
ety (de Haan et al., 2016; Poliakoff et al., 2007;
Rossetti et al., 2015; Sambo and Iannetti, 2013).
For instance, we respond faster to tactile stimuli
on our hand if a spider is approaching that hand,
as compared to a butterfly, especially if we are
afraid of spiders; this occurs only for stimuli loom-
ing toward the hand, and not for stimuli moving
away. Similarly, cynophobic individuals react faster
to touches at their hand if they hear an approach-
ing growling dog, as compared to no dog-phobic
individuals. The examples indicate that the “safety”
peripersonal space enlarges depending on what
situation scares us, clearly supporting its defensive
functions whereby the peripersonal space acts by
preparing our motor reactions to approaching aver-
sive events. Conversely, approaching visual stimuli
with a positive valence reduce the extension of the
peripersonal space facilitating our appetitive motor
responses (Spaccasassi et al., 2021).
To accurately serve defensive or appetitive
functions, the peripersonal space mechanism
could also contribute to learning the positive and
negative value of the stimuli. Such a feature would
allow to learn associations in hand-centered coor-
dinates to update and exploit them when the hand
moves. Indeed, fear conditioning, a form of asso-
ciative learning, has been shown to arise in hand-
centered coordinates (Zanini et al., 2021b). Thus,
not only an external threat is encoded as a function
of its position relative to a specific body part, but
the peripersonal space allows to learn new associa-
tions of stimuli in body part-centered coordinates.
In a more general perspective, these findings show
that the peripersonal space mechanism might be
exploited by a larger range of functions which
needs to build on such a strategic information
as the distance between body parts and external
events (Zanini et al., 2021b).
SOCIAL SIDE OF THE PERIPERSONAL
SPACE
The peripersonal space representation is also
affected by social factors, such as the presence of
people near us and by the nature of interactions
we have with them. Depending on the context,
peripersonal space boundary enlarges, shrinks, or
remaps in relation to others according to our and
their individual characteristics, such as familiarity,
proximity, and personality traits (Bogdanova
et al., 2021). The neural substrate of this social
side of the peripersonal space is possibly linked to
the above-mentioned mirror-like properties of
visuo-tactile neurons, by which they respond not
only to visual stimuli approaching the monkey’s
own body but even to visual stimuli approaching
the body of another person (Ishida et al., 2009), as
well by the existence of neural subpopulations
sensitive to the sector of space (within or outside
the peripersonal space) where others’ actions
occurs (Bonini et al., 2014). The activity of these
neurons may explain some social effects linked to
444 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
the human peripersonal space, such as that touches
on our hand are boosted by visual stimuli near
someone else’s hand (Brozzoli et al., 2013), or the
fact that social interactions (e.g. performing a task
with another person) and the way we perceive
people near us modulate visual-tactile processing
in peripersonal space, in turn changing its extend
(Heed et al., 2010). For instance, if a nearby
person is perceived as collaborative or moral, our
peripersonal space expands (Pellencin et al.,
2018). Even the amplitude of the HBR is enhanced
when the stimulated hand of the participant is
brought close to the face of another person and
this interpersonal modulation depends on the par-
ticipant’s ability to empathize with the other
(Fossataro et al., 2016).
The social side of peripersonal space recalls
the concept of personal space, also called inter-
personal space in social psychology, that is the
space we keep between us and others to avoid
discomfort. However, some caution must be used
in superimposing the peripersonal space to the
interpersonal space, since they are dissociable and
show opposite dynamic features: the expansion of
the peripersonal space during positive social inter-
actions indeed is paralleled by a reduction of the
interpersonal distance (Pellencin et al., 2018).
Beyond other individuals, other social features
can modulate the peripersonal space representation.
When object ownership is at stake, for example, the
recruitment of peripersonal space may be modu-
lated when we grasp the object as a function of
whether it belongs to us or to another person. Most
notably, this ownership effect emerges also dur-
ing action observation, that is when we watch oth-
ers grasping their own object (Patane et al., 2020).
Additionally, observing others’ actions induces a
sensory resonance (Bolognini et al., 2014b), sup-
porting the view that one’s own peripersonal space
also implements a mechanism to map others’ perip-
ersonal space; such mapping may allow the shar-
ing of a common reference frame to interact with
the people around us and anticipate their actions
(Brozzoli et al., 2014). This evidence is in line with
electrophysiological work on nonhuman primates,
showing agent selectivity of visuomotor neurons
in the monkey’s area F6. This neuronal population
responds selectively to the presentation of an object
as a function of whether it is grasped by the mon-
key, by another agent, or by both. When the object
is presented outside of the monkey’s peripersonal
space, the same neurons do not discharge (Livi
et al., 2019). The fact that ownership modulates the
activity of peripersonal space network both dur-
ing action execution and observation is compatible
with the notion that peripersonal space is sensitive
to both which object is grasped and who is the agent
of the action.
PERIPERSONAL SPACE AND
SELF-REPRESENTATION
The sensation of owning a body and of its integrity
has as fundamental basis the continuous integration
of coherent multisensory signals coming not only
from the body, but also from the environment sur-
rounding it. The multisensory integration mecha-
nism underlying the peripersonal space indeed
contributes to the sense of body ownership and to
other components of bodily self-consciousness
(Blanke et al., 2015). Much of the evidence sup-
porting this view comes from the use of the experi-
mental paradigm of the rubber hand illusion.
Basically, the synchronous visuo-tactile stimulation
of a fake hand, positioned next to the real (hidden)
hand, induces in the participant the illusion of
owning the fake hand (Botvinick and Cohen,
1998). The illusory feeling of owning the fake hand
has been related to the activity of the neurons
coding for the peri-hand space and in particular to
a re-tuning of peripersonal space neurons whose
RFs are centered on the hand (Blanke et al., 2015;
Makin et al., 2008). During the rubber hand illu-
sion, the activation of the tactile RF of these neu-
rons would be systematically associated, due to
synchronicity of the visuo-tactile stimulation, with
the activation of a visual RF not perfectly overlap-
ping the hand location. But thanks to the plastic
properties of the peripersonal space, the prolonged
stroking of the hand coupled with visual stimula-
tion from a farther location (namely, from the
rubber hand) is able to re-tune the visuo-tactile RFs
of peripersonal space neurons toward the location
of the visual inputs. Thus, changes in body owner-
ship can be induced by manipulating the spatio-
temporal coherence of multisensory bodily inputs
processed by the peripersonal space system. This
account is strongly supported by neuropsychologi-
cal evidence showing a remission from somatopara-
phrenia, a somatic delusion usually following
right-hemisphere damage, which typically mani-
fests as a feeling of disownership of one’s contral-
esional body parts, by applying synchronous
touches to the patient’s visible disowned hand and
to the invisible unimpaired hand (Bolognini et al.,
2014a). Moreover, the induction and the strength of
the illusory feeling of owning a rubber hand corre-
late with the activity of neurons in the peripersonal
space network, in particular at the level of the pre-
motor and parietal cortices (Ehrsson et al., 2004).
Convergent evidence that the peripersonal space
is involved in generating our feeling of body owner-
ship derives from another illusory effect, the enface-
ment illusion (Tsakiris, 2008). In this illusion, the
participant perceives a touch on the face while see-
ing a stranger’s face being touched, in a spatially
 PERIPERSONAL SPACE REPRESENTATION
and temporally coherent way. After few seconds of
synchronous stimulation, the illusion of ownership
extends to the stranger’s face. The onset of this illu-
sion is linked to the activation of the right intrapa-
rietal sulcus (Apps et al., 2015), the area putatively
corresponding to the monkey VIP region. This
area of the peripersonal space network is strongly
involved in the coding of tactile stimuli on the face
and of visual stimuli close to it, and its activation
during the enfacement illusion leads to recoding
the space near an unknown face as the peripersonal
space of one’s own face (Huang et al., 2012).
By applying a visuo-tactile stimulation similar
to that used for the rubber hand and the enface-
ment illusions to the trunk it is also possible to
elicit the sensation of ownership toward a dif-
ferent whole body (body swap illusion; Petkova
and Ehrsson, 2008), or a dislocation of the “self”
toward a position external to one’s body (full-
body illusion; Lenggenhager et al., 2007). These
illusory experiences indicate that the peripersonal
space does not necessarily reflect the position of
the physical body, rather it may reflect the position
of one’s self.
SUMMARY AND CONCLUSIONS
Our brain has inherited a highly flexible system to
represent the space closely surrounding the body,
the peripersonal space. This space has a clearly
adapting meaning as it is where all physical inter-
actions with objects in the environment occur: it
allows to detect and anticipate potential interac-
tions between the body and an external event,
triggering appropriate motor reactions thanks to
its direct access to the motor system. The periper-
sonal space features itself as an important antici-
patory sensory-motor interface mediating
body–object interactions for appetitive and defen-
sive purposes. The plastic boundaries of the perip-
ersonal space are efficiently and dynamically
shaped by the ongoing sensorimotor experience,
and taking into account environmental and social
changes relevant for our body safety and the rep-
resentation of ourselves as distinct from the envi-
ronment and the others.
Note
1  Neuronal adaptation consists in a suppression of
the response of those neurons that are selective
to one characteristic of the stimulation, when a
stimulus featuring such characteristic is presented
repeatedly (Grill-Spector et al., 2006). The main
445
advantage of fMRI-adaptation is to reveal the pres-
ence of neuronal populations selective to a stimu-
lus feature, such as its proximity to the hand.
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 PART VI
Methodological Advances
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Neural Recordings and
Time Series Analyses
R a n d o l p h F. H e l f r i c h a n d R o b e r t T. K n i g h t
INTRODUCTION
Modern day neuroimaging provides unprece-
dented spatiotemporal resolution to study cogni-
tive processing at the level of whole-brain
large-scale network interactions. For decades
whole-head electroencephalography (EEG) was
restricted to only 19 channels as defined by the
international 10–20 electrode layout (a practice
that prevails in the clinical setting). In contrast,
modern day amplifiers enable simultaneous
recordings of a few hundred channels (Biasiucci
et al., 2019; Cohen, 2017; Lopes da Silva, 2013).
For example, current high-density EEG systems
offer up to 256 channels, which can be sampled at
>1,000 data points per second. When combined
with inverse solutions to project 2D sensor-level
data into 3D source space, as informed by indi-
vidual high-resolution structural MRI (magnetic
resonance imaging) scans, one can obtain densely
sampled time series data for >4,000 voxels inside
the brain at 1 mm3 resolution. A thorough discus-
sion of inverse solutions exceeds the scope of this
chapter, for a detailed discussion see (Lopes da
Silva, 2013; Pascual-Marqui et al., 1994; Van
Veen et al., 1997). This development now places
high-density EEG recordings on par with magne-
toencephalography (MEG; Baillet, 2017; Gross
28
et al., 2013) in terms of spatiotemporal resolution
and approaches the spatial resolution of functional
magnetic resonance imaging (fMRI). This wealth
of data poses a challenge for extraction of mean-
ingful information about the functional architec-
ture underlying human perception, cognition and
action.
In this chapter, we focus on analysis techniques
of time series data. First, we provide a brief over-
view of current methods that enable imaging the
human brain with high spatial and temporal reso-
lution. Throughout the chapter we emphasize that
time series analyses can be applied to different
types of electrophysiological data. Second, we
review analyses strategies for high-dimensional
time-series data. Methods are introduced accord-
ing to their practical importance during data anal-
ysis (i.e., univariate analysis approaches in the
time-domain are covered first, before advancing
into spectral decomposition, bivariate connectivity
analyses, and finally multivariate analysis strate-
gies). We then review methods that go beyond
established linear time- and/or frequency analyses
and discuss non-linear approaches, including infor-
mation-theoretical approaches as well as recent
machine-learning inspired strategies. Finally, we
take recent developments of the last five years into
account, as exemplified by strategies to analyze
454 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
background “noise,” which has recently been
shown to contain important behaviorally relevant
information. In addition, we highlight how analy-
sis strategies can be synergistically combined to
maximize insight into neurophysiological pro-
cesses underlying human cognition. Throughout
the chapter, we highlight potential caveats, with
the goal to provide a roadmap for state-of-the-art
electrophysiological data analysis.
NEURAL RECORDINGS
Traditionally, neural recordings mainly referred to
invasive single unit and local field potential record-
ings in animal models (Buzsáki et al., 2012). In the
human literature, there is often a distinction
between direct neurophysiological recordings, as
for instance EEG, and indirect measures, such as
the fMRI BOLD (blood oxygen level dependent)
response. The goal of this chapter is not to provide
an exhaustive list of imaging modalities, but rather
to survey the analytical possibilities in the context
of time-series analyses and highlight the similari-
ties between different methods. To accomplish
this, we adopt a liberal definition of neural record-
ings, which encompasses every method that ena-
bles quantification of a brain process, irrespective
whether it refers to direct electrophysiological
recordings (voltage differences in scalp and intrac-
ranial EEG), magnetic fields (MEG), indirect
oxygen-dependent responses (fMRI BOLD) or
functional near-infrared spectroscopy; fNIRS) or
motor signals that are obtained at the output stage,
such as time-resolved behavior (quantified by
time-resolved hit rates or reaction times), electro-
myography (EMG; voltage trace) or pupillometry
and pupil size (recorded in millimeters, degree
angles or pixels). These considerations can also be
extrapolated to other types of recordings, such as
two-photon calcium imaging data in rodents. One
exception that we discuss in detail is that certain
analysis approaches are limited by the sampling
rate and recording location, such as extracting
single unit responses from continuous local field
potential recordings, which require recordings at a
fine-grained spatial scale at high temporal
resolution above 30,000 Hz.
To illustrate the analytical approaches, we focus
on electrophysiological recordings in humans,
both by means of scalp EEG as well as intracra-
nial electrophysiology, which encompasses intrac-
ranial EEG, local field potentials, and single unit
activity (Parvizi and Kastner, 2018). While most
readers will be familiar with scalp EEG, which
will not be reviewed in detail (Biasiucci et al.,
2019), we provide a more in-depth account of
intracranial recordings in humans (Fried et al.,
2014; Parvizi and Kastner, 2018).
Intracranial electrophysiological signals can be
obtained from electrodes placed within the human
brain for diagnostic and/or therapeutic purposes
(Figure 28.1). The two most common entities that
require a surgical placement of leads in the human
brain are either placement to deliver therapeutic
deep brain stimulation electrodes for Parkinson’s
disease (target: subthalamic nucleus or internal
globus pallidus; Bronstein et al., 2011), dystonia
(ventral intermediate nucleus of the thalamus) or
epilepsy (anterior nucleus of the thalamus; Fisher
et al., 2010)). In addition, implanted electrodes
are used to guide surgical decision-making for
intratractable epilepsy (Parvizi and Kastner, 2018).
Here, leads are inserted into multiple nodes of the
suspected seizure network to identify the seizure
onset zone. Target areas are identified according
to the non-invasive work-up, which includes scalp
EEG, high-resolution imaging and neuropsychol-
ogy and can be complemented by various other
diagnostic tools, including positron-emission
tomography (PET), voxel-based morphometry
(VBM), or MEG (Zijlmans et al., 2019). An impor-
tant feature of some electrodes is that they feature
a hollow lumen, enabling insertion of additional
wire bundles, which protrude by 2–4 mm at the
electrode tip for recording local field potentials and
unit activity (Fried et al., 2014). Several studies
have demonstrated the feasibility and safety of this
approach (Carlson et al., 2018; Chari et al., 2020;
Despouy et al., 2020; Hefft et al., 2013). Over the
last decade, intracranial recordings in humans have
yielded important insights into the functional archi-
tecture of cognition, such that the method is now
widely regarded as an ideal tool to bridge the gap
between invasive recordings in animal models and
non-invasive recordings in humans.
Ultimately, only a few factors determine the
application of time-series analysis strategies.
Foremost are the sampling rate and the duration of
the recordings. These factors determine the result-
ing Nyquist frequency (the highest frequency that
can be resolved from the data is half the sampling
rate – at 1,000 Hz sampling rate, all frequencies up
to 500 Hz can be resolved; practically one should
rather aim for a 3rd or 4th of the sampling rate).
The duration further determines the Rayleigh fre-
quency resolution, which is defined by 1 divided
by the temporal window. For example, a two
second segment at 1,000 Hz can be analyzed in
steps of 0.5 Hz (1/2), while a 10 second segment
allows a more fine-grained resolution at 0.1 Hz
(1/10). The signal duration also determines the
 Neural Recordings and Time Series Analyses 455

Figure 28.1 Intracranial human electrophysiology.

(A) Upper row: Subdural grid electrode placement from three representative subjects cover-
ing large portions of frontal, temporal, and motor areas. Lower row: Stereotactically placed
depth electrodes targeting medial temporal, orbitofrontal, or medial frontal structures. (B)
Single unit activity can be recorded from additional wire bundles that are inserted through a
hollow lumen of the clinical macro-electrode.
Source: Figure reproduced with permission (Helfrich & Knight, 2019).

digital filtering that can be applied to the data. The
lower cut-off needs to match at the least one whole
cycle of the lower boundary (i.e., filtering a 1 s
second segment at 1 Hz is theoretically possible,
but pushes the limits of signal processing leading
to unstable results). However, filtering at a lower
cut-off of 10 Hz (10 cycles in 1 second) is feasible,
while a cut-off of 0.5 Hz is impossible (only half
a cycle can be fit into the segment). Lastly, one
needs to be aware of the noise floor of both the
environment as well the recording equipment. For
typical EEG amplifiers, the noise floor where the
amplifier yields meaningful results is > 100 Hz.
However, the environmental noise floor is already
present at ∼30–40 Hz given muscle activity in this
recording range. This issue is largely mitigated
in intracranial EEG recordings, which are less
impacted by muscle artifacts. For instance, analy-
ses in the high-frequency activity band (70–200
Hz) have yielded important insights into cognitive
functioning (Leszczyński et al., 2020).
Keeping those theoretical principles in mind
now enables applying spectral analyses to dif-
ferent recording modalities with theoretical
and practical implications (Prerau et al., 2017).
For example, intracranial EEG data that was
recorded over one hour at a frequency resolution
of 5,000 Hz can easily be filtered and spectrally
decomposed in a broad-range of frequencies
up to 2,500 Hz at a fine-grained resolution of
≪0.1 Hz (in practice an upper threshold of 250
Hz and a resolution of 0.5 Hz is often sufficient).
In contrast, whole-brain fMRI BOLD over one
hour typically provides one data point per voxel
every second, thus, resulting in a frequency
resolution of 0.33 Hz, which limits both the
ability to filter as well as to spectrally decom-
pose the data (Fox et al., 2005). For fMRI using
these parameters, he upper frequency cut-off is
at 0.16 Hz, so frequencies between 0.01 and 0.1
Hz can best analyzed at a resolution in the 10-2
to 10-3 Hz range.
456 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
ELECTROPHYSIOLOGICAL DATA
ANALYSIS
The improved spatiotemporal resolution of human
electrophysiological recordings has benefited the
development of numerous algorithms and meth-
ods to extract behaviorally meaningful informa-
tion. However, these high-dimensional and
complex data sets that are governed by non-linear
dynamics, posing unique challenges. For exam-
ple, there are multiple correct answers for ques-
tions regarding (1) how to analyze the data, (2)
which method to choose, and (3) how to statisti-
cally quantify the results. More commonly, the
right answer will be “it depends.” Here, we pro-
vide a practical road map with an initial focus on
EEG analyses that helps narrow the immense
search space and justify analytical choices and
their interpretations.
GENERAL ANALYSIS STRATEGIES
Data analysis does not begin once data collection
ended, but rather starts with data recording and the
experimental structure. During data recording,
researchers make a number of explicit (e.g.,
number of EEG sensors, sampling rate) as well as
implicit choices (task design, duration of trials,
event structure) that limit the subsequent analyses.
Important considerations include whether distinct
events are present (task-based time-locked events
that can be contrasted) or whether a continuous
design (e.g., resting state or experience sampling)
were employed. Within the historical context of
EEG, Hans Berger’s seminal experiments on
alpha oscillations (cf. Berger, 2004) first consti-
tuted a continuous analysis (spontaneous fluctua-
tions in the trace were quantified). Subsequently,
he employed an event-locked approach (eyes
open/close), which later gave rise to the discovery
of event-related potentials by averaging across
several repetitions (Polich, 2007). To illustrate
these methods, we will assume a task-based
design with distinct events that require a behavio-
ral response and thereby, enable time-locked
analyses either relative to the event or the action.
EVENT-RELATED ANALYSIS IN THE
TIME-DOMAIN
Averaging across several events is typically done
to improve the signal-to-noise ratio and to quan-
tify the average response across a number of
events. In the context of EEG, averaging can be
done on the raw trace, thus, yielding event-related
potentials (ERP; Handy, 2005). Likewise, averag-
ing can be performed after extraction of a distinct
spectral component. For example, it had been
observed that the 70–150 Hz (termed high gamma
or high frequency band activity, HFA/HFB) in
intracranial EEG recordings reflects a proxy of
multi-unit activity and contains more behaviorally
relevant information than the broadband signal
(Edwards et al., 2005; Flinker et al., 2015; Kanth
and Ray, 2020; Leszczyński et al., 2020; Ray and
Maunsell, 2011; Rich and Wallis, 2017). Thus,
filtering and extracting the signal envelope by
means of (e.g., a Hilbert transform; Figure 28.2),
are used to distil the relevant signal component
prior to subsequent averaging (Figure 28.2A).
In continuous task designs, such as resting
state or sleep recordings, there are no external
temporal structure for time locking analyses.
Therefore, researchers rely on identification of
intrinsically generated events for subsequent
analysis. Many events have first been described in
the time domain (e.g., alpha waves by Berger as
characteristic 10 Hz bursts of activity in the raw
trace). Likewise, slow waves (< 4 Hz) and sleep
spindles (∼12–16 Hz) have been identified based
on the characteristic waveform shape in continu-
ous recordings (Buzsáki, 1996; Diekelmann and
Born, 2010). Detection of these events in the
time domain can be algorithmically formalized,
typically by introducing constrains with respect to
(a) the frequency content (through band pass fil-
tering), (b) an amplitude criterion, (c) a duration
criterion, and (d) exclusion of unrelated activity
(Helfrich et al., 2019; Staresina et al., 2015). For
example, detection of sleep spindles only consid-
ers bursts in the amplitude series of the 12–16 Hz
filtered signal that exceed a z-score of (e.g., 3 SDs
above the signal mean) for anywhere between 0.5
to 3 seconds. Based on the individual detections,
averaging can be performed in the time domain to
obtain the average waveform shape (Figure 28.3).
Furthermore, the detected event can be con-
ceptualized as a point process, i.e. an event that
occurred precisely at one moment in time (e.g.,
activity peak). To again employ the example of
sleep spindles, time-locking of the raw signal
relative to spindle peaks reveals the presence of a
second spectral signatures in the raw signal. The
spindle does not occur in isolation, but is nested
with a slow wave. This approach exemplifies how
detection of endogenous temporal events can
reveal temporal regularities that otherwise could
not be detected from the raw trace.
The same principle applies to the extraction
of single unit spikes from broadband local field
potentials (LFP). LFPs are sampled at >30,000
Hz, spikes are again extracted based on amplitude
 Neural Recordings and Time Series Analyses
Figure 28.2 High frequency band activity.
(A) Average high frequency band activity
recorded from a motor cortex electrode
relative to the detection of the onset of a
visual target reveals activity after approxi-
mately 500ms. (B) Stacked single trials that
are sorted relative to reaction times (black
trace) reveals that HFA tracks behavior on a
single trial basis.
Source: Unpublished (Helfrich & Knight).
and time criteria (sharp transient in the range
from 2–4 ms) before all waveform shapes are fur-
ther characterized in a process called spike sort-
ing (Fried et al., 2014; Rutishauser et al., 2006).
Here, different waveform shapes are disentangled
in order to isolate activity from distinct neurons.
Subsequently, every spike from every identified
neuron is regarded as one distinct time stamp; thus,
the dimensionality of the data has been reduced,
benefiting subsequent analyses. For example,
spike-triggered averaging of the raw broadband
457
signal has revealed that spikes preferentially occur
at distinct phases of the underlying population
oscillation, which are already present in the down-
sampled signals. Hence, subsequent analyses can
be carried out on signals sampled at 1000 Hz and
not 30,000 Hz, enhancing computational effi-
cacy and speed. Furthermore, from these point
events (“Spikes”), peri-stimulus time histograms
(PTSH) can be created, which are commonly
smoothed into a trace of overall spiking activity;
hence, yielding a signal that is comparable to an
event-related potential, only based on a number of
distinct neuronal spikes. Collectively, this demon-
strates how temporal events can be extracted from
continuous data and then again be analyzed in a
time-locked fashion, either relative to external or
internal events.
SPECTRAL ANALYSIS
Electrophysiological signals are rich and com-
plex. Ever since Berger’s seminal observation, the
community was well aware that different fre-
quency bands might contain distinct information.
Over recent decades, several methods were intro-
duced to either spectrally decompose the signal to
obtain activity in multiple frequency bands or to
isolate activity in a distinct frequency band.
The most common approach is based on the
Fourier transformation, which decomposes the
signal into (co-)sines and provides estimates of
the relative contribution of every frequency band
to the entire signal. Using this approach, the time
domain is typically lost (translation of time- into
frequency-domain), but can be recovered by means
of repeating the analysis in different time windows
by means of convolution. Electrophysiological
power spectra exhibit distinct characteristics,
including a steep 1/fx drop-off, where x typically
scales in the range from –2 to –4 in the healthy
brain (for extended discussion see section on
aperiodic activity; He et al. (2010); Miller et al.
(2009)). Band-limited oscillations arise as distinct
“bumps” (Donoghue et al., 2020) above the back-
ground activity (Figure 28.4).
In addition to the Fourier transform, several
other methods have been introduced, such as
Morlet wavelets (sines multiplied with Gaussians,
which are convoluted with the signal) or the
Hilbert transform, which requires band-pass fil-
tering first and then estimates the instantaneous
amplitude and phase series. One important caveat
is that all spectral decomposition techniques only
provide “estimates,” which differ as a function
of (e.g., signal length, sampling rate, noise and
pre-processing). A common approach to improve
458 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 28.3 Visualization of cross-frequency coupling and raw waveform shapes.

(A) Slow waves in a group of older adults (black) on top of the respective time-frequency
decomposition, indicating an activity peak in the ∼14 Hz spindle range just prior to the slow
wave peak. Inset: Visualization in circular space of the same data, indicating that spindle
activity peaked prior to the slow wave peak (approx. 45°, corresponding to 50–100ms).
(B) Same visualization for a cohort of younger adults, indicating that spindles are precisely
locked to the peak of the slow wave. (C) Visualization relative to detected spindles (colored)
with the slow wave superimposed in black. Note that spindle peak prematurely. Inset:
Illustration of the spindle peak relative to the slow wave (as exemplified by a cosine).
(D) Histogram-based visualization of coupling: Relative amplitude in the spindle-band rela-
tive to different binned slow-wave phases, reveals a non-uniform distribution that is skewed
in older adults. Note all panels depict the same data and illustrate different approaches to
cross-frequency coupling and waveform shape analyses.
Source: Figure reproduced with permission from (Helfrich, Mander, et al., 2018).

estimates is to “window” the data (also called
taper; multiplication of a data segment with, e.g.,
Boxcar window, where the edges are Gaussian
shaped, thus, attenuating edge artifacts). The
signal-to-noise ratio can be improved if multiple
windows are combined and estimates are averaged
(as for instance done when using Welch’s method
or the multi-taper approach based on discrete pro-
late spheroidal sequences (Prerau et al., 2017;
Figure 28.5).
Another major drawback that all methods share
is that they are based on sinusoidal basis functions
(i.e., if these methods are applied to brain data,
then the results will be systematically biased to
reveal sinusoidal oscillations). Inspection of raw
EEG traces reveals that most neuronal oscillations
are not sinusoidal in nature, but are characterized
by biased rise- and decay-times with skewed and
often sharp waveform shapes (Cole and Voytek,
2017). Application of sinusoidal methods can
introduce severe artifacts, which are prone to
misinterpretation (Aru et al., 2015; Gerber et al.,
2016). One example is sensorimotor Mu-Rhythm
at ∼8–12 Hz, which is named “Mu” given that is
often shaped like a “M.” The Fourier transform
will extract the main component at ∼10 Hz, but
also yield peaks at ∼20 Hz as well as all other
subsequent harmonics, given that the sharp peak
is incompletely captured by a single sine wave
(Voytek et al., 2010). In electrophysiological
recordings, researchers are then faced with the
presence of true beta-band activity at ∼20 Hz
 Neural Recordings and Time Series Analyses 459

Figure 28.4 Relationship of oscillatory and broadband activity.

(A) Illustration of Fourier transformation of electrophysiological data that exhibits both an
oscillation in 8-12 Hz alpha range (“bump” exceeding the 1/f background activity within the
gray shaded area) as well as broadband 1/f component. A true increase in oscillatory power
between two conditions (red to green) is illustrated. (B) A broadband shift (i.e., change of
overall offset along y-axis) can mimic an alpha power increase, which is not oscillatory in
nature. (C) Likewise, a change in peak frequency can mimic power changes when power is
averaged within a predefined range. (D) Similarly, a rotation of power spectrum (change in
spectral exponent) can introduce changes in oscillatory power if spectra are not properly
parameterized. Illustrations created using the FOOOF toolbox.
Source: Donoghue et al., 2020.

(a hallmark of the motor system), which is con-
taminated by Mu-harmonics at ∼20 Hz (Stolk
et al., 2019). In recent years, several methods have
been introduced to disentangle true from spurious
oscillatory brain activity (Donoghue et al., 2020;
Kosciessa et al., 2020; Wen and Liu, 2016). For
example, empirical mode decomposition (EMD)
does not rely on sinusoidal basis functions and can
also model a change in the precise peak frequency
over time (Quinn et al., 2021). The same issues
apply when the interaction of multiple frequency
bands is assessed. To date, there is no unique solu-
tion for this issue, but several recent publications
suggest that a set of criteria could be applied to the
data to infer whether non-sinusoidality is present
(Aru et al., 2015).
SEPARATING APERIODIC FROM
OSCILLATORY ACTIVITY
The electrophysiological power spectrum encom-
passes oscillations (discrete “bumps”), exceeding
the general 1/fx drop-off. For decades, both phe-
nomena have been studied together and were not
explicitly disentangled (Donoghue et al., 2021).
Hence, elevated “alpha power” could either be the
results of an amplitude increase of the oscillatory
component or a general increase in activity in all
frequency bands (Figure 28.4). This distinction
has gained more traction recently, since several
groups demonstrated that the background activity
– which had been previously considered to mainly
reflect neuronal noise – in fact contains behavio-
rally relevant information (Donoghue et al., 2020;
He et al., 2010; Lendner et al., 2020; Voytek et al.,
2015). Importantly, the level of information con-
tent about the behavioral state is on par with neu-
ronal information encoded in band-limited
oscillatory activity. To date, the exact physiologi-
cal role of both components is not fully under-
stood, but they can be conceptualized as providing
complementary insights into cognitive processes
(Wainio-Theberge et al., 2021, 2022). Over the
last decade, several approaches have been intro-
duced to parameterize oscillations and to disen-
tangle oscillatory from broadband (also termed
aperiodic, fractal or scale-free) background activ-
ity. The simplest solution to isolate oscillations
entails a linear fit to the power spectrum in dou-
ble-log space (thus the linear fit reflects the aperi-
odic component) and subtraction from the original
spectrum (Lendner et al., 2020; Miller et al.,
2009). More sophisticated algorithms employ
robust fitting (Kosciessa et al., 2020), irregular
spectral resampling (Wen and Liu, 2016) or addi-
tive fitting of Gaussian components to the oscilla-
tory peaks (Donoghue et al., 2020). All methods
have in common that they now provide two com-
ponents that are derived from the same underlying
signal, which can be related to behavior and brain
state. Currently, these concepts are actively being
460 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 28.5 Effect of different spectral decomposition methods.

Upper row: Sleep hypnogram from single case across 8 hours of sleep. Below: Spectral
decomposition of entire night of sleep using either a multi-taper or single-taper approach,
the periodogram or Welch’s method. The resulting estimates become progressively more
coarse-grained. (B) Signal-to-noise ratio per frequency reveals a clear advantage of multi-
tapered spectral analysis.
Source: From Lendner et al., 2020.

explored, with several new notions, such as the
concept of population time constants of relative
stability (also termed temporal integration win-
dows, autocorrelation window or intrinsic neural
timescales; Gao et al., 2020; Golesorkhi et al.,
2021; Ito et al., 2020; Raut et al., 2020; Wolff
et al., 2022), which can be approximated by char-
acteristic bends in the shape of the power spec-
trum in the frequency domain or from the decay of
the autocorrelation function in the time domain.
Population time constants are thought to provide
the necessary means for temporal integration and
exhibit a clear cortical gradient with short time-
scales in sensory cortex and longer timescales in
association areas (Gao et al., 2020; Raut et al.;
2020; Wolff et al., 2022).
OSCILLATORY AND WAVEFORM SHAPE
FEATURES
Definition of oscillations, including their band-
width and amplitude (i.e., power), is most com-
monly done in the spectral domain. However, as
outlined above, spectral analysis also omit impor-
tant wave form features as well as instantaneous
signal characteristics, which are inherently time
dependent, such as oscillatory phase. Hence, it is
best practice to return from the spectral to the time
domain to quantify and assess the oscillatory fea-
tures after the presence of an oscillation was
established using spectral methods. These analy-
ses can either be applied on band-limited or
broadband data. It is important to consider that
both linear as well as non-linear variables can be
obtained from time- and frequency-domain data,
with amplitude reflecting a linear variable, while
phase constitutes a circular, and thereby, non-
linear variable. Both features can be extracted
from the Hilbert transform and can be related to
behavior using either linear or circular-linear cor-
relations (Berens, 2009; Fiebelkorn et al., 2018;
Helfrich, Fiebelkorn, et al., 2018). In this case,
one needs to assume a fixed frequency band to
obtain reliable phase estimates. Again, Fourier
methods are ill suited to assess if the peak fre-
quency changes over time (jitter in peak frequency
reflects a broadening of the spectral peak in the
electrophysiological power spectrum). Several
recent developments, including the EMD, now
aim at mitigating these effects (Quinn et al., 2021;
Watrous and Buchanan, 2020).
Another recent development is the appre-
ciation of waveform shapes (Cole et al., 2017).
Previously, waveform shapes have largely been
ignored given that the Fourier basis functions were
 Neural Recordings and Time Series Analyses 461

Figure 28.6 Effects of non-sinusoidal sharp transients on cross-frequency coupling esti-

mates, (A–H) eight examples of simulated EEG traces (upper left) that are composed of
broadband EEG activity (center left) and sharp transients (lower left) as well as the accom-
panying phase-amplitude comodulogram (right; black outlines indicate significant coupling)
revealing that sharp transients introduce spurious cross-frequency coupling at the primary
frequency (10 Hz) as well as at the subsequent harmonics.
Source: From Gerber et al., 2016.

sinusoidal. The role of physiologic non-sinusoidal
waveform shapes came into focus after it was real-
ized that non-sinusoidality introduces artifacts
in (e.g., cross-frequency coupling analyses; see
below; Aru et al., 2015; Gerber et al., 2016; Figure
28.6). Novel tools now enable assessing waveform
shapes with the goal to relate distinct features (such
as rise- or decay-times, asymmetries or amplitude
bias) to distinct physiological processes. However,
there is currently only limited evidence that sup-
ports a distinct role in cortical processing.
NETWORK CONNECTIVITY ACROSS
SPATIAL AND TEMPORAL SCALES
We have focused on univariate analyses that can be
carried out at the single electrode or single voxel
level. In contrast, network approaches quantify the
interaction between multiple regions. This interac-
tion is often also termed functional connectivity, to
contrast it to structural connectivity, which can be
obtained from tracing or fiber tracking studies
(Buzsáki and Draguhn, 2004; Engel et al., 2001;
Varela et al., 2001). Functional connectivity is
undirected (i.e., it is not quantified who drives the
interaction). Directed connectivity is referred to
effective connectivity implying information flow
from node A to node B. Here, we first discuss undi-
rected connectivity between different nodes, and
then we discuss directed connectivity methods
across spatial scales. The concept of connectivity
can also be extended to interactions in the temporal
domain (i.e., the interaction between different
oscillations or between the LFP and spikes. Lastly,
we discuss the use of information theoretical
approaches in this context.
Undirected connectivity is most commonly stud-
ied by means of coherence or magnitude-squared
462 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
coherence as it is more correctly termed (Bastos
and Schoffelen, 2015). This distinction indicates
that the coherence formula encompasses both the
relationship of amplitude as well the relationship
of phase. Collectively, this relationship is then nor-
malized to yield a number between 0 and 1. If the
amplitude term in the formula is replaced by a 1,
then the formula become amplitude-­independent
and only the contribution of phase synchroniza-
tion is estimated; this normalized variant is also
known as the phase-locking value (Lachaux
et al., 1999). Likewise, one can focus only on the
amplitude contribution by (e.g., correlation of the
amplitude time series; Hipp et al., 2012). The lit-
erature often distinguished between phase-based
and amplitude-based connectivity and several
theoretical accounts postulated distinct roles for
cortical communication (Engel et al., 2013). Both
metrics have in common that they are suscepti-
ble to volume spread in the cortical tissue, which
inflates connectivity metrics. Solutions by means
of orthogonalized amplitude correlations (Hipp
et al., 2012) or imaginary coherence (Nolte et al.,
2004) as well as several variants have been pro-
posed (Bastos and Schoffelen, 2015), which mini-
mize this confound by attenuating the contribution
of zero phase-lag interactions.
Both approaches share that they are undirected
in nature, so it remains equivocal whether node A
is driving node B, or vice versa. Several metrics
that take advantage of statistical regularities in the
data have been introduced to infer directionality,
such as Granger causality (model-based assess-
ment (Seth et al., 2015)) or the phase slope index
(dependence across multiple frequency bands
(Nolte et al., 2008)). However, these methods
operate on statistical dependencies, are suscep-
tible to noise and do not provide a true “causal”
explanation.
The concept of directed and undirected con-
nectivity has also been formalized in an infor-
mation-theoretical framework (Ince et al., 2017;
Panzeri et al., 2015). Shannon Information
Theory (Shannon and Weaver, 1998) is centered
on entropy to quantify the observed distribution
of a given variable (here activity in one region).
Connectivity between two regions can be inferred
if knowledge about the activity in one region
reduces uncertainty about the state of the other
region. This interaction has also been termed
Mutual Information and is undirected. An impor-
tant extension of this idea called sample entropy
basically takes a third signal into account to infer
directionality (Lobier et al., 2014): Does knowl-
edge about the past of region A provide more
information about the future of region B than the
past of region B alone? If the answer is yes, then
this can be interpreted as information flow from A
to B. Again, this approach is not causal, but ena-
bles a statistical comparison based on empirical
signal distributions. One disadvantage of infor-
mation theoretical metrics is that they typically
require binning of the data and thus, reduce the
signal complexity into a finite number of bins at
the expense of losing fine-grained details (Panzeri
et al., 2015).
Lastly, the concepts that apply to interactions
between spatial nodes can be extended to the
spectral domain to infer if two frequency bands
interact (Figure 28.7). This coupling across tem-
poral scales is widely known as cross-frequency
coupling (CFC (Canolty and Knight, 2010)) and
has most prominently studied in the context of
phase-amplitude coupling (PAC), where the phase
of slow frequency (e.g., theta or alpha) predicts
broadband high frequency activity (Canolty et al.,
2006). However, amplitude-amplitude as well as
phase-phase couplings have also been described
for CFC (Aru et al., 2015). CFC analyses are sus-
ceptible to signal artifacts (cf. Figure 28.6) and
signal processing choices; hence, several papers
formulated concrete guidelines to circumvent
these issues (Aru et al., 2015; Gerber et al., 2016).
Similar considerations apply also for LFP-spike
coupling.
MULTIVARIATE REPRESENTATIONS AND
ANALYSES
The analysis of electrophysiological data consti-
tutes an extensive multivariate problem. In order
to better understand the data and help the interpre-
tation, the most common analytical approaches
condense this complex analytical space into serial
univariate tests, which are oftentimes easier to
interpret. From a conceptual standpoint, univari-
ate analyses seem reasonable when data is
approached with the “Neuron Doctrine” in mind,
which states that the single neuron is the central
computational unit of the nervous system (cf.
Yuste, 2015). Within this framework, it is reason-
able to employ univariate analyses approaches.
However, in recent years it became obvious that
the single neuron framework falls short in explain-
ing several cognitive phenomena, such as flexible
context-dependent behavior, which inspired the
concept of a “Population Doctrine” (Eichenbaum,
2017; Ebitz and Hayden, 2021; Saxena and
Cunningham, 2019; Yuste, 2015). This population
framework suggests that transient coalitions of
neurons form the central computational unit of the
nervous system (Eichenbaum, 2017; Siegel et al.,
2012). Therefore, gaining a deeper understanding
 Neural Recordings and Time Series Analyses 463

Figure 28.7 Analysis strategy for cross-frequency coupling analyses.

(A) Raw EEG data (black) can be decomposed into different frequency bands through band-
pass filtering. Instantaneous phase and amplitude estimates are extracted from the Hilbert
transform and can be correlated using either linear or circular correlation analyses.
(B) Visualization of the proposed coupling mechanism, where overall power remains con-
stant, but power is modulated as a function of phase.
Source: From Helfrich et al., 2015.

into cognitive mechanisms requires large-scale
recordings, which are not amendable to classic
univariate analyses. This novel framework was
motivated by a series of new artificial-intelligence
inspired algorithms, which enable uncovering the
organizing principles of seemingly chaotic popu-
lation activity. This is a rapidly emerging field
with many new technical innovations in recent
years, and we are unable to provide a thorough
review, but will focus on two representative exam-
ples to illustrate how to approach population-
based analyses.
The first important approach is that multivari-
ate data can be represented in a so-called state-
space representation (Ebitz and Hayden, 2021;
Gervasoni et al., 2004). Instead of analyzing indi-
vidual time series, the entire channel (or neuron)
x time matrix is conceptualized as a single time
series of adjacent points which travels through
a N-dimensional coordinate system along a tra-
jectory, which is spanned by the individual data
points. Here N refers to the number of observa-
tions (e.g., channels or neurons). If one considers
recordings from three neurons, then the first time
point is a point in a 3D coordinate system. Hence,
using linear algebra, we can infer the Euclidean
distance to either the center point of coordinate
system or to adjacent time points. Here the criti-
cal advantage is that Euclidean distance is again
a single number, hence, the high dimensional data
can effectively be condensed into a single vector.
Thus, the entire matrix can be regarded as a trajec-
tory traveling through N-dimensional space and
given that Euclidean distances can be calculated,
one can also infer (e.g., velocity (distance/time)
or acceleration (velocity/time) of the system –
Figure 28.8).
As humans, we cannot effectively visualize
more than three dimensions, hence, it is com-
mon practice to visualize state space trajectories
in 2D or 3D, and after dimensionality reduction
has been performed (Ebitz and Hayden, 2021).
This conceptualization of population activity gave
rise to several emerging concepts in neuroscience,
including attractor states (points in the system
where the activity patterns are naturally drawn to
and converge on) or neuronal manifolds (activity
patterns fall onto certain planes in the state space
and are not completely randomly distributed along
all possible dimensions, hence, all possible activity
patterns are constrained to a subspace that houses
most observations). To date, these techniques have
464 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 28.8 2D State-space representations of cognitive dynamics.

(Left) Tangled trajectories of three different conditions (varying degree of predictability)
along two dimensions in human PFC indicate a complex representational pattern. (Right) In
contrast, activity in motor cortex is neatly organized along a ring structure, indicating low-
dimensional coding schemes.
Source: From Weber et al., 2021.

mainly been applied in the motor domain, where
they provide additional explanatory power over
univariate analyses, but they are gaining traction
in the cognitive domain (Chaisangmongkon et al.,
2017; Goudar et al., 2021; Murray et al., 2017;
Weber et al., 2021). The second common technique
to address multivariate brain data relies on multi-
variate pattern analysis (MVPA (Grootswagers
et al., 2017; Hebart and Baker, 2018; Kriegeskorte
et al., 2006; Quian Quiroga and Panzeri,
2009)), which is also sometime called pattern
­classification or more commonly “brain decoding”
(Figure 28.9).
Here, researchers take advantage of classifi-
cation algorithms, such as the linear discrimi-
nant analysis (LDA) or support vector machines
(SVM), which learn patterns that are associated
with certain conditions or responses. Importantly,
the classifiers require splitting the data into a train-
ing dataset, where the classifier has access to the
ground truth, and a testing dataset, which consists
of held-out samples. Based on the performance
on the held-out samples, one can infer the accu-
racy of the classifier. Critically, these algorithms
often work as a “black box,” where the algorithm
learns a given association and then is used to pre-
dict held-out data points, but one cannot visualize
the classifier per se. Therefore, it often remains
ambiguous whether the classifier utilizes informa-
tion that is also accessible by the brain itself or
whether it picks up epiphenomenal or noise influ-
ences. In the context of neurophysiological experi-
ments, classifiers are used to infer if a population
contains behaviorally relevant information or not,
i.e. whether the classifier performs better than
chance. In contrast to engineering, the goal is not
to maximize classifier performance, but the goal is
to test if the classifier performs significantly bet-
ter than chance. If above-chance performance is
observed, this is taken as evidence that the brain
contains information about the classified behavior
(i.e., context or movement execution).
In practice, state-space and classification
analyses are often combined (Mante et al., 2013).
Jointly these methods enable extraction of cod-
ing dimensions (i.e., finding a latent or hidden
dimension in the data that cannot be accessed
using univariate analyses, that maximizes a
given behavioral contrast). This approach ena-
bles disentangling (i.e., cognitive from motor
contributions, which can appear superimposed
when using univariate analysis tools; Vyas et al.,
2020). Disentangling the respective contributions
provides the opportunity to study their contribu-
tion to the overall population activity and pro-
vides new insights into the coding mechanisms.
For example, it had repeatedly been shown that
motor activity is confined to a low-dimensional
sub-space (i.e., can be described by only few
activity patterns, which often cycle along a low-
dimensional ring structure; Churchland et al.,
2012; Shenoy et al., 2013). In contrast, more
complex higher-order cognitive operations also
require higher dimensional neuronal representa-
tions, since they rely on distributed computing
(Ebitz and Hayden, 2021). Collectively, novel
population-based analysis strategies extend the
explanatory power of univariate tests and open a
new conceptual space to interpret the functional
architecture underlying human behavior.
 Neural Recordings and Time Series Analyses 465

Figure 28.9 Information-theoretical and decoding approaches.

(A) Illustration of representational similarity. Across several repetitions, similarity in neu-
ronal representations is inferred by correlation, indicating that the same or related concepts
share similar spatiotemporal patterns in electrophysiological recordings. (B) Decoding or
pattern classification analysis relies on training classifiers on distinct features, which then
enable a validation on a held-out testing data set. Here a linear discrimination analysis is
depicted with single points representing observations that are characterized by features
along two dimensions. (C) Information-theoretical analyses between object and EEG features
can be conceptualized as a non-linear correlation analysis.

SCALE-FREE PHENOMENA After applying a Fourier transform, one can

Scale-free phenomena refer to the analysis of sta-
tistical regularities in electrophysiological data
that are not governed by a defining temporal scale
(He et al., 2010). For example, scalp EEG is gov-
erned by alpha oscillations at ∼10 Hz as their
defining temporal scale, while many intracranial
EEG contact often do not exhibit a clear oscilla-
tory peak. The absence of oscillatory peaks raises
the question if there is any underlying hidden
temporal structure present and if yes, then how
could this be quantified. An important concept
that borrowed from physics is fractality, which
describes the self-similarity of a signal irrespec-
tive of the chosen temporal window (Pritchard,
1992). Critically, this self-similarity follows a
power-law (i.e., a law of nature; Miller et al.,
2009). A typical example from nature is the struc-
ture of a Romanesco cauliflower, which exhibits
characteristic florets, which always look similar,
irrespective of their size or magnification
(Hardstone et al., 2012; Linkenkaer-Hansen et al.,
2001). In the context of electrophysiological data,
this means that an EEG trace always exhibits simi-
lar fluctuations, irrespective of whether one hour,
one minute or one second is displayed. While this
phenomenon is difficult to describe in the tempo-
ral domain, it can easily be captured in the fre-
quency domain (Figure 28.10).
easily appreciate the general 1/f drop-off (cf. ape-
riodic activity in EEG), which indicates a stable
relationship between frequency and amplitude,
irrespective of the precise frequency and there-
fore irrespective of the precise temporal scale. In
the past two decades, several methods have been
introduced to quantify this type of behavior, either
in the temporal or spatial domain. For example,
linear fitting of the 1/f background activity is a
common approach to extract the spectral exponent
and thereby, quantify the underlying statistical
regularities. A related approach is the detrended
fluctuation analysis (Hardstone et al., 2012),
which assesses long-range temporal correlations,
i.e. signal correlations that obey the same scaling
behavior irrespective of the chosen temporal win-
dow. Similar 1/f phenomena have been observed
in the spatial domain, where activity peaks across
many electrodes coincide in time and the distri-
bution of the duration and amplitude again follow
a power law with 1/f-like characteristics (Palva
et al., 2013). Going beyond the activity peaks,
analysis of microstates (i.e., quasi-static scalp
topographies in EEG) revealed that brain activity
alternates between four major scalp topographies,
where again a 1/f-like power law can describe the
duration of each topography (Ville et al., 2010). To
date, it remains unclear how these different phe-
nomena are related, but several lines of research
466 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 28.10 Power-law scaling in intracranial recordings.
(A) Experimental approach. (B) 1/fx power law fits of electrophysiological brain activity in
relationship to recording hardware noise floors.
Source: From Miller et al., 2009.
suggest that they might constitute emergent ana-
lytical tools to quantify temporal regularity, which
cannot be appreciated by the naked eye, unlike
neuronal oscillations (Cocchi et al., 2017). It has
been argued that the characterization of temporal
regularities in the form of scale-free dynamics
constitutes a promising avenue to understanding
the neural correlates of consciousness (Lendner
et al., 2020; Tagliazucchi et al., 2013, 2016; Zhang
et al., 2018).
STATISTICAL CONSIDERATIONS
Since brain activity is non-linear, non-stationary,
and non-normally distributed, classic analyses
such as t-tests, analysis-of-variance (ANOVA),
linear correlation or regression often fall short in
capturing the data complexity (Maris and
Oostenveld, 2007). However, these methods are
still widely employed, since they are easy to use
and most researchers know how to interpret their
outcomes (Piai et al., 2015).
To mitigate the issue of unknown distributions
of brain data, which violate the assumptions of
many statistical tests, the currently most accepted
approach includes cluster-based permutation tests
(Maris and Oostenveld, 2007). Here a new surrogate
distribution is build based on randomly assigning
all observations to distinct groups (i.e., shuffling
the condition label), then to repeat the analysis
1,000–10,000 times and then compare the true
observed value to the surrogate distribution. If the
observed value falls outside of the mean ± 2 SDs,
then significance can be assumed (at p < 0.05). This
approach is elegant, since it allows that any type of
primary test statistic can be employed to build the
surrogate distribution. Hence, this test is inherently
non-parametric and can be used in a wide variety
of contexts. An alternative solution that emerged
in recent years, is the use of general linear mixed
effects models, which however, are often difficult
to interpret and difficult to visualize and therefore,
have not been adopted widely.
SUMMARY AND CONCLUSIONS
In the present chapter, we have reviewed the cur-
rent state-of-the-art of neuronal time series analy-
sis through the lens of scalp and intracranial EEG
recordings. Notably, as outlined in beginning, the
same analyses can be applied to other imaging
modalities that produce time series data and most
analyses are only constrained by sampling rate,
signal duration and event types. From a practical
standpoint, we emphasized the need to go from
simple to more complicated analyses, i.e. going
 Neural Recordings and Time Series Analyses
from univariate analyses in the time domain to
univariate analyses in the frequency domain,
before branching off into bivariate connectivity or
multivariate classification analyses. In order to
interpret the result of a bivariate connectivity or
multivariate classification analysis in a meaning-
ful way, one needs to ensure that the observed
differences are not solely driven by univariate dif-
ferences, in (e.g., the overall amplitude), but in
fact can only be attributed to their joint activity.
The example of aperiodic activity analyses
nicely illustrates how one can teach an old dog
(the Fourier transform) a few new tricks that pro-
vide additional explanatory power and enable
linking macroscopic signals to underlying circuit
properties (Gao et al., 2017). In the case of aperi-
odic activity, computationally modeling suggested
that the steepness of the exponential decay of the
power spectrum reflects the excitation-inhibition-
balance of the underlying neuronal population,
which otherwise could not have been inferred
(Chini et al., 2021).
The wealth of available methods also enables
reanalysis of available datasets, especially if the
primary analysis was mainly concerned with uni-
variate analysis approaches. As an example, a
classic working memory experiment in two mon-
keys indicated that single neurons in prefrontal
cortex code distinct aspect of working memory
(Warden and Miller, 2007, 2010). Through careful
reanalysis of the same dataset, a new concept of
working memory emerged. In the first follow-up
publication, the authors demonstrated that spik-
ing is coupled to the underlying LFPs (Siegel
et al., 2009). Subsequently, these LFP signatures
were described in more detail, which triggered
follow-up investigations on neuronal bursts and
how these differ from sustained oscillatory activ-
ity (Lundqvist et al., 2016, 2018). Furthermore,
the same dataset was used to infer the dimen-
sionality of spiking activity, which supported the
notion that high-dimensional representations are
desirable for cognitive flexibility (Rigotti et al.,
2013). With the emergence of more analytical
tools and the availability of more open datasets
novel concepts will be generated based on existing
data (Fusi et al., 2016). Overall, machine learn-
ing is now established as an independent field,
thus, we foresee that more multivariate tools will
become available to experimental neurophysiolo-
gists to assess their data beyond classical univari-
ate analyses (Grootswagers et al., 2017; Hebart
and Baker, 2018).
Overall, experimentalists are nowadays faced
with a wide-array of analysis tools, which requires
careful justification of the employed methods.
However, the wealth of tools also provides an
exciting avenue to unravel the mechanisms behind
human cognition, perception, and action.
467
ACKNOWLEDGMENTS
This work was supported by the German Research
Foundation (Emmy Noether Program, DFG
HE8329/2-1; R.F.H.), the Hertie Foundation
(Network for Excellence in Clinical Neuroscience;
R.F.H.), the Baden Württemberg Foundation
(PostDoc Program; R.F.H.), the Ernst Jung
Foundation for Science and Research (Career
Development Award; R.F.H.), and NINDS grants
R01 NS021135 and U19NS107609-01 (R.T.K.).
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Advances in Psychophysical
Techniques
I r i n a G . S k o t n i k o v a , A l e x e i N . G u s e v, a n d
Alexandr M. Chernorizov
INTRODUCTION
Paradigms in Psychophysics
Historically, in the mid-1900s, Psychophysics was
developed by German physicist Gustav Fechner as
the first experimental field of psychology, based
on a natural-science orientation. Fechner pro-
posed an objective method to study and measure
mental phenomena (instead of the earlier subjec-
tive introspective method) beginning with the
elementary form (sensations). He assumed that
individuals can’t directly estimate their values
quantitatively and proposed an indirect way to
measure them, in terms of the units of stimuli
physical values, and proposed “Psychophysics.”
In 1860, Gustav Fechner presented a magnitude
of sensation as the sum of its just noticeable dif-
ferences (jnd) over the starting point. In order to
determine them he introduced the concept of the
sensation threshold measured in stimulus units.
The absolute threshold and the differential one
(jnd) is the minimum value of a stimulus and a
difference between two stimuli, the increase of
which causes a conscious feeling of this stimulus
and difference, while the decrease does not cause.
Therefore, Fechner’s Psychophysics is called
Objective one or “Psychophysics-I,” that became
29
known as the study of observer’s signal detection
and discrimination. Psychophysics II is a study of
an individual’s quantitative estimation of supra-
threshold sensations, expressed in subjective units
of measurement.
PSYCHOPHYSICS-I: DISCREETNESS/
CONTINUITY PARADIGM
Justification of Sensory Range
Discreteness/Continuity Problem
Fechner’s theory postulates sensory thresholds
reality, dividing all stimuli into felt and impercep-
tible. Thus, a range of sensations appears to be
discrete. A subsequent sensation arises after a
previous one only when a stimulus value increase
exceeds jnd. It was the first classical conception
within the paradigm of the sensory system dis-
creteness. Fechner explained the smooth S-shaped
form of the psychometric function by the thresh-
old fluctuation in time, while his opponents
(Müller, Jastrow, and Urban) associated it with the
threshold absence, proposing a classical concep-
tion within the paradigm of the sensory range
 Advances in Psychophysical Techniques
continuity (a continuous series of intermediate
degrees of clearness). Therefore, there is no
threshold point on the psychometric curve, and its
S-shaped form is due to random distribution of
favorable/unfavorable non sensory variables.
Fechner realized the idea of discreteness method-
ologically: he has developed the three experimen-
tal methods for measuring absolute and differential
thresholds. Yet, within the classical paradigm of
discreteness, no other methods have been sug-
gested, but the same Fechner methods are used
today. The discussion has begun on the sensory
range discreteness/continuity problem, which still
remains one of the fundamental problems of
Psychophysics.
DEVELOPMENT OF SENSORY RANGE
DISCRETENESS/CONTINUITY PROBLEM
Continuity Version: Signal Detection
Theory in Psychophysics
Experimental methods for sensation measurement
were developed in line with the three main theo-
retical approaches (Fechner, Thurstone, and
Stevens). The fourth approach: psychophysical
Signal Detection Theory (SDT: McMillan and
Creelman, 2005) revised the previous psycho-
physical methods by providing a fundamental step
in understanding of sensory responses. The theory
was developed for detecting a weak sound signal
against a background noise (as in radio engineer-
ing initially) and was applied further to other
sensory modalities. In Classical Psychophysics,
sensory impressions were understood as the only
reason of individual’s responses, on the basis of
which the sensitivity value (as the reciprocal of
the threshold value) was assessed. SDT has identi-
fied the two response’s components: the observ-
er’s sensory sensitivity and decision making about
the sensory impression character. The components
are studied and quantitatively assessed by separate
indices via the development of three experimental
methods. Therefore, the thresholds indices are not
characteristics of a “pure” sensitivity, but integral
measures of performance: sensitivity and decision
making.
In SDT detection and discrimination tasks ran-
dom noise is considered to be either an external
or internal noise of a sensory system. During an
experiment, stimulation is stationary and the same
for every observer. Only one pair of stimuli is
given randomly: noise and signal for detection,
a pair of same and a pair of different stimuli for
473
discrimination. Data obtained are presented as
empirical frequencies of one kind of response
or another (Receiver Operating Characteristic
– ROC). While in threshold tasks a stimulus has
more values in different trials (5–7 in the Method
of Constants and an almost unlimited number in
the two other classic methods).
DISCRETE VERSIONS: NEURO-QUANTUM
THEORY, THEORIES OF HIGH THRESHOLD
AND OF 2/3 SENSORY STATES,
CONCEPTION OF TWO THRESHOLDS
Neuro-Quantum Theory using psychometric func-
tion analysis describes the sensory effect as asso-
ciated with activity of hypothetical functional
units in the sensory system – neuro-quants (NQ),
if the incoming irritation reaches their threshold.
Depending on the stimulus value, a different
number of NQ per unit of time is activated, which
determines the different sensation value and a
psychometric function rectilinear (but not
S-shaped) form found experimentally by the
authors, but not others, since all noise suppression
is required.
DISCRETE VERSIONS USING THE SDT
SENSORY AXIS METRIC AND ROC
ANALYSIS
Though SDT describes continues sensory system
functioning, four threshold- (discrete) theories
were developed using the SDT sensory axis metric
(SD of noise sensory effects normal distribution)
and the recognition of false alarms as natural
observer’s responses (in contrast to Fechner’s
Psychophysics). Within these four theories, the
same SDT three methods are used: Yes-No,
Rating, and Forced Choice. Data obtained are
presented by ROC, as well.
High-Threshold Theory
According to High-Threshold Theory, only a
signal, but not noise can cause sensation (i.e., the
threshold is located above the average noise value,
which sensory effect cannot exceed the threshold).
Therefore, false alarms are not sensory-based
but guessing. ROC looks like a straight line.
474 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
In contrast, false alarms may have sensory nature
within the remaining three theories using the SDT
methodology (see below).
Low-Threshold Theory
Low-Threshold Theory assumes a threshold exist-
ence, below which sensory events are indistin-
guishable, and above, the sensory continuum is
continuous. The decision-making mechanism
(including the criterion) is functioning only when
sensory effects exceed the threshold. If not, guess-
ing occurs, as in the High Threshold Theory. ROC
is a straight line for high false alarm rates (as in
the High Threshold Theory) and a part of an arc
for low ones.
Theory of Two States
Theory of Two States of sensory system (detection
and non-detection) assumes a threshold between
them. There is guessing on a sensory basis if the
both states are equiprobable. ROC includes two
rectilinear segments: a shallow one for high false
alarm rates and a steeper one for low rates.
Theory of Three States
In the Three States Theory, two possible states of
sensory system (detection and non-detection)
determine an observer’s responses by their nature.
The third state (uncertainty) has to be overcomed
by response strategy based on non-sensory infor-
mation. The three states are separated by two
thresholds, so ROC includes three rectilinear seg-
ments and approach the arcuate SDT curve.
Moreover, ROC can change its shape due to sen-
sory sensitivity variability. This idea is very fruit-
ful and appeareds later in conceptions shown
below. According experimental tests of the
Modern Threshold Theories and SDT, ROC’s
experimental points scatter doesn’t permit to
prefer any theory.
CONCEPTION OF TWO THRESHOLDS
Conception has been suggested of two successive
thresholds in the detection process: the threshold
of an involuntary orientation reaction and the
threshold of an arbitrary response corresponding
to an observer’s criterion. It is similar to the Low-
Threshold Theory, but describes not the sensory
threshold (which is difficult to identify unambigu-
ously), but the threshold of the local (stable) com-
ponent of the orientation reaction (determined by
objective psychophysiological methods). The
threshold presence was proved not by ROC analy-
sis, but by α-rhythm depression. While the theo-
retical concept of the sensory threshold remains in
doubt, Mikhalevskaya’s concept of a threshold
region (where the detection rate varies from 0 to
1) is objective one.
PSYCHOPHYSICS-II: SCALING
METHODOLOGY
Thurstone’s Approach to Scaling
Theoretical framework
Louis Thurstone’s approach was based on the
principle of an indirect estimation of the per-
ceived quality set in the instructions by a person
via making comparative judgments about stim-
uli. Its main idea is very simple: when a person
compares two stimuli, the impact of each gener-
ates a sensory representation of some subjective
quality of a certain value (e.g., the attractiveness
of the advertised product) and, in order to
­determine the degree of their psychological dif-
ference, these values are subtracted from each
other. The measurement task is to quantify this
difference.
Developing Fechner’s postulate about the
equality of sensory impressions of all jnd
Thurstone emphasized the possibility of measur-
ing sensations s on a continuum of “equally fre-
quently noticed differences.” This idea allows to
create scaling procedure using the preference fre-
quency of one stimulus to another as the basis of
a subjective metric. Thurstone’s model describing
stimuli’ effects on a person and comparing them
is as follows:
a. The scaled set of stimuli (A, B, … N) can be
ordered into a continuum by the magnitude
of a certain quality, and this quality does not
necessarily correspond to a certain physical
characteristic.
b. The impact of each stimulus causes the individual
to have a corresponding discriminal process (ψi).
A lot of these processes constitutes a psychologi-
cal continuum of the values of subjective repre-
sentations or sensory magnitudes (ψA, ψB … ψN).
 Advances in Psychophysical Techniques
Due to random fluctuations on the psychologi-
cal continuum when a person is exposed to the
same stimulus, it will correspond not to one
fixed value, but to a certain distribution of the
discriminal processes, which has the form of a
normal distribution.
c. The mean of this normal distribution ( Ψ i ) is
taken as the value of the impact of the i-th stimu-
lus on a person on a psychological scale, and its
SD is considered as the discriminal dispersion
(σψi).
d. The presentation of a pair of stimuli i and j
causes, respectively, two discriminal processes –
ψi and ψj. The difference between them (ψj − ψi)
is called the discriminal difference. When a pair
of stimuli is repeatedly presented, the corre-
sponding values of the discriminal differences
also form a normal distribution with a mean
equal to ( Ψ i − Ψ j ) and SD equal to
1/ 2
σ ( Ψ j − Ψ i ) = (σ Ψ2 j + σ Ψ2 i − 2rΨjΨiσ Ψjσ Ψi )
where σψi and σψj are the SDs of discriminal pro-
cesses distributions corresponding to i-th and j-th
stimuli, respectively, and rψjψi is the correlation
between the values of these discriminal processes
that occurred when each pair was presented.
It is assumed that if the discriminal difference
(ΨA – ΨB) is > 0, then an assessment will follow
that stimulus B is greater (or preferable) than stim-
ulus A. And, accordingly, when (ΨA – ΨB) < 0, the
opposite comparative assessment will be made.
If the distributions of distinguishing processes
overlap (Figure 29.1A), this means that a person
makes comparative estimates not unambiguously,
but with a certain probability.
The average value of this distribution is equal
to the difference in the scale values of stimuli
A and B (i.e., an estimate of subjective distance
between these stimuli). This value can be found
from the table of areas under the unit (standard)
normal curve. Knowing the proportion of judg-
ments “stimulus A is greater than stimulus B”
from the total number of estimates for a given pair
of stimuli, we can perform the so–called standard
z-transformation, “P→Z.”
In units of variance σ (ΨA – ΨB), this can be
written as:
   Ψ A −Ψ B = z A, B × σ (Ψ A −Ψ B ) ,
where zA,B denotes the desired scale difference.
Substituting this expression into equation
(29.1), we get
475
1/ 2
Ψ A −Ψ B = z A, B × (σ Ψ2 A + σ Ψ2 B − 2rΨAΨBσ ΨAσ ΨB ) .
(29.3)
It is Thurstone’s law of comparative judgments.
With its help, you can build a psychological scale
of intervals, where the unit of measurement is the
SD value of a probability density of discriminat-
ing differences normal distribution. The above
assumptions from Thurstone’s model are incor-
porated in Figure 29.1.A: two hypothetical distri-
butions of the discriminal processes of stimuli A
and B, ex., by taste or beauty. Figure 29.1B shows
the probability density distributions of discrimi-
nal differences (ΨA – ΨB) with a large number of
comparative judgements about these stimuli.
Stevens’ Approach to Scaling
In the century after Fechner’s Psychophysics, a
different paradigm was established in parallel,
, (29.1) based on the possibility of direct subjective quan-
titative assessment of sensations values. Stanley
Stevens in the mid-1900s (following his predeces-
sors – Plateau, Brentano, Thurstone) developed
direct methods for subjective sensory scales con-
structing. They were based on observers’ estima-
tion of their increasing sensations order, or
distances or relationships between them, or on
assigning them numbers. Therefore, Stevens’
Psychophysics is called “Subjective one” or
“Psychophysics-II.”
Stevens’ Psychophysics includes not only the
development of fundamental ideas on the four
types of scales as levels of psychological measure-
ments (the nominal scale, the order scale, the inter-
val or partition scale and the ratio scale), but also
the creation of subjective scaling methods, called
direct scaling methods. Stevens’ methods allow to
construct metric ratio scales (i.e., to designate its
zero point and unit of measurement on the sensory
scale). They differ in the simplicity of procedures
for obtaining scale values, since the value of the
measured feature on the scale is expressed directly
in persons’ responses.
In contrast to indirect scaling methods (Fechner
and Thurstone), Stevens’ approach was based on
two assumptions: (1) the presence of persons’
internal scales of measured psychological traits;
(2) and, as a result – the ability to make quantitative
judgments about their sensations directly. Indirect
(29.2) scaling methods, on the contrary, are based on the
use of intermediate procedures and assumptions
about how to use behavioral or physiological reac-
tions to transform them to scale values, and, as a
rule, the use of a mathematical model describing
476 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

ΨA ΨВ

Psychological scale values, Ψ

ΨВ –ΨA

Figure 29.1
A: Psychological continuum with two partially overlapping distributions of discriminal pro-
cesses, eliciting by multiple presentation of two stimuli. The numbers on the abscissa axis
indicate the magnitude of the stimulus effect.
B: A distribution of discriminal differences between the two discriminal processes (ΨA и ΨB)
resulting from comparative judgments made. 0 on the abscissa axis means the critical value
above which a person makes a judgment about the preference of stimulus B (the light grey
part of the distribution) and below which about the preference of stimulus A (dark grey part).

this transformation. Although direct scaling meth-
ods were mainly used to construct sensory scales
when the physical continuum of stimuli corre-
sponding to sensations is known, Stevens believed
that there are no fundamental limitations of this
approach to construct a scale of any complicated
psychological characteristic.
Psychophysical Laws
Fechner has derived the psychophysical law of a
sensation value dependence on a stimulus value,
based on the Weber’s law about the constancy of
jnd increment regarding a stimulus initial value
and a priori postulate about the equality of jnd
sensory equivalents values in the whole stimuli
range. It is the logarithmic function: R = k ln (S–
S0), where R is the sensation value, S is the actual
stimulus value, S0 is the absolute threshold. Thus,
you can calculate a sensation value for the actual
stimulus by measuring the absolute threshold.
Fechner’s postulate is criticized reasonably for its
groundlessness, and the theory – for the
phenomenon of false alarms ignoring (while
“Modern” Psychophysics pays it great attention).
However, Fechner’s Psychophysics remains the
Classical one.
Sensations subjective values determined by
Stevens’ direct scaling methods, are associated
with stimuli values by power dependence. Stevens
received it empirically and mathematically as
well: R = k (S – S0)n (Stevens’ psychophysical
law), introducing a priority postulate (calling both
criticism and agreement) about the constancy of
jnd sensory equivalent relation regarding this
equivalent initial value in the whole sensations
range. Fechner’s law was confirmed in loudness
estimations, where logarithmic decibel units were
introduced. Stevens’ law became widespread in
scaling tasks (Grondin and Laflamme, 2015).
The origins of the power function exponent have
been shown to derive from the Tweedie probabil-
ity distribution including Gaussian, Poisson, and
Gamma ones. The exponent connections have
been revealed to many properties of sensory trans-
duction (Wong, 2018). Mathematical modeling
has confirmed initial nonlinear relations (power
 Advances in Psychophysical Techniques
ones particularly) between stimulus values and
receptor neuron responses (Fokin, 2021).
The laws have been developed expressing in
other mathematical equations: exponential func-
tion (Putter), tangential one (Zinner), arctgenen-
tial one, integral φ-gamma function, and others,
which are not universal and have narrow appli-
cations. They do not contradict each other, since
describe different sides of sensory and perceptive
processes. The generalized psychophysical law
describes both logarithmic and power functions,
as well as these and any other mathematical func-
tion between them.
Zabrodin has built the sensory space (SP) theo-
retical model. SP structure is characterized by its
local and global regions and by borders – areas
of adequate reflection. Local areas are determined
in signal detection/discrimination tasks, thresh-
olds measurement, and characterize the topology
of images in SP, its resolution. Global areas are
determined in scaling tasks and characterize sub-
jective distances between supra threshold stimuli
(SP metric). Topology and metric are connected
with integral-differential relations which identify
the following.
1 Internal agreement between Fechner’s and
Stevens’ laws: both of them are grounded on
Weber’s law about constancy of the jnd ratio
to the stimulus initial value. The computational
basis of this law has been found further. It is
“time-intensity equivalence in discrimination,”
describing how the distribution of reaction times
changes as a function of their absolute levels
(Pardo-Vazquez et al., 2019). Changes of Weber
fractions have been revealed between forced
and unforced-choice tasks (allowing the “don’t
know” response; Hatzfeld et al., 2018).
2 The main contradiction between Fechner’s and
Stevens’ laws concerns only one item. Fechner’s
law equates the ratio: the differential threshold,
i.e., stimulus jnd minimal increase (dS0) regarding
the initial stimulus value S (dS0 / S) - to the sensa-
tion jnd minimal increase (dR0):
dS0 / S = k dR 0 , from here: R = a ln (S − S0 )
Stevens’ law equates the differential threshold
to the sensation jnd increase, regarding its initial
value:
dS0 / S = k dR 0 / R, from here: R = k(S − S0 )n .
The generalization of these equations leads to
the expression:
477
dS / S = dR / R z , where 0 ≤ z ≤ 1,
where z reflects not an objective, but a subjective
scale: individual’s psychological operations in
stimulus assessing. Zabrodin’s equation describes
signals discrimination (z = 0), their values estima-
tion (z = 1), categorical estimates (0 < z < 1) and
corresponds to some neurophysiological regu-
larities (Zabrodin, Lebedev, 2022). Contemporary
scaling studies indicate that Zabrodin’s equation
cannot cover all psychophysical functions.
Zabrodin has developed a systematic-dynamic
approach to sensory processes analysis and a
model of an adaptive ideal observer, including
other sensory process models as special cases. He
has suggested the general theory of psychophysi-
cal foundations, which has no analogs today. It
has combined four main fields of Psychophysics:
sensory sensitivity, decision-making, subjec-
tive scaling, psychophysical laws. However, this
experimentally theory was not utilized further
experimentally after the 1980s.
NEW METHODOLOGY IN
PSYCHOPHYSICS AND COGNITIVE
PSYCHOLOGY OF ACTIVITY
In traditional Psychophysics a participant is con-
sidered as just an object of experimenter’s influ-
ences, an ideal but not real observer, whose own
activity and individual differences are not taken in
account. Quantitative relations are examined
between external factors used (stimuli values and
instructions) and responses indices obtained.
However, these changes in indices were found in
dependence on the observer’s own variables: dif-
ferent kinds of individual activity or peculiarities
(Fritsche et al., 2017; Grzeczkowski et al., 2017;
Gurler et al., 2015; Siegel and Kelly, 2017; Wilson
et al., 2016) and confidence (Braun et al., 2017;
Schoenherr and Petrusic, 2015; Vickers and Lee,
1998). In particular, the psychometric properties
of confidence scales are described within three-
dimensional framework: whether information is
directly or indirectly scaled from the usual pri-
mary decision (about stimuli presented), the locus
of confidence processing (following the primary
decision or during it), and the source of informa-
tion used to obtain a confidence rating from the
secondary decision (Schoenherr, 2019).
Therefore, the analysis of response propor-
tions obtained, a “machine-like approach” in
Psychophysics has become insufficient (Vickers
and Lee, 1998), and the methodological neces-
sity have become clear to include the variables
478 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
named into psychophysical analysis. However, the
observers’ own variables are examined separately
from each other mostly in the studies mentioned.
In Russian Psychophysics, the new systematic
approach is added to the traditional paradigm. It
develops the general theoretical and methodo-
logical idea of Russian psychology of a person
as an active author of his/her mental life, behav-
ior, and performance. Subject-oriented research
in Psychophysics (Bardin et al., 1993; Gusev,
2013; Skotnikova, 2011) considers the observer’s
own variables as principal ones but not artifacts,
studied via the integrative approach: participants’
individual activity investigation in sensory tasks
(ST) performance. Quantitative psychophysical
analysis is included into this activity qualitative
research.
The task is understood as a person’s goal given
in certain conditions. ST main characteristics are:
stimuli (or their differences) low values; random
order and high (often forced) temp of stimuli pres-
entation, which cause high information load to
the observer having limited mobility. Individual
activity shows matching of person’s capabilities
and ST conditions which actualize observer’s
individual resources in uncertainty situations for
weak signals or small differences between signals
detection. A contribution of subjective factors may
cause up to 30% of psychophysical indices total
dispersions and is comparable with stimuli char-
acteristics contributions (Gusev, 2013).
The hierarchical structure of a participant’s
activity appears to be an internal determinant of
results obtained. This structure components are:
a task as an observer accepted it, his (her) inner
states (activation, effort, confidence degree),
individual peculiarities (cognitive styles, extra-
version–introversion, neuroticism–emotional sta-
bility), performance strategies determined by the
task and individual peculiarities. These compo-
nents have been revealed experimentally in signal
detection and discrimination, where intensities
of visual (brightness) and auditory (loudness)
stimuli have been used as well as visual temporal
(durations) and spatial (line length) stimuli (i.e.,
quantitative” and “qualitative” ones, according
Stevens, 1957) during their simultaneous and suc-
cessive presentation (Gusev, 2013; Skotnikova,
2011). The mathematical model of decision mak-
ing and confidence has been suggested for uni-
dimensional simple sensory stimuli discrimination
(proved experimentally) and for complicated
multi-attributed perceptual objects (Shendiapin,
2018). Our approach is continued regarding ani-
mals’ behavior: their individual activity (of differ-
ent reptile’s species: grass snakes’ and slow-warm
lizards’ moving in the maze) effects visual stimuli
discrimination, and it agrees with data in humans
(Skotnikova and Zhelankin, 2019).
Relations has been found between ST differ-
ent characteristics and the both inter- and intra-
individual factors affecting sensory performance.
High activation, achievement motivation, emo-
tional stability, and low anxiety facilitated visual
signal detection. Observers’ activation level,
cognitive styles, motivational and volitional dis-
positions, self-regulation were revealed, which
determined cognitive resources mobilization and
strategies efficiency in auditory ST (Chekalina
and Gusev, 2011, Emelianova and Gusev, 2018;
Gusev and Utochkin, 2006; Pöppel et al., 2018;
Volkova and Gusev, 2017). Theoretical useful-
ness of a “functional organ” concept was shown,
which allowed to provide a systematic analysis of
observers’ activity (Gusev, 2013).
Thus, the subject-oriented Psychophysics
of sensory tasks is the fundamental approach to
sensory signals detection/discrimination inves-
tigation, which allows expanding psychophysi-
cal studies boundaries and reveals the role of
top-down mechanisms of sensory processes.
In cognitive psychology of activity, it presents
the cultural-historical approach, accounting for
human awareness and attention multiple phenom-
ena (Falikman and Asmolov, 2017).
METHODS OF PSYCHOPHYSICS-I
Fechner’s Methods
One of the main tasks of Psychophysics is the
study of minimum and maximum levels of a per-
son’s sensory abilities. In classical Psychophysics,
the absolute threshold (absolute limen – AL) is the
minimum value of the stimulus that causes a
barely noticeable sensation. AL is a measure of the
lower limit of sensory sensitivity and character-
izes a person’s ability to sense signals of very low
value. Thus, the concept of sensory sensitivity is
defined as the inverse of the absolute threshold:
the higher the threshold, the lower the sensitivity,
and vice versa. The difference threshold (differ-
ence limen – DL) is the minimal difference
between two stimuli in a certain physical param-
eter value, which causes a barely noticeable dif-
ference in sensations. The difference threshold
characterizes the individual discrimination ability
or difference sensitivity.
The range of perceived stimuli has its own upper
limit – the upper or terminal absolute threshold.
This is the maximum permissible stimulus value,
 Advances in Psychophysical Techniques
at which it is still felt as a stimulus of a certain
modality. When it is exceeded, the sensation of
this modality passes into the sensation of another
modality (tactile, painful).
In the Fechner’s work, three methods for meas-
uring the absolute and difference thresholds were
proposed, which were called classical psycho-
physical methods. Distinct from the modern psy-
chophysical methods, Fechner’s approach pays
special attention to stimulus variables, and do
not sufficiently take into account the influence of
subject’s own variables or so-called non-sensory
factors, which are almost always included in psy-
chological measurements. Statistical indices are
accepted in these methods as threshold measures
of sensory task performance, since they are deter-
mined not only by subject’s sensitivity level, but
also by non-sensory factors controlling a response
choice.
METHOD OF LIMITS
The method of limits expresses a direct approach
to psychological measurements, since it gives a
threshold value estimation during the measure-
ment itself. This method procedure most clearly
reflects the understanding of the threshold as a
barrier separating the stimulus series into the two
classes: of sensed and non-sensed stimuli or their
differences.
Absolute Thresholds Measuring
In AL measuring each trial begins with an
“Attention” signal, after which a stimulus is pre-
sented for a short interval. As a rule, a subject is
allowed only two responses categories (ex., “Yes,”
“No”: “I see,” “I don’t see”). Stimuli presentation
is carried out by a descending or an ascending
series – it is the principal difference between this
method and others. In the first case, a severity
degree of a certain stimulus parameter, sensitivity
to which is measured, gradually decreases from a
maximum to a minimum, in the second, on the
contrary. The threshold in this series is taken as the
stimulus value located in the middle of the interval
in which the first change of the subject’s response
category has occurred. In the descending series,
the threshold for the sensation disappearance is
determined – L↓, in the ascending one – the thresh-
old for its appearance – L↑. The absolute threshold
is taken as the arithmetic mean of all the thresh-
olds of appearance and disappearance found:
479
1 N
AL = ∑ Li   (29.4)
N i =1
where AL is the average absolute threshold, Li
is the value of a single threshold in both ascend-
ing and descending series, N represents the total
amount of series.
The regular presentation of stimuli and the cor-
responding expectations of participants result in
the appearance of so-called errors of habituation
and errors of expectation, which are sources of the
accuracy of threshold measurements reducing.
DIFFERENCE THRESHOLDS MEASURING
In DL measuring stimuli are presented in pairs.
Simultaneously or sequentially with a variable
stimulus (Svar), the subject is presented with a
standard stimulus (Sst), which sets the initial
stimulus value, relative to which DL value is
determined. The subject is usually allowed to give
three responses categories: “greater,” “less,”
“equal” (or “I doubt”). The threshold is taken as
the stimulus value corresponding to the middle of
the inter stimulus interval, where the response
category changes for the first time: from “greater”
to “equal” and from “equal” to “less” in the
descending series, and from “less” to “equal” and
from “equal” to “greater” in the ascending series.
Thus, when DL measuring, four threshold values
are estimated (two in each series). This is the
upper threshold (DLh) in the ascending and
descending series (DLh↑ and DLh↓) and the lower
threshold (DLl) in the ascending and descending
series (DLl↑ and DLl↓). In Figure 29.2, they are
marked with dots in each series, which illustrate
the rule of a threshold point setting in the descend-
ing and ascending series.
DLh and DLl are boundaries of IU (i.e., they
limit that stimulus region where equality responses
prevail). IU is that zone of stimuli that is limited
from above by a stimulus that on average barely
differs from the standard one (Sst) as a larger one,
and from below by the stimulus that on average
barely differs from the standard one as a smaller
one. IU contains two barely noticeable differences
(i.e., it is equal to two DLs):
IU = Lh − Ll   (29.5)
IU Lh − Ll
DL = = (29.6)
2 2
480 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Figure 29.2 Illustration of the rule for
determining Lh and Ll and the threshold
indexes in the descending and ascending
series based on the subject’s responses.
The stimulus located in the middle of the IU as the
subjective equivalent of Sst is called the point of
subjective equality (PSE).
METHOD OF ADJUSTMENT
Method of adjustment differs procedurally from
the other threshold methods in that the observer
himself regulates the value of the stimulus varia-
ble parameter. Method of adjustment gives the
lowest threshold values compared to other thresh-
old methods.
Difference Thresholds Measuring
According to Fechner, this method was intended
primarily for measuring difference sensitivity. To
do this, the observer is presented with two stimuli
at the same time: the standard stimulus (Sst) and
the variable one (Svar), the value of which can be
smoothly changed by the subject himself. An
observer’s task is to adjust the Svar to the Sst, no
restrictions on the freedom of movement are intro-
duced during the adjustment process.
The arithmetic mean of several adjustments is
most often used as a statistical measure for evalu-
ating the subject’s performance in the method of
adjustment. In the sense of the concepts intro-
duced above, this index is PSE. To estimate DL,
the value of the PSE distance from the Sst is used:
CE = Sst − PSE   (29.7)
Many authors point out that the value of the SD (σ)
of adjustments made can also serve as a more reli-
able measure of difference sensitivity.
Absolute Thresholds Measuring
In AL measuring the observer adjusts the stimulus
magnitude that initially caused a distinct sensa-
tion, until she/he establishes such a value at which
she/he loses the feeling of the stimulus for the first
time. If the adjusting begins with an obviously
imperceptible stimulus value, then the subject
must find its value at which the sensation appears
firstly. When the adjusting begins from a suprath-
reshold stimulus, the subject reproduces the mag-
nitude of the stimulus at which the sensation
disappears for the first time. The final value of AL
is estimated by averaging all separate trials per-
formed by the observer. Usually, the arithmetic
mean is used.
METHOD OF CONSTANT STIMULI
Method of constant stimuli consists in presenting
the subject with a limited number of stimuli that
remain unchanged throughout the entire session.
The result of the experiment is the subject’s
response frequencies, from which the threshold
values are calculated. Therefore, this method is a
way of thresholds indirectly estimating, as
opposed to the methods of limits and adjustment.
The constant stimuli method has a reputation for
being the most accurate and reliable, since its
procedure eliminates errors of habituation and
expectation.
DIFFERENCE THRESHOLDS MEASURING
When measuring DL in preliminary trials, the
experimenter approximately determines the
threshold zone (i.e., the range of stimuli differ-
ences, at the boundaries of which the observer
almost always begins to feel the difference
between the standard stimulus and the compared
one). Then, within this zone, 5–9 stimuli are
selected that are compared with the Sst. The choice
is made in such a way that the weakest among
 Advances in Psychophysical Techniques
them causes the response “greater” in 5–10% of
cases, and the strongest in 90–95%. Stimuli are
presented in pairs simultaneously or sequentially
in random sequence (i.e., the individual cannot
guess neither the place of the Sst in the pair, nor the
Svar value). Usually, each pair of stimuli is repeated
20–200 times. Two (“greater,” “less”) or three
(“greater,” “less,” “equal”) responses categories
are used. In any case, the threshold calculation is
based on a relative frequency of various kinds of
judgments for stimuli each pair.
As the Svar increases, it increases values the pro-
portion of “greater” responses gradually increases
from 0 to 1. This proportion is convenient to use
when experimental results are presented in the
form of a special graph called the psychomet-
ric function (Figure 29.3). It has the S-shaped
form (the ogive) of the normal distribution inte-
gral function, which is theoretically justified
and empirically confirmed. In z-coordinates, the
psychometric function looks like a straight line
(Figure 29.4).
In the method of constant stimuli, the usual sta-
tistical indices are used: median (Med) or arithme-
tic mean (X), semi-quartile range (Q) or SD (σ),
as well as the first, second and third quartiles (Q1,
Q2, and Q3). With the help of these indices, the
following threshold indices are calculated accord-
ing to an empirical psychometric curve.
The interval of uncertainty is estimated as the
interquartile range: (Q3 − Q1)
IU = S0.75 − S0.25 .   (29.8)
Proportion of “greater” responses
Values of comparison stimulus
Figure 29.3 A typical psychometric func-
tion obtained by the method of constant
stimuli, as a result of the difference thresh-
old measuring. The empirically found points
are superimposed on the S-shaped form
curve (ogive).
481
z-scores of “greater” responses
Values of comparison stimulus
Figure 29.4 Linear psychometric function
in z-coordinates, obtained as a result of the
difference threshold measuring.
The point of subjective equality is defined as the
median: PSE = Med.
The constant error occurs in the case of the
median mismatch regarding the Sst:
CE = Md − Sst   (29.9)
In case of two responses categories, the differ-
ence threshold is defined as a half of the IU and
corresponds to Q and is, in fact, a measure of the
subject’s responses variability (of the psychomet-
ric curve slope):
S0.75 − S0.25
DL ( 2) = Q ( 2) =   (29.10)
2
When using a psychometric function con-
structed in z-coordinates, instead of quartile esti-
mates, the SD and the well-known formula are
used:
    σ = 1.483Q       (29.11)
The median of empirical frequencies distribution
is found as a value corresponding to σ = 0.
ABSOLUTE THRESHOLDS MEASURING
The procedure for AL measuring differs from DL
measuring only in one point: in each sample one of
several constant stimuli is presented, to which a
subject gives one of the two possible responses –
“Yes “(I feel) or “No” (I don’t feel). According to
responses frequencies empirically obtained for
each of the constant stimuli, a psychometric curve
482 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Proportion of “yes” responses

ADAPTIVE THRESHOLD METHODS

Along with Fechner’s methods, adaptive thresh-

Stimulus intensity
Figure 29.5 Typical psychometric function,
obtained in absolute threshold measuring
via the method of constant stimuli. The
empirically found points are superimposed
on the S-shaped curve.
is constructed (Figure 29.5). The 50%-point on this
curve (i.e., median is taken as the estimate of AL).
From classical threshold theory, the 50%-point
corresponds to the minimum stimulus value that
causes sensation only when there is a balance
of favorable and unfavorable factors. The semi-
quartile range (Q) or the SD (σ) characterizes the
threshold estimations reliability.
There is a problem of correlation between
Fechner’s three methods’ threshold indices. For
proprioception testing no significant correlations
have been found, possibly due to different cogni-
tive processes involved in the corresponding tasks
performance (Yang et al., 2018).
olds procedures have been developed in which an
order of stimuli presentation depends on the indi-
vidual’s responses. Such automated procedures
are usually implemented via computer or a techni-
cal device (such as the Bekesy audiometer).
One of adaptive procedures is the method of
limits variant, developed in 1962 by Cornsweet
and called the staircase method (also up-and-
down method). The essence of the method is that
as soon as there is a change in the response cate-
gory, there is immediately a corresponding change
in the direction of the stimulus value change from
a descending series to an ascending one. Thus, the
presentation of stimuli adjusts (adapts) to subject’s
responses, and stimuli values change occurs in a
fairly narrow near-threshold range (Figure 29.6).
In the Psychophysics literature, other adaptive
methods for measuring thresholds are described
too (e.g., threshold tracking method or forced
choice method – Geschheider, 1997).
METHODS BASED ON SIGNAL DETECTION
THEORY IN PSYCHOPHYSICS (SDT)
Yes–No Method
It is one of the most popular SDT methods for
sensory sensitivity measuring. Unlike classical
Psychophysics, we measure not the absolute or
difference threshold, but sensory sensitivity in
signals detection or discrimination tasks. In this
method, only two types of stimuli are used, which

Stimulus Number of trials

intensity 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
10 +
9 +
8 +
7 +
6 +
5 + + +
4 + + + + +
3 - - - -
2 - +
1 -

Figure 29.6 Recording of subject’s responses and changing stimuli values when measuring
the absolute threshold by the staircase method. Plus and minus signs correspond to the
“Yes” and “No” responses, respectively. As a result, AL corresponds to Stimulus 4.
 Advances in Psychophysical Techniques
differ slightly in the value of some physical qual-
ity: one “significant” or “signal” – S (for example,
a weak tone of 1000 Hz on white noise back-
ground), and the other “empty” or “noise” – N
(white noise without tonal additive). Stimuli pres-
entation follows each other many times in a
random order at regular intervals, and each time
the observer answers responds “Yes” if he thinks
there has been a signal (or a difference between
compared signals), or “No” if he does not detect a
signal (or a difference between signals).
There are four possible <stimulus-response>
combinations, with two correct responses: “Yes”
(Correct signal Detection – Hit) and “No” (Correct
signal Rejection – CR) and two erroneous ones:
“Yes, there was a signal,” when only noise was
presented – False Alarm (FA) and “No” – signal
Miss (Miss).
Observer’s results in signal detection or dis-
crimination are usually presented in the form of
conditional probabilities scores: P(Hit), P(FA),
P(Miss), P(CR). P(Hit) and P(FA) fully character-
ize an observer’s performance, since P(Miss) and
P(CR) just complement them up to unity.
Stimuli effects are associated with their sensory
representations randomly or stochastically. In one
of the SDT variants, this relationship is depicted as
two overlapping probability density functions of the
normal distributions (Figure 29.7). The abscissa is
a hypothetical axis of sensory magnitudes that have
appeared under appearance of S (right distribution
f(X/S)) and N (left distribution, f(X/N)).
Their overlap means that the sensory represen-
tations of S and N are similar to each other, and
the observer cannot decide with 100% certainty
each time which stimulus has been presented (or
whether there has been a difference in a pair of
stimuli). Further, in SDT, it is assumed that when
making a decision, the observer sets a strictly
defined rule of correspondence between sensa-
tions obtained and types of response (“Yes” and
“No”). If the current sensation value is above a
certain critical level or criterion, then the observer
says “Yes,” if under, the observer says “No.”
The criterion is a certain memory sensory
image or a sensory standard (point C on the
abscissa axis in Figure 29.7) with which each
sensory representation is compared. Its position
on the sensory magnitude axis may depend on a
number of reasons: subjective weights of various
errors, knowledge of objective probabilities of S
and N presentation, “payments” and “penalties,”
for correct and erroneous responses respectively
(payoff matrix), etc. When using a liberal or a
conservative criterion, there is P(Hit) and P(FA)
increase or decrease respectively. The criterion
position uniquely determines P(Hit) and P(FA)
empirical scores. The theoretical criterion value
483
d'
N S
C Xs
Decision mak
Figure 29.7 The distributions of sensory
magnitudes probability densities under signal
(f(X/S)) and noise (f(X/N)) stimuli effects.
(The abscissa is sensory magnitude, while
ordinate axis is probability density. The light
grey area – False Alarms; The dark grey area –
Misses – the symmetrical criterion position.)
(its strictness) is estimated as the likelihood ratio
(Figures 29.8 and 29.9):
ordinate of S distribution at criterion
β=
ordinate of N distribution at criterion
Each pair of empirical P(Hit) and P(FA) scores
can be matched with a point inside the unit square
(Figure 29.10). It represents observer’s use of
various criteria, for example, from five different
payoff matrices. The curve obtained is called the
Receiver’s Operating Characteristic (ROC) curve.
P(Hit) and P(FA) change together and recip-
rocally (i.e., it is impossible to simultaneously
increase one of them and decrease the other
only by the criterion changing). T Only a pair
of these probabilities and not each of them sepa-
rately, characterize the observers’ sensory ability
(Figure 29.10). The higher the observer’s sensory
N S
Xs
C
β= / =
Figure 29.8 The liberal criterion position
on the sensory magnitude axis.
(The designations the same as in Figure 29.7.
The grey area of S-distribution – Hits, its
light area – Misses.)
484 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

and P(FA), converted into units of SD according to

the normal distribution table.
N S
FORCED CHOICE METHOD (FCM)

FCM has an important advantage over the “Yes–

No” method, since its procedure stabilizes fluctua-
tions of the criterion position, as SDT states. It is
C
Xs achieved by the fact that when a stimulus trial is
β= / = t criterion presented, it always contains a signal stimulus along
with one or two non-signal stimuli. Let’s consider
this procedure on the example of Two Alternative
Figure 29.9 The conservative criterion Forced Choice (2AFC) as the most frequently used
position on the sensory magnitude’s axis. variant. In the 2AFC stimuli presentation is always
(The designations are the same as in Figure carried out in pairs, either sequentially or simultane-
29.8.) ously. One pair always contains S and N, and the
subject knows it, but he must decide himself, which
of the stimuli contains a signal, and which is non-
signal. The place of S and N in the stimulus pair
changes randomly. The experimenters agreed to call
one of the two variants of correct and erroneous
p(H) responses as Hit and FA. In all other respects, 2AFC
is no different from the “Yes–No” method.
If the trial includes 3, 4, or 6 empty stimuli, the
FCM variants are called 3AFC, 4AFC, or 6AFC,
respectively. Since the stimulus procedure of the
p(FA) FCM itself excludes a bias of observer’s responses
in favor of a strict or liberal criterion, a good meas-
ure of sensory sensitivity is the percentage of cor-
Figure 29.10 ROC curve in liner coordinates. rect responses P(C). As in the “Yes–No” method,
the index d’ is also used, calculated by the formula:
sensitivity, the more convex the ROC is and the
closer it is to the upper-left corner of the square d ' 2 AFC = 2d ' Yes − No
(Figure 29.11). On the diagonal corresponds to
the zero level of sensory sensitivity.
SDT introduces a special sensory sensitivity CONFIDENCE RATING METHOD (CRM)
measure d’, as the distance on the horizontal axis
(Figure 29.7) between the centers of the two dis- The CRM using is recommended when it is neces-
tributions f(X/S) and f(X/N), expressed in SD units. sary to build a ROC curve within one session,
Based on empirical data, d’ is calculated as: d’ = without changing either a payoff matrix or a priori
z(Hit) – z(FA), where: z(Hit) and z(FA) are P(Hit) probability of a signal stimulus presentation.

N
1.5 S
d’ =
=1 0.3
d’ d’
=
=0

Xs
d’

N S
p(H)

Xs
N S

Xs
p(FA)

Figure 29.11 A family of ROC curves in observers having different sensory sensitivity (at
left), and corresponding distributions of s and n sensory magnitudes (at right).
 Advances in Psychophysical Techniques
The only CRM distinction from the “Yes–No”
method is that after each trial the subject indicates
a degree of his confidence in the signal presence/
absence instead of responses “Yes” or “No.” As a
rule, a percentage scale is used: 100%, 75%, 50%,
25%, or 0% confidence that there is a signal.
Suppose that the individual is given seven eval-
uation categories (from –3 = “exactly No” to +3 =
“exactly Yes”). Usually, the experiment is carried
out without a payoff matrix or with a symmetric
payment matrix and with P(S) = P(N) = 0.5. The
results of such an experiment can be presented in
the form of Table 29.1, whereby p and q are esti-
mates of an observer’s confidence in s and n detec-
tion, respectively. It is assumed that if the observer
is given seven categories (from complete confi-
dence of the S absence to complete confidence of
the S presence), then, when making a decision, he
is based on a value of a certain sensory quality (as
in the “Yes–No” experiment), but divides a sen-
sory continuum not into two areas, and into seven
areas. In fact, the confidence level sets the level of
criterion strictness for signal detection.
Based on these data, a fairly smooth six-point
ROC curve can be constructed. Of course, in order
to obtain such data, it is required to use a larger
number of trials than in the YNM. Mutual inter-
relations were found experimentally between indi-
ces obtained in the methods of confidence rating,
lumen, and constants (Zabrodin and Shpagonova,
1988). Fifty years of SDT in Psychophysics and
of ROC analysis have been traced (Adams et al.,
2017).
Table 29.1 The theoretical results of the CRM experiment
Stimuli Rating -3 -2 -1
categories
Ss p(-3) p(-2) p(-1)
Nn q(-3) q(-2) q(-1)
Note. According to data, six pairs of P(Hit) and P(FA) values can be calculated, and six criteria can be set on the sensory
effects axis (Table 29.2).
Table 29.2 P(Hit) and P(FA) calculating based on CRM data
Criterion position P(Hit) =
C3 p(3)
C2 p(2) + p(3)
C1 p(1) + p(2) + p(3)
C0 p(0) + p(1) + p(2) + p(3)
C-1 p(-1) + p(0) + p(1) + p(2) + p(3)
C-2 p(-2) + p(-1) + p(0) + p(1) + p(2) +
p(3)
485
ADVANTAGES AND DISADVANTAGES OF
CLASSICAL AND SDT-BASED METHODS
Classical psychophysical methods give integral
performance indices, but not separate estimations
of their components: sensory sensitivity and deci-
sion-making criterion. Nevertheless, they are still
used in sensory measurements, where strictly
precise sensitivity estimation is not necessary.
(1) In preliminary trials before main psychophysi-
cal research. (2) In applied massive measurements
for picking up different stimuli values for different
persons when estimating their individual sensory
thresholds. As distinct, SDT–based methods can’t
do it, since to all persons the same two stimuli are
presented, which may induce 100% detection/
discrimination in some of them, while 0% in some
others because of different individual sensitivity.
(3) Methods of limits and adjustment are economy
and suitable in medicine for express sensory
defects diagnostic. (4) Method of adjustment is
appropriate for performance strategies in uncer-
tainty studies since persons themselves manage
stimuli values actively. (5) Method of constants is
suitable for differential characteristic of threshold
regions obtaining by psychometric functions.
SDT-based methods are used to obtain pre-
cise separate indices of sensitivity and criterion.
Yes–No and Rating Methods are appropriate for
decision making dynamics primarily. Rating gives
the most smooth and stable ROC, but is more
difficult for an observer who has keep and use
0 1 2 3
p(0) p(1) p(2) p(3)
q(0) q(1) q(2) q(3)
P(FA) =
p(3)
p(2) + p(3)
p(1) + p(2) + p(3)
p(0) + p(1) + p(2) + p(3)
p(-1) + p(0) + p(1) + p(2) + p(3)
p(-2) + p(-1) + p(0) + p(1) + p(2) +
p(3)
486 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
several criteria simultaneously. According SDT,
forced choice method estimates sensitivity most
precisely, since criterion is rather stable.
SENSORY SENSITIVITY AND DECISION-
MAKING: MUTUALLY INDEPENDENT IN
EVERY PERSON AND TASK?
According to SDT, sensory sensitivity (deter-
mined by stimuli values and an observer’s physi-
ological limits) and decision-making (determined
by stimuli priory probabilities, responses costs
and payoffs, instructions and feedback) are mutu-
ally independent in every person and every task.
Nevertheless, the opposite data were obtained (by
Russian psychophysicists mostly). Instructions,
induced a criterion shift, led to sensitivity decrease
or violations: in persons with mental disorders
(because they were stressed: Matveeva, 1981), in
healthy, highly trained observers (Mikhalevskaya
and Finkel, 1985; Zabrodin et al., 1984), in intro-
verts and extraverts (opposite dynamics in them;
Zabrodin et al., 1981) – as a result of cortical
information processing primary phases violation
(judging by Evoked Potentials early components:
Mikhalevskaya et al., 1988). Thus, non-sensory
information led to criterion initial shifts and reac-
tively – to sensitivity changes. It points to system-
atic integration between them. Their correlated
dynamics have been described under observers’
activation level changes. In vigilance tasks sensi-
tivity decreased due to activation drop during
monotonous work with low signal probabilities.
The criterion increased when observers assimi-
lated these probabilities and decreased at high
probabilities, while both sensitivity and criterion
increased with increasing differences between
signals (Parasuraman and Moulona, 1987). In
monotony and fatigue sensitivity decreased, while
criterion increased in the first case (to maintain
vigilance, weakening due to the monotonous
work) and decreased in the second one (to com-
pensate “Yes” responses frequency decrease,
caused by sensitivity decrease; Frishman, 1991).
In these works, and under pharmacies, activation
level changes caused sensitivity changes, and
they, in turn evoked the criterion changes. As a
whole, non-sensory information induced criterion
shifts initially and sensitivity changes secondarily,
while activation level changes caused sensitivity
changes, which subsequently led to criterion shifts
(considering this rubric, see Skotnikova, 2008).
Under patients’ stress before a dental treatment,
individually different dynamics of sensitivity and
criterion was found. Line lengths discriminabil-
ity decreased in medium and low stress resist-
ance patients, while criterion decreased in the first
ones and increased in the last ones. But sensitivity
increased and criterion decreased in high stress
resistance patients (Zabrodina and Sorokin, 2019).
METHODS OF PSYCHOPHYSICS II
Stevens’s Paradigm in Subjective
Scaling: Ratio Scales
In all Stevens’s scaling methods, two types sub-
jects’ responses organization are used: estimation
procedure, when they report about the sensations
values that have arisen in numerical form, and
production procedure, in which they produce
specified sensations values, adjusting correspond-
ing stimuli values. Stevens developed the four
main methods for constructing sensory ratio
scales: magnitude estimation, magnitude produc-
tion, ratio estimation and ratio production. Let’s
consider two of them briefly as the most charac-
teristic ones.
Two modifications of ratio production method
are known: the fractionation (or fractioning)
method and the multiplication method. In the frac-
tionation procedure, a subject is presented with
several standard stimuli (Sst) and selects compa-
rable stimuli (Sc), the subjective values of which
equal to a given part of the corresponding Sst val-
ues. Usually, simple fractions (1/n = 1/2, 1/3, etc.)
are given. Most often, 1/n = 1/2 is used (i.e., divi-
sion in half). When selecting a stimulus that is in a
given relation to Sst, either estimation or reproduc-
tion procedures are used. In the first case, a direct
estimation of the Sc to Sst ratio is made, and in the
second case, the Sc value is adjusted in accordance
with the ratio specified in the instruction. The mul-
tiplication procedure is opposite to the fractiona-
tion one: the subject must select a comparable
stimulus that exceeds the standard stimulus by a
given number of times.
To obtain a scale using the magnitude estima-
tion method, an observer is presented with a fixed
set of supra threshold stimuli covering a fairly
wide range of the measured characteristic. There
are two forms of this method: with a set mod-
ule or with a free module (otherwise it is called
without a module). In the first case a subject is
presented with a standard stimulus and a certain
numerical value (e.g., 100), which is signified as
the corresponding sensation The subject should
relate all own estimates of the stimuli values with
 Advances in Psychophysical Techniques
Figure 29.12 The psychophysical loudness
function of 1000 Hz tone signal.
this module. In the second case, no stimulus is
declared as standard, and no restrictions are intro-
duced when choosing numbers for responses. The
only requirement for the individual to try to use
numbers that accurately express the magnitude of
the sensation caused by the stimulus.
In the Stevens’ work, a number of ratio sensory
scales were constructed: scales of loudness, sweet
sensations, and so on (Geschheider, 1997). Some
of them are widely used as international standards
for assessing sensations intensities (e.g., the sone
scale curves of equal loudness; Figure 29.12).
The abscissa axis is the signal intensity in deci-
bels above the absolute threshold. The ordinate
axis is the subjective loudness estimates in sones.
One sone is defined as loudness of 1000 Hz at 40
dB above the absolute threshold. For comparison,
the straight dotted line is a function predicted by
Fechner’s law.
A detailed description of the procedures for
ratio scales constructing and examples of sensory
scales can be found in (Geschheider, 1997).
SUBJECTIVE SCALING PARADIGMS:
PARTITION SCALES: MEASUREMENT OF
PAIRED COMPARISONS
Above, we have already described Thurstone’s
approach. Below we consider the method of
paired comparisons, which allow us to build a
scale of intervals. An empirical procedure for
constructing a scale of intervals based on
487
Thurstone’s law of comparative estimates is the
method of paired comparisons. The material for
constructing the scale is the frequency of com-
parative assessments of the type: “I prefer stimu-
lus j more than stimulus i.” It is fundamentally
important that this is a one-dimensional subjective
characteristic.
In each sample, the individual’s response about
the preferred stimulus in the pair is recorded.
Based on these comparisons, the frequency of
preference of one stimulus to another is deter-
mined for each pair. As a rule, each pair of a set
of n stimuli is presented for comparison several
times. Data processing consists in the transition
from the frequency matrix nxn to the probability
matrix. The element of this matrix - pA,B, is the
relative frequency of the number of preferences of
stimulus A to stimulus B to the total number of
comparisons of these two stimuli. We pass from
the probability matrix to the difference matrix, tak-
ing into account that the value of the subjective
difference between the two stimuli is expressed in
units of the SD of the normal distribution. Thus,
a matrix is obtained, the element of which (zA,B)
in the framework of the Thurstone’s model is an
estimate of the subjective difference (ΨA – ΨB),
measured in units of the SD of the distribution of
discriminable differences.
In the original work of Thurstone five variants
of the application of this law are considered. S
However, simplified version of Thurstone’s law or
its V version (rΨAΨB = 0 and σΨA = σΨB = σ) has
received the greatest application:
Ψ A −Ψ B = z ABσ   (29.12)
In 1958, American mathematical psychologist
(Warren Torgerson) proposed specific computa-
tional algorithms for implementing each of the
five variants of the law.
METHODS BASED ON DIRECT ESTIMATES
Other methods for interval scales constructing are
based on observers’ direct estimations of a certain
feature scaled value. Partition scaling methods
assume that a person is able to divide a given con-
tinuum of stimuli into equal sensory distances.
Within the framework of this paradigm, two
groups of methods have been developed: equisec-
tion method and category scaling method
(Gecsheider, 1997).
The equisection method requires an individual
to divide a range of stimuli set for scaling by
equal sensory distances. Two slightly different
488 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
techniques are usually used for a subjective scale
obtaining. A subject is presented with the smallest
and the largest stimuli from the set of N stimuli,
and asked to choose N-1 stimuli in order to obtain
equal sensory distances between them. This pro-
cedure is called a simultaneous solution, since
all the scale values are evaluated simultaneously
by the observer. A similar procedure is illustrated
in Figure 29.13. First, the individual is asked to
appraise for himself the magnitude of the per-
ceived difference between two extreme stimuli,
for example, 10 (smallest) and 100 (largest). Then
the participant is asked to set the intensities’ val-
ues of the other three stimuli in such a way that the
entire range of the perceived difference between
the extreme stimuli is divided by these three
stimuli into four subjectively equal distances. In
our example, the values 1 and 5 denote sensations
caused by extreme stimuli, 10 and 100, respec-
tively. The values of sensations 2, 3, and 4 cor-
respond to the stimuli selected by the subjects
themselves. As a result, four equal distances are
obtained on the psychological axis: 1-2, 2-3, 3-4,
4-5. On the stimulus magnitude axis, the values
10, 20, 35, 55, and 100 correspond to the scale
values obtained by this procedure ( 1, 2, 3, 4, 5:
Figure 29.13 at top). Based on these data, the psy-
chophysical function is constructed (Figure 29.13,
at bottom).
Subjective magnitude of the stimulus
Adjustable
Smallest
The physical value of the stimulus
Subjective magnitude
of the stimulus
The physical value of the stimulus
Figure 29.13 Equisection scale (at the
bottom) determined by a simultaneous solu-
tion (at top).
An alternative to the simultaneous solution is
the sequential solution procedure, when a sub-
ject is required to select only one stimulus from
a sequential series of stimuli samples that divides
the specified sensory interval in half.
The categorical scaling method is also designed
to measure sensory qualities on the interval scale.
In this method, a subject is presented with a vari-
ety of stimuli and is asked to match them with a
certain number of categories. Usually numbers (1,
2, and 3) or descriptive adjectives (low, medium,
and high) are used as categories. The method of
equal-appearing intervals is one of the most wide-
spread and simple procedures for categorical scal-
ing. It is assumed that a person is able to take into
account the intervals between the boundaries of
the categories used, when he attributes stimuli to
different categories. Based on this assumption, the
categories associated with certain stimuli are con-
sidered as values on the interval scale. To obtain
reliable scale values by this method, averaging of
a large number of judgments is required, which
is achieved by using a large number of individu-
als or presenting a large number of stimuli to one
individual.
MULTIDIMENSIONAL SCALING (MDS)
Advantages of MDS
MDS began its intensive development in the
middle of the twentieth century in the works of
American scientists (Torgerson, Shepard,
Kruskal). The MDS is a field of mathematical
Largest
psychology (psychometric). In the most general
form, MDS can be defined as a mathematical
tool designed to process data on pairwise simi-
larities, connections and relationships between
the analyzed objects (stimuli) in order to repre-
sent these objects as points in a certain coordi-
nate space.
The MDS methods are used to build a model
of human behavior when making judgments
about the similarity between objects of differ-
ent modality and complexity (colors, graphemes,
faces, etc.). The MDS is based on the assumption
that when comparing stimuli, a person (explic-
itly or implicitly) focuses on their basic charac-
teristics. The greater the divergence of stimuli
according to these characteristics (factors), the
higher the subjective measure of the difference
between them. The process of assessing simi-
larities (or differences) between objects by an
­individual can be represented in the form of a
 Advances in Psychophysical Techniques
“black box,” the input and output of which are
formed by evaluated objects and their subjective
estimations, respectively. The task is to uncover
this black box. The MDS allows solving this
problem by building a geometrical coordinate
space where objects are represented as certain
points, and inter points distances correlate with
subjective scores. Such a model is understood as
a system of rules, guided by which it is possible
to generate the same results about objects’ simi-
larities that have been perceived by the subject.
The geometric representation of the objects in the
space of a small number of dimensions provides
a convenient visual analysis and interpretation of
experimental data.
The main task of MDS as a mathematical tech-
nique is to identify a structure of a studied set of
objects. Identification of the structure is under-
stood as identification of a set of main ­factors,
determining objects’ differences, and description
of each object in terms of these factors. The pro-
cedure for constructing the structure is based on
the analysis of objective or subjective information
about the proximity between objects or informa-
tion about preferences of a set of objects.
MDS algorithm includes the following steps:
A) The measurement of large (supraliminal) dif-
ferences1 between all pairs in a sample of n
objects. Values of “pair wise differences” may
be obtained in psychophysical (Steven’s method
of direct scaling) and psycho physiological (EEG,
ERP)2 experiments in humans, in behavioral
(methods of conditioned learning) and neuro-
physiologic (registration of neuronal activity)
experiments with animals. Methods of measuring
large supra threshold differences between stimuli
in humans have a long tradition and are fully
detailed in handbooks on scaling (Torgerson,).
Electrophysiological techniques for such meas-
urements are less well developed. They provide
information on stimuli discrimination by large
neural networks, recording evoked potentials in
the cortex and in the sub cortical brain structures
of humans and animals, as well as by local area
networks, recording extracellular and intracel-
lular neuronal activity. At the foundation of these
measurements is a method first developed by
Bongard for instantaneous exchange of stimuli,
which in the English-language literature has
been then called “stimuli exchange” or “silent
substitution method (Izmailov et al., 2015).
B) Analysis of the resulting matrix of pair wise differ-
ences (n x n) provided by the MDS methods aims
of construction a geometrical coordinate space
489
(“subjective space”). There objects, distinguished
by an individual, are graphically represented as
certain points, and inter point distances depict
“subjective differences” between the objects.3
C) Analysis of objects’ coordinate functions in the
space (specifically, values of their projections on
the axes) is provided with the aim of identifying
the magnitude of contribution of each axe to
object’s characteristics. At this stage, it is impor-
tant to identify the axes that make the greatest
contribution to the spread of coordinates in order
to minimize the dimensionality of the model.
D) Usage the coordinate functions for interpretation
of the space axes as some factors, determin-
ing discrimination between objects. The axes
of the model, which form its orthogonal basis,
may be considered as the quantitative scales
(metric scaling) or the ordinal ones (non-dimen-
sional scaling), reflecting the contribution of
some independent factors (the variables) to
objects’ discrimination. The measure of similar-
ity between two objects is the inverse of the
distance between their corresponding points. The
closer the points are to each other, the higher
the measure of similarity between correspond-
ing objects (and the lower the measure of dif-
ference). Subjective evaluations of differences
between stimuli represent the cumulative effect:
(a) of the activity of all neural networks involved
in stimulus physical characteristics encoding,
and (b) of electrophysiological pattern decoding
into a cognitive image. In order to understand
the overall structure of the cognitive system,
it is necessary to distinguish contributions of
separate links in this integral estimation of inter
stimulus differences. In some cases, it is possible
to interpret objects’ coordinates as a reflection of
the contributions into their characteristics, made
by the neurophysiologic mechanisms (channels).
Thus, the geometric modeling, based on the MDS,
is not simply a technique for the formal descrip-
tion of psychological processes and states, but
a special approach, a formal language that, like
artificial international language Esperanto, ena-
bles to integrate and analyze both psychological
phenomenology and the neurophysiologic data
in one unified mathematical language. The MDS
methods are actively used for big data of expert
information analysis and visualization not only in
psychology, but also in various fields of sociol-
ogy, economics, history, geography, pedagogic,
anthropology, etc. (cf. Davison, 1991; Izmailov
et al., 2005, 2015; Sokolov, 2013).
490 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
METRIC MULTIDIMENSIONAL SCALING
(mMDS)
Given the pair wise dissimilarity matrix D = (dxy),
mMDS seeks the Euclidean space construction,
which allows using quantitative calculations for
representing differences between any pair of
objects in resulting matrix, as some distances
between points in a geometrical model. This
requires that values of pair wise differences
between any objects x and y in an experimental
matrix must satisfy the axioms of a distance, that
is, they must represent the values of a “distance
function,” called “metric”:
1 d (x, y) ≥ 0,
2 d (x, y) = 0 if and only if x = y,
3 d (x, y) = d (y, x),
4 d (x, z) ≤ d (x, y) + d (y, z).
Euclidean models are constructed by orthogonal-
izing the initial matrices. Torgerson’s method is
based on orthogonal projection into a subspace,
formed by axes that are characterized by a signifi-
cant spread of the objects-points. The solution is
sought by factorizing the matrix of initial differ-
ences: its Eigen values and eigenvectors are calcu-
lated that determine the axes orientation. The first
axis is characterized by the maximum spread of
the points along it, the second axis is orthogonal to
the first one and is determined by the next largest
spread, the third axis is orthogonal to the plane of
the first two axes, etc. After determining the
dimensionality of the model, one needs to enter a
metric in the coordinate space, the choice of which
has a great influence on the modeling results and
on interpretation of dataset. Minkowski’s metric
(cf. Billock et al., 2021) is usually used:
r
p Different types of functional are used as stress cri-
d jk = p
∑x jt − x kt
t =1
where r is the dimension of the space, djk is the
distance between the points corresponding to the
j-th and k-th objects; xjt and xrt are the values of the
projections of the j-th and k-th points on the t-th
axis. The most common cases of this metric are
the Euclidean metric:
r
2 One more way to approximate the point-to-
d jk = ∑x jt − x kt
t =1
and city-block metric (p = 1):
r r
d jk = ∑ x jt − x kt
t =1
The use of uniform metrics assumes that when
assessing similarities (or differences), a subject
equally takes all factors into account. One may
resort to a weighted metric, where a certain weight
is attributed to each factor, when there is a reason
to assert that the factors are not equal for the indi-
vidual and he takes them into account in different
degrees. Different persons can take into account
different factors. Then each individual is charac-
terized by his/her own set of the factor’s weights
Wti. The weighted metric of Minkowski has the
form:
r
p
d ijk = p
∑w i
t x jt − x kt
t =1
Such a model is called “individual scaling” or a
“weighted factor model.” Geometrically, it is inter-
preted as follows. Let there be a configuration of
points in the coordinate space that reflects the per-
ception of some “average individual” in the group.
In order to obtain the perception space of the
i-th subject, it is necessary to stretch the “average
configuration” in the direction of those axes, for
which Wti > Wtav, and compress it in the direction
of the axes, for which Wti < Wtav. Let’s consider
the case when in the space of two factors for the
average individual all objects-points lie on a cir-
cle. Then for an individual, which is characterized
by weights W1i = 2, W2i = 1, these stimuli will be
located on an ellipse elongated along the horizontal
axis, and for an individual, which is characterized
by weights W2i = 2, W1i = 1, they will be located on
an ellipse elongated along the vertical axis.
Using this metric, the degree of adequacy of
the model regarding the initial data is evaluated.
For this purpose, a quality criterion is introduced,
called “stress,” which measures a degree of dis-
crepancy between differences Djk in the matrix
and corresponding distances djk in the space.
terion (SD). In the simplest case it looks like this:
2
SD = ∑( d jk − D jk )
j<k
Another formal criterion for the adequacy of the
model can be Pearson’s correlation coefficient
between Djk values in the original matrix and djk
distances in the model (it should be high enough).
point distances is to calculate the scalar products
of the vectors, connecting the object-points with
the center of the space coordinate system:
b jk = ∑ x jt x kt
t =1
 Advances in Psychophysical Techniques 491

In this case, the maximum values of the scalar
product correspond to the minimum values of the
differences between evaluated objects.
One of the ways to increase the accuracy of
the formal solution is the increasing of the space
dimensionality. Figure 29.14 represents the results
of the mMDS application in psychophysical
research of perception (subjective evaluation) of
face emotional expressions. In study by Izmailov
et al. (2015), using the mMDS of the matrix of

Figure 29.14 Projection of schematic face-points on the three planes.

(A) X1X2, (B) X3X4, and (C) X1X3 of a four-dimension space derived through multidimensional
scaling of dissimilarities estimates.
492 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
paired differences between 25 facial stimuli, a
geometric model of schematic facial emotional
expressions perception was constructed. In this
model, the schematic faces were represented by
points in a four-dimensional space so that the
Euclidian distances between points were propor-
tional to perceived differences between the emo-
tional expressions of the presented faces. Three
angles of the four-dimensional sphere are jux-
taposed with subjective characteristics of facial
expressions called “emotional quality” (joy, sor-
row, sadness, etc.) (Figure 29.14, A), “emotional
intensity (activity)” (Figure 29.14, B), and “emo-
tional saturation (fulness)” (Figure 29.14, C). The
four Cartesian coordinates of this space were com-
prised of neural channels activation, coding mouth
and brow linear orientation.
Point numbers correspond to numbers of face-
stimuli (adapted from Izmailov et al., 2005, 2015).
Such structure of the emotional space is simi-
lar to the structure of the color space, where the
color tone corresponds to the emotional tone, the
brightness of the color corresponds to the intensity
of emotions, and the color saturation corresponds
to the emotional saturation. The obtained data
allow shedding light on some general principles of
encoding information in the visual system.
NON-METRIC MULTIDIMENSIONAL
SCALING (nMDS)
If the original difference matrix is not an exact
distance matrix in any metric space, then a non-
metric (or monotonic) approach can be used to
build the model. The essence of the approach
consists of a multi-stage procedure for selecting
such a sequence of numbers d̂ that would be{}
monotonically related to initial differences (de
Leeuw, 2017; Shepard, 1981). The functional of
the following form is used as a stress criterion:
2 space” are used for both humans and experimen-
∑ (d jk − dˆ jk ) tal animals.
j<k
Sd̂ =
∑d 2
jk
j<k
Non-metric scaling is based on gradient proce-
dures for this functional minimizing. The dis-
tances between points are calculated, as a rule,
using the Euclidean metric, which is not sensi-
tive to the axes rotation and the coordinate center
transferring. The quality of the solution does not
depend on the coordinate system direction, and for
a meaningful interpretation they must be oriented
accordingly.
The non-metric approach has some advantage
over the metric one: it is not limited to orthogonal
(linear) design and allows getting a good represen-
tation of a set of objects in the space of a smaller
number of dimensions.
MDS VS FACTORY ANALYSIS
The MDS has some advantages over Factory
Analysis (FA), which also aims at finding latent
variables (factors) underlying estimates of differ-
ences between objects. For example, the MDS can
be applied to any types of distances or similarities,
if the FA algorithms are based on the analysis of a
matrix of normally distributed values of linear
correlation coefficients. If the FA requires obtain-
ing estimates of objects compared for a certain set
of features, then the MDS allows using the direct
ratings (subjective scaling) of differences.
The correlation matrices, used in the FA, can be
converted into difference matrices:
D ij = (2 − 2 rij )1/ 2
The difference measures Dij obtained in this case
do not violate the axioms of distances and can
be processed using mMDS methods (Davison,
1991).
Notes
1  Estimates of the similarity and correlation
between the analyzed objects can also be used as
input data for MDS. For brevity, the text refers to
the “inter stimulus differences.”
2  EEG – electroencephalogram; ERP – event-related
potential.
3  To facilitate comparative analysis, the terms “sub-
ject,” “subjective difference,” and “subjective
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Revolutions in “Wet”
Neurobiology
John Bickle and David J. Parker
INTRODUCTION
This chapter details three historical cases of “revo-
lution” in one branch of neuroscience.
Neuroscience is the scientific study of the nervous
system, from biophysics to behavior, and is com-
posed of numerous fields and disciplines.
Neurobiology and neurophysiology, branches that
study the biology and function of nervous sys-
tems, are conducted in wetlabs, where “wet” is the
colloquial expression for the laboratory materials
necessary to investigate biological processes
experimentally, and the infrastructure needed to
properly use and handle them. Our specific focus
is on cellular and molecular investigations. These
typically manipulate cells and molecules in model
organisms and measure outcomes.1
Neurobiologists routinely refer to numerous
episodes in their field’s history as “revolutions”
or “paradigm shifts,” using terminology intro-
duced by Thomas Kuhn (1962). Parker (2018)
outlined examples of neuroscientific revolutions
using Kuhn’s resources, and pointed out that it
isn’t clear that neurobiologists actually follow
Kuhn’s account. In this chapter we examine some
historical episodes that neurobiologists routinely
recognize as revolutionary which appear not to fit
within Kuhn’s “paradigm-shift” model. Our first
example, the discovery of neurogenesis in adult
30
mammals, seems best characterized as a transition
from Kuhn’s pre-paradigm state into paradigm-
governed normal science (although features of a
Kuhnian “crisis” are present). Our second exam-
ple, the discovery of long-term depression and
mechanisms of metaplasticity seems best char-
acterized as progress in normal science under
the paradigm of Hebbian synaptic plasticity
(Hebb, 1949). Our third example, the develop-
ment of intracellular recording technologies and
basic neurobiological insights generated, seems
better to fit Bickle’s (2016) alternative to Kuhn’s
account, of a scientific revolution driven primar-
ily by development of new research tools. While
our focus here is on historical episodes, our goals
are prospective.2 Revolutions recognized as such
by neurobiologists come in a variety of forms, so
recognizing and pursuing potential revolutions in
development is not a matter of looking for one set
of features (such as Kuhn’s “anomalies,” “crisis
science,” and “emerging new paradigms”).
ADULT NEUROGENESIS
Historically, it has been accepted knowledge that
no new neurons were generated in the adult brain
(Rakic 1985). Neurogenesis was considered
496 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
limited to the pre- or very early-postnatal period.
During the first half of the twentieth century there
were sporadic reports of adult mammalian neuro-
genesis, but little unequivocal evidence of mitotic
figures characteristic of dividing cells in neurons.
Absence of neurogenesis was also consistent with
the assumed fixity of the adult brain considered
necessary for stability of adult brain function
(Gross, 2000).
Evidence of adult mammalian neurogenesis first
appeared during the early 1960s. Joseph Altman
and colleagues used the then-new 3H-thymidine
technique and autoradiography as a marker of
DNA synthesis in adult rats and cats (Altman,
1962; Altman and Dias, 1965). 3H-thymidine is
incorporated into replicating DNA during the
“S phase” of cell division and thus labels new
cells. But as 3H-thymidine labels any newly syn-
thesized DNA (e.g., during DNA repair), cell divi-
sion must also be verified to confirm the presence
of new cells (Nowakowski and Hayes, 2000).
Altman found evidence of adult neurogenesis in
the hippocampus dentate gyrus and olfactory bulb
(Altman, 2011). However, despite this evidence
being reported in major scientific journals, neuro-
genesis was not generally accepted. For example,
in his textbook on developmental neurobiology
Jacobson (1970) insisted that “there is no convinc-
ing evidence of neuron production in the brains of
adult mammals.” Subsequently, there was no men-
tion of Altman’s work in Purves and Lichtman’s
(1985) textbook, while Kandel et al. (1991) stated
dogmatically that “Neurogenesis ceases early in
the development of the mammalian brain.”
Gross (2000) claimed that Altman’s evidence
for adult neurogenesis was ignored because of
his junior status. Altman (2011) denied this as
he was among the top 1000 most cited neurosci-
entists between 1965 and 1978 (Garfield, 1981).
However, Altman eventually shifted his research
focus from neurogenesis to the embryologi-
cal development of the CNS in rats and humans
(Altman, 2011).
In the late 1970s, Michael Kaplan also used
3
H-thymidine labeling combined with electron
microscopy (Altman had used light microscopy)
and found evidence of neurogenesis in the adult
rat dentate gyrus and olfactory bulb, supporting
Altman’s findings. Kaplan also showed neurogen-
esis in rat visual cortex and the subventricular zone
of adult macaque monkeys, suggesting adult neu-
rogenesis in a primate. Kaplan also experienced
negative reactions to his work which prevented him
from challenging the “no-new-neurons” establish-
ment. He later wrote about “the political death”
of his project into neurogenesis (Kaplan, 2001).
Kaplan mentioned that “one of the most fervent
supporters of the dogma of no neurogenesis was
Pasko Rakic.” According to Specter (2001), Rakic
had claimed that, “the cells Kaplan had detected
may look like neurons in New Mexico, but they
don’t in New Haven.” In the paper published
a year later, cited almost 700 times (PubMed,
June 17, 2021), Rakic (1985a) examined slices
from adult rhesus monkey brains at various ages
using 3H-thymidine and claimed that neurogenesis
only occurred in the prenatal or early postnatal
period. Rakic’s authority as one of the most influ-
ential neuroscientists in the world unfortunately
limited continuing work on adult neurogenesis
and acceptance of data already reported (Gould,
2007; Kaplan, 2001).
Acceptance of adult neurogenesis finally
began with studies in songbirds in the 1980s by
Fernando Nottebohm and colleagues (Nottebohm,
1996). They hypothesized that neurogenesis
could underlie seasonal differences in the volume
of two mating song-production nuclei in male
canaries, and using 3H-thymidine and ultras-
tructural analyses showed neurogenesis in song-
related circuits (Nottebohm, 1996). While this
evidence for neurogenesis was readily accepted,
the “no-new-neurons” view was maintained as
orthodoxy by the claim that this more primitive
neural system was not representative of mammals
(Specter, 2001).
By the mid-1990s the thymidine analogue
5-bromo-3-deoxyuridine (bromodeoxyuridine,
BrdU) was being used to label dividing cells to
investigate adult neurogenesis (Gould, 2007).
Immunocytochemical detection of BrdU labeling
was faster and simpler to use than 3H-thymidine
autoradiography (Altman, 2011). In addition, by
the early 1990s antibodies that labeled neuron and
glial cell-specific proteins were available. The use
of BrdU and cell markers was quickly adopted
into rodent and primate studies (Gould, 2007;
Specter, 2001). Several labs replicated Altman’s
and Kaplan’s original data, showing experience-
dependent adult neurogenesis in the olfactory bulb,
dentate gyrus, and neocortex of rats and primates.
Gage and his colleagues also found evidence of
adult neurogenesis in the hippocampus in post-
mortem brains of human cancer patients injected
with BrdU before death to visualize tumor growth
(Eriksson et al., 1998).
This growing evidence for adult neurogen-
esis through the late 1990s continued to be met
with skepticism. Rakic (2002) wrote, “The dis-
covery of neurogenesis in the adult human den-
tate gyrus is exciting … [but an] exception to
the rule of ‘no new neurons’ that still applies to
most of the brain.” Rakic appealed to historical
authorities, Kölliker (1896), and Ramón y Cajal
(1928) who had argued for the irreplaceability
of neurons.3 Focused on the stability argument
 Revolutions in “Wet” Neurobiology
against adult neurogenesis, Rakic (1985a) wrote
that, “The addition of new ‘naïve’ neurons into
existing circuits would interfere with the retention
of acquired experience and learned behavior that
is evolutionarily the most significant advantage of
all primate species including human.” However,
the increasing weight of evidence for adult mam-
malian neurogenesis, and the realization that the
adult brain is not immutable (Buonomano and
Merzenich, 1998), eventually led to the accept-
ance of adult neurogenesis by the early 2000s
(Gould 2007).
A recent study failed to find evidence of adult
hippocampal neurogenesis in humans (Sorrells
et al., 2018), conflicting with the findings of
Boldrini et al. (2018). Despite having found evi-
dence for neurogenesis in the adult primate dentate
gyrus (Kornack and Rakic, 1999), Rakic’s ready
acceptance of the negative findings by Sorrell et al.
(2018) illustrates how evidence can be evaluated
differently by different investigators (Shen, 2018).
Nottebohm, suspecting a psychological factor at
work, commented that, “I think Pasko Rakic single-
handedly held the field of neurogenesis back by
at least a decade” (Specter, 2001). Subsequently,
Altman (2011) remarked that, “Open criticism of a
scientific claim that runs counter to an established
dogma is fully justified; indeed, such a claim must
be subjected to a thorough scrutiny before the
established paradigm is prematurely abandoned.”
However, Gage, mentioned above as an early pro-
ponent of human adult neurogenesis, insisted that
Sorrells et al. (2018) were “not really measuring
neurogenesis… Neurogenesis is a process, not an
event. They just took dead tissue and looked at it
at that moment in time” (Shen 2018; cf. Costandi,
2012). In discussing the different methodological
approaches of Sorrells et al. (2018), and Bolderini
et al. (2018), Kamperman et al. (2018) concluded
that, “there is currently no reason to abandon the
idea that adult-generated neurons make important
functional contributions to neural plasticity and
cognition across the human lifespan.”
Numerous features of this episode have a
Kuhnian ring. The tone and content of debates
about neurogenesis read like Kuhnian crisis sci-
ence. Appeals to authority, selective citing of evi-
dence, attacks on individual scientists, and various
“sociological and psychological factors” appear to
have dominated the debate about adult neurogen-
esis. Adult neurogenesis has directly been referred
to as a “paradigm shift” by prominent neurosci-
entists. Charles Gross commented that, “we are
now in the midst of a paradigm shift” (Kaplan,
2001), while Eric Kandel considered Fernando
Nottebohm’s work as having “led to one of the
great paradigm shifts of modern biology” (Specter,
2001). But determining whether an episode meets
497
Kuhn’s conditions of a genuine paradigm shift
requires detailed historical study. Evidence that
adult neurogenesis extended beyond pre- and
early post-natal development periods, negated the
concept of the brain having its full complement
of neurons around the time of birth (incommen-
surate with the “no-new-neurons” view that had
informed neuroscience throughout the twentieth
century). Indeed, Nowakowski and Hayes (2000)
pointed out that evidence of adult neurogenesis
would require “re-evaluation of virtually all cur-
rent conceptual bases for understanding how
neuronal circuitries in neocortex develop and are
modified,” suggesting that they viewed neurogen-
esis as a potential Kuhnian revolution. Regarding
its broader impact, adult neurogenesis has been
suggested as being involved in memory formation
(Kempermann 2008), potential neurological repair
strategies (Grade and Götz, 2017), and as a new
target for psychopharmacology (Whalley, 2006).
Hence, the case for a Kuhnian paradigm shift
account of adult neurogenesis seems strong.
However, this interpretation faces a difficult
question. Which paradigm did adult neurogenesis
replace? A “no new neurons” paradigm doesn’t
seem correct. For Kuhn a paradigm directs the
scientific work conducted as “normal science,”
but absence of adult neurogenesis leaves no spe-
cific normal science to pursue and thus doesn’t
provide a paradigm to be replaced. Instead,
acceptance of adult neurogenesis constitutes a
new paradigm emerging from a pre-paradigm
stage, generating normal science research ques-
tions (Kuhnian “puzzles”) now needing answers.
How are new neurons made? What determines the
rate of neurogenesis? What is the purpose of adult
neurogenesis? How do new neurons integrate into
existing circuits without disturbing ongoing func-
tions? How can adult neurogenesis be harnessed
clinically for regeneration and repair?
For example, striatal neurogenesis is far greater
in humans than in animal models, suggesting a
potential therapeutic application in striatal motor
disorders (e.g., Parkinson’s and Huntington’s dis-
ease). Changes in the striatum during evolution
also suggests a role in human cognitive function.
Degenerative diseases like Alzheimer’s disease
exhibit reduced neurogenesis in the adult hip-
pocampus that may contribute to depression and
anxiety often seen during the presymptomatic
stage (Bergmann et al., 2015). The utility of neu-
rogenesis in the pathological brain environment
will be questions for normal science conducted
under this first paradigm.
To understand a neural circuit requires iden-
tifying neurons involved, their connections, and
their properties. If neurons are constantly being
added, then conventional wisdom is problematic.
498 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Plasticity has been an acknowledged challenge
for this general understanding, but plasticity oper-
ates within certain bounds on existing cells and
is an extension of conventional circuit analyses
(Selverston, 1980). Having to consider circuit-
ries that add new components is a different issue.
So perhaps adult mammalian neurogenesis can
be seen as an example of a Kuhnian revolution
for some fields (e.g., hippocampal research or
research into neural repair), while marking a tran-
sition from pre-paradigmatic science to a normal
science-generating paradigm for neuroscience
more broadly.4
Clearly any attempt to harness neurogenesis
will require understanding how and why it occurs.
This will require analyses of behavioral effects
that may influence the natural rate of neurogen-
esis and the integration of neurons into existing
circuits, as well as ways it can be manipulated
in animal models of pathology and evidence that
neurons generated by these manipulations in path-
ological conditions have integrated into circuits in
a functionally-relevant way. For example, in some
studies learning can enhance neurogenesis, but in
other contexts it can inhibit it, so the assumption
that neurogenesis is necessarily beneficial is over-
simplified. These analyses will require multiple
approaches that include molecular cell biological
approaches of cell phenotypes and differentiation,
electrophysiological or other ways of monitoring
or manipulating function (including imaging to
determine the activity of cells and optogenetics to
manipulate their function). Clearly, there needs to
be a move away from qualitative analyses show-
ing that neurogenesis occurs to more quantitative
analyses that relate neurogenesis to function and
behavior. This will also require a reconsideration
of traditional views. Understanding of neurogen-
esis in the hippocampus and striatum will depend
on our knowledge of the structure and function of
these regions. Evidence of neurogenesis necessar-
ily forces revision of our previous understanding
of these brain areas, and their broader functions
(Abrous and Wojtowicz 2015).
HEBBIAN SYNAPTIC PLASTICITY
BEYOND LTP
Synaptic plasticity is a ubiquitous feature of all
nervous systems. Under some conditions the
strength or efficiency of transmission at all (chem-
ical) synapses appears to be modifiable by neu-
ronal activity. Synaptic plasticity covers a
multitude of effects that differ in terms of direc-
tion (potentiation or depression of postsynaptic
response), duration (short- or long-term) and
mechanisms that provide flexibility to anatomi-
cally fixed circuits. But with this obvious utility
comes the need of ensuring stability, allowing
changes to occur without disrupting ongoing or
established functions (Abraham and Robins,
2005).5 Failure to satisfy this demand in artificial
systems can lead to “catastrophic interference”
(French 1999), where all stored information is lost
when the number of stored patterns exceeds a
critical threshold (∼0.14N, where N is the number
of network components; Srivastava et al., 2014).
Long-term potentiation (LTP) has dominated
neuroscientific research on synaptic plasticity
for nearly five decades, not least because of its
claimed link to learning and memory (Bliss et al.,
2018; Morris, 2003; Silva et al., 2014; cf. Jeffrey,
1997; Keith and Rudy, 1990; McEachern and
Shaw, 1999; Parker, 2019; Queenan et al., 2017).
LTP relates to Hebb’s rule (Hebb 1949), although
the rule was suggested before Hebb (Berlucci and
Buchtel, 2008). Hebb’s rule holds that correlated
firing of pre- and postsynaptic neurons strength-
ens the “weight” of the connection between them.
Hebb’s rule is not universally neurobiologically
true; for example, in the cerebellum predicted
Hebbian plasticity (Marr, 1969) turned out the
be anti-Hebbian (Feldman, 2012). But Hebbian
effects have been shown at many synapses across
the CNS. So much wetlab research has focused
on investigating Hebbian synaptic plasticity
that it seems appropriate to call it a paradigm of
late-twentieth-century neurobiology.
A well-known shortcoming of Hebbian plastic-
ity is that it has no mechanism to prevent a positive
feedback effect in which potentiated connections
could exceed the plasticity threshold and continu-
ally increase in strength, a synaptic version of the
“Matthew effect” that obviously fails to address
the stability-plasticity dilemma. This means that
Hebbian synaptic mechanisms can only be one
part of any putative storage mechanism, as syn-
apses that follow a Hebbian rule have potential to
grow in strength without limit (assuming graded
rather than binary changes; Petersen et al., 1998;
cf. Enoki et al., 2009), and thus erase any salient
changes at synapses.
Although these concerns came to be focused
on LTP in the hippocampus and its putative role
in memory (Bear, 1995), they were initially raised
in relation to Hebbian changes in development
of the visual cortex (Bear et al., 1997). Von der
Malsburg (1973) proposed rate-based network
models of development of the visual cortex that
included synaptic plasticity using Hebbian synap-
tic potentiation and competition between cells to
account for the formation of orientation selectivity
and ocular dominance maps. He hypothesized that
 Revolutions in “Wet” Neurobiology
potentiation was proportional to the product of
presynaptic and postsynaptic activity and coupled
it with a normalization of the total synaptic weight
to a cell so that the total synaptic input remained
constant. This generated stability by preventing
excessive growth of the excitatory input, and spec-
ificity as cells would become insensitive to stimuli
they had not been trained on. Although his pro-
posed mechanism was Hebbian, von der Malsberg
(1973) did not think that it related to then recently
identified hippocampal LTP, because the reported
duration of LTP (Bliss and Gardner-Medwin,
1973) was insufficient for long-term changes asso-
ciated with visual cortex development.
Stent (1973) addressed the plasticity-stability
issue by predicting the need for bi-directional syn-
aptic plasticity, both potentiation and depression.
For the latter, he hypothesized an anti-Hebbian
process such that, “when a presynaptic neuron
repeatedly fails to excite a postsynaptic cell, meta-
bolic change takes place in one or both cells so
that the presynaptic neuron is less effective in acti-
vating the postsynaptic cell.” He suggested that
this feature could account for the specificity of
connections formed during development by spa-
tial competition, an increase in the strength of a
connection to a region resulting in the weakening
of other connections. Stent’s influence on theo-
retical and computational modelling over the fol-
lowing decade was extensive (Bienenstock et al.,
1982; Cooper et al., 1979; Sejnowski, 1977) but
seemed to have been forgotten in later reviews of
long-term depression (LTD; Bear, 1995; Bear and
Malenka, 1994). Following Stent’s (1973) work,
Sejnowski (1977) asserted that, “unless some
means exist for weakening the plastic synapse,
continual random coincidences inexorably push
it to maximum strength.” Sejnowski suggested
that strengthening would occur through Hebbian
long-term facilitation when there is correlation
between pre- and postsynaptic neuron activity,
but that depression would occur when there is no
correlated firing of neurons.
Cooper et al. (1979) also followed Stent in
suggesting a plasticity threshold above which
inputs potentiate and below which they depress.
This gives some selectivity as neurons will only
respond to potentiated inputs, but as the thresh-
old was fixed there would still be a potential for
runaway cycles of potentiation and depression. A
fixed plasticity threshold could also not account
for monocular or binocular deprivation effects on
visual cortex development (Bear et al., 1987). To
account quantitatively for selective increases and
decreases in inputs in the visual cortex, the BCM
(Bienenstock et al., 1982) model suggested that
when an input evoked a postsynaptic response
that exceeded a threshold θm the synapse was
499
potentiated, and when it did not exceed θm the syn-
apse was depressed. They added the novel sugges-
tion that θm was also modifiable: when a synapse
is potentiated θm shifts to the right, and when it
is depressed θm shifts to the left, and thus poten-
tial positive feedback cycles of potentiation and
depression are prevented. This threshold modifi-
cation is akin to a homeostatic effect that keeps
synaptic strengths within certain bounds, using a
time-dependent average of the postsynaptic activ-
ity to determine the homeostatic sliding thresh-
old that in turn influences subsequent synaptic
modification.
At first glance, the BCM model may not seem
to be a major change to views of synaptic plastic-
ity held over the last four decades, but some con-
siderations reveal its significant implications and
impacts. An obvious influence is that it inspired
the search for LTD and bidirectional synaptic
plasticity (Bear, 1995; Dudek and Bear, 1992).
Bienenstock et al. (1982) stated that “in order to
actually use Hebb’s principle, one must state con-
ditions for synaptic decrease as specific as those
for synaptic increase: if synapses are allowed only
to increase, all synapses will eventually saturate;
no information will be stored and no selectivity
will develop.” Bear (1995) claimed that the BCM
model was the inspiration for his experimental
search for LTD, in the hippocampus (Dudek and
Bear, 1992), and in the visual cortex (Kirkwood
et al., 1996). Evidence quickly emerged that the
same basic mechanisms involved in LTP were
also involved in LTD, with the rate of calcium
ion (Ca2+) influx through activated N-methyl-
D-aspartate receptors (NMDARs) being one
key determinant of which effect occurred. The
higher rate of postsynaptic Ca2+ influx generating
LTP activates calmodulin kinase II (CaMKII) to
increase the number of excitatory AMPA recep-
tors in the postsynaptic density, and the lower
rate of Ca2+ influx generates LTD by activating
postsynaptic phosphatases to internalize AMPA
receptors (Purves et al., 2018). Identifying these
phosphatases and other substrates remains an area
of active research.
A second influential feature of the BCM
model is that it highlights that a plasticity mech-
anism cannot act in isolation; to preserve ongo-
ing functions a plastic change must be integrated
and coordinated with other changes. While the
sliding plasticity threshold has been the main
influence of the BCM model, Bienenstock et al.
(1982) highlighted other aspects that influenced
subsequent research. Exposure to a single input
(e.g., a vertical line) can lead to a visual cortex
neuron responding preferentially to that input,
but it will be less sharply tuned to the input than
if all possible orientations had been presented.
500 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
This is because temporal competition between
incoming patterns and the activation of inhibitory
synapses is required for maximum stimulus selec-
tivity (Bienenstock et al., 1982). The BCM model
thus moved investigations of synaptic plasticity
beyond the traditional focus on single effects on
single cells by highlighting the distributed nature
of synaptic modification: the need to sample mul-
tiple inputs, need for inhibition, as well as need
to modify plasticity thresholds (Bear et al., 1997).
A third influence of the BCM model has
been on attempts to provide a common frame-
work for synaptic plasticity. Plasticity phenom-
ena are diverse, with differences in the duration
(various short and long-term effects), direc-
tion (potentiation or depression), and underly-
ing mechanisms (e.g., diverse second messenger
pathways involved in LTP and LTD; Sanes and
Lichtman, 1999). The same effects can also be
evoked by different stimulus protocols. Thus, in
common with the neuronal code, long-term syn-
aptic plasticity rules typically follow either a rate
code such as that used in conventional LTP studies
where the direction of plasticity reflects frequency
of presynaptic action potentials; or a timing code
where plasticity depends on relative timing of pre-
synaptic and postsynaptic activity (spike timing-
dependent plasticity, STDP; Caporale and Dan,
2008). Plurality of plasticity mechanisms presum-
ably allow nervous systems to respond flexibly,
but they seem to leave us adrift in a sea of effects
and mechanisms. There is obvious utility in find-
ing a unifying basis for these diverse effects. The
BCM model is proving useful in this search, by
inspiring attempts to find links between STDP and
BCM learning rules (Izhikevich and Desai, 2003;
Keck et al., 2017; Pfister and Gerstner, 2006).
Arguably the most influential aspect of the
BCM model is that it highlights that synaptic
changes are context-dependent. This idea has
motivated the fields of metaplasticity and homeo-
static plasticity, which have become major areas of
research over the last three decades (Abraham and
Richter-Levin, 2018). Numerous examples, from
model organisms to the human cortex, have shown
that the history of activity at a synapse, even
when it doesn’t leave any apparent alteration, can
modify the magnitude and direction of subsequent
plasticity. A key component in metaplasticity and
homeostatic plasticity research has been the BCM
model’s sliding potentiation threshold, and this
has significant implications. First, a sliding thresh-
old might account for the variability often reported
in plasticity experiments (for variability in LTP
experiments alone, see Edwards, 1995). A lack of
consistent effects across labs when the same phe-
nomenon is studied in the same way is confusing,
but instead of acquiescing in disagreement and
argument it is obviously better if we can explain
why different reported effects occurred. If syn-
apses in different studies started out in different
functional states depending on prior activities,
metaplasticity suggests that these difference could
produce different functional outcomes under the
same experimental conditions (Parker, 2015). This
feature might even account for the still unresolved
presynaptic versus postsynaptic mechanisms of
LTP debate, as under certain conditions a synapse
may be biased towards a pre- or a postsynaptic
plasticity mechanism (Edwards, 1995). In terms
of translation of basic neurobiological results,
an appreciation of context-dependent effects has
major significance. Any intervention that targets
synapses, whether an educational approach or a
psychopharmacological approach to treat psy-
chological disorders (with notoriously variable
effects; Ninnemann, 2012) or improve function
in the normal brain (e.g., cognitive enhancement;
Sahakian et al., 2015), will need to be tailored to
specific contexts if we are to promote beneficial
effects (or more importantly eliminate deleteri-
ous ones). This context specificity at the level of
synaptic plasticity is not typically considered in
the systematic application of drugs, but in light
of the implication of metaplasticity/homeostatic
plasticity motivated by the BMC model, perhaps
it should become so.
Thus, the BCM model has had a revolutionary
impact on wetlab work on synaptic plasticity. But
is it an exemplar instance of a scientific revolution
involving a paradigm shift? The BCM model was
explicitly developed as, “a general mathematical
framework” (Bienenstock et al. 1982), and “a new
mathematical form for synaptic modification”
whose “theoretical conclusions are consistent
with experimental data.” Indeed, it seems to have
guided many wetlab experimental advances on
the nature and mechanisms of synaptic plasticity,
especially on LTD.
From the perspective of neurobiology, a strict
Kuhnian account of scientific revolutions is open
to criticism that goes beyond more familiar criti-
cisms from the physical sciences (e.g., Kuhn’s use
of a few spectacular examples). Neuroscientists
seem to use the term “paradigm” with appar-
ently agreed-upon meaning, and also frequently
the term “paradigm shift” (although perhaps too
readily). So knowingly or unknowingly, they are
referring to Kuhn. But neuroscientists’ use of the
term “revolutionary” seems to be the crux, because
it can be applied to many episodes in many ways
(e.g., for distinct pragmatic or communicative
purposes). Some episodes that neurobiologists
recognize as revolutionary in their field seem to be
developments within Kuhnian normal science, and
this analysis seems to apply to the BCM model.
 Revolutions in “Wet” Neurobiology
Considerations in the 1970s about Hebbian plas-
ticity in the developing visual cortex inspired
the BCM model. Hebbian plasticity introduced
an immediate problem, a Kuhnian “puzzle,” the
need for depressive plasticity at potentiated syn-
apses to prevent runaway cycles of potentiation.
Mark Bear’s laboratory was prominent in con-
firming LTD as a neurobiological phenomenon
and revealing its mechanisms, and they stressed
the theoretical BCM model’s guidance for their
groundbreaking experimental work. Dudek and
Bear (1993), who first reported homosynaptic LTD
in the hippocampus, began by describing the BCM
model and its shifting modification threshold, and
reported that they had “tested this theoretical pre-
diction in the Schaffer collateral-CA1 pathway in
rat hippocampus slices.” Dudek and Bear (1993)
compared their findings “with the theoretical form
of modification that inspired it.” There was no
anomaly, and no crisis ensued from recognizing
this limitation on strictly Hebbian plasticity, and in
this episode a central component of the paradigm,
LTP, got incorporated as the complementary bi-
directional process alongside LTD. These aspects
all reflect Kuhnian normal rather than revolution-
ary science. Kuhn emphasized the importance of
normal science for scientific progress; it was in no
way a pejorative label for him. The BCM model is
an example in neurobiology that developments in
normal science can have significant implications
to our understanding of synaptic plasticity, and for
basic and translational neuroscience those were
indeed revolutionary.
Instead of new research tools qua physical
devices driving the discovery of LTD, new elec-
trophysiological stimulation procedures were
key. Stanton and Sejnowski (1989), who first
reported associative LTD in hippocampus slices
(where LTP induced in some synapses produces
depression in others), achieved their results by
focusing on a “new stimulus variable,” the time
interval between bursts, to deliver “in-phase” and
“out-of-phase” test inputs to slices. A low fre-
quency test input that was negatively correlated
with a high frequency conditioning input reli-
ably generated LTD, as did activating presynap-
tic terminals while the postsynaptic terminal was
hyperpolarized, although replicating associative
LTD across laboratories proved “experimentally
elusive” (Bear and Malenka, 1994). The more
reliable and reproducible experimental findings
of Bear and colleagues also resulted from a new
stimulation procedure, the use of several hundred
stimuli delivered at low frequencies (1 to 3Hz).
The depressive effect of this novel conditioning
stimulus was specific to synapses receiving it
(hence “homosynaptic” LTD) and depended on
frequency of the stimulation, as the same number
501
of pulses had no effect when presented at 10 Hz
and produced LTP when presented at 60 Hz. And
the LTD induced by this new stimulation proce-
dure was reversibly blocked by NMDAR antago-
nists, suggesting that the same basic mechanisms
were at work in both LTP and LTD induction,
namely postsynaptic Ca2+ influx through acti-
vated NMDARs, only at different rates to initiate
different second messenger effects (cf. Bear and
Malenka, 1994). This too is normal science: the
novel use of conventional research tools to exam-
ine a feature of plasticity known to be necessary
under the Hebbian paradigm (Hebb, 1949).
Many aspects of normal science associated with
metaplastic changes present challenges for future
research. Metaplasticity has obvious implications
for our understanding of learning and memory
beyond traditional Hebbian views that see suprath-
reshold stimuli acting as a switch that evokes a
learning-evoked change, to a focus on understand-
ing the state-dependent metaplastic influences
involved in processing these inputs. This may, for
example, account for the variability between stud-
ies that has dogged the LTP field and generated
controversy over the mechanisms (e.g., presynap-
tic or postsynaptic locus for maintenance) that led
to the complaint that those outside were “mock-
ing” the field (Nicoll 2017). State-dependency
that evokes these metaplastic changes could offer
a solution (suggested early in the pre- versus post-
synaptic debate; Edwards 1995). Understanding
these metaplastic phenomena will require know-
ing the molecular and cellular changes that under-
lie state-dependent influences, which can be
examined using conventional molecular and elec-
trophysiological or imaging approaches in isolated
tissue (e.g., hippocampal slices). Knowing why
these effects occur will require a link to system-
level effects (e.g., circadian or other intrinsic
mechanisms) and behavior (how activity or sen-
sory inputs evoke changes). This will necessitate
approaches that allow us to link behavioral effects
to molecular and cellular changes, which is now
the major question facing neuroscience.
While research into metaplasticity has been
ongoing now for three decades, its mechanisms of
action still remain poorly understood. Given the
focus on translations based on claimed understand-
ing of memory, either in the context of educational
approaches or through more direct pharmacologi-
cal interventions (cognitive enhancement), insight
into state-dependent metaplastic factors that influ-
ence these changes is essential to ensure that
interventions are efficacious and safe. Misguided
educational policies have adversely impacted on
generations of schoolchildren, but potential dan-
gers of pharmacological interventions that claim
“enhancement” based on unknown mechanisms
502 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
of action are far greater, given the modest ben-
efits that result from these invasive approaches.
Remarkably, Bostrom and Sandberg (2009) have
claimed that cognitive enhancement could solve
societal problems by making people “smarter,
wiser, or more creative,” and that “the societal
benefits of effective cognitive enhancement may
even turn out to be so large and unequivocal that
it would be Pareto optimal to subsidize enhance-
ment for the poor just as the state now subsidizes
education.” Taking breaks or a nap significantly
improves cognitive performance (Sievertsen
et al., 2016; Smith-Coggins et al., 2006), so might
we investigate whether an organizational (i.e.,
allowing such breaks or naps) rather than a phar-
macological approach affords better cognitive
performance outcomes?
INTRACELLULAR RECORDING
Intracellular recording has been a keystone of
electrophysiology for decades. It allows measure-
ment and control of the voltage or current across a
cell membrane, typically using a glass micropi-
pette pulled to a fine tip and placed through (or for
patch clamping, sealed onto) the membrane.
While extracellular electrodes can record action
potentials, they cannot easily monitor subthresh-
old events and membrane properties. Few today
might judge intracellular recording as revolution-
ary science, but it should be more widely appreci-
ated as one of the major technical advances in the
history of neuroscience (Bretag, 1983). In this
section we will sketch the historical development
of these techniques and make the case for this
extended episode counting as a revolution in
wetlab neuroscience.
Electrophysiology arguably dates back to the
end of the eighteenth century and Luigi Galvani’s
demonstration of “animal electricity” in the frog
leg. Over the first half of the nineteenth century,
animal electricity replaced the previous view of
animal spirits; constituting an incommensurate
paradigm shift characteristic of a genuine Kuhnian
scientific revolution (Parker, 2018). For the next
several decades nervous system activity was
investigated using extracellular recordings by,
among others, Helmhotz, du Bois-Reymond and
Bernstein. Animal electricity has been described
as “the single most important discovery in the
exploration of nervous mechanisms” (Brazier,
1964).
The development of intracellular record-
ing techniques passed through several stages of
advances and false starts, as expected for any novel
technique that proves useful. A popular belief is
that sharp glass micropipettes were introduced by
Ralph Gerard and his students Judith Graham and
Gilbert Ling in the 1940s (Graham and Gerard,
1946; Ling and Gerard, 1949). But micropipettes
had been used throughout the 1920s and 1930s,
with technology introduced at the start of the
twentieth century by Marshall Barber (Chambers,
1918; Bretag, 2017). Barber had improved cell
manipulation approaches used by nineteenth-cen-
tury embryologists and applied them to bacteriol-
ogy, making micropipettes to isolate a bacterium
for injection into an animal. His techniques for
microinjection and nuclear transfer remain in use
today (Korzh and Strahle, 2002). While the new
micropipettes were not used originally for electro-
physiology, several of the people responsible for
this further development and application learned
about them directly from Barber (Bretag, 2017).
Initial electrophysiological approaches using
Barber’s micropipettes began with the work of
Frederick Pratt in 1917 and Ida Henrietta Hyde in
1921 (Bretag, 2017). They used glass pipettes to
apply graded extracellular electrical stimulation
to frog muscle and to protozoa Vorticella, respec-
tively. Pratt claimed that an even narrower capil-
lary pipette would enable application of chemicals
to a restricted area of a cell’s surface, a technique
that later came to be developed as iontophoresis.
Initial attempts at measuring cellular potentials
began in the early 1920s. This required advances
in micropipette manufacture and also in associated
equipment. Tibor Péterfi developed a microman-
ipulator to guide precise movements of micropi-
pettes that was manufactured commercially by Carl
Zeiss, and Robert Chambers developed a widely
used micromanipulator that was manufactured
commercially by Leitz (Bretag, 2017). Electronic
recording and amplification also advanced at this
time (Gasser and Newcomer, 1921). The string
galvanometer had been a staple recording device
since the early nineteenth century, but its iner-
tia severely limited recording of rapid signals. It
was replaced in this period by technology based
on the cathode ray oscillograph invented by Karl
Ferdinand Braun, modified to give the sensitivity
and speed needed to display small voltage signals
(Bretag, 2017). These advances were essential for
development of intracellular recordings, and on
their own allowed new aspects of cellular activity
to be detected, including the Nobel prize winning
work by Erlanger et al. (1924) on the composition
of the peripheral nerve compound extracellular
action potential.
These developments triggered rapid advances.
Florey (1966) claimed that by 1925 Péterfi was
using fine-tipped micropipette electrodes to
measure small membrane potentials in Amoeba.
 Revolutions in “Wet” Neurobiology
Taylor and Whitaker (1926) described small and
variable membrane potentials in sea urchin eggs
and highlighted the need for better micropipettes.
In 1927 they developed what would become the
standard intracellular glass micropipette electrode
filled with saturated potassium chloride (KCl)
to reduce the electrode resistance, connected to
electrical circuits with nonpolarizable silver chlo-
ride (Ag/AgCl2) junctions. Péterfi’s technique
of hand-pulling glass micropipettes was subse-
quently improved by Gicklhorn and by Umrath.
The resulting sharp-tipped capillary glass micro-
pipettes allowed reliable intracellular potentials to
be first measured in plant cells in the late 1920s
and early 1930s (cf. Bretag 2017). The first pub-
lished account of intracellular recordings from
animal cells seems to have been by Hogg et al.
(1934) from embryonic rat heart cells in tissue
culture (Hoyle, 1983).
After the plant cell studies, the introduction of
another new research tool, the squid giant axon,
initiated the next major advances in neurophysi-
ology. It was identified as an axon, not a blood
vessel, by Young (1936). Soon after, Kenneth
Cole and Howard Curtis switched from working
on algae to the squid giant axon (Cole and Curtis,
1939), and Alan Hodgkin switched from extra-
cellular recordings from frog and crab periph-
eral nerve fibres to the squid giant axon (Huxley,
2002). The large diameter (up to 1000μm) of the
axon meant that micropipettes were not needed,
as intracellular glass cannulae of about 100μm
diameter could be inserted longitudinally down
the axon without damage to the fiber (although
the resting potential was more depolarized than
that measured later with less invasive micropipette
techniques; Brown, 2019). This, together with the
availability of relatively drift-free DC amplifiers
with sufficiently high input impedances and fre-
quency responses, and cathode ray oscilloscopes,
allowed analyses of the action potential and its
propagation (Cole and Curtis, 1939; Huxley,
2002). Importantly, these recordings showed that
that the action potential overshot zero millivolts.
Earlier suggestions of this overshoot in embry-
onic rat cardiac myocytes and frog skeletal muscle
fibres had been considered experimental artefacts
(Cole, 1968), the prevailing view being that dur-
ing an action potential the membrane potential
decayed to zero due to a temporary breakdown
of the membrane resistance that made the mem-
brane permeable to all ions. Work with these more
sophisticated electronic devices and the squid
giant axon quickly showed that the overshooting
action potential reflected a selective increase in
sodium permeability (Hodgkin and Katz, 1949),
contradicting earlier claims (also using intracellu-
lar recordings) by Curtis and Cole (1942).
503
The rapid (sub-millisecond) membrane current-
voltage properties that were responsible for the
action potential still could not be measured using
the available techniques, which led to develop-
ment of the voltage clamp (Cole, 1949; Marmont,
1949). Hodgkin and Huxley modified Cole’s and
Marmont’s original design into a two-electrode
set-up, one to record voltage and one to supply
current via a feedback circuit to “clamp” the mem-
brane of the squid giant axon at the desired volt-
age. Four publications that appeared in the Journal
of Physiology in 1952, the first with Bernard Katz
as third author, detailed their painstaking wetlab
experimental work. Hodgkin and Huxley used
their physiological data to develop their quan-
titative theory of the action potential based on
voltage-dependent sodium and potassium ionic
currents (Hodgkin and Huxley, 1952).
All of these investigations took advantage of
the large diameter of the squid giant axon, and
thus were not generally applicable to all neurons.
Smaller cells became amenable to intracellular
recordings with micropipette developments made
in the lab of Ralph Gerard. Florey (1966) claimed
that Gerard learned micropipette techniques after
visiting Umrath in 1937 (Bretag, 2017), but Stuart
and Brownstone (2016) claim that Umrath had lit-
tle influence as Gerard didn’t cite the plant cell
research. In 1940 Gerard tasked his Ph.D. student
Judith Graham with improving glass micropi-
pettes.6 They ultimately achieved tip diameters
of 2–5μm and were able to measure resting mem-
brane potentials in frog skeletal muscle (Graham
and Gerard, 1946), although producing “obvi-
ous damage” (Ling and Gerard, 1949). Gilbert
Ling next used a stable heat source to consist-
ently obtain pipettes with tips of less than 0.5μm
diameter, a key step in reducing cell damage and
recording lower and more stable resting potentials.
Nastuk and Hodgkin (1950) used Ling’s tech-
nique for preparing micropipettes to record resting
potentials and action potentials from mammalian
muscle fibres. The latter had not been accom-
plished by Graham and Gerard (1946), or Ling
and Gerard (1949), as in addition to the need for
fine-tipped micropipettes, the task required an
amplifier input stage with an improved frequency
response. A micropipette behaves electrically as
a shunt capacitance with a series resistance that
slows the time constant of the recording system
and distorts rapid signals, resulting in smaller,
prolonged action potentials. Nastuk and Hodgkin
reduced capacitance of the input stage of the
recording system using a lead shield and, as Taylor
and Woodward (1927) had originally done, by
filling their micropipettes with 3M KCl to lower
their resistance. Woodbury (1952) independently
improved the recording of action potentials by
504 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
modifying the input stage to electronically com-
pensate for these effects in his recording of action
potentials from the frog sciatic nerve.
Intracellular recording from vertebrate CNS
neurons was first achieved by John Eccles,
Lawrence Brock, and John Coombs in New
Zealand (Brock et al., 1952), and in parallel by
J. Walter Woodbury and Harry Patton in the US
(Stuart and Brownstone, 2011). Eccles recog-
nized the utility of the tapering tips and small
tip diameters that the Ling and Gerard technique
generated for impaling small spinal neurons, and
in 1951 with Brock and Coombs, he began intra-
cellular recordings in the cat spinal cord. Eccles
was already experienced in extracellular record-
ings of motor neuron responses to stimulation of
dorsal and ventral roots. Intracellular recordings
were not a major departure from these techniques,
but modifications to amplifiers, oscilloscopes,
and stimulators were required. This work aimed
to examine “the mode of origin of the so-called
synaptic potentials” – both “excitatory synaptic
action” and “the mode of action of an inhibitory
impulse” (Brock et al., 1952). These recordings
were instrumental in the ultimate acceptance and
development of chemical neurotransmission in the
CNS (although Eccles was previously a staunch
advocate of the electrical transmission view;
Parker, 2018).
Improvements to achieve sub-μm tip micro-
pipettes and in amplification resulted in a rapid
accumulation of intracellular recordings data,
including from frog muscle fibres (Ling and
Gerard, 1949; Nastuk and Hodgkin, 1950); frog
heart muscle; frog and mammalian nerve fibers
(Woodbury and Woodbury, 1950); mammalian
heart muscle (Draper and Weidmann, 1951); frog
dorsal root ganglion cells (Svaetichin, 1951); and
from the electric organ of the electric ray Torpedo
(Stuart and Brownstone, 2011). Intracellular
recordings were also made in invertebrates, includ-
ing photoreceptors in the Limulus eye; motor
neurons controlling sound production in insects;
neurons innervating stomach muscles in cray-
fish and the Aplysia abdominal ganglion (Stuart
and Brownstone, 2011); sensory neurons of lob-
ster and crayfish (Eyzaguirre and Kuffler, 1955);
and several types of neurons forming the lobster
cardiac ganglion circuit (Hagiwara and Bullock,
1957). Paired recordings from the presynaptic and
postsynaptic neurons in the squid giant axon syn-
apse seem to have first been reported by Hagiwara
and Tasaki (1958), and over subsequent decades
this technique provided insight into chemical syn-
aptic transmission and neuronal interactions in
circuits.
Mechanisms, ranging from those of the action
potential to those of chemical neurotransmission
and neuronal interactions, could be examined
directly using advances in micropipette elec-
trodes. These mechanisms are so fundamental to
our knowledge of the nervous system that they
are taught now to high school/pre-university stu-
dents. Hartline et al. (1952) wrote that the intra-
cellular recording technique “offers great promise
of resolving some of the difficulties that we have
encountered in identifying electrical processes.”
Eyzaguirre and Kuffler (1955) highlighted how
intracellular studies had overturned simplistic
assumptions about the activity of sensory recep-
tors; and Hagiwara and Bullock (1957) empha-
sized that these techniques offered the possibility
to examine subthreshold events and evaluate ele-
mentary processes of neuronal integration. Data
gathered using these new techniques removed
the need for extensive theoretical speculation and
assumptions about aspects of neuronal activities
that couldn’t be tested with extracellular elec-
trodes, and led to explanations of effects that pre-
viously had to be couched in uncertainty (e.g., the
graded relationship between nerve response and
muscle response; Lucas 1909). In summarizing
the squid work up to that point, and with an eye to
the future of cardiac muscle analyses, Cole (1957)
wrote that it offered a “completely new level of
analysis and understanding.” This is familiar ter-
minology about scientific revolutions.
In the early 1950s, glass micropipettes began
to be pulled by mechano-electrical pullers rather
than by hand (Alexander and Nastuk, 1953). These
technological developments yielded micropipettes
with reliable characteristics and specific features
(length, taper, and tip diameter). Subsequent
developments in micropipettes included double-
barreled micropipettes to both record voltage and
inject current (Brock and McIntyre, 1953); the use
of a single electrode for stimulation and record-
ing by using a Wheatstone bridge circuit to allow
current to be passed through the recording micro-
electrode (Araki and Otani, 1955); drug applica-
tion delivered iontophoretically to specific sites
in microscopic quantities using single (Nastuk,
1951) or multi-barreled micro-pipettes (Curtis
and Eccles, 1958); development of new cell stains
for better analysis of the morphology of recorded
cells; development of the discontinuous cur-
rent clamp to allow current injection and voltage
recording through the same electrode (Brennecke
and Lindemann, 1971); single electrode voltage
clamps (Merickel and Gray, 1980); and the patch
clamp to record currents flowing through single
ionchannels by sealing the micropipette tip onto
the surface of the membrane (Neher and Sakmann,
1976; Hamill et al., 1981).7
While some claim that intracellular recordings
cannot tell us much about complex behaviors and
 Revolutions in “Wet” Neurobiology
cognition because these involve cell populations
rather than single cells (although single neuron
activity can reflect behaviorally significant effects
in the mammalian brain; Houweling and Brecht,
2008), intracellular recording has been key to our
mechanistic understanding of the nervous system.
The mechanisms of action potential signaling and
the final acceptance of chemical transmission are
obvious examples. Beyond these, the identifica-
tion of GABA-mediated inhibitory transmission
(Otsuka et al., 1966), electrical synaptic transmis-
sion at gap junctions (Furshpan and Potter 1959),
electrically mediated inhibition (Furshpan and
Furukawa, 1962), and mixed electrical and chemi-
cal synapses (Martin and Pilar, 1963) were all dis-
covered from intracellular recordings. Phenomena
that go beyond single cells have been discov-
ered from the use of intracellular recordings, for
example the demonstrations of lateral inhibition
in the horseshoe crab eye (Hartline et al., 1953);
presynaptic inhibition (Dudel and Kuffler, 1961);
and key features of sensory and other processes,
as well as various functional groupings between
neurons (Getting, 1989). Individual neurons and
synapses form the alphabet of neuronal activities,
the building-blocks or motifs that characterize
neuronal circuit activities underlying not just sen-
sory and motor processes, but also cognitive func-
tions. Neuronal properties determine signals and
are to cognitive representations what letters are
to phonemes and phonemes are to semantics. We
need to understand the syntax, the computations
performed on or by these building-blocks, in order
to understand how representations are generated
and transformed. Intracellular recordings are still
valuable in investigating these processes.
Despite newer techniques like functional
imaging and optogenetics leading some to claim
that “the photon will progressively replace the
electron” (Scanziani and Hauser, 2009), electro-
physiology shows no signs of being replaced in
mainstream wetlab neurobiology, at present or in
the foreseeable future. While imaging and optoge-
netics have obvious advantages in the assaying and
manipulation of populations of cells, a limitation
with the low throughput of electrophysiology, the
resolution of single cellular and synaptic effects
using electrophysiology remains unrivalled.
Examining cellular excitability and the underlying
ionic mechanisms is still best undertaken using
electrophysiology. This is as true today as it was
for the historical analyses of the squid giant axon
by Hodgkin and Huxley (1952). Analyses of sub-
threshold events and inhibition imaging lags far
behind electrophysiology in terms of temporal
resolution and signal to noise ratio. While intra-
cellular recording has been replaced by whole cell
recording to some extent, there are advantages
505
and disadvantages of both approaches, and for
recording from cells deep within tissue, intracel-
lular recording remains the technique of choice.
This will be especially important as we move from
tissue slices to study effects in more intact sys-
tems (e.g., to examine metaplastic interactions).
Appealing to methods that are fashionable or
promoted over others can lead to the “Law of the
Instrument,” where we use tools that may not be
appropriate for all problems and we start to look
for questions to address using the technique rather
than using techniques to address unresolved ques-
tions. Clearly, different tools do different jobs and
should be selected on the basis of the question that
is being asked. At each stage in the century-long
development of intracellular recording devices
and techniques, the limitations of tools and tech-
niques and the need for adaptation has changed,
alongside the questions that these evolving tools
have been used to address.
The revolution in wet neurobiology gener-
ated by intracellular recording capabilities fits
Bickle’s (2016) account of revolutions driven
by tool development. This entire history, which
we’ve only sketched in broad outlines, is a series
of events that match Bickle’s meta-scientifically
derived model. At each stage existing technolo-
gies (or lack thereof, in the earlier stages) created
motivating problems for new tools. Extracellular
recordings couldn’t measure subthreshold volt-
ages effectively; glass micropipette electrodes
with large diameter tips could not measure from
smaller neurons or neuronal processes. Solving
these problems and developing the new elec-
trophysiological tools—microelectrodes, tissue
preparations, micro-drivers, amplifiers, and elec-
tronic recording equipment—required practical
ingenuity and engineering solutions. For scien-
tists involved in the specific research endeavours
in which these tools developed, first-phase hook
experiments confirmed their experimental valid-
ity and utility. The publications reporting these
experiments meet Bickle’s (2016) conditions.
They were typically published in top journals
of the field; they used the target experimental
preparations of research interest (the squid giant
axon, smaller myelinated neurons in mammalian
CNS); and they addressed exactly the phenomena
of then-current research interests. Second-phase
hook experiments brought these tools to the atten-
tion and use of a broader group of researchers,
extending the scope of the tools’ impacts. And
the best-confirmed theories that we now possess
across all of neuroscience—the mechanisms of the
action potential, chemical neurotransmission, and
activities in circuits of neurons—followed from
the development and ingenious uses of these tools
on wetlab benches. ¡Viva la revolución!
506 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Notes
1  We adopt this focus because of our professional
training and interests, Bickle in the philosophy of
cellular and molecular neurobiology, Parker in
neurophysiology.
2  Regarding the prospective use of historical
episodes to guide methodology in ongoing neu-
roscience research – see Bickle (2022).
3  Ramó y Cajal (1928) had written, “In the adult
centers, the nerve paths are something fixed,
ended, and immutable. Everything may die, noth-
ing may be regenerated”; he also added, “It is for
the science of the future to change, if possible,
this harsh decree.”
4  A case can also be made for adult mammalian
neurogenesis being a new research tool-driven
revolution in the sense of Bickle (2016). The tool
Altman and colleagues used, 3H-thymidine, was
introduced into genetic studies in 1957 and first
used in mammals in 1958. BrdU and immunocy-
tochemistry tools were developing alongside their
uses in adult neurogenesis studies.
5  This issue was one of the principal arguments
against neurogenesis (see previous section).
6  Gerard’s interest in the nervous system led to
formation of the “Axonologist group” (Bretag
2017). Hodgkin (1976) remarked that this group
was dominant in physiology, and that they were
skeptical of the membrane theory and local cir-
cuit theory of conduction originally outlined by
plant physiologists (the latter being work that
Hodgkin admired – see Bretag 2017). W.O. Fenn
had stated that, “Axonologists were the impor-
tant people, and almost strutted through the cor-
ridors, being very conscious that they alone were
in the frontiers of physiological discovery” (Mar-
shall 1983).
7  Bickle (2021) discusses some detailed episodes in
the history of development of the patch clamp,
as well as the metal microelectrode to withstand
longer recording sessions.
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Human Brain Project and Beyond
J o r g e F. M e j í a s , K a t r i n A m u n t s , J a n G . B j a a l i e ,
Sander M. Bohté, Alain Destexhe, Lars Muckli,
Pier S. Paolucci, Martin J. Pearson,
and Cyriel M. A. Pennartz
INTRODUCTION
Funded as a European Flagship project under the
program for Future and Emerging Technologies
(FET), the Human Brain Project (HBP) to date
has run from 2013 until 2023. It aims to achieve a
better understanding of how the human brain is
structured and how it functions. Also, it translates
fundamental knowledge about the brain into novel
methods, technology, and medicine to treat brain
disorders. Through a multidisciplinary approach,
it addresses brain structure and function at multi-
ple scales of organization, ranging from the
molecular and cellular levels to the network and
systems-level, culminating in studies on complex
behavior, cognition, and consciousness. Not all of
these can be addressed equally well by research
on human brains, as this is mostly restricted to
post-mortem examination, non-invasive brain
imaging, behavioral testing, and intracranial phys-
iological recordings (e.g., from epileptic patients).
Thus, complementary research on animal models
and in silico research on brain simulations is
required. HBP supports these empirical and mod-
eling approaches with strong theoretical research,
as well as ethical and philosophical reflection
addressing the significance of the research for
society, medicine, and ultimately, the neural basis
of the human mind.
31
A core element is that HBP’s scientific ques-
tions are addressed with the help of a digital
research infrastructure – EBRAINS (European
Brain Research Infrastructure), delivering a range
of computing and data-processing technologies
that can be used by empirical and theoretical
neuroscientists. This chapter focuses on cogni-
tive and systems-level research conducted within
the HBP, and how this is supported by its digital
research infrastructure. In addition, we highlight
differences and commonalities with other large-
scale international brain initiatives, and how these
relate to, and collaborate with, each other. The
key rationale behind the HBP approach is that
advances in understanding brain systems’ func-
tioning and cognition are facilitated by combined
theory-driven empirical research and computer
modeling. This leads to predictions that can be
tested in subsequent cycles of neural measure-
ments, analysis, modeling, and theory. Throughout
this innovative methodology tackling cognition
and systems complexity, the use of computational
tools for data curation, analysis, atlasing, mod-
eling, simulation, hardware implementations and
robotics lies is central. Hence the HBP approach
may be captured as “Computing the Brain.”
In this chapter we focus on a subset of HBP
projects that cohere thematically and illustrate use
of EBRAINS’ computational resources. We begin
512 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
with studies into dynamic states characteristic of
the various phases of wakefulness and sleep that
the human brain passes through in the day-night
cycle. These studies illustrate multiscale research
as the alternation between various sleep and awake
states, expressed at the level of single-neuron
dynamics, local and system-wide networks, inter-
linking with macroscopically manifested changes
such as in behavior. Transition from deep sleep to
wakefulness is marked by a return of our percep-
tual capacity: the ability to process sensory stimuli
originating outside the brain, and transform these
sensory inputs into a consciously experienced sen-
sation of stimuli embedded in a spatiotemporal
context (Pennartz, 2015). Here we emphasize how
empirical, modeling, and theoretical researchers
collaborate to underpin perception as a process
of actively constructing latent representations in
corticothalamic brain systems, involving the con-
textualization of individual sensory inputs and the
simulation of predictive cortical hierarchies.
Next, we show how sensory signals originat-
ing from multiple modalities, such as vision and
touch, can be combined to produce multisensory
integration, and how this capacity can be utilized
for cognitive abilities such as episodic memory
and spatial navigation in space. Departing from
neurophysiological and behavioral findings, this
approach illustrates how robotics – via physical
implementation and in silico simulation – provides
a key instrument to test whether computer models
of multisensory prediction enhance behavioral
performance of artificial agents. With or without
robotics, computer models are becoming increas-
ingly sophisticated, not only in their resemblance
to brain physiology, but also in their representa-
tional and cognitive capacities. The final neurosci-
entific topic we touch on concerns the neural basis
of consciousness. On the one hand, we highlight
consciousness as a particular kind of brain state,
reaching back to the differentiation between sleep
and wakeful state dynamics. On the other hand,
we suggest how the ‘contents’ aspect of con-
sciousness can be addressed: the question of, how
conscious representational content can be realized
in neural substrates, and why complex network
operations can give rise to subjective experience
at all.
Following up on the scientific questions HBP
addresses in Cognitive and Systems Neuroscience,
we summarize how services provided by the
EBRAINS research infrastructure act to sup-
port HBP research. Again, we do not provide an
in-depth overview, but emphasize the toolkits of
primary importance to the neuroscientific topics
covered here. Briefly, we highlight the following
services: (i) storage, curation, and analysis of data
in neuroscientific and clinical domains, applying
FAIR principles (to make data findable, accessi-
ble, interoperable, and reusable); (ii) anatomical
atlases of the human and rodent brain, sup-
porting the mapping of electrophysiological
recordings and imaging onto neural structures;
(iii) simulation engines for building brain and neu-
ral-network models, to study both brain dynamics
and cognitive processing; (iv) the neurorobotics
platform for implementing computation-intensive
robotic simulations, (v) neuromorphic comput-
ing services for emulation of neuronal networks
in brain-like hardware; (vi) high-performance
computing resources, including a European net-
work of computers (FENIX) to support all of
these activities. Finally, we pay attention to other
large-scale brain initiatives, including the BRAIN
initiative in the USA, the Brain/MINDS initiative
in Japan, the Korea Brain Initiative (KBRI), the
China Brain Project, the Canadian Brain Research
Strategy (CBRS), the Australian Brain Alliance,
and others. We also review the efforts to coordi-
nate resources and goals of many brain initiatives
via the International Brain Initiative (IB), and the
importance of international collaboration among
these initiatives to achieve worldwide progress in
data standardization, ethical policies, and accessi-
bility of digital tools to move forward to a more
globalized access to resources for brain research.
SYSTEMS-LEVEL MODELS OF
BRAIN STATES
First, we illustrate HBP’s multiscale approach by
a brief overview of computational models of brain
states, such as wakefulness and slow-wave sleep.
Pioneering experiments (Massimini et al., 2005)
have demonstrated that the same stimulus, deliv-
ered to the same brain in different states, can lead
to very different responses. These experiments not
only showed that the response to a given stimulus
is “state-dependent,” but it was also found that in
the awake – but not sleeping brain, the response
spreads in the whole brain according to complex
propagation patterns. The complexity of the
spread of this evoked response is thought to be a
measure of the consciousness level of the
individual.
In parallel, progress in micro-electrode tech-
niques, have enabled the recording of unit activity
in the human brain with unprecedented precision.
Human multi-electrode recordings showed that
“regular-spiking” (RS) cells and “fast-spiking”
(FS) cells can be discriminated (putative pyrami-
dal cells and interneurons, respectively Dehghani
et al., 2016; Peyrache et al., 2012). The high
 Human Brain Project and Beyond
density of the recordings allowed us to demon-
strate that many of the RS cells are excitatory,
while many FS cells are inhibitory (Peyrache
et al., 2012). These data provided, for the first
time, the possibility of characterizing excitatory
and inhibitory populations in humans, during
wake and sleep states, as well as during epilep-
tic seizures (Dehghani et al., 2016). Such data are
invaluable for building computational models.
Motivated by these experiments, we next inves-
tigated models of spiking networks composed
of RS and FS cells. The simplest model display-
ing RS and FS cells is the Adaptive Exponential
(AdEx) integrate-and-fire model (Brette and
Gerstner, 2005). We studied AdEx networks of
RS and FS cells, and determined their firing
characteristics based on human recordings from
these cell types. Such networks, if endowed with
conductance-based synaptic interactions and
spike-frequency adaptation, can display two typi-
cal network states seen experimentally: asynchro-
nous-irregular (AI) states, in which all cells fire
irregularly, as typically seen in wakefulness, and
Up/Down states, where the dynamics oscillates
between periods of AI-like activity (Up state) and
silent periods (Down state), as seen in slow-wave
sleep in humans (Goldman et al., 2019).
To scale up these spiking network models to
large brain areas, we have conceived population-
level models using mean-field techniques. Here,
our motivation was to describe, as realistically
as possible, the dynamics of RS-FS populations,
and obtain mean-field models representing one
small brain area (e.g., a cortical column). A large
number of mean-field units can then be con-
nected according to the structure of large-scale
networks, up to the whole brain (Goldman et al.,
2020, 2022). Because it is important that such
mean-field models capture the dynamics of spik-
ing networks, we needed to use a formalism that
allowed us to consider conductance-based synap-
tic interactions. We have used a Master Equation
formalism (El Boustani and Destexhe, 2009) with
which conductance-based mean-field models are
possible. Adapting this formalism to AdEx net-
works (Zerlaut et al., 2018) and later including
spike-frequency adaptation (di Volo et al., 2019)
yielded mean-field models that can reproduce the
dynamics of AI states and Up/Down states as seen
in the spiking networks. This “Adaptive mean-
field” model was able to simulate, at the popula-
tion level, the different states exhibited by AdEx
spiking networks.
An important test of the accuracy of the adap-
tive mean-field was to simulate state-dependent
responsiveness. This was done by considering net-
works in different states, such that the response to
513
the same stimulus was very different in the two
states. The model was able to capture this differ-
ence in responsiveness. It also captured the fine
details of the timecourse of the response, which
was the first time such a level of realism was
obtained for a conductance-based model (di Volo
et al., 2019).
To scale-up the adaptive mean-field model to
simulate large-scale networks, we first studied
the “mesoscale” dynamics of propagating waves
found in the primary visual cortex of the awake
monkey (Muller et al., 2014). These propagating
waves were found across large cortical distances
(several millimeters up to centimeters), and mod-
eling such phenomena at the cellular level would
require simulating millions of neurons. However,
using mean-field models, one can simulate the
visual cortex at the same resolution as imag-
ing studies, where one “pixel” of the camera is
equivalent to hundreds to thousands of neurons,
and create a network of mean-field units. This
network was calibrated using propagating waves.
Because such waves can be quantified in spatial
extent and in propagation speed, it was possible
to constrain the connectivity between the mean-
field units to reproduce the propagating waves as
measured experimentally (Zerlaut et al., 2018). It
was found later that the same mean-field model
was able to capture the interaction between two
propagating waves, and in particular their sub-
linearity (Chemla et al., 2019). Thus, adaptive
mean-field models, if connected appropriately,
account for mesoscale phenomena in the awake
monkey brain. Next, it is integrated at the whole-
brain scale.
The integration of mean-field models at the
whole human brain scale was done recently (and
is still in progress in the HBP). Using The Virtual
Brain simulator in EBRAINS, it is possible to
reconstruct a large network of mean-field units,
connected according to the human connectome,
thus forming a whole-brain model (Sanz-Leon
et al., 2015). The resolution of this network can
be adjusted from a few tens of nodes (where one
mean-field unit represents one brain area), up to
hundreds of thousands of nodes (one mean-field
unit representing the size of a cortical column).
Recent results (Goldman et al., 2020, 2022) show
that integrating the adaptive mean-field model can
yield a whole-brain model reproducing previous
observations (Massimini et al., 2005). Figure 31.1
illustrates the response obtained in two differ-
ent brain states, asynchronous and synchronized
slow-waves with Up/Down states. As in the exper-
iments, the stimulus evokes complex patterns
spreading across the whole brain, but only in the
asynchronous state.
514 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 31.1 Integration of mean-field models to yield whole-brain models of the human
brain.
A. Scheme of integration of mean-field units (nine squares), each representing a population
of neurons, and connected using excitatory and inhibitory connections.
B. Whole-brain model formed by mean-field units (left) connected according to the human
connectome (RS: regular spiking, FS: fast spiking, W: adaptation variable).
C. Whole-brain simulations of response to stimulus in visual cortex (arrow) during slow-wave
dynamics.
D. Same simulation when the simulated brain activity is made asynchronous (wake-like). In
this case, the firing-rate increase evoked by the stimulus is much larger than during slow
waves.
Source: Adapted from Goldman et al., 2020, 2022.

COMPUTATIONAL MODELS OF BRAIN
DYNAMICS AND THEIR RELATIONSHIP
WITH COGNITION
Besides their use to understand brain states,
large-scale (or systems-level) models may be
used to uncover perceptual and cognitive func-
tions in the brain. In the early years of computa-
tional modeling, the field had a strong focus on
‘microscopic’ models of small, homogeneous
neural populations (Amit and Brunel, 1997;
Hopfield, 1982; Wilson and Cowan, 1972). The
extension to computational models describing the
dynamics of brain activity at larger spatial scales,
or even at the whole-brain level, occurred after
the popularization of neuroimaging techniques,
as researchers started to use structural connec-
tomes as a basis for computational models to
simulate human brain dynamics (Deco et al.,
2008, 2011; Friston et al., 2003). More recently,
large initiatives such as the Human Brain Project,
the Human Connectome Project and the Allen
Institute for Brain Science facilitated to extend
 Human Brain Project and Beyond
the focus on large-scale modeling to other species
such as rodents (Foster et al., 2021; Gămănuţ
et al., 2018; Knox et al., 2018) and nonhuman
primates (Markov et al., 2013, 2014), and to
include further biophysical details in the models.
With large amounts of curated data becoming
available in the HBP (and importantly, following
open access guidelines), researchers have started
to constrain their models with data more often,
leading to a new generation of models which are
more accurate and provide descriptions which are
closer to the real brain. Computational models
constrained by data at different scales have been
able to explain observed neural dynamics across
multiple spatial and temporal levels of descrip-
tion. For example, computational models of the
macaque cortical network have been constrained
using tract-tracing connectivity data which con-
tains information about the cortical layers involved
in each long-range projection between area-to-
area pairs (Chaudhuri et al., 2015; Jaramillo et al.,
2019; Joglekar et al., 2018; Mejías and Wang,
2022; Mejías et al., 2016). When such level of
biological detail is considered, the resulting model
reproduces neural activity at the intra-laminar
level (e.g., enhancement of gamma rhythms by
visual input), inter-laminar level (power-phase
coupling between gamma and alpha rhythms
across layers), inter-areal level (gamma and alpha
rhythms mediating feedforward and feedback
interactions), and large-scale level (emergence of
so-called functional hierarchies, or hierarchical
relationships in the activity patterns of brain areas
(Mejías et al., 2016)). Similar data-constrained
models of macaque networks have shed light on
previously unrecognized problems in our classi-
cal understanding of large-scale communication
(Chaudhuri et al., 2015; Joglekar et al., 2018) and
pointed toward a proper balance between excita-
tion and inhibition as the key factor to achieve
an optimal communication across distant brain
regions, for example during conscious perception.
In other animal models, data-constrained models
of the mouse brain have been able to reproduce
and explain multiple neural signatures linked
to visual perception and processing, providing
insights in fundamental mechanisms of visual
processing and brain communication, such as the
emergence of orientation selectivity and other vis-
ual computations (Billeh et al., 2020; Knox et al.,
2018; Lindeman et al., 2021).
There are, however, important milestones
which data-constrained models of large-scale
brain networks still need to reach. Most notably,
large-scale models have been primarily focused
on neural dynamics and electrophysiological
signatures, with contributions to cognitive func-
tions being descriptive and qualitative rather than
515
mechanistic. In contrast, models of small neural
circuits or local brain regions have traditionally
provided a very useful way to test and explore
neural mechanisms underlying cognition, includ-
ing functions like perception, working mem-
ory and decision making (Compte et al., 2000;
Meijer et al., 2020; Wang, 1999, 2002; Wong and
Wang, 2006). New modeling work combining the
description of accurate large-scale neural dynam-
ics with cognitive functionalities has only started
to emerge. For example, data-constrained models
of large-scale cortical networks have been recently
used to explain the emergence of working mem-
ory-related patterns of persistent activity across
the cortex (Mejías and Wang, 2022). Rather than
a simple extension, this work predicted the exist-
ence of a gradient of ‘counterstream inhibition’
along the cortical hierarchy, a prediction compat-
ible with predictive coding architectures.
More complex cognitive and perceptual func-
tions are still missing a large-scale modeling
description properly rooted in experimental data.
Recent work within the Human Brain Project is
advancing in the exploration of such questions.
For example, the challenge of combining realistic
neural dynamics with informative cognitive archi-
tectures in a common theoretical framework can be
achieved by developing multiple models in parallel.
Each model may have a different balance between
cognitive capacities and biophysical plausibil-
ity, and keeping these models coherent with each
other would ensure that they remain in a similar
theoretical framework despite differences in imple-
mentation. A promising example is a suite of neu-
robiologically realistic models of predictive coding,
for which models combining cognitive capabilities
with biophysically realistic aspects are currently in
development (Dora et al., 2021). We are construct-
ing, in parallel, predictive coding models based on
neurophysiologically detailed spiking networks (to
reproduce biophysical signatures of predictive cod-
ing) and models based on more abstract networks
and rate dynamics (but with greater capacity for
complex cognitive computations). Such models
constitute a common ground to study further per-
ceptual functionalities, such as multisensory inte-
gration and conscious perception.
PERCEPTION, CONTEXTUALIZATION, AND
ALIGNMENT IN HUMAN BRAIN MAPPING
Progress in large-scale modeling of cognition and
perception depends on its interaction with empiri-
cal data acquisition in both human and animal
models. This is illustrated next by the
516 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
contextualization of sensory processing. Human
cognition rests upon the association of our ongo-
ing mental activity with our subjective perceptions
of sensory inputs. Large scale cortical circuitry
reflects this synergy in densely interconnected
processing streams sending information to and
from our sensory brain areas, and between dedi-
cated functional areas. In these streams, neuronal
mechanisms and computations must provide spa-
tiotemporal context to the incoming stream of
sensory information, with precisely tuned levels
of conscious awareness, and while undergoing
shifts in neuromodulatory states. Increasing
empirical evidence from rodent recordings shows
that pyramidal cortical neurons have two function-
ally separate computational compartments
(Larkum, 2013). This knowledge motivates inves-
tigations at larger spatial scales, using multiscale
biological data across humans, monkeys and
rodents to understand the neuronal principles
underlying this contextualization. Along this theo-
retical theme, advances in human brain imaging
technologies and the opportunity to constrain
neuronal data with models and machine learning
approaches is driving a more mechanistic under-
standing of neuronal information processing
underlying human cognitive function, at the same
time delivering innovative testable hypotheses for
systems neuroscience (Phillips, 2017).
At psychological levels of description, count-
less examples can be found of how our brains use
context to fulfill behavioural goals (Bar, 2004).
Take, in visual perception for example, the simple
act of grasping a cup (Figure 31.2). Your hand cov-
ers part of the cup, but we can readily understand
this image; we see discontinued contours of the
cup as part of the larger context, and we under-
stand that shadows cast neither belong to the hand
nor to the mug. Our brains make hundreds of such
inferences every day, and now we are beginning
to understand the neuronal operations that allow
for these contextual computations (Phillips et al.,
2015). A compelling neurobiological description
of contextual processing that is emerging entails
two integration sites in pyramidal neurons, one
at the soma, processing driving inputs, and one
in the apical tuft dendrites computing contextual
modulatory signals. These two sites are computa-
tionally distinct and both sites together determine
a neuron’s output. One operation of the input to
the apical integration site is to amplify the neu-
ron’s response to its driving input in a context-
dependent manner, where context refers to activity
in other brain areas (Phillips, 2017).
One empirical approach for testing contextual
cortical processing utilizes a simple retinotopic
principle. Sensory visual information is processed
topographically by retinotopically organized
maps of neurons responding to the visual field.
A series of interconnected visual areas have dif-
ferent response criteria, for example, in higher
cortical areas, receptive fields process a larger
space in the visual field (Wandell et al., 2007).
When these higher areas project top-down to
earlier levels in the cortical hierarchy, the spread-
ing out of neuronal projections reaches a wider
field than the small, locally tuned receptive fields
selective for feedforward sensory inputs. In these
“feedback receptive fields,” we can read out the
top-down contextual information. In instances of
visual occlusion, there is no feedforward stimula-
tion, offering insight into how the brain infers its
inputs using contextual guesses that influence vis-
ual information processing (Muckli et al., 2015).
We study the spatial specificity and information
content of this top-down contextual information
flow in humans using functional brain imaging
(Morgan et al., 2019; Revina et al., 2018), and
its dynamics in animal models at different spatial
and temporal scales. We can align the cortical net-
works of these vastly different sizes of brains in
humans, monkeys and rodents by aligning them
to a shared functional coordinate system based on
a retinotopic grid system. We can then draw com-
parisons between species on a functionally aligned
reference system and establish the content of top-
down communication, the layer-specific neuronal
compartments and implementation of contextual
computations, all of which we can then extract to
inspire neuronal network models.
SPIKING NEURAL NETWORK MODELS OF
PERCEPTION AND PREDICTION
Thus far we have mainly surveyed large-scale
dynamic models of the brain, but these were
specified at a mean-field level, leaving open the
question how models may be extended to spiking
neural networks that perform perceptual and cog-
nitive tasks. Deep artificial neural networks have
made great strides both in AI and as models of
visual perception in the brain (Güçlü and Gerven,
2015; Kriegeskorte, 2015): activations in a trained
deep feedforward neural network map better to
brain measures as compared to hand-crafted
models (Kriegeskorte, 2015). Moreover, neural
networks that include types of recurrency
(Kubilius et al., 2018) are able to explain certain
response dynamics in the ventral visual stream.
Still, artificial neural networks are at best bio-
inspired, and there is much debate regarding the
degree to which current successes relate to the
functioning in the brain (Jacob et al., 2021).
 Human Brain Project and Beyond 517

Figure 31.2 The brain uses top-down knowledge to make inferences about noisy or incom-
plete bottom-up sensory inputs, such as when objects are occluded.
Both information streams combine in individual pyramidal neurons with cell bodies in corti-
cal layer 5. Feedforward sensory inputs arrive to basal dendrites at the somatic region, and
feedback inputs arrive to the tuft dendrites in layer 1 and contextualise transmission of
information in the feedforward stream. Contextual inputs to superficial layers in human pri-
mary visual cortex can be studied using ultra high-resolution fMRI that offers a spatial scale
to approximately resolve cortical layers and columns.
Source: From Muckli et al., 2015.

At a lower level, artificial neurons are abstract
models as compared to biological neurons, also
in manners that ignore aspects that many argue
are integral to the functioning of the brain. This
includes in particular (i) the fact that biological
neurons communicate via spikes (Figure 31.3),
(ii) the spatial extent of biological neurons; and
(iii) the diversity of influences mediated by vari-
ous neurotransmitters. For instance, the spatial
extent of pyramidal neurons combined with the
selective targeting of feedback connections is
suggested to play a key role in the generation of
consciousness.
The pulsed nature of communication between
biological, spiking neurons contrasts with the
standard “rate-based” abstraction of neuronal com-
munication in artificial neurons, where the rate-
coding paradigm is typically presumed to model a
form of population coding (i.e., the instantaneous
activity in a group of neurons can be read out as
an approximately real-valued activation value by
downstream neurons; Gerstner and Kistler, 2002).
However, the sparse and event-based activation
of spiking neurons allows much richer dynamics.
The exact timing of the pulse can communicate
more information, expressed as bits per spike,
compared to rate-coding models (Nemenman
et al., 2004). The timing of individual spikes may
enable the multiplexing of selective informa-
tion streams between brain areas (Fries, 2005;
Singer and Gray, 1995), and complex spike pat-
terns like bursts and complex spikes in cerebellum
have been suggested as multiplexing learning
signals and representational information (Payeur
et al., 2021; Shadmehr, 2018). In applications
like computer vision, latency coding, where the
relative timing of spikes encodes analogue val-
ues, has been demonstrated to enable the map-
ping of deep neural networks to equally powerful
deep spiking neural networks (Stöckl and Maass,
2021; Tavanaei et al., 2019). When spike timing is
regulated relative to network oscillations such as
theta and gamma rhythms, phasic coding can be
deployed as a mechanism of information transmis-
sion, complementary to firing-rate coding (Huxter
et al., 2003; Pennartz, 2009; Siegel et al., 2009).
Rate-coding by single spiking neurons can be
implemented by considering not the spikes but the
effect of spikes on the membrane potential, like the
resultant postsynaptic potential (PSP). Although
the postsynaptic response of an impinging spike
can be highly diverse, as the neurotransmitter
released may elicit activate multiple receptor sub-
types and involve multiple synapses, in simplified
spiking neuron models like the leaky-integrate-
and-fire neuron the effect of impinging spikes is
typically reduced to the weighted inhibitory and
excitatory responses to the neuron’s membrane
potential, in the form of postsynaptic potentials.
Thus, interpreting neural activations enables
the conversion of deep artificial neural networks
to deep spiking neural networks (Rueckauer et al.,
2017; Zambrano et al., 2019), and to powerful
approximate supervised learning methods like
518 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 31.3 Biological neurons communicate via spikes.

(a) In simplified spiking neuron models, a spike traveling from one neuron to another
contributes a change in the target’s membrane potential in the form of a weighted
(with weight wij) inhibitory (negative) or excitatory (positive) postsynaptic potential (PSP),
denoted by a kernel ε(t).
(b) Schematic model of a simplified spiking neuron: impinging spikes at times ti cause
(weighted) postsynaptic potentials ε(t) that are added linearly to the membrane potential
u(t). A non-linear function f(u(t)) then determines when the target neuron emits a spike (tj)
that then influences downstream neurons k through synaptic weight wjk.
(c) In a simple model, f(u(t)) is determined by a threshold ϑ where a spike is emitted at time
tj when the potential induced by the sum of PSPs crosses the threshold from below. A refrac-
tory response is then subtracted from the membrane potential to reset the state of the
spiking neuron.

surrogate gradient learning (Bohte, 2011; Neftci
et al., 2019). Surrogate gradient approaches to
supervised learning have resulted in competitive
recurrent spiking neural networks for temporal
tasks like ECG-wave and gesture recognition
(Yin et al., 2020), while also allowing investi-
gations into neural circuit dynamics (Keijser
and Sprekeler, 2020; Perez-Nieves et al., 2021).
Biologically plausible reinforcement learning
can furthermore train spiking neural networks
on and cognitive tasks like forced-alternative-
choice (Frémaux et al., 2013; Karamanis et al.,
2018). Together, these studies demonstrate the
computational power of single spiking neurons
as units of neural computation, where spiking
neural networks map to corresponding biological
structures.
A different interpretation of the effect of spikes
on target neurons focuses on the particular shape
of the typical postsynaptic potential, characterized
by a rise and fall time. Effectively, an impinging
spike will affect the membrane potential at the
target neuron in a characteristic manner. Various
studies suggest that this time-course can be inter-
preted as a form of temporal prediction, either in
populations of neurons encoding time-varying
variables (Boerlin and Denève, 2011), or com-
bined with synaptic short-term plasticity (Pfister
et al., 2010).
Predictive coding posits that the brain con-
stantly generates predictions of sensory input
and adjusts its internal model of the environment
based on discrepancies between predictions and
actual input (Dayan et al., 1995; Rao and Ballard,
1999). In such models, deeper layers generate
increasingly abstract top-down hypotheses about
states of the environment, which is compared
against bottom-up input; the observed errors then
influence higher-layers to adjust their hypothesis
such that these errors are minimized.
 Human Brain Project and Beyond
That real neurons are spiking neurons is an
obvious but mostly ignored constraint on pre-
dictive coding models. Not only do inter-neural
connections have to follow Dale’s law (that is,
neurons release the same type of neuro-transmit-
ters to all their respective targets); such networks
also have to operate in a time-continuous man-
ner, where neural state progresses following the
dynamical spiking neuron equations, and with
inherent non-linear responses. At present, these
issues are still open problems, with neurobiologi-
cally realistic models of predictive coding still
defined in rate-based standard artificial neural
networks (Dora et al., 2021). The energy cost of
computational simulations is such that dedicated
hardware in the form of neuromorphic chips,
like BrainScales and SpiNNaker, are crucial for
sustainable scaling to network sizes relevant for
studying learning in large-scale brain structures.
Thus, developing effective and trainable net-
works of spiking neurons is an important step in
increasing our understanding of how the brain
generates perception and cognition at a mecha-
nistic level, forcing researchers to explicitly con-
sider aspects like temporal dynamics and time
scales while at the same time adhering to biologi-
cal constraints like Dale’s law. Recent develop-
ments in learning paradigms have now opened up
novel venues for study, enabling function-guided
approaches that extend beyond hand-crafted
neural circuit models both in realism and in func-
tionality (Zenke et al., 2021).
MULTISENSORY INTEGRATION AND
SPATIAL NAVIGATION, FROM BRAIN
TO ROBOTICS
Whether models are spike-based or not, eventu-
ally their practical effectiveness must meet the
constraints of physical embodiment and environ-
mental ecology. Efforts for bridging models to
embodied agents such as robots are illustrated
here for multisensory integration and spatial navi-
gation. Most animals have the ability to recall
places that they have previously visited to navi-
gate their environment efficiently in their hunt for
food and to find their way safely home. The neural
mechanisms that underlie this ability in mammals
have been extensively investigated with much
research focused on place, motion, head direction,
and boundary sensitive cells (Hafting et al., 2005).
These findings have inspired many computational
models to emulate how these cells respond and
interact in response to simulated or physical
519
agents moving through the world (Bermudez-
Contreras et al., 2020; Byrne et al., 2007). For
robotics the problem of autonomously operating
within novel environments is also an area of
extensive research with examples of interdiscipli-
nary work generating useful insights (Milford and
Wyeth, 2008).
The central problem of navigation is how to
combine information from noisy and intermittent
sensory observations to inform a useful estimate
of place and orientation within the environment,
often referred to as pose in robotics. A distinc-
tion is made between allothetic and idiothetic
sensory cues. “Allothetic” refers to external glob-
ally anchored landmarks; idiothetic refers to those
describing the motion of the animal or robot. For
example, the vestibular system in mammals is
an ever-present source of idiothetic information,
however, it cannot be relied upon for long peri-
ods of time due to accumulative error through
integration. Similarly, the integration of odometry
or inertial measurements of self-motion in robots
suffers from drift. This error can be reduced by
calibrating against allothetic sensory cues that
are anchored to the environment, however, these
are less frequently available and are also subject
to aliasing and other forms of perceptual uncer-
tainty. Such perceptual uncertainty can be reduced
through the integration of information from dif-
ferent sensory modalities, so called sensor fusion
in robotics (Khaleghi et al., 2013). However, the
problem still remains that associating allothetic
sensory cues to places implied through the inte-
gration of noisy idiothetic cues will lead to an
ever-increasing mismatch between an agent’s
perceived location and its ground truth pose. In
robotics this problem has been addressed by incor-
porating mechanisms that recognize and exploit
loop-closure events, in other words, recalling that
the robot is currently in a place that it has visited
in the past when it was less uncertain of its pose.
This prior can then be used to correct for accumu-
lative errors in current self-estimate of pose and
the corresponding relationships associated to other
allothetic cues observed from the start of the loop
(Durrant-Whyte and Bailey, 2006). This iterative
process of exploration and consolidation builds
toward a stable representation of the environment
that can be used to compensate for idiothetic cue
drift and, ultimately, used for route planning and
goal directed behaviour.
In biology, recordings from place cells in rats that
are moved between familiar environments show
that stable representations are maintained between
distinct environments (Alme et al., 2014). This cor-
relation between ensemble place cell activity and
previously explored environments implies that
they maintain a trace memory of spatial contexts.
520 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
How these memories are formed through the con-
solidation of multisensory experience has not been
explicitly identified, however, in the Human Brain
Project we have been exploring the idea of episodic
memory formation through a process of predictive
sensory reconstruction. We have collected multi-
sensory data sets (visual-tactile) sampled from a
biomimetic, whiskered mobile robot “WhiskEye”
as it moves through and interacts with a bounded
environment. These data sets have been used to
train a multisensory deep predictive coding network
we have called MultiPredNet (Pearson et al., 2021)
inspired by work referred to above. The activity of
the multisensory top layer in the network drives pre-
dictions of the activity in lower levels (i.e., toward
the sensory input). These top-down predictions are
compared to the bottom-up activity between layers
(originating from the ground truth sensory input)
and used to modify network weights to give better
predictions in the future. We have found that pre-
dictions can be inferred from one modality in the
absence of another (i.e., we can reconstruct a visual
impression of the view through the presentation
of only touch). This implies that information from
visual cues have been associated with tactile cues
within the multisensory latent representation space.
This approach is interesting to both neurosci-
ence and to robotics for three reasons; firstly, local
Hebbian like learning rules applied in parallel
throughout this network model has a greater affin-
ity to biological neuronal learning mechanisms.
Secondly, information from the two disparate sen-
sory modalities have been associated without any
handcrafted intervention (i.e., this is a model-free
learning approach to sensor fusion). Finally, the
observation that the form of the joint latent repre-
sentation space of the trained network relates to the
actual pose of the robot implies that the network
has formed a rudimentary map of the environment
without explicit reference to conventional refer-
ence frames or metrics. To explore this observa-
tion further we have developed a simulated model
of the WhiskEye for use within the Neurorobotics
platform of EBRAINS such that data sets can be
collected during longer duration experiments not
subject to breakages or battery replacement. This
model is also available as an open-source project
to further encourage open science and collabora-
tion of ideas.
REPRESENTATIONS AND
CONSCIOUSNESS
The subject of consciousness is sufficiently broad
and deep to deserve a chapter in its own right,
hence we can only summarize what is specific
about the HBP approach to this topic, in relation
to the section above. Above we illustrated how
different brain states, including slow-wave sleep
and asynchronous wakeful states can be modeled
by mean-field approaches. This characterization
of brain states is closely linked to the experimen-
tal demonstration of Up and Down states at the
cellular level (Steriade et al., 2001) and has been
linked to the search for a complexity measure of
consciousness.
Following the Integrated Information Theory
of consciousness (Haun et al., 2017; Massimini
et al., 2005; Tononi et al., 2016), it was found that
the Lempel-Ziv complexity of spatiotemporally
unfolding cortical EEG responses elicited by a
transcranial magnetic stimulation (TMS) pulse is
significantly higher in wakeful than slow-wave
sleep states, and this finding was essentially repro-
duced for the anesthetized state (Ferrarelli et al.,
2010). In the HBP, this TMS approach has been
successfully applied to stratify patient groups suf-
fering from Disorders of Consciousness (DoCs)
with different degrees of severity (Casarotto et al.,
2016). Although these findings might be taken to
confirm IIT, caution in the interpretation of results
is in place here, because the TMS results are in line
with a key role of Up and Down states regulating
the spatiotemporal propagation and reverberation
of cortical responses, whereas IIT’s cornerstones
of Information Integration and Differentiation
have been derived from the properties of phe-
nomenal experience, which are not addressed by
the electrophysiological TMS approach (Olcese
et al., 2018).
We have already introduced an alternative, rep-
resentation-oriented way of thinking about con-
sciousness. This approach originates from the idea
that conscious perception reflects a spatiotempo-
rally wide inference on the causes of the sensory
inputs the brain receives continuously (Marcel,
1983; Pennartz, 2015, 2022). All that the brain
receives as fast, discrete inputs informing it about
the state of the environment and the subject’s own
body, comes in the form of action potential trains
along the afferent nerves and pathways from the
spinal cord. For conscious perception to arise,
the brain needs to make sense of these myriads
of spikes trains, which it does by internally con-
structing a model of the world, including the sub-
ject’s body. This line of thinking entails that we
do not consciously experience external reality
directly (in contrast to “Direct Realism,” assuming
that we do experience it directly) but rather a best-
guess representation of reality (even though our
subjective intuition holds that we do seem to expe-
rience the world directly (Lehar, 2003; Pennartz,
2015, 2018).
Computationally, this constructive process is
approached by predictive coding, in which the
 Human Brain Project and Beyond
higher structures (in a sensory cortical hierarchy)
forge predictive representations, which are sent
down to lower structures to produce a compari-
son with bottom-up sensory inputs, resulting in a
prediction error used to improve the inference and
enable the network to learn (Dayan et al., 1995;
Rao and Ballard, 1999). Within the HBP, differ-
ent neural implementations of predictive cod-
ing are pursued, such as those based on different
cell populations encoding representations versus
errors (Dora et al., 2021; Pennartz et al., 2019a) or
on distinct somatodendritic compartments of cor-
tical pyramidal cells having different functions in
bottom-up versus top-down, contextual feedback
(cf. Suzuki and Larkum, 2020).
Likewise, the HBP offers space to develop and
test different theories of how conscious experi-
ence may arise from constructs that are more
complex than the basic implementations of pre-
dictive coding, which are recognized to be insuf-
ficient to explain consciousness on their own.
According to Active Inference theory (Friston
et al., 2020; Hohwy and Seth, 2020), it is particu-
larly the generation of actions that drives predic-
tions on the sensory consequences of movement.
Here, (conscious) perception is considered a
form of belief updating, in which the uncer-
tainty about the causes of sensations is reduced.
Thus, an external object is only consciously seen
when the subject actively looks at it. In contrast,
Neurorepresentationalism (Pennartz, 2015, 2022)
does not assume an essential role for motor action,
but characterizes conscious experience as an
immersive multimodal, situational survey of the
individual’s environment and body state, which
can be built on complex sensory inference alone.
What makes representations ‘conscious’ in this
framework is not such much the activity in senso-
rimotor loops necessarily involving the body, but
rather the upscaling of predictive activity across
the spatial domain (to account for the situational
aspect of conscious experience) and the domain
of multimodal integration (to account for distinct
sense modalities, or “qualia,” which we experi-
ence as being distinct and rich in their totality).
Computational efforts to expand basic predictive
coding models to deep networks and architectures
with more extensive representational scope and
cognitive abilities are ongoing (e.g., Dora et al.,
2021; Mannella et al., 2021).
Importantly, the ethical and philosophical
investigation of the implications of these pluri-
form approaches to consciousness is progress-
ing and has been yielding new perspectives, for
instance on ways to tackle the Hard Problem
(Pennartz, 2015), assessing consciousness in DoC
patients (Farisco et al., 2017; Sanz et al., 2021),
but also on consciousness in animals and artifi-
cial intelligence devices (Pennartz et al., 2019b).
521
The pluriformity of frameworks considered in the
HBP is not conceived of as a problem per se, as
it reflects the current diversity of theories in the
overall field of consciousness research. Instead,
the HBP stimulates initiatives to compare different
approaches, develop adversarial experiments that
discriminate between contrasting predictions from
the various theories, and integrate insights from
different frameworks. For instance, predictive
coding principles may be combined with elements
from global neuronal workspace theory (Dehaene
and Changeux, 2011; Whyte and Smith, 2021) and
studies into information integration-differentiation
in feedforward-feedback cortical architectures.
WORKFLOWS IN THE HUMAN BRAIN
PROJECT: FROM PHYSIOLOGICAL DATA
TO MULTISCALE MODELS
We next take a closer look at the facilities and
tools developed in the HBP to produce, test and
run computational models for cognitive and sys-
tems neuroscience. The quantitative exploration
of the relationships within the brain’s architecture,
the rich repertoire of dynamics it expresses, and
its cognitive functions supports the creation of
theoretical and data-driven models that aim to
capture the essential mechanisms underlying the
capabilities of the brain and its pathologies. The
effectiveness of this effort is being demonstrated
through the reproduction of observable activity
and cognitive capabilities of the brain in large-
scale simulations. The acquisition, demonstration
and application of this knowledge can be sup-
ported through the creation of Workflows dedicated
to acquisition, storage, analysis, and comparison
of experimental acquisitions and simulations.
First, experimental data, models, analysis tools
and simulation results should be Findable: it must
be easy to search and locate the sets of informa-
tion relevant for each investigation. An essen-
tial instrument is the inclusion of machine- and
human-readable Metadata (i.e., data that provide
information about the nature of each piece of
stored information). Second, information must be
Accessible: after identification it must be possible
to get proper authentication and authorization,
retrieve the dataset and use it. Third, interoperable
data, models and tools need to be incrementally
integrated with novel contributions and users need
to interoperate by subjecting the data to further
applications and workflows for analysis, compari-
son, storage, and processing. The fourth target is
that information must be incrementally Reusable.
The quality of the information and the complete-
ness of the accompanying metadata are essential
522 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
and must be certified by appropriate Curation
steps. Among the purposes of the HBP project is
the creation of a research infrastructure platform
(EBRAINS) that adopts such FAIR (Findable,
Accessible, Interoperable, Reproducible) method-
ology to integrate the knowledge body produced
by HBP and by the research community at large.
A number of interoperable workflows are
under development. A first example is the set
of workflows to create and operate rodent and
human Brain Atlases. Brain Atlases provide sys-
tems to integrate neuroscientific knowledge in a
spatial reference framework. Information about
the shape, location, variability, structure, connec-
tivity, and activity of brain regions is collected in
common coordinate spaces, from multiple sub-
jects and, ideally, multiple species. Moreover, the
HBP creates workflows dedicated to more specific
topics. As an example, we mention the HBP
workflow dedicated to the study of slow waves,
brain state transitions, their cognitive functions,
and complexity in the framework of the activities
dedicated to the investigation of networks under-
lying cognition and consciousness. The aim of this
workflow (Figure 31.4) is to integrate multi-scale,
multi-methodology experimental data, models,
and simulation outputs in a reproducible and
adaptable pipeline dedicated to analyzing slow
wave activity (expressed under natural sleep, path-
ological states or anaesthesia), in relation to the
transitions to higher complexity states and finally
to the specificities of awake regimes.
The goal of the slow-wave activity (SWA)
workflow is the study of cognitive functions of
NREM and REM sleep during incremental cycles
of awake learning and sleep, including the creation
of data-driven and theoretical models that repro-
duce and explain the mechanisms at work during
sleep, and how they produce beneficial effects
on awake cognition. In spiking neural network
models, a combination of dominant depression
and selective potentiation of synaptic strengths
optimizes the post-sleep energetic working point
and at the same time creates novel associations
between similar memories that improve post-sleep
cognitive performances (Capone et al., 2019;
Golosio et al., 2021). This workflow supports the
characterization of the complex spatiotemporal
structure of cortical slow waves that travel along
the cortical surface during the different stages of
physiological sleep and pathological sleep-like
states and at different levels of anaesthesia. The
workflow estimates the probability density func-
tions of wave directions, speeds, and wave fre-
quencies from experimental data or simulation
outputs. Furthermore, it includes a set of data
analysis algorithms that can be applied to both
multi-scale, multi-species, multi-methodology
experimental data and to data-driven and theoreti-
cally derived models of thalamo-cortical systems,
to assess their similarity (e.g., using Wasserstein
(Panaretos and Zemel, 2019) or Kullback-Leibler
metrics or automatic estimates of the number and
parameters of modes in multi-gaussian multi-
variate distributions). It also supports methods
to infer from the experimental recordings data-
driven models of the subject-specific brain under
investigation (Capone et al., 2021). The pipeline is
composed of modular Blocks, Stages and Cycles
organized at incremental levels according to work-
flow Description Charts that specify the nature of
experimental recordings, simulation models or
simulation outputs to be analyzed and compared.
Looking at the global future of neuroscience,
the creation of solid foundations and method-
ologies for neuroscience workflows to be made
available the EBRAINS research infrastructure
is among the cornerstones on which incremental,
large-scale cooperative endeavors in cognitive
and systems neuroscience across the next decades
can rely.
MULTI-LEVEL HUMAN BRAIN ATLAS OF
THE HUMAN BRAIN PROJECT
A main service supplied by HBP’s research infra-
structure EBRAINS for Cognitive and Systems
Neuroscience is the multi-level human brain atlas.
This atlas is a tool to explore brain complexity at
multiple spatial sales and link it with cognitive
function and behavior. The atlas integrates state-
of-the-art maps of the human brain in a common
3D space. It combines in vivo neuroimaging data
(e.g., functional MRI and DTI) to study networks
with microstructurally defined areas of the Julich-
Brain Atlas, data on receptor architecture, gene
expression, or the axonal architecture. The atlas
allows to zoom into microscopical details of brain
organization. Its siibra tool allows to extract data
in an automated way using Python. The atlas
provides an increasing range of maps, data, and
accompanying tools to serve as a resource for
clinical research targeting manipulations to allevi-
ate brain disorders, neural interfaces, brain mod-
eling, AI research, and cognitive neuroimaging.
Starting from Korbinian Brodmann’s idea in
1909 of structure-function relationships at the
level of cortical areas, evidence has been pro-
vided that the cortical architecture (including its
cytoarchitecture) is more differentiated than his
map suggests (Amunts and Zilles, 2015). Key in
developing new maps of the human brain is to
formulate quantitative, reproducible criteria for
 Human Brain Project and Beyond 523

Figure 31.4 Example of scientific workflow diagram: Characterization of spatio-temporal

features of cortical slow wave activity.
The workflow includes algorithmic blocks that support a quantitative and reproducible
comparison among experimental data acquired with multiple methodologies and/or the
outputs of different kinds of simulation models. Systematic curation of experimental data,
models, signals, and analysis outputs is essential to support HBP’s FAIR methodology.
Abbreviations: SWA, slow-wave activity; AW: awake state; TMS, transcranial magnetic
stimulation; ECoG, electrocorticography.

defining a cortical area, to consider novel prepara-
tions, neuroimaging, and optical methods, as well
as 2D & 3D quantitative measures. The large size
of the human brain with its billions of nerve cells,
forming complex networks, implies to collect
and analyze large amounts of data, making high-
performance computing necessary. Deep learning
has become a valuable tool to support brain map-
ping, and to derive features describing its micro-
structure. To integrate the different aspects of the
cortical architecture such as its cytoarchitecture,
connectivity, molecular, and genetic maps into a
common spatial reference system, and to investi-
gate their role in cognitive functions and behavior,
a multimodal human brain atlas is mandatory. The
atlas developed in the HBP offers an increasing
number of high-quality and well-annotated data
resulting from different experiments, coming from
different labs while addressing different levels of
brain organization.
The Julich Brain Atlas with its cytoarchitec-
tonic probability maps serves as microstructural
reference of the atlas. It is based on mapping
serial, cell-body-stained sections in a sample of
10 postmortem human brains in order to take into
account intersubject variability of brain organiza-
tion (Amunts et al., 2020). The maps have been 3D
reconstructed for each postmortem brain, and then
superimposed to a common reference space, and
probability maps have been calculated. Different
templates are being supported by the atlas, to
address the needs of the neuroimaging commu-
nity. The cytoarchitectonic maps are linked with
a comprehensive map of DTI-based fibre tracts in
healthy subjects or patients (Ji et al., 2019), and
functional parcellations schemes based on fMRI,
524 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
which provide insights into the cognitive dimen-
sion of brain parcellation (Pinho et al., 2020, 2021).
The BigBrain (Amunts et al., 2013) allows us
to zoom into brain organization even to a resolu-
tion of 20 micrometers. It is created from thou-
sands of microscopically imaged brain sections,
stitched together into a 3D whole-brain volume. It
allows us to anchor volumes of interest from opti-
cal methods going down to the nanometer scale
(e.g., light-sheet imaging, using the VoluBA tool
of EBRAINS). The BigBrain is also a resource
to study cognition, and a specialized toolbox
“BigBrainWarp” has been developed to link it
with multi-modal neuroimaging data, for studying
resting state, functional networks (Paquola et al.,
2021). The BigBrain is also a tool to study neuro-
imaging results obtained with high-field MRI, as
shown in Figure 31.2, to study visual processing
at laminar level.
On the genetic level, the Jugex-tool allows to
link cytoarchitecture and gene expression, inte-
grating tissue transcriptomic data from the Allen
Brain Atlas and cytoarchitectonic segregation of
the Julich Brain Atlas (Bludau et al., 2018). So
far, the molecular level of receptor maps has been
integrated in a number of areas (Goulas et al.,
2021). Linking the molecular fingerprint of an
area to other structural and functional modalities
thus comes into reach. Area-to-area connectivity
is integrated on multiple scales, with Polarized
Light Imaging and DTI data sources (Caspers and
Axer, 2019) and connectivity profiles are being
computed on the fly for brain areas. Clinical data
is being integrated from the HBP Human intracer-
ebral EEG data database.
In future work, the aim is to both go more
broadly and more deeply into human brain atlas-
ing, and to establish the multi-modal HBP atlas
further as an impactful community platform serv-
ing basic science, medicine, and technology devel-
opment. Going more broadly means connecting
more modalities such a coming from immuno-
histological studies revealing cell types and their
distribution or spatial connectomics, to make brain
models ever more comprehensive. For cognitive
neuroscience, enhanced precision of studies of
structure-function relations is made possible. The
atlas framework allows to link the scales, and con-
nects different communities of neuroscience. A
major frontier of brain research is understanding
and interspecies differences, for instance between
mammalian and avian brains (Stacho et al., 2020).
Such comparative work has not only importance
in basic neuroscience, but has concrete conse-
quences in the field of neurological and psychiat-
ric disorders, considering that evolution has a role
in several brain disorders and models designed to
replicate human brain diseases are not “perfect”
(Brune and Schiefenhovel, 2019).
Going more deeply means connecting anatomic
scales, and going to the next step in terms of detail.
With its partners in Canada, the HBP team aims
to develop an atlas with 1-micrometer resolution
(Hiball; https://bigbrainproject.org/hiball.html). On
this level, not only the cellular architecture, but also
the fine-scale detail of cellular morphology is vis-
ible. Here, the mapping is increasingly sped up by
deep-learning methods (Kiwitz et al., 2020). This
is relevant for cognitive research and brain medi-
cine, because important details of connectivity,
for example, only become visible at such resolu-
tion. The perforant path is an example – it projects
to the cornu ammonis and subiculum, and plays a
major role in learning and memory but also in the
pathogenesis of Alzheimer’s. Microscopical studies
based on 3D-PLI have shown that it does not form a
uniform tract but rather a multi-component system
that originates in the entorhinal cortex with many
thin bundles (Zeineh et al., 2017). These data are
part of the HBP atlas, and accessible to the research
community via EBRAINS (https://ebrains.eu/).
The HBP brought major developments in cre-
ating the first truly multi-level and multi-modal
atlases of the human brain. In EBRAINS, users can
navigate and find well-curated, high-quality data
with the help of the EBRAINS Knowledge Graph,
or explore the same data visually in the EBRAINS
atlas viewer. Future uses for surgery and brain
stimulation in Parkinson’s disease, or other brain
implants are on the horizon. In the HBP, existing
new connections have also been made to brain
modeling communities. Of note here is ongoing
work on the Virtual Big Brain Epilepsy project
(Hashemi et al., 2020) and the creation of cogni-
tive architectures for robotics control. Moreover,
individualized brain models of patients and their
simulation play an increasing role in medicine.
The Virtual Brain (www.humanbrainproject.
eu/en/medicine/the-virtual-brain/) is a technol-
ogy that has pioneered progress in this area. It
may serve as an in-silico platform for clinical
hypothesis testing, improved diagnosis and devel-
opment of novel interventions (Jirsa et al., 2017).
The general entry point for EBRAINS atlas ser-
vices is the EBRAINS web portal, which provides
information about the atlases and the most impor-
tant related tools. (see https://ebrains.eu/service/
human-brain-atlas/)
HUMAN BRAIN PROJECT –
INTERNATIONAL CONTEXT:
COLLABORATIVE BRAIN INITIATIVES
The second decade of this century saw a remark-
able growth in large brain initiatives around the
world. HBP and the US BRAIN (United States
 Human Brain Project and Beyond 525

Figure 31.5 The multi-level human brain atlas of the HBP includes BigBrain (Amunts et al.,
2013) as a template space at microscopical resolution. Different modalities such as cortical
layers, the extent of cortical areas or receptor fingerprints of different neurotransmitter
systems (polar plot) are available.

Brain Research through Advancing Innovative
Neurotechnologies), both launched in 2013, were
the first in a wave of new initiatives (Kandel et al.,
2013), later followed by Brain/MINDS (Brain
Mapping by Integrated Neurotechnologies for
Disease Studies) in Japan and several other initia-
tives. In 2017, the initiatives from Europe, the
United States, Japan, Korea, and Australia, have
agreed on a Declaration of intent to collaborate
and join forces through the International Brain
Initiative (IBI). The primary motivation was the
common recognition that “no single initiative can
tackle the challenge to measure, map, image,
model, simulate, understand, imitate, diagnose
and heal the brain.” The new organization (IBI)
was formed one year later, with two additional
initiatives in China and in Canada (Adams et al.,
2020). Details about the constituent initiatives are
included in Table 31.1.
The declaration to instigate the IBI included a
series of commitments. In brief, the commitments
were centered around leveraging and aligning
efforts to maximize efficiency, working with key
stakeholders, exploring and implementing data
sharing and standardization mechanisms, and col-
laborating in the fields of neuro-ethics and respon-
sible data stewardship and privacy protection. The
declaration also covered engagement with citizens,
patients, and relevant communities to understand
their concerns and communicate the opportunities
and challenges arising from brain research. These
commitments were fully compatible with the mis-
sions of the HBP and the actions that the project
had initiated and later pursued with increasing
intensity, in the areas of international collabora-
tion, education, outreach, community building,
capacities for shared research data, neuro-ethics,
and data governance (e.g., Amunts et al., 2016,
2019; Bjerke et al., 2018; Salles et al., 2019).
Neuroethics and data sharing are two pri-
mary examples of overlapping areas of interest
between the HBP and the other brain initiatives.
Neuroethics addresses questions of relevance for
neuroscience in general and of primary impor-
tance for cognitive neuroscience. Neuroethics
research relates to understanding of the nature of
the self and identity, the existence and meaning of
free will, and defining the role of reason in human
behaviour. The IBI has been active in aligning
efforts in the field of neuroethics, as exempli-
fied by a list of neuroethics questions serving as
a guidance for ethical research, developed by the
Neuroethics working group of the IBI (Amadio
et al., 2018; also see Box 29.1).
526 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Table 31.1 List of large-scale neuroscience projects included in the International

Brain Initiative
Project/initiative Country Focus Starting year

Human Brain Project European Union Development of tools and software for data analysis, 2013
modeling, cognitive neuroscience and neuromorphics
US BRAIN Initiative USA Development of innovative brain technologies 2013
Brain/MINDS Japan Developing of brain mapping technologies for human and 2014
other animals (marmoset)
Australian Brain Alliance Australia “Cracking the brain’s code,” developing neural interfaces and 2016
brain-inspired computing
Korean Brain Initiative South Korea Advancing brain mapping, AI-related R&D, multidisciplinary 2016
research and personalized medicine
China Brain Project China Advancing research in cognitive function, diagnosis of brain 2016
disorders and brain-inspired AI
Canadian Brain Canada Establishing open, transdisciplinary and collaborative research 2017
Research Strategy in brain science and brain-inspired AI

Note. All the projects listed above share common principles and complementary goals (including topics in neurosci-
ence, cognitive science, medicine, AI, and novel technologies), and engage in a framework of cooperation and knowledge
dissemination.

Box 29.1 Neuroethical questions guiding ethical research in the International Brain
Initiatives (from Amadio et al., 2018)

Q1. What is the potential impact of a model or neuroscientific account of disease on individuals,
communities, and society?
Q2. What are the ethical standards of biological material and data collection and how do local standards
compare to those of global collaborators?
Q3. What is the moral significance of neural systems that are under development in neuroscience research
laboratories?
Q4. How could brain interventions impact or reduce autonomy?
Q5. In which contexts might a neuroscientific technology/innovation be used or deployed?

SUMMARY AND CONCLUSIONS
Neuroscience is in the midst of a revolution as to
how the field manages compiled research data
within a new era of international collaborative
sharing, driven by relatively recently introduced
technical/technological opportunities enabling the
making of large amounts of data widely available
in combination with computing resources. All
brain initiatives around the world are facing
equivalent implementation challenges.
Consequently, the International Brain Initiative
(IBI) has initiated a new working group in relation
to maintaining data standards and sharing aimed
at facilitating discovery, harmonization, and use of
data across brain projects and initiatives globally.
The working group was tasked to deliver guidance
to the international neuroscience community
within the areas of data governance (Eke et al.,
2021), findability of data across projects and
assuring interoperability and training of a new
researchers prepared for the next generation solu-
tions for data management. New training material
is disseminated through the International
Neuroinformatics Coordinating Facility ( INCF)
Training Space (https://training.incf.org/).
The Human Brain Project (HBP) has defined
the sharing of open data, models, and tools, as crit-
ical for reaching its goal of integrating brain sci-
ence across research modalities and spatial scales.
The HBP launched the European Brain Research
Infrastructure (EBRAINS) in 2019, and since the
beginning of the project has been very active in
developing solutions for data governance, data
sharing, and standards, and training of research-
ers. Services for FAIR data, open to the broader
 Human Brain Project and Beyond
research community, aimed both at researchers
producing data and those using data for analysis
and modeling, are embedded within EBRAINS.
The future development and these and other ser-
vices in EBRAINS is influencing, and is influ-
enced by the activities and results achieved by the
several other brain initiatives all around the world.
Finally, the HBP has been a major driver of neu-
roethics research, as well as ethics related actions
also involving societal engagement. The HBP has
placed a strong emphasis on ethics management
and ethics rapporteur functions at the project level.
Data sharing is another common area of priority
within both both the HBP and the IBI. Data shar-
ing is a prerequisite for large scale data integration
across modalities and addresses fundamental chal-
lenges within the fields of neuroscientific research
reproducibility and replicability.
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Advances in Brain Imaging
S i c o n g Tu , W i l l i a m H u y n h , a n d
INTRODUCTION
The advancement of cognitive and systems neuro-
science is intricately tied to our ability to capture
in-vivo brain function in real-time. This can be
achieved through various non-invasive functional
neuroimaging methods, including functional mag-
netic resonance imaging (fMRI), magnetoencepha-
lography (MEG), and positron emission
tomography (PET). Traditionally, the goal of func-
tional neuroimaging has been to localize cognitive
processes by tracking changes in brain activity
through controlled experimental paradigms. By
modulating brain activity across specific task-based
conditions, associated neural substrates underlying
cognition can be localized and quantified. More
recently, the trend has shifted towards interpreting
neural activity at the systems level across the whole
brain, namely how brain networks facilitate the
mind’s functional states. In contrast to task-based
approaches, connectivity of the functional connec-
tome is typically studied while the brain is in a
resting-state. In doing so we can map the functional
organization of neural connections by investigating
the association in spontaneous fluctuation between
widespread regions throughout the brain. This chap-
ter covers advances in localization and connectivity-
based brain imaging and current methodology in
fMRI, MEG, and PET.
32
Matthew C. Kiernan
MEASURES OF FUNCTIONAL
BRAIN ACTIVITY
At the most basic level, consciousness can be
viewed as the result of billions of neurons firing
rapidly. While non-invasive in-vivo measurement of
individual neuron activity remains a vision of the
future, current neuroimaging methods provide
increasingly powerful non-invasive methods for
inferring brain function of neuronal populations
through various modalities, the most prevalent being
fMRI, MEG, and PET. Crucially, each method
records brain activity in a fundamentally different
manner, resulting in unique strengths and weak-
nesses for inferring underlying brain function.
FUNCTIONAL MAGNETIC RESONANCE
IMAGING (FMRI)
Functional Magnetic Resonance Imaging (fMRI)
is a measure of blood oxygenation level-dependent
(BOLD) contrast of the brain’s microvasculature.
Hemoglobin in blood is the body’s primary oxygen-
transport for sustaining metabolic function. The
release of oxygen results in the formation of
deoxyhemoglobin, a paramagnetic molecule that
534 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

provides a naturally occurring BOLD contrast
which can be accentuated through application of
gradient-echo MR sequences. The seminal paper
by Ogawa et al. (1990) demonstrated that the
BOLD contrast can be used to generate real-time
maps that reflects induced physiological changes
associated with metabolic demand and blood flow.
Using a standard 3 Tesla (3T) MRI scanner, fMRI
allows for very high spatial resolution (∼1-2mm)
and signal depth, allowing activity to be recorded
from all cortical and subcortical regions of the
brain. This can be further enhanced to sub-­
millimeter spatial resolution when scanning at
ultra-high field strengths of 7T and above (Kemper
et al., 2018). Change in blood oxygenation is,
however, a relatively slow biological process, thus
the temporal resolution of fMRI is typically lim-
ited to differentiating changes in brain activity
around one second or more apart.
Despite its relatively recent development, fMRI
has emerged as the most widely employed func-
tional brain imaging modality in neuroscience and
provides a good balance between spatial resolution,
temporal resolution, and signal depth. The greatest
strength of fMRI relates to the ease of implemen-
tation and acquisition of data using conventional
MRI scanners and head coil. As such, fMRI can be
integrated as part of a seamless research protocol
with multi-modal weighted sequences (T1, T2, dif-
fusion, spectroscopy). This facet has made fMRI a
core component of large-scale open access research
initiatives for mapping out the brain’s connectome
(Van Essen et al., 2013) and biological factors that
influence brain structure and function (Miller et al.,
2016), and led to its rapid development and wide-
spread application in neuroscience research. Over
the past decade ultra-high field fMRI acquired at
7T has emerged, but this remains a developing
area constrained by scanner accessibility. Only in
the past year has the first 7T MRI scanner been
approved for clinical practice.
An early comparison study of the sensitiv-
ity of standard 3T and 7T fMRI for detecting
BOLD changes, elicited through simple repetitive
hand opening/closing, demonstrated a significant
increase in mean peak signal of the hand knob
region of the motor cortex (Beisteiner et al., 2011).
The increase in signal sensitivity is the primary

Figure 32.1 Characteristics of the fMRI signal. The BOLD contrast represents the ratio of local
oxygenated (Hb) and deoxygenated (dHb) blood, and typically demonstrates a 3-stage stimulus
evoked hemodynamic response (initial dip, overshoot, and undershoot). Hb = hemoglobin;
dHB = deoxyhemoglobin.
 Advances in Brain Imaging 535

benefit of moving to a higher field strength and has
opened the door for more fine-grained localization
of functional brain changes by reducing voxel
sizes to sub-millimeter resolution. For exam-
ple, advancing our understanding of the laminar
organization of sensory processing (Lawrence
et al., 2019). It is, however, necessary to highlight
that significant technical and practical challenges
currently exist for fMRI acquisition at 7T (and
beyond) besides scanner accessibility. From a
technical standpoint, inhomogeneity of the applied
magnetic fields (B0, B1) is significantly more pro-
nounced across the brain, leading to greater signal
loss in the basal temporal lobe and cerebellum,
as well as increased geometric distortion. From
a practical standpoint, even healthy young adults
report significant subjective discomfort within
a 7T magnetic field resulting in vertigo, and to a
lesser degree, nausea (Rauschenberg et al., 2014).
Current non-ferromagnetic medical devices are
also not made to be compliant beyond 3T. This
poses challenges for the application of ultra-high
field MRI at both ends of the age spectrum, in
early developmental as well as neurodegenerative
research. Technical improvements addressing field
inhomogeneity are available using dielectric pads
(passive modulation), or through more advanced
solutions such as parallel transmit radiofrequency
coil arrays (active modulation). Participant scan-
ning discomfort remains a challenge, which can
significantly impact the quality of acquired data.
In contrast, MRI at 3T is a mature technology
that is widely accessible and the current staple for
research in functional brain networks with pro-
gressive advances made in both data acquisition
and analysis techniques in recent years.
MAGNETOENCEPHALOGRAPHY (MEG)
MEG is a measure of the magnetic induction gener-
ated by dendritic post-synaptic potential of the
brain’s neuronal activity. Unlike fMRI and PET,
MEG directly measures the net magnetic field
changes induced by intracellular postsynaptic cur-
rent flows (excitatory/inhibitory) and does not rely
on secondary effects induced by brain activity. The
measured pattern of electrical potential change
resembles that of traditional electroencephalogram
(EEG), as demonstrated by Cohen (1972). MEG
measures changes in magnetic field which travels at
the speed of light and suffers minimal spatial blur-
ring from passing through distortive tissue (i.e.,
skull). This allows for excellent temporal (<1ms) and
spatial (∼2-6mm) resolution, with high sensitivity in
the order of 100 femtoTesla (1013 orders smaller than
a 1.5T MRI scanner). The strength of magnetic field
changes does, however, decrease rapidly with dis-
tance, making recording of neural activity from
deep-gray brain structures (i.e., thalamus, hippocam-
pus, amygdala) challenging to implement. Another
consideration is that anatomical localization is not
inherent to the acquired MEG signal and requires
inverse mapping from sensors to source.

Figure 32.2 Characteristics of the MEG signal. Neuronal activity detected by MEG represents
the sum of local magnetic field changes generated by synaptic transmission. Magnetic fields
occur perpendicular to the synaptic potential in accordance with Maxwell’s right-hand rule.
Recorded signal primarily represents local post-synaptic activity. Pre-synaptic potential is
extremely short-lived and biphasic, such that spiking activity would be cancelled out unless
perfectly synchronized.
536 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
MEG was first introduced in 1972 as a highly
sensitive magnetic field-based alternative to tra-
ditional EEG for directly measuring the brain’s
neuronal activity (Cohen, 1972). The seminal
study by Cohen utilized a novel superconducting
quantum interference device (SQUID) to demon-
strate that MEG recordings could be directly taken
without noise averaging. Modern commercial
MEG systems have since undergone substantial
technological advances, capable of housing over
300 SQUID sensors to provide multi-channel
whole-brain measurement of neuronal activity at
a temporal resolution of <1ms, sufficient to track
even the fastest neuronal processes. Cryogenic
temperatures are required for the operation of
SQUID sensors, which are housed within a liquid
helium-filled Dewar surrounding a circular recess
to accommodate the participant’s head, typically
adjustable for a supine or seated position. In direct
contrast to MRI, MEG is a passive and contactless
measurement technique that is silent to operate.
While MEG is considered less demanding on par-
ticipants relative to the acquisition of other func-
tional imaging measures (fMRI, PET), whereby
the hardware forms an enclosed space around the
whole head, participants are still required to main-
tain a motionless head position and will typically
have several secondary sensors placed on both
wrists (electrocardiogram) and close to the eyes
(electrooculogram) to control for physiological
artifacts during analysis. Furthermore, comple-
mentary structural MRI is typically also acquired
(independently) for more precise anatomical
co-localization.
MEG sensors are extremely sensitive to mag-
netic field changes and capture neural evoked
fields as small as 10−14T (the earth’s magnetic field
is approximately 10−4T) and requires installation
within a heavily magnetic shielded room to pre-
vent signal contamination from external sources.
An early combined MEG and subdural EEG study
by Oishi et al. (2002) demonstrated 3–4cm2 of cor-
tex is required to be activated for an identifiable
spike on MEG recordings. Relative to MRI, MEG
installations are more limited, primarily located in
specialized settings, which has been a key factor
restricting its more widespread adoption clinically
and for research. A second barrier is the relative
lack of standardization in study protocols and
analytical methods, which has been a focal point
for the increasing push toward open-source fMRI
brain connectivity research (Esteban et al., 2019).
This is despite MEG being a better suited tech-
nique for directly capturing the underlying tempo-
ral characteristics of localized neuronal processes.
MEG has provided significant contributions to
current understanding of the dynamic role of brain
oscillations in task-evoked cognitive processes,
including perception/memory encoding, and
modulation of attentional states (Lopes da Silva,
2013). Progressive improvements in whole-head
coverage, spatial resolution, and prospective head
position monitoring and correction have also led
to the direct translation of MEG as a clinical tool
with accepted practice guidelines, notably in epi-
lepsy for the localization of epileptic foci (Bagic
et al., 2011) and presurgical functional mapping
(Burgess et al., 2011) (albeit EEG remains the
standard clinical approach). This is attributed to
the higher accuracy of source localization of MEG
over conventional EEG, which would require inva-
sive intracranial monitoring to achieve the same
level of accuracy. In principle, MEG is primarily
sensitive to cortical sources arranged in a tangen-
tial orientation to the skull with the converse being
true for EEG (i.e., sulcal bank and gyral crown,
respectively). In practice, it is rare to see corti-
cal activity picked up through EEG but absent on
MEG, due to its higher sensitivity. Progressive
methodological advances in source localization
and artifact removal in the analysis of MEG data
have also led to its increasing application beyond
the study of more fundamental localized neuro-
physiological phenomena to whole-brain activity
at the network level (Brookes et al., 2011).
POSITRON EMISSION TOMOGRAPHY (PET)
PET is a measure of metabolic brain activity by
monitoring positron annihilation associated with
the decay of radiolabeled tracers. Since the incep-
tion of PET imaging in the early 1950s, it has
shown significant clinical application, in particu-
lar for localizing and differentiating brain tumors
(Sweet, 1951). PET is a technique for counting
radioisotope decay. Reconstructed images can
provide an averaged static image or dynamic
image of regional tracer uptake throughout the
brain. Radiolabeled tracers are introduced through
a bolus injection, and comprise a positron emit-
ting isotope (11C, 13N, 15O, 18F) attached to a mol-
ecule of interest (e.g., glucose) to synthesize a
radioisotope, such as the widely used (18)
F-fluorodeoxyglucose (FDG-PET). Over time, the
injected tracer accumulates in brain regions of
high molecular affinity and levels can be quanti-
fied by measuring the resulting photon annihila-
tion associated with positron emission decay. The
spatial resolution of PET is relatively poor com-
pared to MRI/MEG and is impacted by both hard-
ware and chemical elements. Resolution will vary
depending on the type of tracer used, but typically
varies between 4mm and 10mm.
 Advances in Brain Imaging 537

Figure 32.3 Characteristics of the PET signal. PET counts the number of positron annihilation
events resulting from the decay of proton-rich radionuclides, resulting in the release of a
positron (e+) and neutrino (v). The emitted positron travels through tissue giving up kinetic
energy by Coulomb interactions with electrons (e−), large deviations in direction occur with
each interaction. Continual loss of kinetic energy ultimately results in a collision leading to
an annihilation event, emitting two anti-parallel 511 keV photons (γ ) detected by PET array
sensors. Localization of the annihilation event is made along the estimated line of response.
P = proton; N = neutron; v = neutrino; e+ = positron; e− = electron.

PET emerged in the 1950s, but its expanded
application occurred alongside the development
of complementary radiopharmaceutical tracers,
namely FDG, in the late 1970s. In contrast to
fMRI and MEG, a core component of PET is the
use of radiotracers administered via bolus injec-
tion prior to scanning. Methodological advances
are tied not only to scanning hardware and data
analysis, but also progressive radiopharmaceutical
development of novel pre/post-synaptic markers
for molecular targets of interest (e.g., neurotrans-
mitter systems, metabolism, inflammation, pro-
teinopathies). The development, generational
improvements, and validation of radiotracers is an
extensive field that falls outside the scope of the
current chapter. Radiotracer reviews are plentiful,
but typically disease and/or mechanism specific
(cf. van Waarde et al., 2021).
PET installations are now common in clini-
cal settings due to the widespread adoption of
FDG-PET as a marker for diagnosis and staging
in oncology and neurological disorders (Brown
et al., 2014; Chen, 2007). However, accessibility
remains a problem due to high scanning costs,
which can be double that of MRI. The design of
conventional PET systems remains fundamen-
tally unchanged (Cho et al., 1976) with sensors
arranged in a cylindrical array for the detection of
positron annihilation events along a 180-degree
line of response. Over the past two decades, the
type of sensors used within the array has, however,
increasingly transitioned from traditional bismuth
germanate (BGO) scintillators coupled to photo-
multiplier tubes, to the more recently developed
lutetium-based scintillators read out by silicon
photomultipliers (SiPMs). SiPMs not only provide
538 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
a high light-collecting efficiency and comparable
stopping power to BGO, but also significantly
improved coincident timing resolution (200–
400ps), allowing time-of-flight (TOF) PET imag-
ing for more precise signal localization (Surti,
2015). Currently, lutetium-based scintillators are
found in all modern state-of-the-art PET scanners
offered by mainstream commercial manufacturers.
PET imaging is intrinsically complementary
with MRI (albeit primarily used in combination
with computed tomography [CT]), yielding addi-
tional insights of specific molecular mechanisms
impacting structural, functional, and connectivity
brain changes. This has been complemented by
recent hardware advances leading to the devel-
opment of hybrid PET-MRI scanners for simul-
taneous image acquisition (Catana, 2017). An
advantage of integrated PET-MRI systems is the
improved spatial correspondence between PET
and MR images due to the inherent co-registration
carried out during data acquisition. Quantification
of PET tracer tissue uptake can be more reliably
calculated by leveraging the higher spatial reso-
lution of structural MRI images (1mm) to reduce
partial volume effects (i.e., tissue heterogeneity
due to a mixture of gray and white matter phar-
macokinetics), a significant limitation affect-
ing the reliability of quantifying tracer uptake
in subcortical brain structures (Brown et al.,
2014; Catana et al., 2012; Jucaite et al., 2012).
The combined application of PET and MRI has
been widely employed across neurodegenerative
conditions in support of the “network-opathy”
hypothesis for progressive propagation of dis-
ease pathology in the brain (Seeley et al., 2009).
Studies in Alzheimer’s disease have consistently
demonstrated an association between altered con-
nectivity of large scale rsfMRI brain networks
and underlying disease burden as reflected by
PET tracers of b-amyloid (Drzezga et al., 2011),
and more recently, tau (Franzmeier et al., 2020)
proteinopathies. Relative to fMRI, PET imaging
data of brain function is both temporally and spa-
tially limited. Functional connectivity between
brain structures through standalone PET imaging
(i.e., metabolic connectivity) can only be derived
through significant correlations at the group level,
not dynamic signal fluctuations at the subject level
(fMRI, MEG). Methodological advances in PET
imaging are ongoing, aimed at improving data
reconstruction for localization while optimizing
for spatial and temporal resolution.
Each of the imaging modalities outlined above
can be applied to examine changes in local and
global “brain activity.” Their underlying princi-
ples, however, vary greatly and so too does their
inherent strengths and weaknesses which impacts
experimental design and interpretation of results.
ADVANCES IN FMRI
Multiband Acquisition
Virtually all fMRI acquisitions employ echo
planar imaging (EPI) (Mansfield, 1977) for spatial
encoding of the MR image due to its fast scan
time (∼3 seconds for whole brain coverage) and
BOLD sensitivity (Ogawa et al., 1990). Ideally,
only localized intensity changes relating to neu-
ronal activity should be detected. In practice, the
image-to-image signal is contaminated by multi-
ple sources, namely system instability, subject
movement, and physiological motion (Hu et al.,
1995). Improving the temporal resolution (the rate
at which sequential brain images are acquired) is
critical for reducing temporal instabilities.
Conventional fMRI data is acquired slice-by-slice,
meaning that whole brain data is acquired sequen-
tially in a slab like manner. Such an approach
poses clear limitations for the degree of accelera-
tion possible for acquisition. Over the past decade,
simultaneous multi-slice (or multiband) EPI
sequences have been increasingly adopted as a
novel approach to improve temporal resolution to
achieve 1s and even sub-second whole brain cov-
erage (Feinberg et al., 2010).
Multiband acquisition leverages modern MRI
hardware to simultaneously measure signal
from multiple detector coils simultaneously and
separate overlapping images into their separate
slices (un-aliasing) through multi-channel radi-
ofrequency head coils (32 channels and higher;
Larkman et al., 2001). The degree of multiband
acceleration implemented can be as low as 2 (i.e.,
acquiring 2 simultaneous brain slices) to 8, as
implemented by large scale neuroimaging initia-
tives (Human Connectome Project; UK Biobank;
Miller et al., 2016; Van Essen et al., 2013). The
primary benefit of implementing multiband accel-
eration is the reduction in repetition time (TR),
which is the amount of time taken to acquire a
single whole-brain volume. This results in two
main advantages for the acquired data: (i) wider
range of signal sampling to identify physiological
noise, (ii) greater number of sampled time-points
for improved statistical power (i.e., a multiband
factor of 8 is an 8-fold increase in number of col-
lected volumes for a given acquisition period). As
with all MRI techniques, employing multiband
EPI sequences does come at a cost. A shorter
TR results in brain tissue being excited in a more
rapid succession allowing less recovery time. This
translates into reduced gray and white matter tis-
sue contrast, which can be addressed with the
additional acquisition of a single-band reference
volume. Multiband data also suffers from more
 Advances in Brain Imaging
Figure 32.4 Simultaneous multi-slice (multiband) acquisition. Data is acquired from multiple
slices simultaneously rather than sequential slice-by-slice acquisition.
artifacts relative to conventional data. This is
exacerbated at higher multiband acceleration fac-
tors (i.e., 8) but allows fMRI data to be acquired
at 2mm isotropic spatial resolution with ∼1s TR at
3T field strength (Miller et al., 2016; Van Essen
et al., 2013). In contrast, conventional fMRI data
is acquired at 2.5–3.5mm isotropic voxels with
∼3s TR. More recently, it has been shown that high
multiband acceleration also poses challenges for
quantifying functional connectivity. Noise ampli-
fication from multiband acceleration creates large
spatial biases (particularly at 8 and higher) which
can lead to an underestimation of subcortical con-
nectivity (Risk et al., 2021). Notably, multiband
acceleration factors of 3-4 provide significant
benefits to the spatial and temporal resolution of
fMRI data (2.5mm isotropic; ∼1s TR) and argu-
ably a more balanced tradeoff between spatial
biases and effect size when examining the correla-
tion in subcortical-cortical (e.g., thalamocortical)
connectivity.
MULTI-ECHO ACQUISITION
As previously raised, the observed BOLD signal
from fMRI data is impacted to varying degrees by
artifacts relating to subject and physiological
motion, and hardware. The control and removal of
structured noise from fMRI data is a critical
aspect of the analysis pipeline. To date, this has
largely been addressed during the preprocessing
stage involving regression of structured noise,
frequency-restricting temporal filtering for the
539
removal of signal drift and high frequency noise,
and volume deletion. Despite the significant data
reduction imposed by these steps it is clear that
systematic but spurious correlations still arise
throughout the brain (Power et al., 2012). An
approach that has a long theoretical history but is
only recently starting to gain popularity in fMRI
acquisition is the application of multi-echo EPI
sequences.
Echo time (TE) is the time gap between the
excitation of brain tissue and read out of the result-
ing signal. The optimal echo time varies accord-
ing to tissue type, biological process of interest,
and scanner field strength. For the BOLD effect
in gray matter at 3T, 30ms is typically used.
Conventional EPI sequences use a single echo
time, however, multiple echo times (i.e., additional
signal read outs at shorter/longer delays resulting
in n>1 volumes per TR) is proposed as a method
to separate BOLD from non-BOLD signal to bet-
ter clean fMRI data to improve statistical power
(Kundu et al., 2017). This follows the observa-
tion of TE-dependent scaling of the percent signal
change associated with the BOLD signal compo-
nent across both task (Lombardo et al., 2016) and
resting-sate (Kundu et al., 2013) fMRI. In contrast,
non-BOLD components show TE-independence
remaining relatively similar across varying TE.
The penalty associated with employing multi-
echo acquisition is, understandably, an increase
in TR (to accommodate multiple-signal read outs)
relative to single-echo acquisition, regardless of
whether it is paired with multiband acquisition.
Whether multi-echo acquisition is a better choice
overall depends on how well artifact removal from
fMRI data can be achieved.
540 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
INDEPENDENT COMPONENTS
ANALYSIS (ICA)
The estimation and localization of the spatial dis-
tribution of BOLD changes at the voxel level has
been fundamental to modern cognitive neurosci-
ence. Traditionally, fMRI has been used in combi-
nation with tightly controlled task-based paradigms
to investigate hypotheses for identifying localized
functional contributions of specific brain struc-
tures in cognitive processing. This has led to the
application of signal processing approaches to
decoding localized mental representations, such
as multivariate pattern analysis, whereby machine
learning is used to train a classifier to recognize
dynamic patterns of BOLD change, most interest-
ingly in the memory literature (Chen et al., 2017;
Polyn et al., 2005). Increasingly, however, a
­systems-level approach is being adopted as we
recognize it is the communication, modulation,
and integration of sensory and higher order neural
signals across interconnected networks of brain
structures that underlies everyday cognition and
behavior, and their dysfunction. In combination
with large-scale brain imaging initiatives (Miller
et al., 2016; Van Essen et al., 2013) that have made
high quality neuroimaging data sets publicly
available, data-driven approaches for mapping
functional brain networks and their connectivity,
such as independent components analysis (ICA),
has pervaded the neuroscience literature.
ICA is a model free data analysis approach
for decomposing a multivariate signal, such as
fMRI acquired while the brain is in a “resting-
state” (rsfMRI), into independent components
with unique sets of structured features that can be
applied during pre-processing to identify noise,
as well as post-processing to identify large scale
brain networks. This follows the assumption that,
at rest, brain regions that share a similar function
demonstrate similar dynamics in spontaneous neu-
ronal activity. ICA results in the decomposition of
unique spatial and/or temporal components (i.e.,
no correlation or higher order statistical relation-
ship) that are maximally independent of each other
based on a cost function, such as measuring nega-
tive entropy, to determine the best set of linear com-
ponents that are maximally non-­Gaussian from the
full rsfMRI data. The advantage of using ICA over
traditional seed-based (hypothesis driven) correla-
tion analysis is estimation of the full (e.g., spatial)
structure of a brain network. Rather than being
sensitive to the functional connectivity pattern of
a specified seed region, ICA simultaneously char-
acterizes multiple independent resting-state brain
networks, as captured by the data set. ICA derived
brain network maps have advanced understanding
of changes in the spatial organization of systems-
level dysfunction across clinical populations, such
as major depressive disorder (Hamilton et al.,
2015) and Alzheimer’s disease (Greicius et al.,
2004). The independent nature of components
identified by ICA, however, can be a disadvantage
to understanding the “true” network structure of
underlying brain networks. For example, in data
sets with very little noise, partially overlapping
components would be spatially correlated and
therefore not allowed as independent components.
This has a significant impact for evaluating the
functional role of key subcortical structures (e.g.,
thalamus) that play an active role in the relay and
modulation of brain signaling to widespread corti-
cal regions. It is also difficult to disentangle inter/
intra-hemispheric in brain networks differences
given the strong correlation between correspond-
ing brain regions across hemispheres.
NODE BASED ANALYSIS
While ICA is a powerful technique for comparing
the spatial organization of large-scale brain net-
works, it does not allow investigation of the
strength of functional connections between two
regions or their comparison at a group level. For
these questions node-based connectivity modeling
is a widespread approach increasingly employed
in cognitive and systems neuroscience. The pri-
mary difference between voxel-based approaches
(e.g., ICA) and node-based analysis of rsfMRI
relates to spatial scale. Node-based analysis
requires a-priori definition of “nodes” as different
brain regions of interest. These nodes can: (i)
cover the whole brain and be defined by brain
atlas parcelations (structural/functional), (ii) cover
limited brain regions of a specific system of inter-
est, (iii) be used in conjunction with seed-based
correlation maps to define regions connected with
a specific brain structure. In essence a node
assigns labels to groups of voxels considered
functionally homogenous. For each node, the
functional connectivity (i.e., similarity in the
rsfMRI timecourse) between all other nodes is
calculated as “edges” to generate a network
matrix of pair-wise connections that can be com-
pared at the group level. How an edge is defined
varies greatly according to the research question
and directly impacts interpretation of connectivity.
At its most basic form an edge between each pair
of nodes can be binary (i.e., 0 or 1) to simply
represent whether a connection is present or
absent, for a given statistical threshold. A range
between +1 and -1 is more typically used to pro-
 Advances in Brain Imaging
Figure 32.5 Data-driven parcellation
of rsfMRI data captures the whole-brain
spatial structure of large-scale brain
networks. Number of independent brain
networks identified from a dataset is
variable depending on analysis parameters.
Parcellation masks are publicly available
and were generated from a data set of 1000
healthy young adults (Yeo et al., 2011).
vide more meaningful information, namely
the strength and relationship (correlation or anti-­
correlation, respectively) of the connection
between brain regions. Node-based analysis has
played an important role in mapping the func-
tional connectome and topographical organization
of the human brain (Yeo et al., 2011). The primary
limitation of node-based analysis is the a-priori
definition of nodes that maintain the same shape
and size throughout downstream analysis stages
when gradient-based boundaries are arguably
more appropriate for parcellating cortical brain
regions (Glasser et al., 2016). If the spatial bound-
aries of nodes do not accurately reflect the under-
lying functional organization of the brain it is
difficult to reproduce connectivity patterns present
at the voxel scale (Craddock et al., 2012).
ADVANCES IN MEG
Source Localization
A central problem that lacks a general solution in
MEG is source localization. Localization of the
MEG signal requires inverse mapping from sen-
sors to source as the acquired raw data does not
hold inherent spatial information. Every source
estimation procedure faces the same “inverse
problem,” that is the forward modeling of the
estimated current distribution within the brain
from the net observed magnetic field measured
externally (as an input) into three-dimensional
space (i.e., along the cortical surface or within the
brain volume; McMackin et al., 2019). Conceptually,
541
solving this problem requires a-­priori knowledge
of the currents and magnetic field, while consider-
ing volume geometry and properties of the
medium. This is, however, an ill-posed problem as
the measured magnetic fields could be caused by
an infinite number of neuronal sources, or at least
more than available sensors. As such, there is no
unique solution. This is reflected by the absence
of a general model for source reconstruction with
multiple approaches employed in the literature.
Overall, reconstruction models demonstrate good
consistency but differ in the degree of complexity
of the modeled source and imposed physiological
assumptions, which impacts the spatial extent of
source images and subsequent statistical inference
(Samuelsson et al., 2021).
The equivalent current dipole (ECD) method is
the simplest and most widely used estimation tech-
nique due to its relatively high accuracy and prac-
ticality, particularly in a clinical setting (Burgess
et al., 2011). Dipole fitting assumes that a small
number of point-like ECDs can describe the spa-
tial average of all evoked currents within a local-
ized area of the brain. Each dipole is characterized
by six parameters that describes its position, ori-
entation, and strength within the head volume.
Comparisons are performed between measured
and modeled field distributions using a non-linear
iterative algorithm to determine parameters of
best fit according to the measured data. At each
iterative step, parameters are adjusted to minimize
measured and modeled field differences based on
a cost function. Different conductor models can be
applied to approximate head volume, including a
single homogenous sphere or ellipsoid, multiple
spheres fitted according to head curvature (bound-
ary elements), or in combination with structural
MRI. The ECD method is not a perfect representa-
tion of all brain activity but provides a good esti-
mation of early cortical activity that involves only
a few square centimeters of cortex.
An increasingly popular alternative technique
for extracting the origins of a MEG signal is to use
beamforming. Beamforming approaches extract
signal from a prespecified spatial location through
the use of an adaptive spatial filter (Woolrich et al.,
2011). An optimal spatial filter estimates the neu-
ral activation at a given location independent (i.e.,
uncorrelated) of those generated elsewhere in the
brain. In essence, beamformers do not attempt to
explain the complete measured field, rather what
is the unique contribution of a single position to
the field. A distinct advantage of beamforming is
its ability to suppress artifactual signal (e.g., car-
diac interference) whose spatial profile cannot be
modeled by a dipolar source within the head. This,
however, does raise a fundamental problem with
beamforming approaches as correlated sources
542 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 32.6 Source localization using MEG and structural MRI. (A) MRI geometry is used
for building biophysical models of the brain to account for differences in tissue properties.
(B) Localized neuronal activity can be projected between sensor and source space through
inverse and forward modeling (McMackin et al., 2019).

cancel each other out depending on the correlation ARTIFACT REMOVAL

coefficient (i.e., spatially separate but temporally
correlated sources are suppressed), with fully cor-
related sources being undetectable. Beamforming
is therefore not appropriate for certain experimen-
tal MEG paradigms, for example signal locali-
zation in bilateral auditory cortices following
binaural stimuli (Wipf et al., 2010). Suppression
of correlated sources may not be a physiologically
justifiable approach for studying brain activity,
however, beamformer approaches have increas-
ingly demonstrated sufficient robustness for deriv-
ing large scale resting-state brain networks from
MEG (Brookes et al., 2011). MEG derived resting-
state brain networks show a remarkably similar
spatial structure to rsfMRI and have been used as
evidence of a neural oscillatory basis for BOLD
functional connectivity (Brookes et al., 2011).
The high sensitivity of MEG is a double-edged
sword and, like all functional brain imaging meas-
ures, is highly susceptible to a variety of physio-
logical and environmental induced artifacts.
Artifactual sources present in MEG arise from the
same sources as those present in EEG, including
movement, external electrical apparatus, as well
as cardiac and muscle interference. The control
and removal of artifacts is not trivial and exacer-
bated by elevated physiological responses, such as
heartbeat and eyeblink, the two most dominant
sources of noise. Control measures currently applied
during data acquisition typically include compensa-
tory real-time noise cancelation through active field
coils to counteract residual environmental
 Advances in Brain Imaging
magnetic interference, simultaneous secondary
physiological recordings of eyeblink (electroocu-
logram) and heartbeat (electrocardiogram), and
continuous head position monitoring.
Physiological artifacts resulting from oculomo-
tor muscle movement during routine blinking, and
electrical current induced magnetic fields associ-
ated with a heartbeat, are two inherent sources of
noise present in the recorded MEG timecourse
(Hari, 2011). For spontaneous eyeblink, the arti-
fact timecourse corresponds with eyelid motion
and demonstrates a structured pattern, on average
120ms after initiation and after returning to a fully
open state. Cardiac related artifacts demonstrate a
relatively less structured pattern and are observable
to varying degrees in MEG recordings resembling
epileptic spikes and slow waves (Hari, 2011). The
timecourse corresponds to the propagation of heart
muscle electrical activity passing from the atria
through the ventricles as measured by electrocar-
diogram (i.e., P wave, QRS complex, T wave).
Various approaches are suggested for denoising
physiological artifacts from MEG recordings,
the most straightforward (and long-standing)
approach being epoch rejection, which involves
discarding raw data within specific time-windows
from the continuous data with high artifactual
contamination. This is a time-consuming process
that is highly operator-dependent and can result in
significant data loss in cases of widespread epoch
rejection. Alternatively, regression of artifacts by
projecting secondary physiological measures (i.e.,
electrooculogram) is a widely applied approach
for denoising the data, particularly for subtract-
ing ocular related signal from the recorded data.
More recently, development has focused on blind
source separation methods, specifically con-
strained blind source separation (cBSS), to allow
for more automated and objective denoising
using ICA (Escudero et al., 2011). As described
earlier in the chapter, ICA is a model free data-
driven approach for decomposing a multivariate
source signal into its independent linear compo-
nents. Blind source separation methods isolate
artifactual signal sources contaminating the full
timecourse, however, visual inspection is still
required for identification. A direct extension
to blind source separation is cBSS, which intro-
duces the use of statistical metrics (e.g., kurtosis,
entropy) to define criteria for the identification of
artifactual source components. This can be aided
by the inclusion of simultaneous secondary phys-
iological recordings to improve ocular and car-
diac artifact identification (Dammers et al., 2008;
Klados et al., 2011), which have been shown to
be practical for artifact removal from real world
MEG recordings (Escudero et al., 2011).
543
NETWORK CONNECTIVITY
The derivation of functional brain networks and
their statistical comparisons are not unique across
functional brain imaging modalities. Large-scale
brain networks in MEG can be generated using
the same data-driven ICA approach used in fMRI
with considerable overlapping spatial structure of
correlated spontaneous fluctuations in neuronal
activity at rest (Brookes et al., 2011), or using a
node-based hypothesis driven approach (Stam
et al., 2009). However, the type of signal charac-
teristics and post-processing steps applied to the
acquired data to measure the degree of functional
connectivity between brain regions differs signifi-
cantly across imaging modalities. The MEG
signal primarily represents the net magnetic field
changes generated by postsynaptic currents of
pyramidal neurons but is in essence a compound
signal, comprising multiple sources superim-
posed. Given its extremely high temporal resolu-
tion, each sensor captures the oscillatory activity
of local neuronal populations, such that functional
connectivity is determined by how closely neu-
ronal populations oscillate in synchrony (i.e.,
amplitude and phase-coupling). This follows the
influential “communication through coherence”
hypothesis (Fries, 2005), which proposes a mech-
anistic principle whereby coherently oscillating
neuronal groups reach peak inter-communication
efficiency if they share a similar timecourse for
maximum/minimum spiking threshold for send-
ing and receiving a barrage of action potentials. It
is important to note that synchrony does not
reflect real information exchange, rather it reflects
the relative conditions best suited to allow effi-
cient physiological information exchange between
different neuronal populations. Neuronal oscilla-
tions are measured in a range from around 0.05Hz
to 500Hz and commonly classified into five fre-
quency bands (i.e., δ [2–4], θ [4–7], α [8–12], β
[12–30], γ [30–80]) that demonstrate marked top-
ological differences in neuronal networks. High
frequency bands are characteristic of smaller spa-
tial scale brain networks, and low frequency bands
for large-scale networks (Brookes et al., 2011;
Florin and Baillet, 2015). Coupled oscillations are
also not limited to within the brain, but also
extend between brain and body (cardiac, gastric,
muscle) activity rhythms (Klimesch, 2018).
For estimating functional connectivity between
two regions with MEG, two types of measures are
commonly used, coherence (for linear relation-
ships), and phase locking (for non-linear relation-
ships). Coherence measures the degree of similarity
between two timeseries and is the equivalent of a
cross-correlation function for the frequency domain,
544 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 32.7. Characteristics of high and low synchronous signals in MEG. Neural oscillations
(i.e., brain waves) are sinusoidal, following a repeating rhythmic pattern demonstrating
frequency fluctuations in terms of amplitude and phase. Complex changes over time can be
depicted as changing points on a 2D cartesian co-ordinate system to visualize the spectral
representation of individual MEG signals, or the complex conjugation of the frequency
of two signals (i.e., cross-spectral density [CSD]). Connectivity can be conceptualized as
the synchronicity of frequency fluctuations of MEG signals over time, represented by the
consistency of CSD across observations. Coherence is calculated as the weighted sum of CSD
across observations as a measure of connectivity. Phase locking value is conceptually similar,
but only considers the consistency of phase differences, disregarding amplitude correlations
of the MEG signal.

representing a normalized coefficient between 0 estimating functional connectivity in MEG is not

and 1 that quantifies the amount of variance that
can be explained between two signals. Yet, recorded
neuronal activity more closely resembles noisy
deterministic patterns of chaotic activity, particu-
larly for sensory neural systems, which may actu-
ally contribute to enhance functionality (Freeman,
1987). The intricate complexity of feed-forward
and feed-back mechanisms in the brain means that
activity at the level of neural synapses is non-linear
with high variability in short term dynamics associ-
ated with neuromodulation processes. To this end,
phase locking provides a non-linear measure of
the temporal relationship between two timeseries
independent of their signal amplitude and is argu-
ably better suited for measuring functional connec-
tivity with MEG. In practice, however, non-linear
measures are highly susceptible to noise and dem-
onstrate less robust performance relative to linear
measures in real world application. The case for
using coherence or phase locking measures for best
clear cut when they in fact provide complementary
information on the dynamic nature of brain func-
tion. In particular, their combined application better
encapsulate linear and non-linear interdependen-
cies of cortical dysfunction in patient populations
(Sakkalis et al., 2009).
ADVANCES IN PET
Time-of-Flight (TOF) PET
PET is a radioisotope decay counting technique
whereby the signal is produced by the time-­
coincidence detection of two 511-keV photons
emitted almost back-to-back along a line of response
(LOR) and picked up by surrounding sensor arrays.
The role of the sensor is to capture the trajectory and
 Advances in Brain Imaging
timing of released photons to reconstruct the origin
of the emission along the LOR. In theory, the differ-
ence in arrival time of the emitted pair of photons
can be used to precisely localize where along the
LOR emission occurred, otherwise known as TOF
PET, a concept considered since the early days of
PET imaging. In practice, however, traditional BGO
scintillators cannot resolve the time difference in
detection necessary for the precision of TOF meas-
urements (< 2ns). Instead, emission location is
reconstructed by collecting all possible LORs meas-
ured around an object and a uniform probability of
the event location is assumed along the full LOR
length. Noise correlations from different emission
events significantly increases the uncertainty of
localization. Early alternatives to BGO detectors
with significantly greater timing gain were consid-
ered (BaF2; CsF) but ultimately rejected due to poor
mechanical properties (i.e., low stopping power,
light output, attenuation) resulting in overall worse
spatial resolution due to reduced detection sensitiv-
ity that offset any effective gains provided by TOF
(Lewellen, 1998). This changed with the develop-
ment of SiPMs and led to the reintroduction of TOF
PET in the late 2000s. With TOF PET, the emission
point along a LOR can be directly determined (with
a degree of uncertainty) by measuring the difference
in arrival times of the emitted photons. The tech-
nique has been shown to significantly improve
image quality and/or reduce image acquisition time
for low-count clinical imaging applications (Surti,
2015). The use of increasingly fast timing detectors
is now an integral component of modern PET imag-
ing as developments such as SiPMs have shown that
increased timing performance does not need to come
at a trade-off with sensitivity and spatial resolution.
KINETIC MODELING
The goal of PET imaging is to measure a selected
in-vivo physiological parameter of interest (e.g.,
glucose metabolism, enzyme activity, receptor/
transporter concentration, hypoxia). Injected radi-
otracers are distributed through arterial blood to
allow binding with tissue in brain regions of high
molecular affinity. Direct measurements of radi-
otracer concentration from raw PET images are,
however, not representative (or even directly pro-
portional) to underlying physiological function
(Gallezot et al., 2020). Reconstruction algorithms
are required to accurately model confounding
kinetic parameters, notably, tracer concentration in
blood plasma, motion (head, cardiac, respiratory),
and noise, for meaningful interpretation of quantita-
tive tracer uptake values.
545
Acquisition protocols used for PET imaging
varies greatly depending on application. The data
acquired by PET imaging represents the detection
counts of coincident timed positron annihilation
events over time. Statistical accuracy is primar-
ily determined by the number of acquired counts,
which in turn is constrained by administered tracer
radiation dose and desired temporal resolution.
Clinical protocols (primarily for FDG) favor brief
scans (∼10–20min) after a set post-injection delay,
pre-determined by validated intervals for greatest
sensitivity depending on tissue and/or region of
interest, to reconstruct “static” images averaging
all event counts. The primary benefit of a static
imaging approach is fast data acquisition with low
noise to generate a spatial distribution map of radi-
oactivity in the brain (with no temporal informa-
tion) that can be used for qualitative assessment or
simple dimensionless region of interest standard
uptake value (SUV) comparisons (i.e., “normal”
or “abnormal”). Static PET imaging is simple to
acquire, standardize, interpret, and provides clini-
cally meaningful biological information. A sig-
nificant confound for such an approach, however,
is the presence of inter-individual differences in
tracer delivery or flow effects resulting in variable
values that can lower qualitative and quantitative
tracer sensitivity (Gallezot et al., 2020).
An alternative approach is “dynamic” imaging
whereby a time series of images are acquired over
an extended duration (∼60min) to better capture
the time-activity curve of tracer concentration.
Dynamic imaging is necessary for kinetic mod-
eling and extraction of quantitative features hid-
den from visual inspection and semi-quantitative
clinical parameters (i.e., SUV). Dynamic PET also
allows for more advanced research applications
such as investigating real-time neurotransmitter
receptor release/occupancy (Wey et al., 2014).
This comes at the cost of significantly longer
scanning time, increased motion susceptibility,
and noisier data, requiring more advanced models
for reconstruction, but in most cases significantly
improves sensitivity and specificity of focal tracer
uptake (Gallezot et al., 2020). The increased noise
contained within individual voxels of dynamic
PET images is one of the main limitations that
needs to be addressed with image reconstruction
algorithms (e.g., Gaussian smoothing for spatial
smoothing; principal components analysis for
temporal smoothing) to facilitate clinical adoption
beyond research purposes. A variety of models
can be used for estimating the time-varying tissue
concentration of a tracer, broadly categorized into
three categories: compartmental models, graphi-
cal analyses, and spectral analyses (Gallezot
et al., 2020). Compartmental models are the
most widely used approach, defining one or more
546 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 32.8 Standard uptake value images of serotonin radiotracer (11)C-AFM. Averaged
uptake across brain regions at different post-injection time periods, over time tracer clears
from regions with low binding affinity. Kinetic modeling can be applied to calculate and
separate flow effects associated with tracer delivery to better identify sites of focal uptake,
such as the raphe nucleus, a key midbrain site of serotonergic fibers (Gallezot et al., 2020).

compartments, each with an associated kinetic
flow rate, to account for any individual state (i.e.,
physical environment: plasma, tissue; binding sta-
tus: free, specific, non-specific; chemical form:
pure tracer, metabolite) a tracer can assume.
The primary consideration for deciding between
a static versus dynamic protocol is acquisition
time and repeated blood sampling (although see
Gallezot et al., 2020). A dynamic acquisition is
always required for quantitative PET metrics and
can also be averaged over specific time frames to
generate a “static” weighted average if required.
METABOLIC CONNECTIVITY
Functional connectivity, or more accurately meta-
bolic connectivity, derived from PET is fundamen-
tally quite different from fMRI and MEG. The
limited temporal resolution of conventional static
PET imaging results in images with a steady-state
signal, typically resulting in a single representative
image per subject, a stark contrast to the dynamic
signal variation present in the rich MRI/MEG data
timeseries. Consequently, connectivity between
two regions depends on the significance of their
correlation across subjects at a group level (i.e., not
spatial patterns of temporal activation per subject).
The derived connectivity from PET does, however,
provide a more specific indicator of the physiologi-
cal relationship between brain regions. For exam-
ple, (15)oxygen (15O) labeled PET imaging is an
alternative method for quantifying the metabolic
rate of oxygen for functional brain imaging that has
been phased out by fMRI, given its higher spatial
and temporal resolution, and lack of radiation
exposure. Nevertheless, 15O-PET has the distinct
advantage of being able to separate and account for
confounding vascular effects (blood flow/volume)
associated with brain oxygenation, and potentially
better suited as a reliable inter-­individual physio-
logical marker of underlying brain “activation,”
particularly in the context of longitudinal measure-
ment, which remains a significant challenge for
fMRI. It is notable that the “default mode network,”
a large-scale brain network continuously engaged
in the absence of external stimuli or conscious
engagement and widely popularized by rsfMRI
studies in cognition and neurological disorders
(Buckner et al., 2008), was originally conceptual-
ized and characterized through 15O-PET imaging
(Raichle et al., 2001; Shulman et al., 1997).
As mentioned earlier, the analysis methods used
to analyze network connectivity is not unique to
specific functional brain imaging modalities and
the same holds true for PET imaging data, which
draws on general signal processing approaches
such as data-driven principal components analy-
sis and ICA (Pagani et al., 2016; Tripathi et al.,
2016), and node-based approaches such as inter-
regional correlation analysis and sparse inverse
covariance estimation (Arthuis et al., 2015; Zou
et al., 2015). The bulk of connectivity stud-
ies published in the literature is based on static
FDG-PET, which typically relies on intensity-
based analysis approaches, following image
reconstruction, similar to structural MRI. The
advantage of assessing network connectivity with
 Advances in Brain Imaging
FDG-PET is the additional inferences that can be
drawn, for example, between the reorganization
of local and long-distance energy consumption
and pathogenesis of disease in neurodegenerative
disorders (Sala et al., 2017). Of greater interest
are increasing studies employing dynamic PET/
MRI connectivity to advance our understanding
of the physiological basis for network changes
observed in rsfMRI (Passow et al., 2015; Tomasi
et al., 2017). Traditionally, dynamic PET data
is used to extract kinetic parameters, but with
respect to the association of time-varying effects
with rsfMRI, more subtle variations in the tracer
timecourse are of interest. There does remain a
significant difference in the timescale between
PET and fMRI (minutes vs. seconds), leading to
reported mismatches between outcome measures
of metabolic and functional connectivity patterns
that requires methodological advances in time-
varying kinetic modeling to resolve (Tomasi et al.,
2017). Development of dynamic PET/MRI meth-
odology opens new avenues of research inquiry,
such as pharmacological modulation of neural
receptor occupancy to assess neurovascular cou-
pling mechanisms with hemodynamic change
across brain networks, and cognition. Growing
developments in this area are a good example of
how methodological advances in functional brain
imaging goes hand-in-hand with advancing cogni-
tive and systems neuroscience.
FUTURE DIRECTIONS
Multimodal Brain Imaging
Multimodal brain imaging is increasingly recog-
nized as a necessary step for advancing cognitive
and systems neuroscience to overcome the inherent
limitations underlying traditional functional brain
imaging techniques. The impact of hardware devel-
opments such as hybrid PET/MRI are already evi-
dent, with studies advancing current understanding
of neuroreceptor function across dopamine, seroto-
nin, and opioid primary neurotransmitter systems
in the context of behavioral modulation (Sander
et al., 2020). Studies have employed this approach
for examining neural mechanisms of pain percep-
tion through simultaneous, rather than separate,
data acquisition (Karjalainen et al., 2017; Linnman
et al., 2018; Wey et al., 2014). The simultaneous
nature of the data acquisition allowed accurate co-
localization of PET and fMRI signal change in a
common domain for: (i) characterization of an
extended cortical/subcortical network of pain pro-
cessing structures (Wey et al., 2014), and
547
(ii) exploring regional neurotransmission/neurovas-
cular coupling, supporting a divergent association
for experienced as compared with observed pain
(Karjalainen et al., 2017; Wey et al., 2014), and a
dissociation for placebo analgesic drug paradigms
(Linnman et al., 2018). The equivalent simultane-
ous acquisition of MEG and fMRI data is not tech-
nically possible (except for EEG/fMRI). However,
the analysis of their combined data, collected
through separate experimental sessions under simi-
lar task conditions, is possible and can be per-
formed in a common domain through techniques
such as representational similarity analysis (Cichy
and Oliva, 2020; Kriegeskorte and Kievit, 2013).
The framework only considers the timing of neural
activity from MEG, and space from fMRI, estab-
lishing a representational link between spatial and
temporal domains for a given study condition. Such
an approach constrains the experimental design,
including the optimization of the same experimen-
tal condition for both MEG and fMRI, ensuring a
high signal can be detected within each imaging
modality. A fundamental limitation is that the
recorded neural activity is not concurrent and origi-
nates from separate recordings which will include
nuisance variability. Nevertheless, the synthesis of
MEG and fMRI data for reducing their respective
spatial and temporal limitations has resulted in a
number of well-constructed paradigms examining
underlying spatiotemporal dynamics of object,
scene, and higher order attention processing (Cichy
et al., 2014; Hebart et al., 2018; Henriksson et al.,
2019). Development of novel analytical frame-
works for multi-modal imaging are ongoing, aided
through open-source datasets of combined fMRI,
MEG, and PET imaging data (Jamadar et al., 2020;
Schoffelen et al., 2019).
MAGNETIC RESONANCE SPECTROSCOPY
While not covered in this chapter, another func-
tional MRI modality that has significant potential
for characterizing the neuromodulatory influences
of biological mechanisms underlying cognition,
is magnetic resonance spectroscopy. MRS is a
non-invasive technique for quantifying tissue
metabolite concentrations derived through differ-
ences in the resonance frequency exerted by the
nucleus structure of constituent molecules includ-
ing hydrogen (1H), phosphorus (31P), fluorine
(19F), and carbon (13C). 1H-MRS is by far the most
prevalent form of MRS reported in the literature
and can be acquired using a conventional head
coil as an additional sequence in a standard MR
protocol. Clinically, it is widely used for the
548 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
identification, grading, and evaluation of tumour
subtypes to inform diagnosis and treatment. In
research, it has been widely used to quantify
abnormalities in steady-state metabolite concen-
trations in patient populations to infer pathomech-
anisms of disease, and also in combination with
task-based fMRI studies of basic visual and
motor, and higher order cognitive processing, to
infer the influence of localized excitation-­
inhibition balance on neuronal activity, although
with variable findings (Kiemes et al., 2021).
A key consideration for brain MRS is relatively
low concentrations of the metabolites of great-
est interest in regard to cognition (i.e., 1H-MRS:
glutamate/glutamine [Glu/Gln], γ-aminobutyric
acid [GABA], myoinositol [mIns], glutathione
[GSH]; 31P-MRS: nicotinamide adenine dinu-
cleotide ratio [NAD+/NADH]). Depending on the
metabolite(s) of interest and anatomical location,
a high number of signal averages are required for
detection, or use of spectral edited sequences to
resolve the overlapping nature of their signal (i.e.,
GABA) from more concentrated metabolites.
Consequently, single voxel spectroscopy is the
most feasible means of MRS acquisition (∼5–10
min), with additional voxels acquired as needed
through additional sequences. Whole-brain 1H-
MRS is possible but currently impractical due
to high acquisition time (>20 min), high motion
susceptibility, and most importantly, only reliable
for quantifying high concentration metabolites
(i.e., N-acetylaspartate) (Stagg et al., 2013). The
shift to ultra-high field 7T MRI holds significant
benefits for MRS and improves not only the sig-
nal to noise ratio, but also increases the chemical
shift dispersion allowing further spectral separa-
tion of overlapping metabolite signals (i.e., Glu/
Gln; NAD+/NADH) that can only be measured
as a pooled concentration at 3T. This can be fur-
ther paired with functional MRS, a conceptual
framework whereby dynamic metabolite change
is assessed across block conditions of a behavio-
ral paradigm (Stanley and Raz, 2018). Increased
accuracy to resolve the relative concentrations of
individual metabolites and robust assessment of
their dynamic change will undoubtedly generate
advances in current understanding of changes in
metabolic brain states and their impact on neu-
ronal circuits and cognition.
MACHINE LEARNING
On a final note, a noteworthy area that has seen a
rapid resurgence of recent development, and holds
significant potential for functional brain imaging, is
the increasing application of machine learning
based image classification algorithms, specifically
deep learning neural networks, being developed for
neuroimaging (Ronneberger et al., 2015). In
essence, neural networks specify an architecture for
extracting features contained within a dataset that is
refined and modeled with increasing complexity
through successive “layers” to learn, and conse-
quently, allow automated recognition and classifica-
tion of prospective data, according to modeled
features. To date, neural networks have demon-
strated remarkable accuracy and, more importantly,
generalizability for structural neuroimaging, facili-
tating precise segmentation of brain structures
(Manjon and Coupe, 2016), and automated disease
classification of neurodegenerative disorders based
on atrophy patterns (Basaia et al., 2019; Eshaghi
et al., 2021), that have led to their widespread adop-
tion in research and promising clinical adoption.
The successes of neural networks in structural neu-
roimaging are in part due to the relatively standard-
ized acquisition protocols, limited confounding
factors impacting signal intensity, and simplicity of
tissue contrast and anatomical morphology as mod-
eled features. While neural networks have also been
applied for similar application across functional
brain imaging modalities, generalizability across
independent data sets remains low but presents a
promising direction for future development.
SUMMARY AND CONCLUSIONS
In the current chapter we have highlighted techni-
cal advances, practical considerations, and inter-
pretability of current implementations of fMRI,
MEG, and PET brain imaging to assess neural
function and connectivity. Despite the distinct con-
ceptual differences that underlie each functional
imaging modality, methodological advances are
uniformly aimed at improving signal localization
while controlling for artifacts and noise. While this
is always best handled at the acquisition stage, a
key part of preprocessing any dynamic brain imag-
ing dataset is cleaning the data. ICA-based meth-
ods are widely used given their robustness for
identifying and removing structured noise, particu-
larly for known physiological noise signatures,
whereby individual noise components are identi-
fied and regressed resulting in a “cleaned” signal.
Currently, fMRI strikes the best balance between
accessibility, ease of implementation, sensitivity of
spatial localization, and capture of dynamic changes
in brain function, but is fundamentally limited
by slow, delayed, changes in blood oxygenation.
When we consider the multitude and physical dis-
tance covered by concurrent synaptic transmission
 Advances in Brain Imaging
occurring within a 1s time frame throughout the
brain, the limitations of fMRI to deliver systems-
level interpretation of brain function is clear when
used in isolation. In contrast, MEG directly meas-
ures neuronal activity with exceptional temporal
resolution to best capture dynamic fluctuations in
whole-brain function, while PET provides the best
specificity of neural mechanisms underlying brain
function. Multi-modal functional brain imaging is
critical to overcome inherent limitations of indi-
vidual functional neuroimaging modalities and is
an increasingly common approach in neuroscience,
with MRI serving as an independent or embedded
complementary measure for MEG and PET, respec-
tively. In regard to deriving functional brain net-
works, while there is considerable overlap between
fMRI and MEG, the timescale difference with PET
remains a barrier that needs to be overcome.
ABBREVIATIONS
15O – (15)Oxygen
BOLD - Blood Oxygenation Level-Dependent
cBSS – Constrained Blind Source Separation
CSD – Cross-spectral Density
CT – Computed Tomography
EEG - Electroencephalogram
EPI – Echo Planar Imaging
fMRI – Functional Magnetic Resonance Imaging
FDG – Fluorodeoxyglucose
ICA – Independent Components Analysis
LOR – Line of Response
MEG – Magnetoencephalography
MRS – Magnetic Resonance Spectroscopy
PET – Positron Emission Tomography
SiPMs - Silicon Photomultipliers
SQUID - Superconducting Quantum Interference Device
TE – Time Echo
TOF – Time of Flight
TR – Time Repeat
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Novel Approaches to Large-Scale
Data in Neuroimaging
M a t t h e w T h a r p , S h a n n o n L . R i s a c h e r,
Paula Bice, Paul M. Thompson,
A n d r e w J . S a y k i n , a n d M e i c h e n Yu
INTRODUCTION
Numerous techniques have been proposed to
advance data applications in neuroimaging, resulting
in some uncertainty as to which techniques are best
suited to address the wide variety of unique chal-
lenges. While an exhaustive overview of available
techniques is beyond the scope of this chapter, we
highlight some promising novel neuroimaging
approaches that may be particularly crucial for future
large-scale data analyses. In particular, we address
novel approaches with neuroimaging modalities,
machine learning (ML), and deep learning (DL) as
well as considering statistical advances and tech-
niques for managing high dimensionality data via
source separation. Given the specificity of much of
the neuroscientific and neuroimaging terminology, a
list of briefly-defined key terms is presented below.
NEUROIMAGING MODALITIES
Before addressing large-scale data analysis
approaches in neuroimaging, it is helpful to pro-
vide an overview of commonly used neuroimag-
ing modalities. In this section we will introduce
each neuroimaging modality while highlighting
novel developments.
33
Structural magnetic resonance imaging (sMRI)
is rooted in the spatial domain and can be captured
with different imaging sequence variations that are
sensitive to different tissue properties such as T1,
T2, T2*, and FLAIR (Symms et al., 2004). One
advantage of sMRI is the ability to image subcor-
tical structures, such as the thalamus (Su et al.,
2019), where post-processing methods, including
voxel-based morphometry (VBM), surface-based
morphometry (SBM), and MR-relaxometry enable
different views of structural brain features (Martin
et al., 2015). More recently, the MP2RAGEME
sequence has been developed, allowing T1, T2*
and quantitative susceptibility maps (QSMs) to be
acquired simultaneously (Caan et al., 2019).
Functional MRI (fMRI) acquires blood-oxygen-
level-dependent (BOLD) signals to provide a
noisy indication of underlying neural activity at
low spatiotemporal resolution. Atlases such as the
Yeo-17 (Yeo et al., 2011) are commonly used to
represent fMRI acquisitions, providing a set of
regions of interest (ROIs) that may be used for
network analyses of functional connectivity (FC).
Most commonly, FC is assessed in a static manner
with large time windows, although dynamic FC
approaches that utilize a sliding time window are
becoming increasingly popular (Hutchison et al.,
2013). Recently, ultrafast fMRI has been explored
with mice to address spatiotemporal limitations of
conventional fMRI (Gil et al., 2021).
554 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Table 33.1 Key terms and brief definitions

Key Terms Definitions

Autoencoder
Bayesian network
Canonical correlation analysis
Convolutional neural network
Data harmonization
Deep belief network
Dynamic causal modeling
Generalized additive model
Generative adversarial network
Independent component analysis
Markov model
Meta/mega-analysis
Multi-layer perceptron
Principal component analysis
Recurrent neural network
Residual neural network
Support vector machine
Deep learning model which learns data encodings via dimensionality reduction
with neural networks
Machine learning method which uses graphical models to represent variables and
dependencies as directed acyclic graphs
Source separation method which finds the maximum correlation of different linear
combinations of two vectors
Deep learning method typically used with images which uses convolutions to
extract patterns from feature maps
A set of statistical methods which can be used to reduce site/scanner effects from
neuroimaging measurements
Deep learning method which uses multiple layers of other deep learning models
such as restricted Boltzmann machines or autoencoders
Statistical method used for causal inference by comparing information between
Bayesian models
Statistical method which uses generalized linear models to relate a response
variable to several predictor variables
Deep learning method which generates new data by placing two neural networks
in competition with one another
Source separation method which separates a signal into subcomponents by
identifying maximal statistical independence
Machine learning method which uses stochastic models to represent variables and
dependencies graphically
Statistical method which pools data from multiple sites to improve statistical power
Deep learning method which uses multiple layers of perceptrons guided by
activation functions for pattern extraction
Source separation method which separates a signal into subcomponents by
identifying maximal orthogonality
Deep learning method where outputs from nodes connect to previous nodes
cyclically to extract patterns recurrently
Deep learning method which uniquely includes skip connections to allow one
extraction layer skip over subsequent layers
Supervised machine learning method which uses a training dataset as a model for
assigning categories to data

Diffusion weighted imaging (DWI) is a MR approach, position-orientation adaptive smoothing

technique that measures the displacement of water
molecules across tissue, allowing white matter pro-
jections in the brain to be detected. Diffusion tensor
imaging (DTI) is commonly used as an extension of
DWI to indicate the directionality of image voxels
via tensors, including fractional anisotropy (FA), a
metric used to quantify the magnitude of direction-
ality of individual DTI tensors. Additional exten-
sions of DWI exist including neurite orientation
dispersion and density imaging (NODDI) (Zhang
et al., 2012), fiber-based analysis (FBA) (Pecheva
et al., 2018), constrained spherical deconvolution
(CSD) (Tournier et al., 2008), informed CSD (Roine
et al., 2015), deterministic tractography (Alexander,
2010), and probabilistic tractography (Sarwar
et al., 2019). A recent novel DWI post-processing
(POAS), has been proposed as an alternative trac-
tography approach (Yang et al., 2020).
Perfusion weighted imaging (PWI) can be used
to study blood flow throughout the brain. Popular
PWI techniques include arterial spin labeling
(ASL) and dynamic susceptibility contrast imag-
ing (DSC) (Bergamino et al., 2020). Another
modality, functional near-infrared spectroscopy
(fNIRS), can monitor changes in blood flow by
measuring cerebral hemoglobin concentrations
(Hoshi and Michael, 2005). This modality pro-
vides opportunities for naturalistic imaging set-
tings as it can acquire measures in non-laboratory
environments (Pinti et al., 2020).
Techniques such as positron emission tomogra-
phy (PET) and single photon emission computed
 Novel Approaches to Large-Scale Data in Neuroimaging
tomography (SPECT) can be used to acquire
images of radioactive tracers within the brain.
Both techniques are limited by spatial resolution,
but their promise is exemplified by their abil-
ity to measure highly specific brain processes.
For example, with PET, radiotracers have been
developed for imaging neurotransmitter activ-
ity, amyloid plaques, neurofibrillary tangles, and
intracellular signals (Hooker and Carson, 2019).
Finally, techniques such as electroencepha-
lography (EEG) and magnetoencephalography
(MEG) can be used to measure electrical signals
within the brain. Commonly, EEG/MEG are uti-
lized for studies of brain connectivity, making
them useful for studying connectivity-related dis-
orders at higher temporal resolution than fMRI (da
Cruz et al., 2020; Nentwich et al., 2020).
STATISTICAL ADVANCES
With increasing amounts of data, several statisti-
cal challenges have arisen in neuroimaging includ-
ing difficulties due to effect sizes (Reddan et al.,
2017), increased vulnerability to confounding
variables (Smith and Nichols, 2018), underreport-
ing of statistical power calculations (Szucs and
Ioannidis, 2020), and concerns about the reliabil-
ity of statistical significance tests (Hupé, 2015).
Other issues related to causal inference and statis-
tical methodologies for multi-site meta-analyses
have also garnered significant interest. In this
section we will further introduce these statistical
challenges and discuss novel approaches toward
addressing them.
Earlier methods for neuroimaging analyses
have been criticized, as the statistical tests were
performed on thousands of voxels, thus increas-
ing susceptibility to selection bias (Reddan et al.,
2017). To address this issue, many studies have
used multiple comparisons corrections such as the
false discovery rate (FDR); however, these cor-
rections are also prone to bias (Hupé, 2015). One
solution to this problem is to reduce the number
of statistical tests required for a given study via
dimensionality reduction techniques.
Another concern for future statistical analyses is
causal inference, specifically regarding the misinter-
pretation of directionality with causality in graphi-
cal models (Lindquist and Sobel, 2011). To address
this, various causal inference methods have been
proposed such as Bayesian methods (Cao et al.,
2019), dynamic causal modeling (DCM) (Moran
et al., 2013), and Granger causality analysis (Seth
et al., 2015). In addition, another study developed a
method to quantify the extent of confounding using
555
the information theoretic Kolmogorov complexity
metric (Wachinger et al., 2019).
Some significant advancements for statistical
analyses can be found within multi-institutional
collaborations, which are becoming commonplace
to enhance statistical power via dataset integration
from multiple imaging sites. Specifically, methods
related to data harmonization, meta-analysis, and
mega-analysis have brought promise to the reliabil-
ity of future statistical analyses in neuroimaging.
For example, the ComBat technique (Johnson et al.,
2007) is a popular method for modeling and remov-
ing site-specific effects of multi-site neuroimaging
studies from DTI (Fortin et al., 2017), sMRI (Fortin
et al., 2018), or fMRI (Yu et al., 2018), and longitu-
dinal ComBat has recently been developed for lon-
gitudinal multi-scanner data (Beer et al., 2020). In
addition, ComBat-GAM has been proposed for use
in generalized additive models (GAMs) (Pomponio
et al., 2020). A recent study compared the perfor-
mance of multiple data harmonization techniques
and found that the use of ComBat-GAM for har-
monizing multisite cortical thickness data can more
effectively minimize confounds and increase statis-
tical power than other techniques (Sun et al., 2021).
Nonetheless, some limitations to the ComBat meth-
odology have been discussed, such as an inability
to preserve effect sizes from sites with several non-
linear scanner effects and the means by which small
pre-processing differences may lead to different
harmonization outcomes (Cetin-Karayumak et al.,
2020). ComBat also requires spatial registration
to a population template, although an alternative
approach, known as multisite image harmoniza-
tion by cumulative distribution function alignment
(mica), has been proposed to address this issue
by comparing several scans on a single subject
(Wrobel et al., 2020). Similarly, Neuroharmony,
which enables scanner bias reduction via DL with-
out reference to a prior population, has also been
suggested (Garcia-Dias et al., 2020). Other novel
approaches to data harmonization have been pro-
posed in a DL context, including a dual generative
adversarial network (GAN) approach (Zhong et al.,
2020), an attention-guided deep domain adaptation
(AD2A) approach (Guan et al., 2021), and a con-
volutional neural network (CNN) approach called
DeepHarmony (Dewey et al., 2019). GAN methods
can also address biases in training ML methods on
multisite data, extending beyond scanner protocols
to adjust for age, sex, and other demographic effects
more completely (Zhao et al., 2020). When apply-
ing highly nonlinear methods such as DL to mul-
tisite data, it can be extremely difficult to remove
confounders, and predictive models can lock onto
features that are coincidentally related to the out-
come, leading to poor generalization performance.
GANs provide an attractive and novel solution to
556 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
this problem when typical linear regression meth-
ods are insufficient (Dinsdale et al., 2021; Dockès
et al., 2021). Lastly, various additional harmoniza-
tion approaches may yet be important for future
statistical analyses such as adaptive linear map-
ping of rotational invariant spherical harmonics
(LinearRISH) developed for dMRI (Ning et al.,
2020), diffusion parametric map harmonization
(DPMH) (Pinto et al., 2020), and nonlinear distri-
bution mapping for amyloid-PET harmonization
(Properzi et al., 2019).
Besides data harmonization, meta-analytic,
and mega-analytic methods have increased the
reliability of statistical analyses. Meta-analytic
methods refer to multi-site endeavors for coordi-
nating data acquisition, processing, and analysis to
ensure methodological consistency between sites,
enabling data pooling for larger sample sizes.
Notably, the Enhancing Neuroimaging Genetics
through Meta-Analysis (ENIGMA) consortium
has used both mega- and meta-analytic practices
extensively to discover relationships between
neuroimaging and genetics, yielding the largest
MRI and DTI studies to date of over 15 psychi-
atric, neurological, and developmental disorders
(Thompson et al., 2020). The use of standardized
analysis pipelines for MRI, DTI, fMRI, and most
recently EEG (Smit et al., 2018) has led to well
powered studies relating brain metrics to common
and rare genetic variations (Grasby et al., 2020;
Van Der Meer et al., 2020) and even epigenetic
variation (Jia et al., 2019) by pooling data from
over 45 countries worldwide. Most commonly,
coordinate-based meta-analysis (CBMA) meth-
ods have been used to enable comparisons within
standard stereotaxic spaces between studies (Fox
et al., 2014), and toolboxes such as the CluB tool-
box (Berlingeri et al., 2019) and the ENIGMA
toolbox (Lariviere et al., 2020) have made it easier
to integrate meta-analytic methods and to test asso-
ciations between neuroimaging and molecular,
transcriptomic, or histologic data in other bioin-
formatics databases such as the Allen Brain Atlas.
Beyond meta-analysis, another technique known
as mega-analysis pools raw data from multiple
sites instead of combining pre-­processed data.
This technique has been adopted by the ENIGMA
consortium for the investigation of various brain
disorders (Jalbrzikowski et al., 2021; Koshiyama
et al., 2020; Wang et al., 2020).
SOURCE SEPARATION
Source separation, or blind source separation
(BSS), refers to a set of techniques that may be
used in different noise or dimensionality reduction
contexts to separate a signal of interest (SOI) from
acquired data. These techniques are especially
important for neuroimaging where numerous
SOIs may be masked by noise or higher dimen-
sional representations. BSS methods can be cate-
gorized into four overarching categories: single
data unidimensional (SDU), multiple dataset unidi-
mensional (MDU), single dataset multidimensional
(SDM), and multiple dataset multidimensional
(MDM) (Silva et al., 2016).
When analyzing data from a single modal-
ity, oftentimes a single dataset unidimensional
approach is needed. Principal component anal-
ysis (PCA) is a popular SDU approach, and
different versions have been proposed for neuro-
imaging contexts such as sparse PCA (SPCA) (De
Pierrefeu et al., 2017), sparse principal component
of mediation (SPCM) (Zhao et al., 2020), and
shared component analysis (De Cheveigné, 2021).
Independent component analysis (ICA) is another
SDU approach with several variations used for
neuroimaging, including Infomax (Fedorov et al.,
2019), FastICA (Ge et al., 2016), probabilistic
ICA (PICA) (Sarraf et al., 2014), and longitudinal
ICA (Wang and Guo, 2019).
In some cases, researchers may desire a uni-
dimensional representation of multiple datasets.
Canonical correlation analysis (CCA) can be used
to identify correlations between datasets, and a
popular version known as multiset CCA (mCCA)
has been applied to data fusion in neuroimaging
(Correa et al., 2010). In addition, mCCA with
reference (MCCAR) has also been proposed
for data fusion with joint ICA (jICA) (Qi et al.,
2016). Likewise, group ICA (GICA) (Calhoun
et al., 2009) and parallel ICA (pICA) (Laforce Jr
et al., 2014) can be used for MDU purposes along
with additional ICA-based methods such as ten-
sor ICA (TICA) (Koush et al., 2019), linked ICA
(LICA) (Groves et al., 2011), hierarchical group
PICA (Guo and Tang, 2013), and group informa-
tion guided ICA (GIG-ICA) (Du and Fan, 2013).
Some additional approaches worth considering
for MDU contexts include non-Gaussian meth-
ods such as non-Gaussian component analysis
(NGCA) (Diederichs et al., 2010), and simultane-
ous NGCA (SING) (Risk and Gaynanova, 2020).
In other instances, a multidimensional rep-
resentation of a single dataset may be desir-
able. In these cases, independent vector analysis
(IVA) methods such as Laplacian IVA (IVA-L),
Gaussian IVA (IVA-G) (Anderson et al., 2011)
or subspace analysis methods such as independ-
ent subspace analysis (ISA) (Ma et al., 2010),
adaptive independent subspace analysis (AISA)
(Ke et al., 2019), and stationary subspace analy-
sis (SSA) (Khan et al., 2016) may be useful. In
 Novel Approaches to Large-Scale Data in Neuroimaging
addition, a technique based on statistical physics
known as energy landscape analysis (Ezaki et al.,
2017) has been proposed for a SDM neuroimag-
ing context.
Finally, MDM approaches may be crucial for
future complex neuroimaging analyses where
a multidimensional representation of multiple
datasets is needed, as with multi-omics applica-
tions (Subramanian et al., 2020). Some MDM
approaches suitable for neuroimaging applica-
tions include multi-dataset ISA (MISA) (Silva
et al., 2020) and joint ISA (JISA) (Lahat and
Jutten, 2016). In addition, a technique known as
Laplacian eigenmaps for group ICA decompo-
sition (LEICA) can extract group-level spatial
maps (Liu et al., 2018), and the kernel machine
by detecting higher order interactions (KMDHOI)
(Alam et al., 2018) incorporates an infinite-­
dimensional Hilbert space, which can be used for
modeling higher order interactions such as epi-
static factors between genetics and imaging data.
MACHINE LEARNING
Machine learning (ML) methods in neuroimaging
are becoming increasingly popular, and several
novel approaches with fundamental ML applica-
tions, including regression-based methods, cluster
analysis, and graphical models, have been pro-
posed in recent years. While in depth explanations
of individual ML methods are beyond the scope of
this chapter, we will briefly highlight some prom-
ising approaches.
Several variations of regression methods have
been proposed in recent years. Notably, robust
iteratively weighted least squares (IRLS) has been
proposed as an alternative to ordinary least squares
(OLS) for fMRI analysis (Wager et al., 2005), and
the sandwich estimator (SwE) has been proposed
to expand the OLS model for longitudinal appli-
cations (Guillaume et al., 2014). Penalized least
squares methods (Bunea et al., 2011), which intro-
duce a regression penalty for bias minimization,
have also been proposed. Ridge regression (RR)
is a penalized least squares method that has been
used for predictive modeling with connectomes
(Gao et al., 2019), and a kernelized RR (KRR)
method has been used for fMRI pattern prediction
(Chu et al., 2011). Other RR techniques include
Bayesian RR (BRR) for biological age predic-
tion (Ball et al., 2021; Roudbar et al., 2021) and
Bayesian Rician regression for use with DWI data
(Wegmann et al., 2017). The least absolute shrink-
age and selection operator (LASSO), another
penalized least squares method, has also been
557
used to predict psychometric relationships with
multimodal data (Rasero et al., 2021), and several
variations of group LASSO have been proposed
for neuroimaging applications to analyze sub-
groups of data (Beer et al., 2019; Liu et al., 2018,
2019). Another penalized least squares method,
the elastic net (ENET), has been used with the
total variation (TV) penalty in a few novel varia-
tions for neuroimaging applications (Hadj-Selem
et al., 2018; Pietrosanu et al., 2021), and some
other novel ENET-based techniques have been
proposed including a combined ENET and mul-
tiple kernel learning (MKL) approach (Mourao-
Miranda et al., 2012), a sparse partial correlation
with ENET (SPC-EN) approach (Ryali et al.,
2012), and a combined group LASSO and ENET
approach (Guo et al., 2018).
Another popular technique is the support vec-
tor machine (SVM), which has been used to
classify various diseases (Steardo Jr et al., 2020;
Zhou et al., 2018). Notably, one study combined
MKL with the SVM for psychosis classification
(Squarcina et al., 2017), and ensemble SVM tech-
niques have been proposed to combine multiple
SVMs for enhanced classification (Bi et al., 2018;
Sørensen et al., 2018). SVMs have also been com-
bined with methods such as mutual information
(MI) (Fan and Chou, 2016) or recursive feature
elimination (RFE) for enhanced feature selection
(Richhariya et al., 2020). In addition, several neu-
roimaging applications have been proposed using
support vector regression (SVR) (Shi et al., 2018;
Singer et al., 2019; Sperber et al., 2019) and the
relevance vector machine (RVM) (Lin et al., 2021;
Meyer et al., 2019).
Graphical models including Bayesian networks
or Markov models have also shown promise as
meaningful ML applications for neuroimaging.
For example, dynamic Bayesian networks have
been used to jointly model structure-function
relationships between DTI and fMRI (Dang et al.
2017) and to assess connectivity with fMRI (Dang
et al., 2017). Likewise, several novel approaches
have employed Markov models (Ficiarà et al.,
2021; Zhang et al., 2019), with the hidden Markov
model (HMM) being commonly utilized (Jamaloo
et al., 2020; Tao et al., 2021; Tessadori et al.,
2021). In addition, extensions of the HMM have
been proposed for neuroimaging contexts such as
the hidden semi-Markov model (HSMM) (Fiecas
et al., 2021) and semiparametric HMMs (Kang
et al., 2019), and Markov random fields (MRFs)
have been proposed as undirected Markov mod-
els to evaluate the spread of AD (Dyrba et al.,
2018). Furthermore, the hidden MRF (HMRF) has
also been used for many neuroimaging applica-
tions (Górriz et al., 2018; Guerrout et al., 2020;
Lukashenko and Chernyaev, 2020).
558 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Lastly, the random forest (RF) model is a
hybrid ML model that uses an ensemble classifi-
cation approach known as bagging. An advantage
of the RF is its versatility, which is exemplified
by a wide range of recently proposed neuroimag-
ing applications (Cordova et al., 2020; Dimitriadis
et al., 2021; Kamarajan et al., 2020; McKinley
et al., 2017; Zhao et al., 2017; Zhu et al., 2018).
DEEP LEARNING
Deep learning (DL) techniques are a more com-
plex subset of ML techniques that use several
iterations of pattern-finding algorithms to extract
meaningful information from data. While an
exhaustive overview of DL applications in neuro-
imaging is beyond the scope of this chapter, we
will review some promising approaches.
Specifically, we will address novel approaches
with multi-layer perceptrons (MLPs), autoencod-
ers (AEs), deep belief networks (DBNs), and
CNNs. Some additional approaches that are not
covered due to limited space but may be of inter-
est to the reader include residual neural networks
(ResNets) (Sun et al., 2021; Zhang et al., 2021),
recurrent neural networks (RNNs) (Nguyen et al.,
2020; Thomas et al., 2019), and generative adver-
sarial networks (GANs) (Liu et al., 2020; Yan
Zhao et al., 2020).
MLPs are fundamental DL models that use
multiple layers of perceptrons guided by activa-
tion functions. In recent years, several neuroim-
aging studies have utilized MLPs for various
applications (Yun et al., 2019; Javed et al., 2021;
Karami et al., 2020), and some novel MLP frame-
works have been proposed including the moving
local window MLP (MLW-MLP) used with MR
electrical properties tomography (MREPT) (Lee
et al., 2021) and the multi-head self-attention
model (MSAM) used for temporal lobe epilepsy
classification (Gu et al., 2020). In addition, a nota-
ble study proposed a method for integrating DL
into clinical practice by using MLPs to enhance
stereotactic navigation in neurosurgical proce-
dures (Leuthardt et al., 2018).
Autoencoders (AEs) are similar to MLPs with
hidden layers that contain fewer nodes than the
input and output layers. Many notable applica-
tions have employed AEs (Akramifard et al.,
2021; Legarreta et al., 2021; Pinaya et al., 2019),
and some additional variations of the AE model
have been proposed for neuroimaging applications
including the sparse AE (Almuqhim and Saeed,
2021), modified k-sparse AE (σKSA) (Bhatkoti
and Paul, 2016), stacked AE (Ferri et al., 2021),
denoising AE (DAE) (Duffy et al., 2020), stacked
denoising AE (SDAE) (Zheng-Lin et al., 2018),
randomized denoising AE (rDAE) (Ithapu et al.,
2014), variational AE (VAE) (Kim et al., 2021),
and the discriminative margin-sensitive AE
(MSAE) (Zhang et al., 2020).
DBNs use several layers of separate simplis-
tic two-layer DL models known as restricted
Boltzmann machines (RBMs). A few recent stud-
ies have reported novel neuroimaging applica-
tions with DBNs (Huang et al., 2020; Latha and
Kavitha, 2019; Zeng et al., 2021), and some novel
variations of the DBN framework include the
group LASSO sparse DBN (GLS-DBN) (Shen
et al., 2019), the neural architecture search with
particle swarm optimization DBN (NAS-DBN)
(Qiang et al., 2020; Ren and Liu, 2021), and the
volumetric sparse DBN (VS-DBN) (Dong et al.,
2019).
Finally, convolutional neural networks (CNNs)
have been used in a wide range of neuroimaging
applications, with several noteworthy approaches
being used in AD prediction (Jo et al., 2019; Jo
et al., 2020; Yang et al., 2020; Zhang et al., 2021),
hippocampal segmentation (Liu et al., 2020;
Nobakht et al., 2021), white matter hyperintensity
segmentation (Rudie et al., 2019; Umapathy et al.,
2021), and brain connectomics (Khosla et al.,
2019; Phang et al., 2019).
SUMMARY AND CONCLUSIONS
In this chapter we have provided a brief overview
of novel large-scale data applications in neuroim-
aging while discussing advances with neuroimag-
ing modalities, statistics and novel techniques
with BSS, ML, and DL. Nonetheless, data science
applications that use neuroimaging are expansive
and several other approaches, including data man-
agement, computational advances, and data fusion
have not been covered. As neuroimaging evolves,
numerous additional large-scale data applications
are expected to emerge.
 Novel Approaches to Large-Scale Data in Neuroimaging 559

Table 33.2 Acronyms with their definitions

Acronym Definition Acronym Definition

AD Alzheimer’s disease HSMM Hidden semi-Markov model

AD2A Attention-guided deep domain adaptation ICA Independent component analysis
AE Autoencoder IRLS Robust iteratively reweighted least squares
AISA Adaptive independent subspace analysis ISA Independent subspace analysis
ALE Activation likelihood estimation IVA Independent vector analysis
ASL Arterial spin labeling IVA-G Gaussian independent vector analysis
BHICP Bayesian hierarchical independent cluster IVA-L Laplacian independent vector analysis
process modeling jICA Joint independent component analysis
BRR Bayesian ridge regression JISA Joint independent subspace analysis
BSS Blind source separation KMDHOI Kernel machine by detecting higher order
CBMA Coordinate-based meta-analysis interactions
CCA Canonical correlation analysis KRR Kernelized ridge regression
CNN Convolutional neural network LASSO Least absolute shrinkage and selection
CSD Constrained spherical deconvolution operator
DAE Denoising autoencoder LEICA Laplacian eigenmaps for group independent
DBN Deep belief network component analysis decomposition
DCM Dynamic causal modeling LICA Linked independent component analysis
DL Deep learning LinearRISH Adaptive linear mapping of rotational
invariant spherical harmonics
DPMH Diffusion parametric map harmonization
LR Logistic regression
DSC Dynamic susceptibility contrast imaging
mCCA Multiset canonical correlation analysis
DTI Diffusion tensor imaging
MCCAR Multiset canonical correlation analysis with
DWI Diffusion weighted imaging
reference
EEG Electroencephalography
MDM Multiple dataset multidimensional
EIC Eigen clustering
MDU Multiple dataset unidimensional
ENET Elastic net
MEG Magnetoencephalography
ENIGMA Enhancing Neuroimaging Genetics through
MI Mutual information
Meta-analysis
MICA Multisite image harmonization by cumulative
ES-SDM Effect size signed differential mapping
distribution function alignment
FA Fractional anisotropy
MISA Multi-dataset independent subspace
FBA Fixel based analysis, fiber based analysis analysis
FDR False discovery rate MKDA Multilevel kernel density analysis
fMRI Functional magnetic resonance imaging MKL Multiple kernel learning
fNIRS Functional near-infrared spectroscopy ML Machine learning
GAM Generalized additive models MLP Multi-layer perceptron
GAN Generative adversarial network MLW-MLP Moving local window multilayer perceptron
GICA Group independent component analysis MREPT Magnetic resonance electrical properties
GIG-ICA Group information guided independent tomography
component analysis MRF Markov random fields
GIPCA Generalized integrative principal MSAE Discriminative margin-sensitive autoencoder
component analysis
MSAM Multi-head self-attention model
GLS-DBN Group least absolute shrinkage selection
MWK-Means Minkowski-weighted K-means
operator sparse deep belief network
NAS-DBN Neural architecture search deep belief
GMM Gaussian mixture modeling
network
HMM Hidden Markov modeling
NGCA Non-Gaussian component analysis
HMRF Hidden Markov random field
NODDI Neurite orientation dispersion and density
HPGRF Hierarchical Poisson/Gamma random field imaging
modeling
(continued)
560 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Table 33.2 Continued

Acronym Definition Acronym Definition

OLS Ordinary least squares SDU Single dataset unidimensional

PCA Principal component analysis SING Simultaneous non-Gaussian component
PET Positron emission tomography analysis
PICA Probabilistic independent component sMRI Structural magnetic resonance imaging
analysis SOI Signal of interest
pICA Parallel independent component analysis SPCA Sparse principal component analysis
POAS Position-orientation adaptive smoothing SPC-EN Sparse partial correlation with elastic net
PWI Perfusion weighted imaging SPCM Sparse principal component of mediation
QSM Quantitative susceptibility maps SPECT Single photon emission computed
RBM Restricted Boltzmann machine tomography
rDAE Randomized denoising autoencoder SSA Stationary subspace analysis
ResNets Residual neural networks SVM Support vector machine
RF Random forest SVR Support vector regression
RFE Recursive feature elimination TC-GICA Temporal-concatenation group independent
component analysis
RNN Recurrent neural networks
TICA Tensor independent component analysis
RR Ridge regression
TV Total variation
RVM Relevance vector machine
VAE Variational autoencoder
SampEn Sample entropy
VBM Voxel-based morphometry
SBM Surface-based morphometry
VS-DBN Volumetric sparse deep belief network
SDAE Stacked denoising autoencoder
σKSA Modified k-sparse autoencoder
SDM Single dataset multidimensional

ACKNOWLEDGMENTS and applications (pp. 383–395). Oxford, UK:

The preparation of this chapter was supported in part
by U.S. National Institutes of Health grants: R01
AG197711, P30 AG10133, P30 AG072976,
U01AG072177, U01AG024904, R01 CA129769,
R01 AG057739, R01 LM013463, R01 AG068193,
R01 AG061788, K01 AG049050, and U01 AG068057.
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Advancing Cognitive Neuroscience
R o t e m B o t v i n i k - N e z e r a n d To r D . W a g e r
INTRODUCTION
Since the establishment of cognitive neuroscience,
researchers have mapped associations between
brain topography and a variety of cognitive, affec-
tive, and social tasks. The field has grown rapidly,
with rising numbers of laboratories, researchers,
data, tools, and publications. Exciting findings
have been uncovered and tremendous methodo-
logical and conceptual developments have been
made. Overall, the field has laid a solid layer of
foundation for the central goal of cognitive neuro-
science: Deciphering how the brain gives rise to
mental states. Yet, the most prominent inroads
have been made into basic aspects of where differ-
ent mental events occur. While this knowledge
constraints how we think of mental processes and
their similarity, advances in understanding how
mental processes occur have been more modest.
Cognitive neuroscience has followed a largely
analytic strategy, dissecting systems into small
components and building deep knowledge about
details within each area. Accordingly, deep valleys
of research have been developed, accessible only
to more specialized audiences, with area-specific
terms and relative separation from other closely
related and highly relevant areas. We now have
an abundance of detailed findings within specific
34
research areas, but very few attempts have been
made to develop theories and models that can be
tested and that potentially can explain and inter-
relate these distinct chunks of information.
Over recent decades, there has been a rise in
synthesis-oriented thinking. Systems biology
involves creating models of interacting compo-
nents such as proteins and molecules. Systems
neuroscience has shifted in focus from isolated
brain regions and single monosynaptic pathways
to broader characterizations of large-scale brain
dynamics, supported by advances such as wide-
field optical imaging and two-photon microscopy.
Neuroimaging has undergone a similar sea change
when it comes to brain regions, gradually shifting
from focusing on isolated regions as meditators of
psychological functions to large-scale interactions,
characterized by networks and brain patterns.
A driver of recent scientific developments has
been prominent technological advancement in the
digital age. Quantity, complexity, and dimension-
ality of data collected in the field have all grown
tremendously. Analyses that were impossible until
recently due to computational limitations are now
becoming possible, and computations that used
to take weeks or months can now be performed
within hours or days. As a consequence, new
methods are gaining popularity, from Bayesian
models to machine learning and deep learning.
570 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
This progress carries both opportunities and chal-
lenges. First, with these new abilities, researchers
can now ask research questions they could not
address before. While this undoubtedly advances
the field and adds priceless knowledge, it also sub-
stantially broadens the skills required in perform-
ing research and the knowledge required from
peers to understand the methods and findings.
Second, as magnitude of data increases, automa-
tion of research methods, from data collection and
quality control to data processing, statistical anal-
ysis and visualizations, is needed more than ever.
Programming skills are becoming a necessity, but
are not always taught in neuroscience programs.
As the quantity and complexity of data increases,
so does the necessity of reproducible and trans-
parent analyses, and tools and practices to identify
errors, since these are becoming harder to spot and
more potent in changing results.
Cognitive neuroscience is on the verge of a par-
adigm shift, at multiple levels, advancing toward a
more systematic and integrative approach toward
labs and studies, psychological domains, and brain
representations. We believe that the field must
develop new approaches to manage the tension
between often-competing goals of rigor and repro-
ducibility, innovation, and the practical constraints
and limitations of human researchers and aca-
demia more generally (e.g., incentive and funding
structures). Below, we describe the recent devel-
opment and our ideas for such novel approaches.
ENHANCING REPRODUCIBILITY,
REPLICABILITY, AND ROBUSTNESS
Reproducibility and replicability of findings in
many fields, from biomedical to social sciences,
have been called into question over the last decade.
Large studies have shown concerning rates of
unsuccessful replications and much lower effect
sizes than in original studies (Camerer et al., 2016,
2018; Errington et al., 2021; Klein et al., 2014,
2018; Nosek and Errington, 2017; OSC, 2015). For
example, only 36 out of 100 impactful results in
Psychology were replicated with effect sizes half
that of the original on average (OSC, 2015), and in
preclinical cancer biology, only 23/50 results repli-
cated (for another 143 results, it was not even pos-
sible to conduct a replication) with effect sizes 15%
that of the original on average (Errington et al.,
2021). While a failed replication does not necessar-
ily imply that the original finding was wrong
(Nosek and Errington, 2020a,b), consistently low
replication rates reveal that many reported findings
are likely false positives, and that even replicable
effects are often smaller and less important for
real-world behavior than claimed in initial
publications.
Cumulative knowledge is often not flashy or
surprising, and may require sacrificing short-term
interest value, including opportunities to publish
or otherwise gain attention, in favor of long-term
accuracy. Prioritizing replicability of findings and
unbiased estimation of their effect sizes helps to
align incentives with the goal of developing a
shared understanding of how the world actually
works.
Various causes have been suggested for this
“replication crisis.” First, low statistical power is a
major problem (Button et al., 2013; Munafò et al.,,
2019; Yarkoni, 2009). The estimated median sam-
ple size of fMRI studies in 2015 was merely 28.5
(Poldrack et al., 2017), far from being sufficiently
powered to detect larger than typical effect sizes
in fMRI studies, given the multiple comparison
challenge inherent such studies. Underpowered
studies do not affect the likelihood of mistakenly
rejecting the null hypothesis. However, they do
increase the false discovery rate. This problem
is inflated by publication bias (Ioannidis et al.,
2014). Significant findings are more likely to be
reported and accepted for publication in scientific
journals, while reports with many null findings
often end up in researchers’ “file drawers,” allow-
ing positive results (including a disproportionate
number of false positive results) to dominate the
literature (Fanelli, 2012; Rosenthal, 1979). In the
context where most published studies report sig-
nificant findings, despite many being underpow-
ered, the likelihood of any reported finding being
true is alarmingly low (Ioannidis, 2005).
Second, some research practices that increase
the likelihood of false positives are quite common
(John et al., 2012). The most common questionable
research practice is p-hacking, whereby researchers
run different statistical tests and selectively report
only ones that yield significant results (Simmons
et al., 2011; Simonsohn et al., 2014). Another exam-
ple is hypothesizing after the results are known
(HARKing), when researchers present a post hoc
hypothesis (informed by results) as an a priori
one (Kerr, 1998). These practices are incentivized,
since researchers are measured and promoted based
on their publication records, whereby statistically
significant results are almost always a prerequisite
for publication (Nelson et al., 2018). Furthermore,
such questionable research practices could happen
unconsciously, since human inference is biased by
prior beliefs (Nickerson, 1998) and desires (Kunda,
1990; Sharot and Garrett, 2016).
Third, analytical flexibility within the field is
very high (a thriving “garden of forking paths”;
Gelman and Loken, 2013). Turning data into an
 Advancing Cognitive Neuroscience
hypothesis test typically requires numerous ana-
lytical choices, with multiple justifiable alter-
natives at each step. “Optimal” choices often
do not exist or depend strongly on the specific
domain, hypothesis, dataset, sample size, effect
sizes, and artifact patterns, among other features.
Furthermore, analysis is often performed by early
career researchers who are learning the methods
and tools while using them. Indeed, it is common
for researchers to conduct preliminary analy-
ses, which are later changed based on additional
knowledge acquired about the methods (e.g., from
reading more papers or from discussions with
other researchers) or about the data (e.g., from
observed artifacts or covariates). Researchers are
more likely to “improve” their analysis or test
additional ones if the original analysis did not
yield a significant result in the expected direction.
Thus, attempts to improve rigor and optimize anal-
yses can easily manifest (perhaps unconsciously)
as p-hacking.
Analytical flexibility is a major challenge even if
it does not involve p-hacking and only one analysis
is performed. A recent collaborative project includ-
ing almost 200 researchers made this abstract prob-
lem concrete by demonstrating startling analytical
variability with substantial effects on reported
results in fMRI (Botvinik-Nezer et al., 2020).
Seventy independent analysis teams received the
same fMRI dataset and were instructed to analyze
the data to test the same pre-defined nine hypothe-
ses. Notably, no two teams chose exactly the same
analysis pipeline. This analytical variability led to
substantial variability in reported statistical maps
and binary conclusions about hypothesis tests
across teams (although statistical maps in earlier
stages of analysis were more similar across teams).
Other studies have also demonstrated the effects of
analytical choices on results in fMRI (Carp, 2012;
Li et al., 2021). A similar project is in progress in
EEG (EEGManyPipelines.org), while in PET it has
been shown that choice of preprocessing strategy
can have a major impact on outcomes (Nørgaard
et al., 2020), and in diffusion-based tractography
high variability was found for tractography dissec-
tion (Schilling et al., 2021). Similar results have
been obtained in the social sciences (Bastiaansen
et al., 2020; Breznau et al., 2022; Silberzahn et al.,
2018). Results are often not robust to arbitrary ana-
lytical choices, in which case the value of a single
study using a single analysis pipeline becomes
questionable, and testing the robustness of results
to arbitrary analytical choices becomes essential.
Finally, most cognitive neuroscience stud-
ies are conducted with participants (and by
researchers) from “WEIRD” (Western, Educated,
Industrialized, Rich, and Democratic) societies,
most commonly in North America or Europe
571
(Henrich et al., 2010). Hence, it is unclear whether
findings within the field would in fact general-
ize across the human population (Arnett, 2008;
Barrett, 2020; Chiao and Cheon, 2010; Rad et al.,
2018; Thalmayer et al., 2021).
Awareness of these problems is increasing, and
there is a prominent “open science” or “science
reform” movement rapidly growing, calling for
improved scientific practices to enhance repro-
ducibility, replicability, and generalizability, with
an emphasis on openness, transparency and inclu-
sivity (Munafò et al., 2017; Nelson et al., 2018;
Nosek, 2015; Poldrack et al., 2017). Cognitive
neuroscientists have been taking an active role in
this movement, demonstrating self-reflection and
self-criticism (Gilmore et al., 2017). This sug-
gests an optimistic future, and indeed, tools and
practices to mitigate current challenges are being
developed, thereby increasing the rigor of research
into cognitive neuroscience.
For example, sample sizes have been slowly
increasing in recent years. One recent study
showed that while high impact neuroimaging
studies from 1990 to 2012 had a sample size of 12
participants on average, similar studies in 2017–
2018 had sample sizes of about 23–24 partici-
pants (Szucs and Ioannidis, 2020). One trend that
is substantially increasing statistical power is use
of publicly shared data, particularly large datasets
with thousands of participants, such as the Human
Connectome Project (HCP) (Elam et al., 2021;
Van Essen et al., 2013), the Adolescent Brain
Cognitive Development (ABCD) study (Casey
et al. 2018), and UK BioBank (Alfaro-Almagro
et al., 2018) (Table 34.1 and Figure 34.2). While
this indicates a trend toward larger sample sizes
and more powerful studies, the statistical power of
most studies is still relatively small and needs to
be improved considerably.
Similarly, questionable research practices such
as p-hacking and HARKing, which have been
common in the past, are slowly becoming less
acceptable and consequently less prevalent. This
is a result of the surging focus on their implica-
tions, in addition to new tools that are making such
practices explicit and conscious, and prevent them
in some cases. For instance, it is becoming more
common to pre-register studies prior to data col-
lection (or at least prior to data analysis), although
it is still far from routine (Borghi and Van Gulick,
2018; Button, 2019; Hardwicke et al., 2021; Paret
et al., 2022). In a pre-registration, a frozen time-
stamped description of the experimental design,
sample size, hypotheses, analysis plan, and pre-
dictions is registered on a public platform, thus
constraining the researchers’ analytical flexibility
and making explicit which hypotheses are tested
and which choices are made, and whether they
572 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
are made prior to or after observing the data. Pre-
registration distinguishes between confirmatory
(hypothesis testing) and exploratory (hypothesis
generating) research (Nosek et al., 2018; Simmons
et al., 2021). While both are necessary for scien-
tific progress, interpretation of results gener-
ated by each approach is different. Registered
reports is a form of “extended” pre-registration,
where the study plan is submitted to a journal and
goes through peer review prior to data collection
(Chambers, 2019; Hardwicke and Ioannidis, 2018;
Nosek and Lakens, 2014). The review process can
result in an “in-principle acceptance,” meaning
that the study would be published as long as it
follows the accepted research plan, whatever the
results show. This format helps mitigate p-hacking
as well as publication bias, since once a study
has been accepted as a registered report, the pres-
sure to find a significant result for publication is
removed, and there is less incentive to p-hack.
Code and data sharing are also becoming more
common, and studies are becoming more repro-
ducible (Borghi and Van Gulick, 2018; Hardwicke
et al., 2021; Houtkoop et al., 2018; Paret et al.,
2022; Poldrack and Gorgolewski, 2014). This pro-
cess is facilitated in part by recent methodological
and technological advancement such as guidelines
for best practices (Knudsen et al., 2020; Nichols
et al., 2017; Pernet et al., 2020), standards for
data organization (e.g., the Brain Imaging Data
Structure (Gorgolewski et al., 2016)), platforms
for data analysis and sharing (e.g., brainlife.io and
OpenNeuro (Hayashi et al., 2023; Markiewicz
et al., 2021)), and tools for data and code man-
agement from version control and data provenance
tracking to reproducible analyses and data shar-
ing (e.g., DataLad (Halchenko et al., 2021)). For
example, our laboratory (Tor Wager, PI) maintains
a growing repository of general-use, object-ori-
ented code for neuroimaging data analysis that is
publicly available at CANlab neuroimaging analy-
sis tools (https://canlab.github.io).
Beyond ensuring more reproducible analy-
ses and replicable findings, data sharing efforts
increase the value of each dataset, and therefore
the (frequently public) resources invested in
collecting it, as researchers outside the original
group can later further examine it and use it to
study additional directions. Data sharing further
facilitates projects that integrate data across mul-
tiple studies and labs, studying research questions
that frequently cannot be adequately addressed
by a single study. Furthermore, it helps miti-
gate problems of p-hacking and irreproducibil-
ity. When researchers share their data and code,
others can test whether they can reproduce the
claimed results using the same dataset or inde-
pendent data.
While data and code sharing are becoming
more prevalent, another type of sharing that is
just beginning to gain traction in cognitive neu-
roscience is model sharing (Poldrack et al., 2019).
Models are powerful tools for both simulating and
understanding processes and for making quan-
titative, testable predictions. Machine learning
and deep learning-based models can provide new
measures, reducing complex data to patterns or
effects of interest. For example, they may reduce
people’s speech patterns and language during an
interview into a measure that predicts risk for sui-
cide, reduce complex electrocardiogram patterns
to a measure of heart attack risk, and many more.
In neuroimaging, models can reduce images with
hundreds of thousands of voxels and billions of
pairwise connections–each of which provides a
potential measure and hypothesis to test–into a sin-
gle, focused measure that can be tested as a target
for task manipulations or other interventions, rela-
tionships with behavior or performance, and pre-
diction of future behaviors, clinical diagnosis, or
clinical risk (Woo et al., 2017). Inspired by “Model
Zoos” in artificial intelligence, our Cognitive
and Affective Neuorscience Lab (Tor Wager, PI)
maintains a shared library of pre-trained predic-
tive models applicable to neuroimaging data from
new individuals and scanners (https://github.com/
canlab/Neuroimaging_Pattern_Masks). Testing a
priori brain models reduces the “garden of forking
paths” and potential for p-­hacking, eliminates need
for multiple comparisons’ correction when testing
effects on a single model-based measure, and can
dramatically increase effect sizes and replicability
(Kragel et al., 2018; Reddan et al., 2017). Model
sharing complements sharing of data and code,
making these measures available to all. Moreover,
the more widely models are used and tested, the
more extensively validated they become, and the
more is known about their generalizability and
other measurement properties such as sensitivity
and specificity to particular task conditions and
populations.
While issues of low power and questionable
research practices are slowly improving with cur-
rent tools and approaches that are focused on
reproducibility and transparency, there is still a
long way to go, and other issues are even further
away from being solved. For example, the problem
of analytical variability is drawing more attention
with recent demonstrations of its magnitude and
importance in the social sciences and neuroimag-
ing (Botvinik-Nezer et al., 2020; Nørgaard et al.,
2020; Silberzahn et al., 2018). Pre-registration
and sharing of code, data, and models help ensure
that the analytical variability is not exploited to
find and report a single pipeline that yields sig-
nificant results, and to allow other researchers to
 Advancing Cognitive Neuroscience
test whether results are robust to other analytical
choices. However, it does not solve the problem
completely, since the result of a single analysis
pipeline is still dependent on arbitrary choices
made, whether they were the only ones tested
or not. Clearly, a first crucial step is to fully and
transparently report all analytical choices.
A more complete solution to this problem is a
“multiverse analysis,” in which the same data are
analyzed with multiple validated analysis pipe-
lines, which are all reported, and the researcher
tests for convergence (and divergence) across
them (thus testing robustness of findings to arbi-
trary analytical choices). While such approaches
have been suggested (Strother et al., 2002), mul-
tiple conceptual and practical developments are
needed for full solutions to be available. First,
and perhaps most challenging, one needs to select
which analysis pipelines to include. As mentioned
above, it is hard or even impossible to generalize
optimal, best approaches across domains, hypoth-
eses, and datasets (e.g., fMRI data obtained with
spiral vs. EPI acquisition protocols involve differ-
ent artifact patterns and edge-of-brain brightness,
which can interact with segmentation and normali-
zation algorithms). Hence, the default approach of
using an analysis pipeline that works well on aver-
age with some specific customized adaptations
is sensible, but developing methods for choosing
multiple analysis pipelines to test over is likely a
better approach. Second, once a “multiverse” of
analysis pipelines is defined, methods to test for
convergence across these dependent pipelines are
needed. Third, tools are needed to conduct such
analysis with reasonable computational resources
at a single lab level. Forth, tools and guidelines
are needed for the reporting and visualization of
the tested pipelines and the results. Such devel-
opments are currently in progress, but may take
time to mature, mainly for complex and high-­
dimensional datasets typical to cognitive neuro-
science (Aczel et al., 2021; Clayson et al., 2021;
Dafflon et al., 2020; Li et al., 2021; Liu et al.,
2021; Simonsohn et al., 2020).
The diversity of researchers and participants
populations has been gaining a lot of attention
alongside societal movements toward inclusiv-
ity, diversity, equality, and equity (Carroll et al.,
2021; Rad et al., 2018). The recent rise of “big
team science” may solve a fundamental prob-
lem of limited resources in the typical single-
lab studies, by allowing many research teams to
pool together their resources (Coles et al., 2022;
Forscher et al., 2020). It can also lead to global
collaborations, allowing more statistically pow-
ered, diverse, and therefore generalizable stud-
ies, as exemplified by the “Many Labs” projects
(Ebersole et al., 2016; Klein et al., 2014, 2018;
573
Stroebe, 2019) and the Psychological Science
Accelerator (PSA; Moshontz et al., 2018). PSA
is an ongoing, globally distributed, diverse, and
inclusive network of researchers in psychology.
It includes over 1000 members from dozens of
countries worldwide. Though it is only a few
years old, it has already produced a few publica-
tions, preprints and in-principle-accepted regis-
tered reports, each reporting results from multiple
and very diverse samples (Bago et al., 2019; Chen
et al., 2018; Forscher et al., 2019, 2020; Hall et al.,
2018; Jones et al., 2021). Resolving these issues
and making cognitive neuroscience diverse, inclu-
sive and representative is still in its infancy, and
major attempts alongside creative adaptations of
existing structures and ways of thought are needed
to make s­ ubstantial progress. Also, current fund-
ing structures and authorship assignment may be
problematic for large-scale collaborations (Coles
et al., 2021, 2022).
The last decade has marked the rise of more
reproducible, replicable, and generalizable cog-
nitive neuroscience. Growing emphasis on these
topics, together with an abundance of developed
tools and practices to enhance them (Niso et al.,
2022), are already “bearing fruit.” A prominent
challenge that is becoming apparent as “open
science” becomes more prevalent is the tension
between theoretical ideals and practical con-
straints. We turn to this next.
Balancing Theoretical Ideals and
Practical Constraints
In practice, research into cognitive neuroscience
often is carried out with limited resources – from
funding to participant pools to skilled and experi-
enced personnel – and within systems that often
incentivize novel, positive, publishable findings
(Munafò et al., 2017; Nosek et al., 2012). Putting
things into perspective, Phase III clinical trials of
pharmaceutical agents are designed to test a single,
well-specified hypothesis: that a drug produces a
non-zero benefit over a placebo or other compara-
tor. Measures, methods, and statistical techniques
are well-established, as they follow blueprints laid
out by regulatory agencies and many previous stud-
ies. Endpoints are standard clinical assessments,
and complex biological assays are rare. Nonetheless,
such trials often cost tens to hundreds of millions of
dollars each. This is due largely to the inherently
very challenging endeavors of establishing rigor-
ous and well-documented protocols, ensuring com-
pliance with them, and establishing effects that
generalize to a population. Can we expect scientists
working on new, innovative ideas, developing, and
574 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
testing new complex measures (like fMRI, EEG,
language, social media data) for which analyses not
yet established and evolve rapidly from year to
year, to meet expected standards for documenta-
tion, reproducibility, replicability, data sharing, and
generalizability when compromises between the
ideal and reality are inevitable? In addition, rigor of
large-scale clinical trials comes at an extraordinary
cost in innovation and development of new ideas
and methods. Below, we present our suggestions
for how to advance cognitive neuroscience with
innovative approaches and formalizing such
compromises.
We suggest transitioning toward a “phase
model” (Figure 34.1), similar to models used in
biomedical research from preclinical through
phase III clinical trials (Borsook et al., 2011),
and to the gradual approach we previously sug-
gested for developing brain biomarkers (Woo
et al., 2017). The rationale is to lower barriers
for entry and encourage exploration and devel-
opment in Phase 1, but then impose increasingly
more constraints in later phases to ensure repro-
ducibility, generalizability, and robustness of find-
ings. Specification of different phases requires a
consensus group, but here we lay out a general
proposed architecture. The different phases are
designed to have different criteria across two main
dimensions: First, each phase imposes additional
requirements, such as code and data sharing, ana-
lytical reproducibility, and analytical robustness,
for establishing stronger findings. Second, studies
in each phase could be either exploratory (group
A) or confirmatory (i.e., pre-registered; group B).
Figure 34.1 An illustration of the suggested “phase model” for cognitive neuroscience.
Phase A1: “Exploratory.” Exploratory studies (with
minimal constraints and requirements) are used
to discover preliminary findings for later valida-
tion. Practices described above, such as data and
code sharing are recommended, but not required.
Many previous and current studies in cognitive
neuroscience are at this phase. However, it is
desirable that specific findings are validated in
Phase B1 or B2 studies before being accepted by
the scientific community.
Phase A2: “Shared Exploratory.” These are explor-
atory studies whose data and code are shared with
the research community. Publications from phase 2
studies are accompanied by shared data and code.
Phase A3: “Reproducible Exploratory.” Studies
with fully reproducible analyses, as validated by
external researchers. Shared code and data are
reviewed by independent parties prior to publica-
tion, to ensure results are analytically reproduc-
ible (i.e., identical results are obtained by other
researchers using the same data and code).
Phase A4: “Robust Exploratory.” Exploratory stud-
ies may be both fully reproducible and robust to
analytical variability, as determined by a multi-
verse analysis. Studies in this category specify
and justify a systematic set of analysis pipelines
over which to generalize and report robustness of
results across these analytical choices.
Phase B1: “Confirmatory.” Confirmatory studies
are used to test specific hypotheses, validate mea-
sures and biomarkers, and estimate effect sizes.
 Advancing Cognitive Neuroscience
These activities require precisely defined targets.
In this phase, pre-registered hypotheses and pre-
dictions are tested with a pre-registered analysis
plan.
Phase B2: “Shared Confirmatory.” Confirmatory
studies with publicly shared data and code (as
in A2).
Phase B3: “Reproducible Confirmatory.” Confir-
matory studies that are fully reproducible (as in
phase A3).
Phase B4: “Robust Confirmatory.” Studies that are
fully reproducible and tested for analytical robust-
ness (as in phase A4), which were pre-registered
(including plan for analytical robustness).
Pre-registration is key to distinguishing between
group A and group B studies. It is critical to deter-
mine when a study needs to be pre-registered in
order to be considered confirmatory. We suggest
that pre-registration be recommended prior to data
collection, and required before critical outcome
data are observed. Critical outcome data are data
required to test the hypothesis. For example, pri-
mary outcomes in a clinical trial, task condition
labels in a hypothesis test of task-evoked brain
responses, and group labels in between-groups
comparisons are critical outcome data. Analyses
can examine distribution of other variables prior to
hypothesis pre-registration (e.g., for the purposes
of checking data integrity, study procedures, and
statistical distributions, if outcome data are not
available to the analyst). Data or results available
prior to pre-registration should be described.
Studies should be powered to detect the pre-­
registered effects of interest, as is standard for
clinical trials.
The concept of critical outcome data is important
for maintaining appropriate controlled flexibility at
this stage. It is advantageous, and often critical, to
examine data in order to know which modeling
choices should be made (e.g., how to identify and
correct invalid or missing values during data collec-
tion, deal with outliers, specify error distributions
and variable transformations, test assumptions,
and determine the structure and nature of statisti-
cal models). If all hypotheses must be specified
prior to data collection, their specification must
be imprecise with respect to all of these choices.
This leads to substantial analytical variability later,
allowing thousands of variations on tests of a single
pre-­registered hypothesis. Indeed, almost all pub-
lications of pre-registered studies report deviations
from the pre-registered plan that are explained and
justified. Pre-registering at a later stage, but before
outcome measures are observed, could thus con-
strain analytical flexibility better than pre-registering
575
prior to data collection. An alternative is to use
one dataset to optimize the analysis, and then pre-
register and apply the optimized analysis to a new
dataset. This could be done either by dividing the
dataset to a “training” set and an independent “test”
set or by collecting new data after the analysis of the
original dataset (i.e., a pre-registered replication).
Second, as studies grow in size and complexity,
it becomes impractical to specify all hypotheses
before data collection, and requiring this would
either impose an uneven standard across stud-
ies or preclude virtually any Phase B1 hypoth-
esis tests on large-scale studies. For example,
the UK Biobank study began data collection in
about 2010, and neuroimaging data collection
is expected to be completed around 2025. Thus,
requiring pre-registration prior to data collection
would preclude confirmatory studies on this data-
set and similar ones. A reasonable standard is to
allow the formulation of hypotheses as long as the
critical outcome data used to test them have not
been examined. For example, researchers could
pre-register a hypothesis about effects of sleep on
brain connectivity, as long as they formulate the
hypothesis before any examination of the relation-
ship. Examining or extracting brain connectivity
components in advance would be acceptable, as
long as the researchers did not examine their rela-
tionship with sleep (or, ideally, did not have access
to the sleep variables) before pre-registration. This
standard is consistent with the practice of blinded
analysis, in which effects are analyzed without
awareness of the labels on the critical outcome
data (e.g., patient group or task conditions). Such a
phase model can facilitate gradual progress toward
more reproducible, replicable, and robust findings,
while still encouraging innovation and risk taking
(but acknowledging practical barriers).
Another critical trade-off exists between statisti-
cal power and replicability, which require large sam-
ple sizes, and the need for innovation and diversity
of approaches (Figure 34.2). This is a fundamental
tradeoff, though there are other objectives that trade
off with these goals as well, such as generalizabil-
ity to diverse populations. There has been a strong
trend toward larger and more diverse datasets, with
substantial public funds devoted to collecting and
sharing ultra-large datasets like the HCP, ABCD, and
UK BioBank. While these datasets are exceptionally
useful for many research questions, they focus by
necessity on a few widely used measures and task
paradigms. They are not designed for methodologi-
cal innovation. One critical type of innovation is the
development of new tasks and computational models
that could provide novel measures with larger effect
sizes and greater inferential precision. Another kind
of innovation is the development of new techniques
for collecting data (e.g., new imaging sequences and
576 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Figure 34.2 Tradeoff between sample size and task and context diversity. For description of
studies based on the acronym, see Table 34.1. Note that here we focus on diversity of task fMRI
(and its context) specifically, and thus studies that are diverse in other aspects (e.g., imaging
modalities) may still be low on the Y axis. There is a prominent trade-off between sample size
and task and context diversity that could be addressed by multi-task, multi-study consortia like
the Placebo Imaging Consortium and the Affective Neuroimaging Collaboratory (ANiC).

modalities). Thus, while large shared projects have
provided a tremendous step forward, they are limited
to a very small portion of the space of cognitive and
affective processes that might be assessed and meth-
ods for assessing them.
One solution is to leverage the advantages of small,
innovative studies and large, well-powered studies by
combining them. For example, predictive models and
measures from smaller studies can be correlated and
combined with those from large shared datasets (He
et al., 2022). A broader, more ambitious solution is
to establish multi-lab, multi-study, multi-task consor-
tia. In such consortia, researchers collaborate to share
datasets collected within broad domains but with
diverse designs and tasks and by different labs. Such
multi-study datasets are already yielding more robust,
generalizable findings (Zunhammer et al., 2021).
progress requires integration of findings into test-
able theories, and models, that organize and for-
malize previous knowledge and predict new
findings. Psychological sciences may suffer from
a “theory crisis,” manifested in weak connections
between theories and their empirical tests, as well
as underappreciation of computational modeling
in theory building (Muthukrishna and Henrich,
2019; Oberauer and Lewandowsky, 2019).
Likewise, in the field of cognitive neuroscience,
several developments are needed to shift the focus
toward integration and theory building. Here, we
focus on two such developments: (1) Integrative
empirical analyses and ontologies; and
(2) Cognitive architectures and unifying princi-
ples, particularly those based on predictive coding.

Integrative Empirical Analyses

TOWARD UNIFYING THEORETICAL
FRAMEWORKS
Achieving the goal of reproducible, replicable,
and robust findings is a major cornerstone in the
advancement of cognitive neuroscience. However,
a collection of rigorous, true findings is not
enough to lead us toward deciphering how the
brain gives rise to human cognition. Scientific
and Ontologies
More systematic reviews and meta-analyses are
needed to better integrate existing knowledge in a
specific research domain. Data sharing practices
are already starting to improve meta-analyses by
providing researchers with richer information to
integrate over. Furthermore, as data sharing becomes
more common, advanced meta-analytic methods are
likely to be developed (Han and Park, 2019).
Table 34.1 Overview of large population-based studies, ordered based on sample size
Acronym Study / database Reference Sample Population

UKB United Kingdom Biobank (Alfaro-Almagro et al., 2018; 100,000 UK adults; many data types, six MRI modalities but only one fMRI task Population
Miller et al., 2016)
ENIGMA Enhancing Neuroimaging Genetics through (Adhikari et al., 2019; ∼60,000 from various studies with genetic and neuroimaging data Multiple
Meta Analysis Thompson et al., 2014)
ABCD Adolescent Brain Cognitive Development Study (Casey et al., 2018) 10,000 US adolescents, longitudinal, three fMRI tasks Development
FCP & INDI 1000 Functional Connectomes Project and the (Mennes et al., 2013) 1,300+ (FCP), thousands (INDI); focused on resting-state fMRI Multiple
International Neuroimaging Data-sharing
Initiative
ROS-MAP Religious Orders Study and Rush Memory and (Bennett et al., 2018) 3,500, with omics and postmortem, multi-modal MRI including resting-state Dementia
(RM) Aging Project fMRI
HCP & Human Connectome Project Somerville et al., 2018; ∼2500 Healthy US adults + children; different MRI modalities and six fMRI task Healthy,
dHCP Van Essen et al., 2013b) domains development
ABIDE I & II Autism Imaging Data Exchange (Di Martino et al., 2014, Multi-lab data sharing, ∼2200 with ASD and controls; focused on resting-state ASD
2017) fMRI
IMAGEN IMAGEN (Schumann et al., 2010) 2,000 adolescents, longitudinal; behavioral and neuropsychological measures, Development
structural and functional MRI (three tasks)
ADNI 1,2,3 The Alzheimer’s Disease Neuroimaging (Jack et al., 2008) Multi-lab data sharing, ∼1800 with Alzheimer’s, MCI, and controls; includes Dementia
Initiative structural MRI, PET, clinical, cognitive, biochemical, and genetic data
PPMI Parkinson’s Progression Markers Initiative (Marek et al., 2011) Aiming at ∼4000; including clinical data, biologic samples, genetic data, Parkinson’s
structural and diffusion MRI
OASIS Open Access Series of Imaging Studies (Marcus et al., 2007) Thousands, including cross-sectional and longitudinal data, multiple MRI modalities Dementia
Advancing Cognitive Neuroscience

(varies across sub projects, includes resting-state fMRI from OASIS 3 on)
GSP Brain Genomics Superstruct Project (Holmes et al., 2015) 1,570, some longitudinal; genetics, cognitive, personality, structural MRI and Healthy
resting state fMRI
IBC Individual Brain Charting (Pinho et al., 2018) 12 participants, multiple tasks Limited
MSC Midnight Scan Club (Gordon et al., 2017) 10 participants, 12 two-hours long sessions from each, including multiple modalities Limited
and five and a half hours of task fMRI data across three different tasks
NSD Natural Scenes Dataset (Allen et al., 2022) 8 participants, task data while viewing thousands of color natural scenes and Limited
performing a recognition task across 30–40 sessions
MC My Connectome (Poldrack et al., 2015) A single participant with data collected over 18 months including resting-state Single participant
fMRI, memory tasks, and many other types of data (physiological, structural,
577

physical health, gene expression, metabolism)

578 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
In neuroimaging, for example, coordination-based
meta-analyses have traditionally been the norm,
but image-based meta-analyses (Salimi-Khorshidi
et al., 2009) are now becoming more accessible as
more and more researchers share their statistical
brain maps via platforms such as NeuroVault
(Gorgolewski et al., 2015).
In addition, cognitive neuroscientists should
be expected to (and therefore trained to) formal-
ize their theories prior to testing (falsifying) them,
preferably in the form of quantitative, testable
computational models (Guest and Martin, 2021).
This would require a higher level of formal sta-
tistical and computational training in the field
(Neuromatch Academy (NMA), 2021) as well as
a better alignment between theories, or hypoth-
eses, and the empirical and statistical procedures
they rely on (Yarkoni, 2020). Furthermore, even
when researchers are using formal models, these
are frequently not shared in a way that allows
other researchers to test them. It is crucial that
researchers provide the full details of their mod-
els, whether it is the formulations and algorithms,
the code, or ways of applying pre-trained models
to new data (Woo et al., 2017). Finally, a clearer
distinction between confirmatory (theory-testing)
and exploratory (discovery-oriented) research is
needed. This is already happening with the grow-
ing use of pre-registration (Nosek et al., 2018).
The framework for classifying studies outlined
above is aligned with this need: The specification
of exploratory and confirmatory goals is built into
the classification system.
Notably, to facilitate successful integration of
findings, it is crucial to have a common language
(or ontologies, which are explicit specifications
of concepts (Gruber, 1993)) to base theories on,
as well as dedicated databases and tools based
on such ontologies. Researchers need to under-
stand what other researchers mean when they
use a specific term, within and between differ-
ent subdisciplines. Unfortunately, this is far from
being the reality in cognitive neuroscience. The
field’s reality is closer to the “Tower of Babel,”
with different researchers speaking different “lan-
guages” and using different terms to describe
similar phenomena, thus compromising the ability
to integrate findings into a tower toward the truth.
Novel informatics-driven big data approaches to
brain-cognition mapping are particularly depend-
ent on common annotations and integration tools
(Poldrack and Yarkoni, 2016).
Several attempts have been made to create a
joint knowledge base or ontologies for cognitive
neuroscience. For example, the BrainMap pro-
ject aims to facilitate data mining, aggregation,
and meta-analyses by providing annotated data
of published human structural and functional
neuroimaging studies along with their methods
(sample size, modality, task, etc.) and the coordinate-
based results (the location of the peak activation
in standard space) (Fox and Lancaster, 2002; Fox
et al., 2005; Laird et al., 2005). It includes soft-
ware and tools for neuroimaging data sharing
and has already yielded hundreds of publications.
Importantly, it also developed a taxonomy for
classifying studies in a space of cognitive, affec-
tive, sensory, and motor processes to facilitate
aggregation and analysis. The Cognitive Paradigm
Ontology (CogPo; Turner and Laird, 2012) is built
upon the BrainMap taxonomy to categorize task
paradigms based on the stimuli, instructions and
response rather than the cognitive function they
putatively measure, avoiding constructed and
potentially heterogeneous categories like “work-
ing memory.”
Despite the enormous contributions of
BrainMap and other similar projects to the field,
they are limited because they depend on manual
annotation of studies. NeuroSynth is a more
recent tool that took a very different approach.
It exchanged quality with quantity: Instead of
high-quality but limited manual annotation of
single studies, it relies on automated extraction
of reported activations and semantic annota-
tions from a large number of published studies
(Yarkoni et al., 2011). Analyses can be performed
based on a flexible set of thousands of concepts
used in the papers and semantic topics based on
them (Poldrack and Yarkoni, 2016). Other recent
approaches, like Neuroquery.org, build on this
concept (Dockès et al., 2020).
The Cognitive Atlas is a more systematic
attempt to formally represent mental processes,
and the cognitive tasks used to manipulate and
measure them, in order to later map these pro-
cesses to brain functions (Poldrack et al., 2011). It
is built collaboratively by any interested researcher
within cognitive neuroscience and related fields,
and facilitates a more precise use of terms across
the fields, better data mining of the published lit-
erature, metadata annotation, meta-analyses, and
theory conceptualization and testing in general.
These attempts to develop common terminol-
ogy, data annotation, and literature aggregation
tools have advanced the field and increased the
ability to achieve scientific consensus and dis-
seminate findings, as well as providing more rig-
orously defined hypotheses and targets for new
studies. Yet, cognitive neuroscience is still closer
to the “Tower of Babel” than to the vision of
these tools, and much work is needed for a fun-
damental change (Hastings et al., 2014). It is also
debated whether ontologies used to study the brain
should be based on psychological concepts or
neurobiological objects (Buzsáki, 2020; Poeppel
 Advancing Cognitive Neuroscience
and Adolfi, 2020). Recent initiatives, such as the
Research Domain Criteria (RDoC) framework ini-
tiated by the National Institutes of Mental Health
(NIMH), aim to shift the classification of mental
disorders from symptom-based to neuroscience-
based (Insel, 2014; Insel et al., 2010).
Cognitive Architectures and Unifying
Principles
Combination of highly specialized and isolated
research areas without shared, formalized termi-
nology creates a new, broader challenge: The need
for unifying, integrative theories that relate vari-
ous isolated research areas and findings together.
Integrating different research areas into a unifying
theory is extremely challenging, but it is arguably
the most pressing challenge of cognitive neurosci-
ence. Some early attempts to construct integrative
cognitive architectures, for example the Soar
architecture for general cognition (Newell, 1992,
1994), the Adaptive Control of Thought—Rational
(ACT-R) cognitive architecture (Anderson et al.,
1998) and the executive-process interactive con-
trol (EPIC) theoretical framework (Kieras, 2016;
Meyer and Kieras, 1997), have not been used and
developed nearly as widely as they might have
been, although they continued to be developed to
some extent (Anderson, 2009; Borst and Anderson,
2015; Laird, 2019).
One reason for this may be because they did
not provide a level of description compatible with
the field’s understanding at the neural circuit level.
Early neural networks (Rumelhart et al., 1994)
were compatible with principles of neural func-
tion and information representation, but suffered
from a lack of computational power to implement
larger models and a lack of tools to interpret their
function. Recently, the former limitations have
been partially overcome with technological, meth-
odological, and statistical developments. Indeed,
neural networks and deep learning have become
immensely popular, substantially advancing both
basic cognitive neuroscience and applications
such as artificial intelligence (AI) (Hasson et al.,
2020; LeCun et al., 2015; Richards et al., 2019;
Saxe et al., 2021). However, the second limita-
tion remains. Neural networks and deep learning
provide only a high-level description of how neu-
ral information representation might occur, but
they are difficult to test, and to understand, and
therefore lack explanatory power (though some
researchers suggest that understanding how the
brain develops and learns is a better goal than
understanding the properties resulting from these
processes (Lillicrap and Kording, 2019)).
579
Another important direction is the development
of computational principles. Recently, the idea of
predictive coding subsumes several broad con-
cepts that have great current appeal: that instead
of a stimulus–response machine, the brain has
evolved to predict future events and select actions
that minimize entropy (or, equivalently, surprise
or prediction error) with respect to the organism,
maximizing predictive control and thus future sur-
vival and wellbeing (Clark, 2013; Friston, 2010;
Rao and Ballard, 1999). In essence, the theoreti-
cal framework is that the brain generates and opti-
mizes internal mental models that predict sensory
input and physiological states. These models are
updated and optimized based on prediction errors–
the difference between the predicted and the actual
input. Top-down signals generated by internal
models convey the predictions and ­bottom-up
signals convey prediction errors (Bastos et al.,
2012; Rao and Ballard, 1999). The minimization
of prediction errors across hierarchical layers
occurs either by updating the internal model or by
action. In this framework, perception, decision-
making, emotion, and action are a matter of quasi-
optimal, quasi-Bayesian (or Bayesian) inference.
Information representation is efficient, so that
only deviations from predictions are passed for-
ward to update internal mental models (Aitchison
and Lengyel, 2017; Knill and Pouget, 2004).
The predictive coding theoretical framework
revolutionized many research areas in cognitive
neuroscience and beyond, and has the potential to
integrate across areas. It already unifies percep-
tion (for example vision (Rao and Ballard, 1999),
audition (Chennu et al., 2013), pain (Büchel et al.,
2014; Song et al., 2021) and interoception (Barrett
and Simmons, 2015), motor action (active infer-
ence (Adams et al., 2013; Friston et al., 2010)),
attention (Hohwy, 2012), emotions (Barrett, 2017;
Seth, 2013), theory of mind (Koster-Hale and
Saxe, 2013), mental health (Kaye and Krystal,
2020; Kube et al., 2020; Smith et al., 2021; Sterzer
et al., 2018; Van de Cruys et al., 2014), and can
also be related to structure and representational
learning (or latent cause attribution (Niv, 2019;
Tenenbaum et al., 2011)) and other domains.
Nonetheless, while predictive coding is compu-
tationally specific at the level of general informa-
tion processing principles, it is underconstrained
in terms of the neural mechanisms: what is rep-
resented where in the brain and how precisely it
is coded (Kogo and Trengove, 2015; Kwisthout
and van Rooij, 2020). It is also still not well inte-
grated with learning theory, including reinforce-
ment learning (K. Friston, 2018) and other types
of learning and memory, although the prediction
error idea is central to reinforcement learning
(Schultz et al., 1997; Tobler et al., 2005). Like
580 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
other integrative attempts, predictive coding has
strengths and weaknesses, and the future will tell
whether it will continue to grow as a unifying
theoretical framework or be replaced with oth-
ers. Whatever the future holds, it has undoubtedly
advanced cognitive neuroscience, both within and
across research areas, demonstrating the value of
unifying, fundamental theoretical frameworks to
the advancement of the field.
TOWARD INTEGRATIVE BRAIN MODELS:
FROM SINGLE REGIONS TO PREDICTIVE
MODELS
In addition to new, integrative theoretical principles,
the future of cognitive neuroscience lies in develop-
ing integrative, empirical models of brain organiza-
tion and representation. Cognitive neuroscience
aims to describe the neural mechanisms of cogni-
tion. The field has been predominantly focused on
mapping specific cognitive processes to localized
brain regions. This approach has deep historical
roots, from phrenology, the localizationist view and
the parcellation of the brain to sub-regions by
Broadman and others in the nineteenth century.
Traditional approaches in neuroimaging in particu-
lar are focused on localized regions and are based on
analysis of isolated brain regions. In other words,
they describe which brain regions encode specific
types of mental functions. Indeed, prominent dis-
coveries in cognitive neuroscience include the local-
ization of specific mental processes, such as the
fusiform face area (FFA) for face perception
(Kanwisher et al., 1997), the hippocampus for
memory (Squire, 1992), and the ventro-medial pre-
frontal cortex for value-based decision making
(Chib et al., 2009; Levy and Glimcher, 2012).
However, this approach has a fundamental problem:
Individual brain regions are related to multiple cog-
nitive and affective processes, and individual cogni-
tive/affective processes are related to multiple
regions. The efforts to understand what processes
and types of information the ventro-medial prefron-
tal cortex (Delgado et al., 2016) or the insula (Chang
et al., 2013; Kurth et al., 2010) represent, for exam-
ple, nicely illustrate these issues. Therefore, it is
problematic to reverse-infer mental functions from
activations of single brain regions (Poldrack, 2011).
Recently, the field has been shifting focus
toward integrated, multivariate, system-level pre-
dictive models of cognitive processes (Haynes,
2015; Kragel, Koban, et al., 2018; Norman et al.,
2006; Poldrack and Farah, 2015). In neuroimag-
ing, instead of using mental measures to explain
(statistically relate to) brain activations, in a
predictive mapping approach brain patterns are
used to predict (or decode) mental outcomes.
These analyses are largely based on computational
approaches, particularly machine-learning tools,
and have been facilitated by recent technological
and computational developments, substantially
reducing the required time and resources (Cohen
et al., 2017). This paradigm shift in neuroimaging
is also grounded on the theoretical shift in cellular
neuroscience from the modular view of cognitive
processes as modular, separately-­implemented
processes, to a distributed view of neural popu-
lation coding and distributed representation
(Averbeck et al., 2006; Ni et al., 2018; Pouget
et al., 2000; Rigotti et al., 2013).
The predictive modeling approach develops
brain models that predict specific mental functions
or health-related outcomes. Predictive models can
serve as biomarkers for these processes, and are
much more likely to generalize to new popula-
tions compared to findings of the traditional
region or voxel-based methods, because they are
statistically measured on their ability to do so.
Such models have been advancing knowledge
across cognitive neuroscience research areas, for
example object recognition (Haxby et al., 2011),
memory (Harrison and Tong, 2009), pain (Ceko
et al., 2022; Wager et al., 2013; Woo and Wager,
2015; Woo et al., 2017), emotions (Kragel and
LaBar, 2015), attention (Rosenberg et al., 2016),
reinforcement signals (Vickery et al., 2011), and
neurological and mental disorders (Arbabshirani
et al., 2017; Fan et al., 2008; Hahn et al., 2015;
Koutsouleris et al., 2009; Woo et al., 2017). In
addition to integration across brain regions, pre-
dictive models can also integrate across measure-
ments, such as functional and structural features,
diffusion-based measures, connectivity patterns,
neurochemistry, electrical signals, and more.
This approach is likely to continue to lead the
way for cognitive neuroscience. However, to real-
ize its promise, emphasis is needed on the ability
of the predictive brain models to accurately predict
completely independent data. Many studies with
predictive modeling make claims of prediction
although statistically they only establish correla-
tion (Poldrack et al., 2020). Importantly, in order
to establish their predictive power, models that are
being trained on a dataset should be tested on new,
completely independent data. If cross-­validation
is being performed, with the model tested on
held-out data, all operations on the data includ-
ing preprocessing and feature selection must be
separately performed in each validation iteration,
to ensure independence between the training and
test sets. Since data from the same dataset are
likely to be dependent, it is preferred that models
will be trained and validated in a cross-validation
 Advancing Cognitive Neuroscience
procedure, and once a model has been selected and
optimized, it can be tested on completely new data
to establish predictivity, without additional opti-
mization procedures (Kragel, Koban, et al., 2018).
Brain signatures, or neuromarkers, are a specific
type of predictive model, aiming to use brain pat-
terns to predict mental processes across partici-
pants (i.e., population-level models) (Gabrieli et al.,
2015). It is crucial to evaluate the diagnostic value
of such signatures: their ability to correctly identify
true cases (sensitivity, or how robustly the measure
is induced by the outcome) and correctly identify
false cases (specificity, or how robustly the meas-
ure only responds to its outcome and not to other
outcomes) (Kragel, Koban, et al., 2018; Woo et al.,
2017). This is because a signature that was devel-
oped to predict a particular outcome (i.e., behavior)
based on a specific type of data does not necessarily
capture the behavior’s unique features. For exam-
ple, signatures that aim to identify pain can in fact
identify negative affect more generally, arousal, or
other processes that co-occur with pain.
Predictive performance characteristics of brain
signatures are already becoming central to their
evaluation, and are likely to become more com-
mon practice in the future as the methods develop.
Such evaluation of diagnostic value can be part
of the original study, but could also be done pro-
spectively. New findings about which processes
are predicted by the signature can gradually
refine the definition of the construct it assumes to
measure, just as science progresses gradually and
theories are refined based on new observations.
Prospective tests of brain signatures, or predictive
models more broadly, require researchers to share
their published models in a way that allows other
researchers to apply them on new data. This is
challenging in the current atmosphere in which, as
was nicely stated more than a decade ago (Mischel,
2008), researchers in the field “treat other peoples’
theories [or in our case, models] like toothbrushes
– no self-respecting person wants to use anyone
else’s.” The field will have to overcome this ten-
dency in order to work together toward integrative
and useful models and theories.
A fundamental challenge is to ensure that the
predictive models are indeed reflecting brain
representations of mental processes, rather than
confounding or contextual variables like head
movement, eye movement patterns, or physiologi-
cal noise. While such variables can contribute to
the knowledge base (for example, it is valuable
to learn that eye movement patterns predict the
valence of visual information), they indicate that
the model does not capture the neural represen-
tation of the mental process (Woo et al., 2017).
One approach to mitigate this challenge is to test
models on varying contexts, for example varying
581
stimulus modalities (pictures, sounds) (Chikazoe
et al., 2014; Wager et al., 2015) or integrating
across multiple studies with different contexts
when possible (Kragel et al., 2018a,b). Multi-lab
consortia, as suggested above, lend themselves to
this kind of generalization.
Another important aspect is the interpretability
of predictive models. Interpable models can pro-
vide explanations for the outcome, beyond predict-
ing it. Unlike activations in single brain regions,
distributed patterns across voxels might be harder
to interpret, particularly (but not only) when
non-linear models are used (Haufe et al., 2014).
A protocol for interpreting predictive models in
neuroimaging was recently published (Kohoutová
et al., 2020). One key idea is the ability to evalu-
ate models’ sensitivity, specificity, and generaliz-
ability, defining the “boundary conditions” of the
processes and tasks they relate to and those they
do not. This is the process of construct valida-
tion (Cronbach and Meehl, 1955; Kragel et al.,
2018a,b). A second key idea is to develop models
whose parts are interpretable and can be related
to mechanistic literature in nonhuman animals and
humans (pharmacology, brain stimulation, inva-
sive neuronal recordings, optogenetic and chemo-
genetic manipulation of circuits, etc.). Models that
are sparse (have few predictors) can help if the few
predictive variables make sense (Grosenick et al.,
2013). Another approach is using structure coef-
ficients (or model encoding maps) to identify how
individual brain voxels relate to a more integra-
tive model (Čeko et al., 2022; Haufe et al., 2014).
Finally, a third idea is to build integrative models
up hierarchically from combinations of individual
regions (Schrouff et al., 2013) or neural pathways
(Kragel et al., 2021).
Paradigm shift from single regions and single
measurement types to integrative and distributed
predictive brain models holds promise for advanc-
ing cognitive neuroscience by systematically
developing models that can represent, predict, and
explain cognitive outcomes. Continuous methodo-
logical and conceptual progress is likely to lead to
more fundamental contributions to the fields that
can potentially change the way cognitive neuro-
scientists think about specific cognitive processes,
and the brain.
SUMMARY AND CONCLUSIONS
Studying how the brain gives rise to cognition is
like solving an extremely challenging jigsaw
puzzle. Until now, cognitive neuroscience has
largely focused on producing more and more
582 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
pieces of information, and putting them together in
localized, specific, and frequently narrow research
areas. Consequently, we constructed parts of the
image, but are relatively far from connecting these
isolated partial images together. Moreover, alarm-
ing findings about the reproducibility, replicability,
reliability, generalizability, and validity of findings
in cognitive neuroscience and related fields are sug-
gesting that many of the puzzle pieces we are trying
to put together do not belong in this puzzle. Since
we have no idea what the final picture looks like,
identifying such false positive findings is extremely
hard. We suggest that to advance cognitive neuro-
science toward integrative, robust, and valid knowl-
edge and theories, we need to (1) improve our
ability to identify true (reproducible, replicable,
robust) pieces by balancing between theoretical
ideals and practical constraints; (2) develop better
and testable models and theories for sub-areas of
the puzzle and how they all connect together to
represent the broader picture; and (3) integrate
across brain regions to build predictive models
based on multivariate information that can accu-
rately predict cognitive outcome. By doing so, the
picture of the neural basis of cognition, as repre-
sented by the puzzle picture, will start to emerge.
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 Index

Note: Page numbers followed by f or t indicate material in figures or tables respectively.

ABC transporters, 90 task-based fMRI, 36–37

Abdollahi, R. O., 289 white matter trajectory, 34–35
absolute pitch, 338 alertness–sleepiness rhythm, 318, 322, 329, 330
acetylcholine (ACh) signaling, 151–152 alpha rhythm, sleepiness, and alertness, 322–323
acquired MEG signal, 535 Altman, J., 496, 497
Adenosine A2A receptors Altschuler, E. L., 289
aged and neurodegenerative brains, 175–176 amygdala
behavioral inhibition, 175 aggression, 232–233
caffeine, 177 anxiety-related stimuli, 230f
cue-motivated behavior, 175 basolateral amygdala (BLA), 232
dopamine and glutamate signaling, 173 basolateral limbic circuit, 228f
memory impairment, 173–174 description of, 227
mood-related behaviors, 175 fear, 229–231
motivation, 175 functional neurological disorders, 233
No-Go pathway, 171–172 input–output relations, 229, 229t
overview of, 171 limbic system, 227–229
reverse cognitive impairments in AD and PD neurological disorders, 233
models, 176–177 neurons, 71, 71f
striatopallidal medium spiny neurons, 171–172 positive emotions, 231
synaptic plasticity, 172–173 prefrontal connectivity, 232
value sensitivity vs. action-outcome smell, 231
contingency, 175 Urbach-Wiethe disease, 233–234
Adolescent Brain Cognitive Development amygdala-precuneus connectivity, 230
(ABCD) study, 571 anatomical cerebro-cerebellar loops, 215–216
Adolfi, F., 18, 23 anterior middle cingulate cortex (aMCC), 295f, 296
Adolphs, R., 234 Apolipoprotein E (APOE), 33
adult neurogenesis Aquino, T. G., 231
acceptance of, 496 Aristotle, 360, 415
behavioral effects, 498 Arnolds, D. E., 186
degenerative diseases, 497 Aron, A. R., 2
evidence of, 496 artifact removal, 542–543
in humans, 497 astroglia
Aeschbach, D., 323 Ca2+ signal generation, 86
age-related alterations classification of, 82, 83f
cognitive control and working memory, 120 diversity, 81–83
episodic memory, 120–121 endfeet, 83
reward learning and decision making, extracellular K+ homeostasis, 88
121–122 functions of, 81–82, 82f, 88–90, 88t
aging brain changes, lifespan glycogen synthesize, 89
BOLD signal, 31 glymphatic system, 89, 89f
brain maintenance (BM) model, 39 homeostatic transporters, 90
changes in gray matter (GM), 31–33 ionic signalling, 87
changes in white matter (WM), 33 morphological appearance, 81–83
environmental effects and models, 38–39 secretory cells, 90–91
functional connectivity with rs-fMRI, 35–36 synaptic transmission, 90, 91f, 92f
future aspects, 39 types of, 84f
genetic effects, 37–38 ATP-dependent transporters, 90
resting state networks (RSN), 35 attention deficit-hyperactivity disorder (ADHD), 268
 INDEX 591

auditory attention basolateral amygdala (BLA), 232

description of, 344–345 Bayesian network, 554t, 557
involuntary attention, 345–346 Bear, M. F., 499, 501
voluntary attention, 345 behaviorism, 2, 17
auditory information processing brain’s inner time–space shapes, 24
absolute pitch, 338 input–output relation vs. cognitive function,
auditory attention, 344–346 20–22
auditory processing pathway, 341–342 inside–out vs. outside–in approach, 23–24
auditory representations. see auditory outer time–space of cognition, 24
representations spontaneous activity vs. task-related activity, 22
cocktail-party problem, 337 spontaneous and stimulus induced activity,
high-pitched tone, 338 22–23
instantaneous auditory scene analysis, 343 Bellugi, U., 234
location, 339–340 Berger, H., 22
loudness, 339 Bernstein, M. A., 502
loud sound, 338 Besser, G., 401
neural encoding of sounds, 339–341 Betka, S., 422f
neuronal activation patterns, 340 Bickle, J., 495, 505
organ of Corti, 340 bidirectional activation, 72
pitch, 338 Bienenstock, E., 499
sequential auditory scene analysis, 343–344 Bishop, D. V. M., 22
sound source separation, 342–343 Bizley, J. K., 337
timbre, 339 blood-brain barrier (BBB), 185
tonotopy, 341 blood oxygen level dependent (BOLD) signals, 17, 36,
auditory representations 116, 121, 310, 533, 534
event representations and memory, 346 Bocchio, M., 232
neural representation and predictive coding, Bolognini, N., 2, 4, 5, 291, 438, 440, 444
343–344 Bouton, M. E., 159
autism spectrum disorder (ASD), 268 Boyle, G. J., 1–3, 102, 190, 242
autocorrelation window (ACW), 24 brain
autoencoders (AEs), 554t, 558 aging, 38–39
amygdala, 186
Barber, M., 502 cognitive functioning, 105, 186
Barbey, A. K., 2, 3 disorders, 268–269
Bard, P., 415 dynamic rhythms of, 306–310
Bares, M., 221 functional activity measurement, 533
Barrett, L. F., 415 functions of, 18
basal ganglia (BG) genetic and functional expression, 105–106
action selection, 204–205, 205f genetic effects, 37–38
anatomical structure vs. function, 197–198 hippocampus, 186
anatomy of, 198 imaging. see brain imaging
biophysical modeling, PD. see also Parkinson’s inner time-space, 24
disease (PD) prefrontal cortex (PFC), 186
computational models, 202–203, 206 structural neuroanatomy, 65
direct BG pathway, 200f, 202 structure of, 186
dorsal striatum, 198 brain asymmetries
globus pallidus, 198, 201 body asymmetries, 264, 265f
individual nuclei, 198–201 brain disorders, 268–269
isolated anatomical information, 202 cerebral lobes, 260
model description, 198, 200f ciliopathies, 264–266, 266t
post-mortem anatomical images, 199, 199f experiential and environmental factors, 267
reinforcement learning, 204–205 fetal brain, 261f
striatum (STR), 199–201 genetics and heritability, 266–267
substantia nigra (SN), 198, 201–202 left planum temporale, 260
subthalamic nucleus (STN), 198, 201 sex hormones, 267–268
synergistic approach, 206 sylvian/planum temporale asymmetry, 260
ventral striatum, 198 Yakovlevian counter-clockwise torque, 261
592 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

brain imaging case-controlled study, 268

functional magnetic resonance imaging (fMRI), Catani, M., 229
533–535 Cattaneo, G., 288
future aspects, 547–548 central nervous system (CNS)
machine learning, 548 astroglia, 88, 89
magnetic resonance spectroscopy, 547–548 functional principles, 66
magnetoencephalography (MEG), 535–536, 535f informational complexity, 67
multimodal brain imaging, 547 microglia, 81
positron emission tomography (PET), 536–538, multilevel processing, 66
537f secretory cells, astrocytes, 90–91
brain maintenance (BM) model, 38, 39 structural principles, 66
brain network activity cerebellar motor syndrome (CMS), 221
aversive learning tasks, 155–156 cerebellar reserve, 219
cholinergic activity, 151–152 cerebello-cortical circuits, 218–219
context complexity, 157–158 cerebellum
dopaminergic neurons, 153–154 amphibians, 213
emotional balance, 155 anatomical cerebro-cerebellar loops, 215–216
exteroceptive context, 158–159 cerebellar reserve, 219
glutamatergic activity, 154 cerebello-cortical circuits, 218–219
hedonic and/or reward processing, 157 cerebro-cerebellar connectivity, 215–218
hypothetical scheme, 156f climbing fibers, 213
interoceptive influences, 159 clinical syndromes, 221–222
learning and memory, 151 complex spikes, 214
noradrenergic activity, 152–153 description of, 212
peptides and endocannabinoid systems, 154–155 emotions assesment, 217–218
regulate reward and affective processing, 155 fish and amphibians, 213
reward learning, 156–157 functional anatomy, 216–217
brain rhythms in mammals, 213
connectivity mediated, 310–311 modulator of, 219–221
spatio-temporal dynamics, 306–310 modules, 215
Brain, W. R., 435 mossy fibers, 213
Braun, K. F., 502 motor and non-motor operations, 219–221
Bregman, A. S., 342 multiple climbing fibers, 213
Bremmer, F., 439 neurophysiological aspects, 218–219
Broca, P., 1, 2, 18, 227 physiological aspects, 214–215
Brock, L., 504 plasticity mechanisms, 214–215
Brodmann, K., 280, 374, 380, 522 posterolateral fissure, 213
Brownstone, R.M., 503 primary fissure, 213
Buccino, G., 288, 289 rebound depolarization, 214
Buchanan, T. W., 232 Schmahmann syndrome, 221–222
Buckner, R. L., 36 simple spikes, 214
build–measure–learn process, 50 structural anatomy, 213–214
Bullock, T. H., 504 vestibulospinal tract, 214
Burdach, K. F., 227 cerebral lateralization
brain asymmetries, 260–262
Calvo-Merino, B., 289 emotions and cognition, 262
Cambridge Neuropsychological Test Automated Battery fetal brain, 261f
(CANTAB), 3 handedness, 263–264
Canadian Study of Health and Aging (CSHA) study, hemispheric specialization, 260
177 language lateralization, 262–263
Candy Smell Test (CST), 401, 402 overview of, 259–260
Canli, T., 232 right hemisphere hypothesis (RHH), 262, 262t
Cannon, W. B., 415 valence hypothesis (VH), 262, 262t
canonical correlation analysis (CCA), 554t, 556 cerebro-cerebellar connectivity, 215–218
Cardiovascular risk factors, Aging and Dementia Cerkevich, C. M., 374
(CAIDE), 177 Chamberlain, S. R., 2
Carlson, J. M., 230 Chambers, R., 502
Caruana, F., 295 Chen, B., 403
 INDEX 593

Cherry, E. C., 345 Cohen, Y. E., 337

cholinergic activity, 151–152 Cole, K. S., 503
cingulate-amygdala connectivity, 230 connectivity mediated, brain rhythms, 310–311
circuit-based mechanisms, 71, 72 connexins (Cx), 84
Cisek, P., 285 connexons, 83
Cochin, S., 289 continuity illusion, 343
cocktail-party problem, 337 convolutional neural network, 554t, 558
cognition, brain, and aging (COBRA) study, 122–123 Coombs, J., 504
cognitive-behavioral response, 67 Cooper, L. N., 499
cognitive control, 120 cortical responsivity, 72
cognitive neurogenetics Cox, S. R., 33
behavioral genetics, 104 Crawford, J., 358
cultural neurogenetics, 108 cultural neurogenetics, 108
functional pathways, 105 Curtis, H. J., 503
genes and brain function, 103t
genetic and functional expression, 105–107 Daan, S., 319
genetic and neural basis, 107–108, 109f Damasio, A., 415
genetic influences, 103 data harmonization, 554t, 556
genotype-to-phenotype model, 104, 104f Davis, S. W., 34
neurochemical signaling, 102 D1DR stimulation, 116
neurocognitive function, 106 D2DR stimulation, 116
neurotransmission, 104 deep belief network (DBN), 554t, 558
overview of, 102–103 default-mode network (DMN), 17
cognitive neuroscience Denenberg, V. H., 263
architectures and unifying principles, 579–580 Di Cesare, G., 297
BOLD fluctuations, 17 diffusion weighted imaging (DWI), 554
brain function, 18 Dimberg, U., 293
brain signatures/neuromarkers, 581 Ding, S.-L., 245
CANTAB, 3 Dolcos, S., 232
cognitive Atlas, 578 dopamine (DA)
cognitive ontology, 19–20 age-related alterations, 119–122
decade of the brain, 5 cognition, brain, and aging (COBRA) study,
development of, 2 122–123
emotions and nonconscious process, 3 cognitive control and working memory, 117–118
empirical analyses and ontologies, 576, 578–579 cytosolic DA, 115
fMRI research, 17, 18 depletion, 176
historical origin of, 2 dopaminergic pathways, 114–115, 115f
integrative theoretical principles, 580–581 episodic memory, 118–119
interpable models, 581 post-synaptic dopaminergic mechanisms,
large population-based studies, 577t 115–116, 115f
localizationism, 18–20 pre-synaptic dopaminergic mechanisms, 115–116,
methodologies and techniques, 4–5 115f
non-human primates, 6 reward learning and value-based decision making,
overview of, 1 116–117
phase model, 574–575, 574f dopaminergic activity, 153–154
practical constraints, 573–576 Dow, R., 213
predictive modeling approach, 580 Dudek, S. M., 501
from regions to modules, 18–19 dynamic causal modeling (DCM), 204, 554t, 557
replicability of findings, 570–573 dyslexia, 268
replication crisis, 570
reproducibility, 570–573 Ebner, T. J., 220
response inhibition, 2 Eccles, J., 504
robustness, 570–575 Edde, M., 35
scientific developments, 569 electroencephalography (EEG), 198
spatiotemporal cognitive neuroscience, 6 EMOTICOM battery, 3
stimulus–response (S–R) reflexes, 21 emotional memory, 187
cognitive revolution, 3 endogenous opioid system, 154–155
Cohen, D., 535 Engel, A. K., 310
594 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Enhancing Neuro-Imaging Genetics through Garcia, J., 21

Meta-Analysis (ENIGMA), 270 Gazzola, V., 289
epigenome-wide association study (EWAS), 37 Gee, D. G., 231
episodic- autobiographical memory, 232 generative adversarial network, 554t, 558
episodic memory, 120–121 genetic regulation, 107–108
equilibrium potential (EK), 85 genome-wide association study (GWAS), 37, 266, 267
Errante, A., 291 genotype modulation, 105, 106f
event-related brain potential (ERP), 343 genotype-to-phenotype model, 104, 104f
executive functioning (EF) Gerard, R., 502, 503
cognitive flexibility, 188 Gerard, R. W., 503, 504
experimental manipulation, 188–189 Ge, S., 291
inhibition, 188 Gestalt law of common fate, 344
natural hormone fluctuations, 189 Gibson, W. S., 294
pharmacological application, 188 globus pallidus, 201
explicit memory, 133 glutamate (GABA)-glutamine shuttle, 90, 92f
Eyzaguirre, C., 504 glutamatergic activity, 154
Golesorkhi, M., 24
Fadiga, L., 287 Gorbach, T., 33
familiarity-consolidation process Graham, J., 502, 503
catecholaminergic activity, 138 granularity mismatch problem (GMP), 24
cholinergic response, 139 Gray, C. M., 310
dopaminergic release, 138 Gross, C. G., 496
insular cortex, 139 Guell, X., 216
muscarinic administration, 139 gustatory dysfunction
norepinephrine administration, 140 clinical examinations, 405–406
Fechner, G., 472, 474–476, 478–480 description of, 405
Ferrari, P. F., 290 psychophysical tests, 401f
Ferri, J., 230 treatments, 405–406
Finland, Italy, Netherlands Elderly (FINE) study, 177 gustatory sensation
Florey, E., 502, 503 anatomy, 404–405
Flourens, M. J. P., 212, 351 description of, 398–399
Fluid Attenuation Inversion Recovery (FLAIR) gustatory dysfunction, 405–406
acquisitions, 33 physiology, 404–405
Frangou, S., 32
Frank, M. J., 204, 206 Hagiwara, S., 504
Frasnelli, J., 399 Haith, A. M., 387
Fregni, F., 3, 4 Haller, J., 232
French Three Cities study, 177 Hari, R., 289
functional magnetic resonance imaging (fMRI), 74, 116 Hartline, H. K., 504
blood oxygenation level-dependent (BOLD), 533, Hassler, R., 311
534 Hayes, N. L., 497
characteristics of, 534f head-related transfer function (HRTF), 340
independent components analysis (ICA), 540 Hebbian learning, 204
multiband acquisition, 538–539 He, B. J., 457
multi-echo acquisition, 539 hippocampal amnesia, 250
node based analysis, 540–541 hippocampal formation
slice-by-slice acquisition, 538, 539f afferents, 247
study, 2, 231, 232, 439 anatomy of, 243–246
temporal resolution, 534 body, 243, 244f, 246
ultra-high field fMRI, 534 cellular composition, 246–247, 246f
description of, 242–243
GABA neurotransmitter system, 67 efferent, 248
Gage, F. H., 496, 497 encoding, 252
Gallese, V., 293 entorhinal cortex inputs, 247
Galvani, L., 502 episodic memory, 250
Gangitano, M., 287 extrinsic connectivity, 247
gap junctional pathway, 86 head, 245–246
gap junction plaques, 83 intrinsic connectivity, 247
 INDEX 595

location of, 244 immuno-competent receptors, 96

long-axis organization, 248–249 implicit memory, 133
long-term declarative memory, 252–253 independent component analysis (ICA), 216, 307,
macrostructural definitions, 243–245 540, 554t, 556
material specificity of, 252 instantaneous auditory scene analysis, 343
memory retrieval, 251 interaural time differences (ITDs), 339
microstructural definitions, 246–247 intercellular signalling system, 85
neurochemical composition, 246–247 interoception
parcellation scheme, 242 anatomy of, 418–419
post-mortem hippocampal tissue, 242, 243f aspects of, 415–416
ram’s horn, 243 central chemoreception, 417
relational memory, 250–251 chemoreception, 416
short- and long-term memory, 251–252 computational modeling, 424–425, 425f
spatial navigation, 252–253 detecting temperature, 417
structural and functional properties, 243 dimensions and clinical symptoms, 423
structure–function relationships, 249–250 dimensions of, 423t
tail, 244, 244f disorders of, 425–426, 427t
vascular supply, 248 emotion, 415
white matter structures, 246–247 exteroceptive senses, 414
Hodgkin, A., 503, 505 functions, 414
Holmes, G., 212 heartbeat detection tasks, 421, 422f
Ho, N. F., 232 humoral physiology, 419
Honolulu-Asia Aging study, 177 interoceptors, 416
hormones interregional functional connectivity, 420
bidirectionality, 190–191 levels of, 421–423
classes of, 185 mechanoreception, 416
cognitive function assesment, 189–190 NTS neurons, 418–419
description of, 185 pathways to brain, 418
effects of, 186 perception, 414–415
executive functioning (EF), 188–189 phasic interoceptive signals, 422
interactions, 186–189 psychological representations, 420–421
memory, 186–188 therapeutic targeting, 427–428
natural fluctuations, 186 thermal information, 419–420
peptide hormones, 185 intracellular recording
steroid hormones, 185 complex behaviors and cognition,
human astrocytes, 82 504–505
Human Brain Project (HBP) development of, 502
biological neurons communication, 517, 518f electrophysiology approach, 502
brain to robotics, 519–520 functional imaging and optogenetics, 505
cognition and perception, 515 investigations, 503
computational models, 514–515 mammalian muscle fibres, 503
EBRAINS’ computational resources, micropipette electrode, 503
511, 512 neurotransmission, 504
international context, 524–525, 526t revolution in, 505
mean-field models, 513, 514f vertebrate CNS neurons, 504
multidisciplinary approach, 511 intra-CNS pathways, 185
multi-level human brain Atlas, 522–524, 525f intrinsic connectivity, 72
neuroethical questions, 526 involuntary attention, 345–346
overview of, 511–512 Ishida, H., 290
psychological levels, 516 Ito, M., 220
representations and consciousness, 520–521 Ivry, R. B., 218
spiking neural network models, 516–519 Izmailov, C. A., 491
systems-level models, 512–513
testing contextual cortical processing, 516 Jahanshahi, M., 2, 4, 5, 386–389, 392
workflows, 521–522, 523f James–Lange therapy, 415
Hummel, T., 399 James, W., 351, 415, 421
Huntington’s disease, A2AR blockade, 176 Jansen, J., 213
Huxley, A., 503, 505 Jiang, R.-S., 152
596 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

Kaas, J. H., 374 characteristics of, 544f

Kalaska, J. F., 285 network connectivity, 543–544
Kandel, E., 497 presurgical functional mapping, 536
Kant, I., 18, 19 sensors, 536
Kaplan, M., 496 source localization, 541–542, 542f
Karhu, J. J., 218 superconducting quantum interference device
Katsumi, Y., 232 (SQUID), 536
Kawato, M., 220 task-evoked cognitive process, 536
Keysers, C., 290, 293 major depressive disorder (MDD), 232
Koelling, R. A., 21 Malacarne, V., 212
Kohler, E., 283 Manan, H. A., 403
Kolliker, A., 496 many-to-one mapping, 68
Kraskov, A., 283 Mao, Y., 230
Krolak-Salmon, P., 293 Markov model, 554t, 557
Kuffler, S. W., 504 Marr-Albus-Ito theory, 215
Kuhn, T., 495, 497, 500 Marreiros, A. C., 206
Masssatricht Aging Study, 177
Lange, K. G., 415, 421 maternal aggressive behavior, 232
Langley, C., 3 Matsunaga, M., 294
Lanteaume, L., 294 Mattos, J. L., 400
Lanzilotto, M., 287 McDermott, J. H., 343
large-scale data, neuroimaging medium spiny projection neurons (MSN), 200
deep learning (DL) techniques, 558 Mehta, M. A., 3
machine learning (ML) methods, 557–558 Meltzoff, A. N., 290
modalities, 553–555 memory, hormone interactions
random forest (RF) model, 558 cortisol, 187
source separation, 556–557 experimental manipulation, 187–188
statistical challenges, 555–556 glucocorticoid cortisol, 187
Larsell, O., 213 natural hormone fluctuations, 188
Lashley, K., 2 pharmacological application, 187
lateral geniculate nucleus (LGN), 68 memory retrieval, 134
Laurent, V., 156 Merton, P. A., 385
L-DOPA administration, 121 Merzenich, M., 267
LeDoux, J. E., 229, 230 mesolimbic pathway, 118
Lew, C. H., 233 Mesulam, M.-M., 229
Ling, G., 502, 503, 504 Meyer, M. F., 20
Liu, X., 400 microglia
Li, X., 231 description of, 93–94
locus coeruleus (LC), 185 diversity of, 94t
locus coeruleus neurons, 118 ion signaling, 95–98
long-term episodic memory, 118–119 morphological properties, 94–95
long-term memory (LTM), 133, 134f physiological functions, 94, 95f
Lopes da Silva, F. H., 186 physiological microglial morphotypes, 95, 96f
loudness, 339 P2X7 receptors, 96
Luciani, L., 212 Midlife in the US (MIDUS) study, 190
Lui, F., 231 Mikhalevskaya, M. B., 474
Luria, A., 21 Mild Cognitive Impairment (MCI), 3, 31, 177
mirror mechanism
Mach, E., 351 anterior middle cingulate cortex (aMCC), 296
machine learning, 5, 39, 55, 56, 467, 516, 540, 548, cortical areas, 285
557, 569, 572, 580 cortical motor system and properties, 280–281,
MacLean, P. D., 227, 228f 280f
Maeda, K., 287 disgust and anterior insula, 293–294
magnetic resonance imaging (MRI), 198 electrophysiological studies, 289–290
magnetic resonance spectroscopy, 547–548 emotions, 293
magnetoencephalography (MEG) fear and amygdala, 294
acquired MEG signal, 535 frontal cortex, 285–286
artifact removal, 542–543 goal coding, 289
 INDEX 597

historical premise, 279–280 overview of, 435

human mirror system, 287–288 RFs of visuo-tactile neuron, 436, 437f
in monkey, 282–284, 282f, 284f schematic representation, 436f
motor goals, 281 social side of, 443–444
neurons and intention, 292–293, 292f visuo-tactile stimulation, 444, 445
overview of, 279 neural communication, 65
parietal cortex, 286–287 neural encoding, 339–341
parieto-frontal mirror, 284–285 neural processes and activity
phylogenesis and development, 290 cognition and higher-level processes, 74–75
pregenual anterior cingulate cortex (pACC ), cognitive neural networks, 72–73
294–295, 295f cultural neuroscience, 72
somatosensory cortices, 290–291 facial recognition, 69, 70f
somatotopy of observed acts, 288–289 functional principles, 66
subcortical structures, 291 neural networks, 73–74
vitality forms, 296–297, 297f neurons types, 66–68
Mismatch Negativity (MMN) component, 344 sensation and perception, 68, 69f
molecular-imaging method, 116 social perception, 69–71
Moore, M. K., 290 structural principles, 66
Moran, R. J., 204, 206 type representataion, 68
motor control system neurite orientation dispersion and density imaging
afferent sensory information, 384 (NODDI), 34
building blocks, 380–382, 381f neurodegenerative disorders
internal forward and inverse models, 382–385, corticobasal degeneration, 269
383f Pick’s disease, 269
motor chauvinist’s perspective, 379 neurodevelopmental disorders
putative stages, 387 attention deficit-hyperactivity disorder (ADHD),
reaction time (RT) tasks, 386, 386f 268
response inhibition, 389–393, 391f autism spectrum disorder (ASD), 268
response preparation and initiation, 385–389 dyslexia, 268
roles, 379–380 neuroglia
transcranial magnetic stimulation, 385 astrocytic networks/syncytia, 83–85, 85f
MSN D1 receptors, 204 astroglia, 81–83, 88–90
MSN D2 receptors, 204 classification of, 80–81, 81f
Mukamel, R., 289 CNS neuroglia, 80
multiband acquisition, 538–539 defined, 79–80
Multidimensional Scale of Perceived Social Support, gliocrine system, 90–91
231 intracellular excitability, 86–88
multi-echo acquisition, 539 ion channels, 85–86
multi-layer perceptron (MLP), 554t, 558 ion distribution, 85–86
multimodal brain imaging, 547 mammalian nervous system, 80
multimodal neuroimaging study, 121, 122 membrane potential, 85–86
muscarinic receptors, 141 microglia, 93–95
myelination, 93 neurohormones, 86
neuromodulators, 86
Nastuk, W. L., 503 neurotransmitters, 86
natural sound waves, 339 numbers of, 81
nervous tissue oligodendrocyte precursors (NG2-glia), 92, 93
active milieu, 79, 80f overview of, 79
multicellular nature, 79 pathophysiology of, 97t–98t, 98–99
network connectivity, 543–544 PNS neuroglia, 80
neural bases, peripersonal space representation Neuroimaging Meta-Analysis Research Environment
appetitive function, 441–442 (NiMARE), 5
convergent evidence, 444 neuromodulators, 134
defensive function, 442–443 neuronal activation, 65
functional significance, 441 neuronal mechanisms
hand blink reflex (HBR), 442, 443f cortical specialization, 72
in humans, 438–441, 439f, 440f functional and emergent properties, 72
in monkey, 435–438, 436f, 437f response properties, 74
598 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE

role of, 75 olfactory sensation

social perception, 71 age and gender, 398
neurotechnology startups anatomy, 399
advances in, 48 assessment, 399–400
application of, 59 description of, 398
brain–computer interfaces, 56 electrophysiology and functional brain
brain imaging, 54–55 imaging, 402–403
brain–machine interface technology, 53 neuroepithelium, 399
build–measure–learn process, 50 olfactory dysfunction, 403
cognitive and learning neurotechnologies, orthonasal olfaction, 399
58–59 physiology, 399
data ownership, 54 psychometric questionnaires, 399–400
development and innovation chain, 54f psychophysical tests, 400–402, 401f
electrophysiologic activity, 55–56 retronasal olfaction, 399
emphatic stimulation and investment, 53 structural brain imaging, 403
gene therapy, 55 testing in children, 402
innovation translation, 57–58 women, 398
innovative implementations, 48 oligodendroglia
investment, 52–53 functional properties of, 92–93
lean startup method, 50–51 myelination, 93
minimal viable product (MVB), 50 NG2-glia, 92, 93
neurostimulation devices, 57, 57t orientation dispersion index (ODI), 34
overview of, 48–49 orthonasal olfactory function, 400–401
pharmacological drugs, 55
pivoting, 51 Padlubnaya, D. B., 155
real-life neuroscience startups, 54 panglial syncytium, 84
remote EEG system, 56 Papez Circuit, 227
risk of failure, 49 Parker, D., 495
Stanford University’s Biodesign Model, Parkinson’s disease (PD)
49–50 beta oscillations, 204
user experience and innovation cycle, 49 biologically constrained computational
world’s brain research projects, 51–52 model, 205f
Nishitani, N., 289 cardinal symptoms, 203
nociception mechanism, 154 dopamine availability, 203
non-invasive neuromodulation techniques, 4–5 dynamical systems theory, 203
noradrenergic activity, 152–153 dynamic causal modelling (DCM), 204
norepinephrine system, 105 long feedback loops, 203
Northoff, G., 1, 3, 6, 17, 18, 20, 22–24 Pascual-Leone, A., 4, 5, 38, 306, 308
novel object recognition (NOR), 136 Patton, H., 504
novelty signaling Pavlov, I., 21
c-Fos expression, 136 Pearson, 490
dopamine reuptake, 137 Penfield, W., 358
dopaminergic response, 138 peptide hormones, 185
neurochemistry, 138–140 perfusion weighted imaging (PWI), 554
norepinephrine administration, 137 peripersonal space representation
Nowakowski, R. S., 497 appetitive function, 441–442
Nucleus of the Solitary Tract (NTS), 418 convergent evidence, 444
defensive function, 442–443
object location memory (OLM), 136–138 functional significance, 441
object-related negativity (ORN), 343, 344, 399 hand blink reflex (HBR), 442, 443f
Ogawa, S., 534 in humans, 438–441, 439f, 440f
Olbrich, S., 329 in monkey, 435–438, 436f, 437f
olfactory dysfunction overview of, 435
classification, 403 RFs of visuo-tactile neuron, 436, 437f
clinical examinations and treatments, 403–404 schematic representation, 436f
description of, 403 social side of, 443–444
epidemiology, 403 visuo-tactile stimulation, 444, 445
prevalence of, 403 Peterfi, T., 502
 INDEX 599

Phillips, W. A., 293 psychophysical tests

Pick’s disease, 269 orthonasal olfactory function, 400–401
Pieniak, M., 402 retronasal olfactory function, 401–402
Pishnamazi, M., 234 Puccetti, N. A., 231
Poeppel, D., 18, 23 Purkinje cell layer, 213
positron emission tomography (PET) Purkinje, J. E., 351
advance methadology, 538 Purkyn, J. E., 212
characteristics of, 537f
kinetic modeling, 545–546 Raichle, M. E., 18, 22
metabolic connectivity, 546–547 Rakic, P., 496, 497
radiolabeled tracers, 536 Ramón y Cajal, S., 212, 496
radiopharmaceutical development, 537 rebound depolarization, 214
silicon photomultipliers (SiPMs), 537 recognition memory
time-of-flight (TOF) PET, 544–545 consolidation of, 138–139
Postema, M. C., 268 description of, 135
posterior inferior cerebellar artery (PICA), 221 familiarity, 135, 135f
pregenual anterior cingulate cortex (pACC ), hippocampal formation, 135
294–295, 295f learning and relearning, 140–141
presurgical functional mapping, 536
memory updating, 140–141
primary somatosensory cortex, 372–373
novel object recognition (NOR), 136
proprioceptive afferents, 367
novelty signaling, 136–138
protoplasmic astrocytes, 83, 86
object location memory (OLM), 136
psychiatric disorder
recollection, 135, 135f
bipolar affective disorder, 269
taste recognition memory, 135
major depressive disorder (MDD), 270
reconsolidation, 134
obsessive-compulsive disorder (OCD), 270
recurrent neural network (RNNs), 554t, 558
schizophrenia, 269
residual neural network, 554t, 558
psychophysical techniques
response inhibition
conception of two thresholds, 474
automatic mechanism, 390, 391, 393
confidence rating method (CRM), 484–485,
behavioral assessment, 389, 390, 391f
485t
conditional stop-signal task (CSST), 390
Fechner’s methods, 478–479
electrophysiological recordings, 392
forced choice method (FCM), 484
proactive inhibition, 390
High-Threshold Theory, 473–474
reactive inhibition, 389, 390
Low-Threshold Theory, 474
SMA impairments, 393
machine-like approach, 477
supplementary eye field (SEF), 393
MDS vs. factory analysis, 492
resting-state networks (RSN), 310, 311
method of adjustment, 480
restricted Boltzmann machines (RBMs), 558
method of constant stimuli, 480–482
Restuccia, D., 218
method of limits, 479–480
retronasal olfactory function, 401–402
metric multidimensional scaling (mMDS),
reward learning, 121–122
490–492
reward prediction error (RPE), 116
multidimensional scaling (MDS), 488–490
Rizzolatti, G., 293
neuro-quantum (NQ) theory, 473
Rolando, L., 212
non-metric multidimensional scaling (nMDS),
Rolls, E., 231
492
Rubin, J. E., 206
overview of, 472
Rutishauser, U., 232
psychology activity, 477–478
psychophysical law, 476–477
SDT sensory axis, 473–474 Sahakian, B. J., 1, 3, 5, 6, 138, 500
sensory range discreteness/continuity problem, Sanami, M., 58
472–473 sarco-endo-plasm reticulum (SERCA), 86
sensory sensitivity and decision making, 486 Sato, M., 231
signal detection theory, 473 Schepers, S. T., 159
Stevens’s scaling methods, 475–476, 486–487 Schmahmann, J. D., 212, 216
Theory of Two States, 474 Schmahmann syndrome, 221–222
Three States Theory, 474 Schwab, S., 310
Thurstone’s approach to scaling, 474–475 Schwann cells, 80
600 THE SAGE HANDBOOK OF COGNITIVE AND SYSTEMS NEUROSCIENCE
Sejnowski, T. J., 499
Sejnowski, T.J., 501
Self-Reported Mini Olfactory Questionnaire
(Self-MOQ), 400
Seligman, M., 21
sensory stimulus, 68, 72, 73, 340, 341, 438
sequential auditory scene analysis, 343–344
Sherrington, C. S., 415, 416
short-term memory (STM), 133, 139
silicon photomultipliers (SiPMs), 537
Simoncelli, E. P., 343
Sinek, S., 49
Singer, T., 296
single nucleotide polymorphism (SNP), 266, 267
Sjogard, M., 312
Skeldon, A. C., 319
Skinner, B. F., 20, 21
sleep, alertness, and circadian rhythms
alertness–sleepiness rhythm, 322
alpha rhythm, sleepiness, and alertness, 322–323
EEG slow wave activity, 319
overview of, 318–319
sleep times and sleepiness levels, 321t
sleep–wake regulation (SWA), 319–321, 320f
sleepiness, alpha waves
artifact-free epochs, 324
diurnal variation, 329
EEG recording session, 324, 325
experimental deprivation studies, 325–326
independent factors, 328t
methods of deprivation studies, 324–325
objective and subjective measures, 328t
power spectra and time courses, 326, 327f
repeated measure ANOVAs (rANOVAs), 325
self-ratings of sleepiness, 326
subjective sensation, 323
sleep–wake regulation (SWA), 319–321, 320f
slice-by-slice acquisition, 538, 539f
solute carrier transporters (SLCs), 90
somatosensory cortex, 370–372, 371f
somatosensory midbrain, 369
somatosensory nuclei, 370f
somatosensory processing
afferent pathways and target nuclei, 367–368
contralateral body surface, 373
glabrous skin and hairy skin, 366–367
primary somatosensory cortex, 372–373
processing levels, 368f
proprioceptive inputs, 373–374
somatosensory cortex, 370–372, 371f
somatosensory midbrain, 369
somatosensory nuclei, 370f
somatosensory thalamus, 369–370
spinothalamic pathways, 368–369
tactile receptors and afferents, 366–367
upper bank of lateral sulcus, 374
somatosensory thalamus, 369–370
Sorrells, S. F., 497
sound pressure level (SPL), 281, 339
sound source separation, 342–343
source localization, 541–542, 542f
spatial navigation, 252–253
spatiotemporal cognitive neuroscience, 6
spatio-temporal dynamics, brain rhythms
advantages, 308
decomposition of EEG signal, 308, 309f
EEG oscillations, 305, 306, 308
generalized eigenvalue decompositions (GED),
307, 308
ongoing debate, 308
overview, 305–306
quantitative EEG (qEEG) approach, 306
spatial non-stationarity of Alpha-EEG, 306, 307f
time-frequency approach, 310
Specter, M., 496
spinothalamic pathways, 368–369
Sprengelmeyer, R., 293
Stanford University’s Biodesign Model
identification phase, 49–50
implementation phase, 50
invention phase, 50
in neurotech field, 50
Stanton, P.K., 501
Stent, G. S., 499
Stern, D., 296
steroid hormones, 185
Stevens, S., 475–476, 487
Stevens’s scaling methods, 475–476, 486–487
striatal neurogenesis, 497
striatal neurons, 202, 204
striatum (STR)
anatomo-functional specificity, 200
dorsal STR, 199
microscopic appearance, 200
topographical zonation, 201
Strick, P. L., 216
Stuart, D.G., 503
substantia nigra (SN), 114, 115, 201–202
subthalamic nucleus, 201
superconducting quantum interference device (SQUID),
536
superior colliculus (SC), 369
superior temporal sulcus (STS), 69
cellular mechanisms, 70
electrophysiological signaling, 71
response selectivity, 70
support vector machine, 464, 554t, 557
sympathetic nervous system (SNS), 190
synaptic plasticity, 204
anti-Hebbian process, 499
BCM model, 499, 500
long-term depression (LTD), 172, 173
long-term potentiation (LTP), 172, 173, 498, 501
LTD-LTP shift, 173
NMDAR activity, 173
wet neurobiology, 498–502
 INDEX 601

tactile afferents, 367 EEG signature, 358

Takahashi, R. N., 231 endolymph, 351
Talairach, J., 296 galvanic vestibular stimulation (GVS) effect,
Tang, Y., 232 356, 358
Tasaki, I., 504 hair cells, 352–353, 353f
taste powders, 402 head movement and sensation, 351, 352f
Taylor, C. V., 503 human subcortical regions, 353–354
Tesche, C. D., 218 multimodal representation of verticality, 357
thermoreception, 418–419 multisensory guidance of action, 356–357
Thurstone, L., 474, 487 nucleus tractus solitarius (NTS), 359
timbre, 339 otolith organs, 352
time-of-flight (TOF) PET, 544–545 sensory organs, 351
time series data spatial resolution and compatibility, 355–356
cross-frequency coupling, 458f, 463f thalamic neuronal responses, 355
data analysis, 456 vestibulo-ocular reflexes (VORs), 354
electrophysiological data analysis, 456 visually induced motion sickness (VIMS), 359
event-related analysis, 456–457, 457f visually induced vestibular subjective
intracranial human electrophysiology, 455f experiences, 358–359
multivariate representations and analyses, vestibulo-cerebellar syndrome (VCS), 221
462–465, 464f, 465f vitality forms, 296–297, 297f
neural recordings, 454–455 voluntary attention, 345
oscillatory and broadband activity, 459–460, 459f Von der Heide, R. J., 233
oscillatory and waveform shape features, Von der Malsburg, C., 498, 499
460–461, 461f von Holst, E., 21
overview of, 453–454 von Monakov, C., 2
peri-stimulus time histograms (PTSH), 457 Voogd, J., 213
scale-free phenomena, 465–466, 466f
spatial and temporal scales, 461–462 Watson, J. B., 20
spectral analysis, 457–459, 459f, 460f Wernicke, C., 2
statistical considerations, 466 wet neurobiology
theoretical and decoding approaches, 464, 465f adult neurogenesis, 495–498
Tkach, D., 285 intracellular recording, 502–505
Tolman, E., 21 overview of, 495
tonotopy, 341 synaptic plasticity, 498–502
Torgerson, W., 490 Whitaker, D. M., 503
transcranial electrical stimulation, 218 Wolff, A., 23
transcranial magnetic stimulation (TMS), 51, 218 Woodbury, J. W., 503, 504
transient receptor potential (TRP), 87 working memory, 120, 188
Trier Social Stress Test (TSST), 190 World’s brain research projects
two-day and one-night sleep deprivation study, 325, 326 China Brain Project (CBP), 51
two-day deprivation study, 326 Human Brain Project (HBP), 51
two-day sleep deprivation study, 324 International Brain Initiative (IBI), 52
Neurotechnology Industry Organization
UK Biobank study, 575 (NIO), 52
ultra-high field fMRI, 534 US BRAIN initiative project, 51
Urbach-Wiethe disease, 233–234
Yoshino, A., 285, 286, 402
valence hypothesis (VH), 262, 262t Yuval-Greenberg, S., 311
Van Hoesen, G. W., 245
ventral tegmental area (VTA), 114, 115, 185 Zabrodin, Yu. M., 477
ventroposterior nucleus (VP), 369 Zeiss, C., 502
verbal fluency, 188 zero-phase synchronization
vestibular processing EEG/MEG recording, 311
benign paroxysmal positioning vertigo (BPPV), meaning phase-lagged connectivity, 312
359 simultaneous synchronous network, 312
body representation in space, 357–358 volume conduction, 311, 312, 313f
cortical processing, 354–355 Zou, L. Q., 400