Clinical Brain Mapping

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Clinical Brain Mapping
Daniel Yoshor, MD
Associate Professor
Department of Neurosurgery
Baylor College of Medicine
Chief of Neurosurgery
St. Luke’s Episcopal Hospital
Houston, Texas

Eli M. Mizrahi, MD
Chair, Department of Neurology
Professor of Neurology and Pediatrics
Baylor College of Medicine
Chief of Neurophysiology
St. Luke’s Episcopal Hospital
Houston, Texas

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 Dedication

To our parents, Shulamit and Joseph Yoshor, and Julia and Isaac D. Mizrahi, who encouraged and
sustained us; and to our patients who inspire and teach us.

v
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 Contents

Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

SECTION I: TECHNIQUES

Chapter 1. Surface Anatomy as a Guide to Cerebral Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Gareth Adams, Jared Fridley, and Daniel Yoshor

Chapter 2. Structural Imaging for Identification of Functional Brain Regions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Jean C. Tamraz and Youssef G. Comair

Chapter 3. Functional MRI for Cerebral Localization: Principles and Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
Michael S. Beauchamp

Chapter 4. Functional MRI: Application to Clinical Practice in Surgical Planning and

Intraoperative Guidance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Michael Schulder and Robin Wellington

Chapter 5. Neuropsychological Testing: Understanding Brain–behavior Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .55

Mario F. Dulay, Corwin Boake, Daniel Yoshor, and Harvey S. Levin

Chapter 6. The Wada Test: Intracarotid Injection of Sodium Amobarbital to Evaluate Language
and Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Brian D. Bell, Bruce P. Hermann, and Paul Rutecki

Chapter 7. Extraoperative Brain Mapping Using Chronically Implanted Subdural Electrodes. . . . . . . . . . . . . . . . . . . . . . . .93
David E. Friedman and James J. Riviello, Jr.

Chapter 8. Brain Mapping in the Operating Room . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103

Sepehr Sani, Edward F. Chang, and Nicholas M. Barbaro

Chapter 9. Anesthesia for Brain Mapping Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109

Nicholas P. Carling, Chris D. Glover, Daryn H. Moller, and Ira J. Rampil

Chapter 10. Clinical Applications of Magnetoencephalography in Neurology and Neurosurgery . . . . . . . . . . . . . . . . . . .119

Panagiotis G. Simos, Eduardo M. Castillo, and Andrew C. Papanicolaou

Chapter 11. Optical Spectroscopic Imaging of the Human Brain—Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
Hongtao Ma, Minah Suh, Mingrui Zhao, Challon Perry, Andrew Geneslaw, and Theodore H. Schwartz

vii
viii CONTENTS

Chapter 12. Electrocorticographic Spectral Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .151

Mackenzie C. Cervenka and Nathan E. Crone

Chapter 13. Pediatric Brain Mapping: Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .167

Robert J. Bollo, Chad Carlson, Orrin Devinsky, and Howard L. Weiner

SECTION II: SYSTEMS

Chapter 14. Mapping of the Sensorimotor Cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .189

Roukoz Chamoun, Krishna Satyan, and Youssef G. Comair

Chapter 15. Mapping of Human Language . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .203

Nitin Tandon

Chapter 16. Mapping of the Human Visual System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219

Muhammad M. Abd-El-Barr, Mario F. Dulay, Paul Richard, William H. Bosking, and Daniel Yoshor

Chapter 17. Mapping of Hearing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .241

Albert J. Fenoy and Matthew A. Howard

Chapter 18. Mapping of Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .269

Jeffrey G. Ojemann and Richard G. Ellenbogen

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
 Contributors

Muhammad M. Abd-El-Barr, MD, PhD Nicholas P. Carling, MD

Department of Neurosurgery Department of Pediatrics (Anesthesiology)
University of Florida Texas Children’s Hospital
Gainesville, Florida Baylor College of Medicine
Houston, Texas
Gareth Adams, MD, PhD
Department of Neurosurgery Chad Carlson, MD
Baylor College of Medicine Comprehensive Epilepsy Center
Houston, Texas Department of Neurology
New York University School of Medicine
Nicholas M. Barbaro, MD New York, New York
Department of Neurological Surgery
Indiana University School of Medicine Eduardo M. Castillo, PhD
Indianapolis, Indiana Department of Pediatrics, Center for
Clinical Neurosciences
Michael S. Beauchamp, PhD Departments of Neurosurgery and Neurology
Department of Neurobiology & Anatomy University of Texas—Health Science Center at Houston
University of Texas Health Science Center Houston, Texas
Houston, Texas
Mackenzie C. Cervenka, MD
Brian D. Bell, PhD Department of Neurology
Department of Neurology The Johns Hopkins University School of Medicine
University of Wisconsin School of Medicine and Baltimore, Maryland
Public Health
Department of Neurology Roukoz Chamoun, MD
W.S. Middleton Memorial Veterans Hospital Department of Neurosurgery
Madison, Wisconsin Baylor College of Medicine
Houston, Texas
Corwin Boake, PhD
Department of Physical Medicine & Rehabilitation Edward F. Chang, MD, PhD
University of Texas Medical School Department of Neurological Surgery
Houston, Texas University of California
San Francisco, California
Robert J. Bollo, MD
Department of Neurosurgery Youssef G. Comair, MD
Baylor College of Medicine Department of Neurosurgery
Neurosurgery Service American University of Beirut
Texas Children’s Hospital Beirut, Lebanon
Houston, Texas
Nathan E. Crone, MD
William H. Bosking, PhD Department of Neurology
Max Planck Florida Institute The Johns Hopkins University School of Medicine
Jupiter, Florida Baltimore, Maryland

ix
x CONTRIBUTORS

Orrin Devinsky, MD Hongtao Ma, PhD

Comprehensive Epilepsy Center Department of Neurosurgery
Department of Neurology Weill Medical College of Cornell University
New York University School of Medicine New York, New York
New York, New York
Eli M. Mizrahi, MD
Mario F. Dulay, PhD Departments of Neurology and Pediatrics
Department of Neurosurgery Baylor College of Medicine
The Methodist Hospital Neurological Institute Houston, Texas
Houston, Texas
Daryn H. Moller, MD
Richard G. Ellenbogen, MD
Department of Anesthesiology
Department of Neurological Surgery
University at Stony Brook
University of Washington School of Medicine
Stony Brook, New York
Seattle, Washington

Albert J. Fenoy, MD Jeffrey G. Ojemann, MD

Department of Neurosurgery Department of Neurological Surgery
University of Texas Health Science Center University of Washington School of Medicine
Houston, Texas Seattle, Washington

Jared Fridley, MD Andrew C. Papanicolaou, PhD

Department of Neurosurgery Department of Pediatrics, Center for
Baylor College of Medicine Clinical Neurosciences
Houston, Texas Departments of Neurosurgery and Neurology
University of Texas—Health Science Center at Houston
David E. Friedman, MD Houston, Texas
Department of Neurosciences
Winthrop-University Hospital Challon Perry, MD
Mineola, New York Department of Neurosurgery
Weill Medical College of Cornell University
Andrew Geneslaw New York, New York
Department of Neurosurgery
Weill Medical College of Cornell University Ira J. Rampil, MD
New York, New York Department of Anesthesiology
University at Stony Brook
Chris D. Glover, MD
Stony Brook, New York
Department of Pediatrics (Anesthesiology)
Texas Children’s Hospital
Paul Richard, MD
Baylor College of Medicine
Department of Neurological Surgery
Houston, Texas
University of Pittsburgh Medical Center
Bruce P. Hermann, PhD Pittsburgh, Pennsylvania
Department of Neurology
University of Wisconsin School of Medicine and James J. Riviello, Jr., MD
Public Health Division of Pediatric Neurology
Madison, Wisconsin Department of Neurology
NYU Comprehensive Epilepsy Center
Matthew A. Howard, MD New York University
Department of Neurosurgery New York, New York
University of Iowa Hospitals and Clinics
Iowa City, Iowa Paul Rutecki, MD
Department of Neurology
Harvey S. Levin, PhD University of Wisconsin School of Medicine and
Departments of Physical Medicine & Rehabilitation, Public Health
Pediatrics, Neurosurgery, and Neurology Department of Neurology
Baylor College of Medicine W.S. Middleton Memorial Veterans Hospital
Houston, Texas Madison, Wisconsin

Sepehr Sani, MD
Department of Neurosurgery
Rush University Medical Center
Chicago, Illinois
Krishna Satyan, MD
Department of Neurosurgery
Baylor College of Medicine
Houston, Texas
Michael Schulder, MD
Department of Neurosurgery
North Shore-LIJ Health System
Manhasset, New York
Theodore H. Schwartz, MD
Department of Neurosurgery
Weill Medical College of Cornell University
New York, New York
Panagiotis G. Simos, PhD
Department of Psychology
University of Crete
Rethymno, Greece
Minah Suh, PhD
Department of Neurosurgery
Weill Medical College of Cornell University
New York, New York
CONTRIBUTORS xi
Jean C. Tamraz, MD, PhD
Department of Neuroscience & Neuroradiology
Saint-Joseph University
Beirut, Lebanon
Nitin Tandon, MD
Department of Neurosurgery
University of Texas Medical School
Houston, Texas
Howard L. Weiner, MD
Department of Neurosurgery
Division of Pediatric Neurosurgery
Comprehensive Epilepsy Center
Department of Neurology
New York University School of Medicine
New York, New York
Robin Wellington, PhD
Department of Psychology
St. John’s University
Flushing, New York
Daniel Yoshor, MD
Department of Neurosurgery
Baylor College of Medicine
Neuroscience Center
St. Luke’s Episcopal Hospital
Houston, Texas
Mingrui Zhao, MD, PhD
Department of Neurosurgery
Weill Medical College of Cornell University
New York, New York
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 Preface
The localization of cerebral function is a critical task
for both neurosurgeons and neurologists. In Clinical
Brain Mapping we have addressed these localization ef-
forts from the perspectives of our different but, at times,
overlapping backgrounds and clinical interests. One of
us is a neurosurgeon (Daniel Yoshor) and the other a
neurologist (Eli M. Mizrahi). We began our discussions
about clinical brain mapping early in our careers as we
cared for adults and children with medically intractable
epilepsy who were being evaluated for epilepsy surgery.
We have worked together for several years at the Baylor
Comprehensive Epilepsy Center considering the issues
of cerebral localization and weighing relative risks and
benefits of resective surgery for potential seizure con-
trol, as well as in resective surgery for brain tumors. In
the course of our clinical practice, we realized the need
for a concise and practical, but comprehensive, guide to
clinical brain mapping. In addition to our efforts with
patients, through our interactions with colleagues and
trainees, we realized that such a volume would be of
value to them both for reference and training. This was
beginning of the current volume.
Although initially considered within the context of
epilepsy surgery, Clinical Brain Mapping addresses a
wide range of clinical concerns. It addresses the tech-
niques and functional bases for all clinical situations that
may require cerebral localization for diagnosis and man-
agement. Most of the techniques described are now part
of clinical care, others are just now emerging technology
xiii
and not yet fully integrated into clinical practice, and
some techniques have their greatest utility in clinical re-
search. It is meant as a reference for neurosurgeons, neu-
rologists, neuroradiologists, neuropsychologists, clinical
neuroscientists and others actively involved in the care
of those with or who are at risk for neurological impair-
ment through intervention.
We have organized the volume into two sections:
Techniques and Systems. The Techniques section con-
sists of chapters considering specific methods of cere-
bral location: operative anatomy, structural neuroimag-
ing, functional MRI, magnetoencephalography, optical
imaging, neuropsychological testing, Wada testing, spe-
cial intraoperative mapping techniques, extraoperative
brain mapping with implanted electrodes, electrocortico-
graphic spectral analysis, special brain mapping tech-
niques for pediatric patients and anesthetic techniques
for intraoperative brain mapping. In the Systems section
there are discussions of somatomotor and somotosen-
sory function, language, vision, hearing, and memory.
Each is written by experts in their respective fields.
This book is intended to serve two purposes. It has
been developed as a practical guide to brain mapping
in the clinical setting and it is also designed to present
the scientific basis of the cortical systems that we wish
to localize and preserve in the care of our patients.
Daniel Yoshor, MD
Eli M. Mizrahi, MD
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 Acknowledgments
Brain mapping is typically a collaborative effort in both
the clinical and research settings. The development of
Clinical Brain Mapping has also been collaborative.
We are grateful to those who have been instrumen-
tal in its production, including the 47 contributors to
this volume who have given generously of their time
and expertise to write timely, insightful, and instructive
manuscripts.
We have been fortunate to work in an enriched
environment that fosters expert patient care and excel-
lence in research. The clinicians, scientists, trainees and
students at Baylor College of Medicine form an invig-
orating intellectual community, which has fostered our
interests and growth as researchers and clinicians. Simi-
larly, St. Luke’s Episcopal Hospital has encouraged and
supported our work and has proved to be a unique in-
stitution which promotes outstanding clinical care and
clinical research.
We are also grateful to Robert G. Grossman, MD,
and the late Peter Kellaway, PhD. They initially taught
and mentored us, and then became professional col-
leagues and personal friends.
Dr. Yoshor acknowledges the influence of Nicholas
M. Barbaro, MD, Mitchel S. Berger, MD, and Raymond
L. Sawaya, MD, in developing his interest in applying
brain mapping to clinical practice, and of John H.R.
xv
Maunsell, PhD, and Michael S. Beauchamp, PhD, in de-
veloping a research program that strives to use rigor-
ous scientific methodology in studying human cortical
function.
Dr. Mizrahi is grateful to his long-time colleagues
and collaborators in the Peter Kellaway Section of Neu-
rophysiology, Department of Neurology, Baylor College
of Medicine, particularly James D. Frost, Jr., MD, and
Richard A. Hrachovy, MD. They continue to provide
valuable insights into the neurophysiological aspects of
cortical mapping.
As with any collaborative effort, there are many
people who have contributed directly and indirectly to
Clinical Brain Mapping. We are most grateful to our
co-workers, clinical and research colleagues, technolo-
gists, trainees, and administrative staff for their diligence
and hard work on our behalf. In particular, Lisa Rhodes,
R EEG/EP T., CLTM, has provided outstanding techni-
cal support for brain mapping studies in our patients
for many years. Kathleen Pierson and May-Lin Basso
provided critical and expert administrative assistance. Fi-
nally, we express our sincere thanks to the editorial staff
at McGraw-Hill Medical Publishing, Anne Sydor, PhD,
Executive Editor, and Regina Y. Brown, Senior Project
Development Editor and to Tilak Raj, Project Manager,
Aptara Corporation, Inc.
This page intentionally left blank
 SECTION I

TECHNIQUES

1
This page intentionally left blank
 Chapter 1
Surface Anatomy as a Guide to
Cerebral Function
Gareth Adams1 , Jared Fridley 1 , and Daniel Yoshor 1,2
1
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
2
Neuroscience Center, St. Luke’s Episcopal Hospital, Houston, Texas
䉴 INTRODUCTION AND
HISTORICAL PERSPECTIVE
Our existing knowledge of a number of consistent re-
lationships between specific anatomic landmarks and
local cortical function allows the use of anatomy to pre-
dict function with considerable accuracy, even without
direct physiological confirmation in an individual sub-
ject. Defining these landmarks with noninvasive struc-
tural magnetic resonance imaging (MRI) is routinely
used to infer regional function, as described in Chap-
ter 2, “Structural Imaging for Identification of Functional
Brain Regions.” Direct inspection of anatomic clues, in
particular examination of the exposed cortical anatomy
of the brain during craniotomy, can provide highly
useful clues to functional localization. Because intersub-
ject variation in cortical anatomy and functional local-
ization is not insignificant, and because local pathology
such as a brain tumor maybe obscure anatomic clues,
accurate identification of functional regions often re-
quires physiological mapping through other techniques
presented in this book. But anatomic landmarks re-
main invaluable, both as a primary method and as
an adjunct to the physiological techniques described
in this book, for plotting regional brain function. This
chapter reviews anatomic methods for estimating re-
gional functional by simple visual inspection. It is bro-
ken down into sections detailing anatomic techniques
for surface localization of underlying cortical anatomy,
and clues for localization of speech, motor and sensory
function, vision and hearing based on cortical surface
anatomy.
Historically, the understanding of the presence of
localized brain function has been based on experimen-
tally created lesions in animals. During a prominent pub-
lic lecture and scientific debate in 1881, Sir David Ferrier
convincingly showed that creating a lesion in a monkey’s
left posterior frontal cortex resulted in a right-sided hemi-
plegia, and that bilateral lesions in the superior tempo-
ral lobes resulted in deafness.1 This evidence buttressed
3
the localizationist theory, which held that brain func-
tions are localized to specific areas of the brain. Further
understanding of the localization of human brain func-
tion was based on correlating the neurological deficits
in patients with specific cortical lesions defined on post-
mortem examinations.2 For example, by performing au-
topsies on patients with aphasia, Paul Broca was able
to localize the functional areas responsible for the pro-
duction of speech to the pars triangularis and pars oper-
cularis of the dominant frontal lobe. Carl Wernicke was
able to localize language comprehension to the poste-
rior, superior temporal gyrus. Correlation of lesions in
the occipital lobes from shrapnel and penetrating trauma
with the visual field defects sustained by soldiers in
World War II combat provided further localization of
visual function in humans.3 Similarly, studies of sub-
jects with cortical lesions and sensory and motor deficits
demonstrated that motor and sensory functions are local-
ized around the central sulcus.3 Collectively over a pe-
riod of decades, a crude understanding of the anatomic
location of functional regions emerged from these
studies.
Two other methods have greatly further extended
our understanding of the functional organization of
human cerebral cortex. Pioneering studies employing
direct cortical electrical stimulation in human neurosur-
gical patients demonstrated consistent relationships be-
tween cortical anatomy and cortical eloquence among
many different subjects. For example, Wilder Penfield
demonstrated through human cortical mapping during
planning for cortical excisions that motor and sensory
function is localized around the central sulcus, and was
able to map a motor and sensory homunculus to the
central area.2,4 More recently, the advent of structural
and functional MRI (fMRI) has had an explosive im-
pact on our understanding of the consistent relation-
ship between anatomy and regional function.5,6 Studies
that combine both electrical stimulation and fMRI map-
ping in individual subjects has further validated these
relationships.7−9
4 SECTION I TECHNIQUES

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Figure 1–1. Taylor–Haughton lines.Method for approximating the central sulcus and
sylvian fissure using the Taylor–Haughton lines. (From Taylor and Haughton’s Some
Recent Researches on the Topography and Convolutions of the Brain.)

䉴 APPROXIMATE LOCALIZATION
OF CORTICAL STRUCTURAL
ANATOMY USING
EXTERNAL CRANIAL
LANDMARKS
The location of important cortical anatomic features,
such as the sylvian fissure and central sulcus, can be
approximated from the external anatomy of the skull.10
Taylor–Haughton lines (Fig. 1–1) can be simply con-
structed from external landmarks by drawing four lines
on the cranium. The baseline, or Frankfurt plane, is de-
fined as a line passing the inferior margin of the or-
bit through the superior margin of the external audi-
tory meatus. A second line is drawn from the nasion
to the inion across the top of the cranium and divided
into quarters. Two more lines are drawn perpendicular
to the baseline. The posterior ear line is perpendicular
to the baseline and passes through the mastoid process.
The condylar line is perpendicular to the baseline and
passes through the mandibular condyle.11
The location of the sylvian fissure can be approx-
imated by drawing a line from the lateral canthus to
the three-quarter point along the Taylor–Haughton line
from the nasion to the inion. The central sulcus can be
approximated by multiple methods. One method to ap-
proximate the central sulcus is to connect a point 2 cm
posterior to the halfway point of the Taylor–Haughton
line across the top of the cranium with a point 5 cm
above the external auditory meatus. A second method is
to connect the point on the Taylor–Haughton line across
the top of the cranium where it is intersected by the
posterior ear line with the point on the approximated
sylvian fissure intersected by the condylar line.11 Other
techniques of localizing the sylvian fissure and central
sulcus based on external cranial landmarks have been
described, and like Taylor–Haughton lines, are also
quite accurate.12
䉴 ANATOMICAL LOCALIZATION OF
MOTOR AND SENSORY
FUNCTION IN THE EXPOSED
BRAIN
Motor and sensory functions are located in the Rolandic
cortex surrounding the central, or Rolandic, fissure.
Motor function is predominantly located in the anterior
 CHAPTER 1 SURFACE ANATOMY AS A GUIDE TO CEREBRAL FUNCTION
wall of the central sulcus and in the precentral gyrus,
whereas sensory function is predominantly located in
the posterior wall of the central sulcus and in the post-
central gyrus. The first step in identifying the Rolandic
cortex is to identify the central sulcus. The position of
the central sulcus can be approximated on the surface of
the cranium using the techniques detailed in the previ-
ous section, and with the adjuvant use of image guidance
at surgery. However, definitively identifying the central
sulcus at surgery can be difficult even in the absence of
anatomic abnormalities such as tumors or dysplasia, par-
ticularly since much of the sulcal and gyral anatomy may
be obscured by the draining veins and the pial vessels.
The central sulcus separates the frontal and pari-
etal lobes. Broca described the central sulcus containing
three curves and a superior and inferior genu. Superiorly
the central sulcus extends from the interhemispheric
fissure and often extends onto the mesial aspect of
the hemisphere. Inferiorly it is usually separated from
the sylvian fissure by the subcentral gyrus. It is rarely
interrupted.13−15 Localizing the central sulcus is possible
through its relationship to the sylvian fissure and to the
other surrounding sulci and gyri of the frontal, temporal,
and parietal lobes (Fig. 1–2).
Naidich et al. published a systematic method of
identifying the anatomic relationships of the low-middle
convexity in 1995.16 The first step is to identify the syl-
vian fissure, which separates the frontal and tempo-
ral lobes. It is composed of five rami, with the long
obliquely oriented section visible on the cortical surface
designated as the posterior horizontal ramus. The ante-
rior horizontal ramus and anterior ascending ramus ex-
tend superiorly from the anterior section of the posterior
horizontal ramus forming a characteristic V or Y pattern.
These rami divide the inferior frontal gyrus from anterior
to posterior, into the pars orbitalis, pars triangularis, and
pars opercularis. The frontal convexity is divided into
superior, middle, and inferior gyri by the superior and
inferior frontal sulci. These sulci extend posteriorly and
fuse with the precentral sulcus. Anterior and parallel to
the precentral sulcus is the precentral gyrus. The middle
frontal gyrus often run into and fuses with the precentral
gyrus, forming a characteristic sideways capital T shape.
The postcentral gyrus lies posterior to the central
sulcus. It is typically narrower than the precentral sul-
cus. At its inferior border, it is bounded posteriorly by
the posterior subcentral sulcus, giving the inferior end of
the postcentral gyrus a characteristic widened appear-
ance. The postcentral sulcus is located parallel to the
central sulcus immediately posterior to the postcentral
gyrus. It can be a single long sulcus or may be divided
into multiple segments. The parietal convexity is sepa-
rated into the superior and inferior parietal lobules by
the intraparietal sulcus. The posterior ascending ramus
of the sylvian fissure hooks superiorly into the inferior
parietal lobule. The horseshoe-shaped gyrus in the ante-
rior inferior parietal lobule superior to and surrounding
5
the termination of the posterior ascending ramus of the
sylvian fissure is the supramarginal gyrus. The superior
temporal gyrus runs parallel to the sylvian fissure, first
posteriorly then superiorly. It is capped by the angular
gyrus, another horseshoe-shaped gyrus making up the
posterior portion of the inferior parietal lobule. The char-
acteristic roles of these areas in language-related func-
tion are described in a separate section later.
Primary motor and sensory function (Fig. 1–3), as
demonstrated by Penfield,4 are organized along the pre-
central and postcentral gyri in a somatotopic map, which
he represented with a homunculus superimposed onto
the cortex. This homunculus is positioned with its feet
within the interhemispheric fissure and its head ex-
tending toward the sylvian fissure, and represents a
somewhat crude, albeit useful, oversimplification of the
organization of motor cortex.
The cortical representation of motor hand function
is typically located in the superior portion of the precen-
tral sulcus along the middle genu of the central sulcus.
The curve of the middle genu of the central sulcus be-
comes more pronounced in the depths of the central
sulcus, forming a knob or omega shape. This knob was
identified by Broca as the pli de passage moyen. Stud-
ies using fMRI have demonstrated that this area is the
cortical functional location of hand motor function, in
the precentral gyrus and on the anterior surface of the
central sulcus, and hand sensory function, in the pos-
terior surface of the central sulcus and the postcentral
gyrus.14,17−19 This precentral knob is usually not visible
initially during surgery as it is obscured by the arachnoid
and bridging veins and is deep within the central sulcus.
The same area can be located intraoperatively by rely-
ing on other landmarks of the frontal lobe, as it is on the
central sulcus opposite the intersection of the superior
frontal sulcus with the precentral sulcus.
Tongue sensory function is located within the in-
ferior widening of the postcentral gyrus immediately
above the sylvian fissure. Face sensory function is lo-
cated in the narrow portion of the postcentral gyrus su-
perior to the tongue functional region.20
While these anatomic landmarks do provide some
localization of motor and sensory cortical function, it can
be very difficult intraoperatively to identify the associ-
ated gyri and sulci, especially with a limited exposure.
These landmarks can provide initial localization allow-
ing the targeting of further studies to verify the location
of the motor and sensory cortex, by phase reversal of so-
matosensory evoked potentials waveforms or by direct
cortical electrical stimulation.21
䉴 LOCALIZATION OF LANGUAGE-
RELATED FUNCTION
Language function is classically separated into two main
cortical areas. Wernicke’s area is involved in language
6 SECTION I TECHNIQUES

A B

C D

E F

Figure 1–2. Identification of the central sulcus. A stepwise method for identifying the
central sulcus and the surrounding sulci and gyri. In panel A, the sylvian or lateral
fissure is identified with a (1). In panel B, the anterior horizontal ramus (2) and the
anterior ascending ramus (3) are identified in their typical Y shape. These rami define
the pars orbitalis (PObr), pars triangularis (PTr), and pars opercularis (POp). In panel C,
the precentral sulcus (4) is identified. In panel D, the central sulcus (5) and precentral
gyrus (PreC) are identified. In panel E, the postcentral sulcus (6) and the postcentral
gyrus (PostC) are identified. In panel F, the superior temporal sulcus (7), superior
temporal gyrus (STG), and middle temporal gyrus (MTG) are identified. (continued)
 CHAPTER 1 SURFACE ANATOMY AS A GUIDE TO CEREBRAL FUNCTION 7

fused across the temporal lobe outside of the classical

G and pars opercularis, from anterior to posterior. The in-
Figure 1–2. (Continued) In panel G, the intraparietal
sulcus (8), the supramarginal gyrus (SMG), and the
angular gyrus (AG) are identified.
comprehension, including both spoken and read lan-
guage and is located in the posterior, superior tempo-
ral gyrus. Broca’s area is involved in the production
of speech and is located in the inferior frontal gyrus,
classically localized to the pars triangularis and pars op-
ercularis. These two areas are connected by the arcu-
ate fasciculus. In reality, there is significant variation in
the location of speech function between subjects.22−24
Surgical resections involving potential speech areas are
usually performed with the patient awake, which allows
cortical mapping of speech function through intraopera-
tive stimulation. Recent studies have shown that speech
function has a much wider distribution across the frontal
lobe outside of the classical Broca’s area and is more dif-
Wernicke’s area.24,25 However, it is still useful to be able
to identify the classical locations of these areas to serve
as a starting point for cortical mapping (Fig. 1–4).
Broca’s area is classically described as being located
in the pars triangularis and pars opercularis of the infe-
rior frontal gyrus. The inferior frontal gyrus is bounded
by the sylvian fissure inferiorly and the inferior frontal
sulcus superiorly. The anterior horizontal ramus and an-
terior ascending sylvian ramus extend superiorly from
the sylvian fissure into the inferior frontal gyrus in a Y or
V shape.16 These two rami divide the inferior frontal sul-
cus into three parts, the pars orbitalis, pars triangularis,
ferior frontal gyrus is bounded posteriorly by the central
sulcus. Quinones-Hinojosa and colleagues used intraop-
erative mapping correlated with MRI to locate Broca’s
area in relation to the sulci defining the inferior frontal
gyrus.7 They proposed a method for localizing Broca’s
area based on the intersection of lines drawn from de-
fined points in the inferior frontal gyrus. The first line is
drawn from the opercular tip posteriorly at a 45◦ angle
between the sylvian fissure and the anterior ascending
sylvian ramus. The second line is drawn superiorly, per-
pendicular from the sylvian fissure at the level of the pre-
central sulcus. The third line is drawn anteriorly, parallel
to the sylvian fissure at the level of the inferior tip of the
central sulcus. The intersection of these three lines pro-
vides an estimate of the location of Broca’s area. While
this technique does provide an estimated location for
Broca’s area, it is only an estimate and accurate localiza-
tion of speech function is best determined with intraop-
erative or extraoperative cortical stimulation mapping.

A B

Figure 1–3. Identification of motor and sensory cortex. A. In the left panel, primary
motor cortex is located in the precentral gyrus, with hand function (H) localized
perpendicular to the end of the superior frontal gyrus. B. In the right panel, primary
sensory cortex is located in the postcentral gyrus. Tongue sensory (T) is located in
the widened area of the postcentral gyrus close to the sylvian fissure. Face sensory
(F) is located in the narrow strip superior to tongue sensory, and hand sensory (H)
superior to face sensory.
8 SECTION I TECHNIQUES

Figure 1–4. Localization of speech. Broca’s area (B) is classically located in the pars
triangularis and pars opercularis of the inferior frontal gyrus. Wernicke’s area (W) is
located in the posterior portion of the superior temporal gyrus and the supramarginal
gyrus. However, direct stimulation during awake craniotomy has demonstrated
speech function over a much wider area than the classical speech areas, as indicated
by the red outlines compared to the blue outlines of the classical speech areas.

Wernicke’s area is classically located in the poste-

fissure. The fovea is located posteriorly near the occipi-
rior, superior temporal gyrus and in the supramarginal
tal pole. Peripheral vision is located anteriorly. There is
gyrus of the inferior parietal lobule adjacent to the syl-
significant magnification of the retinotopic map near the
vian fissure. These areas can be identified by locating
fovea, with a much larger cortical area corresponding
the sylvian fissure. The superior temporal gyrus runs
to the area around the fovea. Other visual areas extend
between the sylvian fissure and the superior temporal
superiorly and inferiorly from the calcarine fissure, cor-
sulcus, which runs parallel to the sylvian fissure. The
responding to areas V2, V3, and V4.26−29 An area homol-
posterior portions of both the sylvian fissure and the
ogous to the middle temporal (MT) region is located at
superior temporal sulcus hook superiorly and terminate
the junction of the temporal, parietal, and occipital lobes
in the inferior lobule of the parietal lobe. The supra-
in humans (Fig. 1–5). This area is involved in processing
marginal gyrus is the anterior portion of the parietal
of movement.30−32
lobe, which forms a horseshoe shape over the poste-
The calcarine sulcus is located on the mesial sur-
rior end of the sylvian fissure. The angular gyrus forms
face of the occipital lobe. It extends posteriorly from the
a similar horseshoe shape over the posterior end of
splenium of the corpus callosum to the occipital pole.
the superior temporal gyrus.13,16 Intraoperative mapping
It is divided into an anterior and posterior portion by
during awake craniotomy has demonstrated that lan-
the parietal-occipital sulcus. The posterior portion of the
guage function is highly variable between subjects and
calcarine sulcus splits into a Y shape as it approaches
can be widely dispersed over the temporal lobe and pari-
the occipital pole, with the superior portion of the Y
etal lobe outside the classical Wernicke’s area.24
sometimes extending onto the lateral surface of the oc-
cipital lobe. The calcarine sulcus ranges from 2.5 to 3 cm
deep.14,15 The MT region is located near the junction of
䉴 LOCALIZATION OF VISUAL
the temporal, parietal, and occipital lobes.30−32
FUNCTION
Primary visual cortex (V1) is located in the occipital lobe
on the mesial surface both within the calcarine sulcus 䉴 LOCALIZATION OF AUDITORY
and on the surrounding cortex. The visual cortex is or- FUNCTION
ganized in a retinotopic map with the fovea located pos-
teriorly near the occipital pole. The vertical meridian is Penfield and Rasmussen localized hearing function to
located at the calcarine fissure and the horizontal merid- the superior temporal gyrus by direct electrical stim-
ian is deep within the calcarine fissure. Functional MRI ulation of the human cortex. Further studies using
mapping of the visual cortex has demonstrated that the positron emission tomography, fMRI, and direct cortical
V1 is located mostly within the folds of the calcarine recordings have demonstrated that the auditory cortex is
 CHAPTER 1 SURFACE ANATOMY AS A GUIDE TO CEREBRAL FUNCTION 9

Figure 1–5. Localization of vision. The primary visual cortex (V1) is located within the
calcarine sulcus, extending slightly out onto the medial surface of the occipital lobe
(left panel). The fovea (F) is represented at the occipital pole. Additional retinotopic
visual areas spread out from the calcarine sulcus and extend onto the lateral surface
of the occipital lobe. Middle temporal (MT), which is involved in motion tracking, is
located near the parieto-occipital-temporal junction.

located bilaterally on the superior temporal gyrus both
on the exposed cortical surface and in the depths of
the sylvian fissure on the transverse temporal gyrus of
Heschl (Fig. 1–6). The primal auditory field is thought
to be primarily located in the posteromedial portion
of Heschl’s gyrus. Brugge et al. have demonstrated the
presence of three auditory cortical fields, with two on
Heschl’s gyrus and one on the posterolateral surface of
the superior temporal gyrus.33−35
Heschl’s gyrus is located completely within the syl-
vian fissure. It is bounded posteriorly by the posterior
transverse supratemporal sulcus, which originates at the
sylvian fissure and extends from the lateral surface of
the temporal lobe with an anterior oblique orientation.
Anteriorly, Heschl’s gyrus is bounded by the anterior
transverse temporal sulcus. The gyrus extends either
obliquely or perpendicularly to the sylvian fissure.13

䉴 SUMMARY

While there is significant variation in the cortical surface

Figure 1–6. Localization of hearing. Primary auditory
cortex is located in Heschl’s gyrus (H) buried on the
temporal lobe surface buried within the sylvian
fissure. Auditory cortex also extends onto the lateral
temporal lobe on the posterior superior temporal
gyrus, as indicated by the blue outline.
anatomy of the human brain there are some constants
that can be used to roughly identify functional locations
of motor function, sensory function, speech, and vision
on the cortex. Anatomic and functional imaging prior
to surgery can provide initial localization of function.
Combining these imaging techniques with knowledge
of the relationship between cranial anatomy and the un-
derlying cortex allows the planning of a targeted cran-
iotomy. Once the craniotomy has been performed the
combination of image guidance and the anatomical land-
marks described in the preceding sections can be used
for initial targeting of further localization of function us-
ing techniques such as awake craniotomy with direct
stimulation for speech mapping or phase inversion for
locating the motor and sensory cortex. Because there
is significant variation in the location of cortical func-
tion between subjects, anatomical clues should only be
used as a starting point for other mapping techniques to
definitively identify the cortical functional locations.
10 SECTION I TECHNIQUES
䉴 PEARLS AND PITFALLS
t There is significant variation between subjects 3.
both in the sulcal and gyral anatomy and in the
location of function on the cortex.
t 4.
During a craniotomy, even locating the central
sulcus and the surrounding Rolandic cortex can
be difficult due to limited exposure, overlying 5.
arachnoid membrane, and surface vessels.
t The central sulcus is best identified by following a
stepwise pattern of identification of surrounding 6.
sulci that have relatively little variance between
subjects. The sylvian fissure is the most reliable
starting landmark. 7.
t Broca’s area is classically located in the pars trian-
gularis and pars opercularis, which can be iden-
tified by finding the classic V or Y shape of 8.
the anterior ascending and anterior horizontal ra-
mus of the sylvian fissure. However, intraopera-
tive mapping has shown that speech function is
distributed over a much larger region of the
frontal lobe outside the classic Broca’s area. 9.
t Wernicke’s area is classically located in the su-
perior temporal gyrus at the posterior end of
the sylvian fissure, sometimes extending into the
supramarginal gyrus of the parietal lobe. Lan- 10.
guage mapping has shown that language function
is distributed over a larger region of the tempo- 11.
ral lobe, particularly posterior and inferior to the
classic Wernicke’s area.
t Primary visual cortex is reliably located on the 12.
mesial aspect of the occipital lobe mostly within
the folds of the calcarine sulcus with the fovea
represented at the occipital pole. Other areas of
the visual cortex extend out onto the surface of 13.
the occipital lobe. Area MT, involved with tracking
of motion, is located on the lateral cortical surface 14.
near the junction of the occipital, parietal, and
temporal lobes. 15.
t Auditory cortex is located bilaterally in Heschl’s
gyrus buried within the sylvian fissure and in the 16.
posterior portion of the superior temporal gyrus.
t Anatomical landmarks should only be considered
as a starting point for further localization using
other techniques, particularly when working close 17.
to eloquent areas involved in motor, sensory, and
speech function.
18.
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 Chapter 2
Structural Imaging for Identification of
Functional Brain Regions
Jean C. Tamraz1 and Youssef G. Comair 2
1
Department of Neuroscience and Neuroradiology, Saint-Joseph University, Beirut, Lebanon
2
Department of Neurosurgery, American University of Beirut, Beirut, Lebanon
䉴 HISTORICAL LANDMARKS
Leuret and his pupil Gratiolet1 first attempted to classify
brain fissures before Meynert2 expanded on this find-
ing and gave a detailed account of the regional varia-
tions existing in the cortical mantle and their structural
and functional relationships. A large body of literature
from the second part of the 19th and the early 20th cen-
turies reported on sulcal patterns in the human brain.
Encephalometry, pioneered by Ariens Kappers in 1847,3
was one of the most extensively used methods to study
the brain. Major contributions to our understanding of
cortical architecture and surface morphology were made
by von Economo and Koskinas,4 who in 1925 developed
a highly detailed nomenclature for cortical surface pat-
terns, accompanied by a description of the cytoarchitec-
tural peculiarities of each region.
The evolution of brain imaging followed a sim-
ilar path. High-field, 3.0-T MR now provides a high-
resolution sectional atlas of each imaged brain region
and allows us to obtain a comprehensive rendering of
an entire brain in three dimensions (3D). Knowledge of
the gyral and sulcal anatomy and its variations remains
essential in understanding the relationship between mor-
phology and function.
䉴 BRAIN MORPHOLOGY AND
FISSURAL PATTERNS
The classification of cerebral sulci as primary, secondary,
or tertiary is widely used by neuroanatomists. Primary
fissures can be described using comparative and ontoge-
netic approaches. On the basis of comparative anatomy,
sulci found in all gyrencephalic primates may be defined
as primary. Embryologically, these fissures appear early
in telencephalic development. On reviewing previous
works and the work of Larroche and Feess-Higgins,5 we
classified primary sulci as those appearing before the
13
30th week of gestation (Table 2–1). Secondary (Table
2–2) and tertiary sulci (Table 2–3) occur later in devel-
opment and are responsible for giving the adult brain
its characteristic highly involuted and gyriform appear-
ance. For a better understanding of the sulcal and gyral
anatomy, we will focus primarily on the primary and
secondary sulci. Tertiary sulci are subject to marked in-
dividual variations and are, therefore, difficult to iden-
tify on MRI; only those that are relatively constant across
subjects will be annotated.
䉴 THE LATERAL SURFACE OF THE
CEREBRAL HEMISPHERE
Brain sulcation is most efficiently investigated using 3D-
MRI surface renderings. However, anatomic correlations
may also be achieved indirectly using cross-sectional
anatomic atlases based on definite referentials6,7,8,9,10,11
or by using two-dimensional (2D) MR slices12 typically
encountered in clinical practice, particularly those ex-
tending from the lateral aspect of the hemisphere to
reach the insular level, or those showing a parasagittal
view.
䉴 THE LATERAL SULCUS AND THE
SYLVIAN OPERCULA
The lateral or sylvian fissure is the major landmark on
the lateral surface of the brain. It develops in the 14th
week of gestation and is the most important and con-
stant of the cerebral sulci. It may be divided into three
segments. The first, or hidden stem segment, extends
from the lateral border of the anterior perforated sub-
stance and courses over the limen insula in a posteriorly
concave path before ending at the falciform sulcus, sep-
arating the lateral orbital gyrus from the temporal pole.
The second, or the horizontal segment, is the longest and
14 SECTION I TECHNIQUES

䉴 TABLE 2–1. CLASSIFICATION OF BRAIN 䉴 TABLE 2–3. CLASSIFICATION OF FAIRLY

PRIMARY SULCI75 CONSTANT TERTIARY BRAIN SULCI75

Weeks of Gestation Sulcal Maturation Lobe Sulcus

13–15 Early sylvian fissure Frontal lobe Intermediate frontal

16–17 Cingulate sulcus Diagonal
Callosal sulcus Radiate
Parieto-occipital sulcus Anterior subcentral
19–20 Calcarine Parietal lobe Transverse parietal
22–23 Circular sulcus Intermediate sulci
25–26 Central sulcus Primary intermediate
Superior temporal sulcus (left) Temporal lobe Sulcus acousticus
Superior part of precentral sulcus Occipital lobe Various individual variations
Olfactory sulcus
28–30 Intraparietal sulcus
Inferior frontal sulcus
Branching of lateral sulcus terminal segment usually bifurcates at its terminus, form-
Paracentral sulcus ing long terminal ascending and short terminal descend-
Collateral sulcus ing branches. The latter is the shallower posterior trans-
Superior frontal sulcus verse supratemporal sulcus found on the right in about
two-thirds of cases. The cortical regions adjacent to the
lateral sulcus are the frontal, parietal, and temporal op-
ercula covering the insular lobe.
the deepest, coursing on the lateral surface of the hemi-
sphere. The third segment is limited anteriorly by the
transverse supratemporal sulcus, separating Heschl’s gyri
from the planum temporale and cutting into the superior
temporal gyrus. This last segment is complex and asym-
metrical, and correlates with hemispheric dominance. In
right-handed individuals, it ascends at an acute angle on
the nondominant right side, whereas on the left side it
assumes a superiorly directed oblique course (Fig. 2–1).
Several branches are distinguished on the second
segment; two sulci of similar length (2–3 cm) are noted
cutting into the inferior frontal gyrus: the horizontal ra-
mus and the vertical ramus run divergent courses and
define a triangular space whose apex faces the sylvian
fissure. These rami begin as branches from the sylvian
fissure, either separately in about two-thirds of subjects
or from a common trunk in the other one-third. The

䉴 TABLE 2–2. CLASSIFICATION OF BRAIN

SECONDARY SULCI75 Figure 2–1. Three-dimensional MR sagittal cut
through the perisylvian region. 1, lateral fissure; 1a,
Lobe Sulcus ascending ramus of lateral fissure; 1b, horizontal
ramus of lateral fissure; 1c, common trunk of
Frontal lobe Precentral ascending and horizontal rami; 1d, terminal ascending
Frontomarginal ramus; 1e, terminal descending ramus; 1f, temporal
Orbitofrontal planum; 1g, anterior transverse supratemporal sulcus;
Rostral sulci 1h, posterior transverse temporal sulcus; 1i;
Parietal lobe Subparietal intermediate transverse temporal sulcus; 2, central
Occipital lobe Paracalcarine sulci sulcus; 3, inferior precentral sulcus; 4, inferior
Lateral occipital postcentral sulcus; 5, inferior frontal gyrus; 6,
Transverse occipital precentral gyrus; 7, postcentral gyrus; 8, frontal
Lunate operculum; 9, parietal operculum; 10, superior
Temporal lobe Rhinal temporal gyrus; 11, supramarginal gyrus; 12, inferior
Transverse temporal frontal gyrus, pars triangularis; 13, inferior frontal
Inferior temporal gyrus, pars orbitalis; 14, inferior frontal gyrus, pars
Insular lobe Sulcus centralis insulae opercularis; 15, transverse temporal gyri; 16, superior
temporal sulcus; 17, middle temporal gyrus.
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
The horizontal ramus is a deep sulcus originating
from the lateral sulcus and cutting through the inferior
frontal gyrus to reach the circular sulcus of the insula
at its anterior border. Superiorly, it does not reach the
inferior frontal sulcus. It is absent on the right in 8% and
on the left in 16% of cases, according to Ono et al.13
This ramus forms the anterior border of the pars trian-
gularis (part of the classic Broca’s area), which is limited
posteriorly by the vertical ramus. In the absence of the
horizontal ramus, a diagonal sulcus may mimic the usual
triangular shape of the pars triangularis, but will not ex-
tend to the insular level.
The vertical ramus is defined by its extension to the
circular sulcus of the insula.14 It arises from the lateral
fissure as a separate sulcus or from a common trunk
with the horizontal ramus in one-third of the cases. It is
almost constant, absent in 3% of cases,14 and does not
reach superiorly the inferior frontal sulcus.
䉴 THE INFERIOR PRECENTRAL
SULCUS
The inferior precentral sulcus is an important landmark,
representing an extension of the inferior frontal sulcus
in about 30% of subjects.
䉴 THE CENTRAL SULCUS
The central sulcus is a deep sulcus that extends verti-
cally across the convexity and separates the frontal lobe
from the parietal lobe. The central sulcus runs anteri-
orly oblique from superior to inferior. It is typically com-
posed of three curves defined by a superior genu (knee)
and an inferior genu. These genua are convex anteriorly
with an intervening concave bend. The cortex located
between these genua represents the portion of the pre-
central gyrus that innervates the arm. Smaller spurs cut
into the adjacent gyri as well as two submerged and an-
nectant gyri are often noted, one at the superior and
one at the inferior end of the central sulcus. The straight
length of the adult central sulcus is 9 cm ± 0.6 cm, and
when the central sulcus is measured with its curves, it
measures 10 cm ± 0.7 cm.15
The central sulcus is deepest at the level of the
hand–arm representation, which lies roughly at the mid-
portion of the sulcus. At the level of the face represen-
tation, corresponding to its first 3 cm, it is slightly less
deep, averaging 15 mm. At the level of the trunk repre-
sentation, the recurrence of the annectant gyrus reduces
its depth to 12 mm. In the interhemispheric portion,
which is the site of the leg representation, the sulcal
depth approaches 13 mm. The central sulcus is rarely
interrupted along most of its course along the lateral
15
Figure 2–2. Three-dimensional MR view of the lateral
aspect of the brain. 1, central sulcus; 2, superior
frontal sulcus; 3, superior precentral sulcus; 4, inferior
frontal sulcus; 5, inferior precentral sulcus; 6,
intermediate frontal sulcus; 7, lateral sulcus; 8,
postcentral sulcus or ascending segment of
intraparietal sulcus; 9, superior postcentral sulcus; 10,
intraparietal sulcus, horizontal segment; 11, lateral
occipital or descending ramus of intraparietal sulcus;
12, Central gyrus; 13, annectent gyrus or “pli de
passage” between middle frontal gyrus and
precentral gyrus; 14, postcentral gyrus; 15, superior
frontal gyrus; 16, middle frontal gyrus; 17, inferior
frontal gyrus; 18, superior parietal gyrus; 19, inferior
parietal lobule; 20, common stem of vertical and
horizontal rami; 21, diagonal sulcus; 22, posterior
subcentral sulcus; 23, transverse temporal sulcus;
24, superior temporal sulcus; 25, inferior temporal
sulcus; 26, superior temporal gyrus; 27, middle
temporal gyrus.
hemisphere, until it terminates inferiorly just short of the
lateral fissure, with a hook-like end at its inferior margin
that contributes to the frontoparietal operculum. Anas-
tomoses with the subcentral, precentral, and postcentral
sulci occur in about 50% of cases. Extension into the
lateral fissure is found in less than 20% of cases, with
an anastomosis with the anterior or posterior subcentral
sulci. Superiorly, the rolandic sulcus reaches the supe-
rior border of the hemisphere and may extend over the
mesial aspect of the hemisphere as a small sulcus giving
the appearance of a comma,16 found in about 70% of
cases (Fig. 2–2).
䉴 THE INFERIOR FRONTAL SULCUS
The inferior frontal sulcus arises anteriorly at the level
of the lateral orbital gyrus, and courses roughly parallel
to the lateral sulcus. It is a deep sulcus almost reaching
16 SECTION I TECHNIQUES
Figure 2–3. Three-dimensional MR view of the
superior aspect of the brain showing the sulcation
and gyration of the upper central region. 1, central
sulcus; 2, superior precentral sulcus; 3, superior
postcentral sulcus; 4, medial precentral sulcus; 5,
superior frontal sulcus; 6, marginal ramus of callosal
sulcus; 7, Precentral gyrus; 8, superior extent of
precentral gyrus; 9, postcentral gyrus; 10, superior
extent of postcentral gyrus; 11, superior frontal gyrus;
12, superior parietal gyrus; 13, interhemispheric
fissure.
the insular plane and ending at the inferior precentral
sulcus. More developed and constant than the superior
frontal sulcus, it is interrupted in about 30% of cases.
䉴 THE SUPERIOR FRONTAL
SULCUS
The superior frontal sulcus arises from the orbital
margin of the hemisphere and courses parallel to the
interhemispheric fissure, extends along about two-thirds
of the frontal lobe and gradually separates from the
interhemispheric fissure. It is frequently doubled or
interrupted along its course,13 and ends posteriorly at
the precentral sulcus in a T-shaped branching in half of
cases (Fig. 2–3). Anteriorly, it may anastomose with the
frontomarginal sulcus.
䉴 THE PRECENTRAL SULCUS
In two-thirds of cases, the precentral sulcus is divided
into superior and inferior precentral sulci, which are sep-
arated by a connection between the precentral and the
middle frontal gyri, with the latter extending into the
central motor cortex. It is composed of three segments
in about 15% of cases. The precentral sulcus courses an-
terior and parallel to the central sulcus and is formed by
the posterior bifurcations of the inferior and the superior
frontal sulci. The superior end of the inferior precentral
sulcus is located anterior to the inferior end of the supe-
rior precentral sulcus (Fig. 2–1). The inferior end of the
inferior precentral sulcus may connect with the lateral
sulcus either directly or through the anterior subcentral
or the diagonal sulcus. The superior precentral sulcus is
usually smaller than the inferior precentral sulcus, and
has a complex relationship with the rolandic motor cor-
tex. It rarely reaches the superior hemispheric border,
and instead is replaced by one or two sulci: a horizontal
sulcus running parallel to the interhemispheric fissure,
that is, the shallow marginal precentral sulcus; and the
medial precentral sulcus, a vertical sulcus situated an-
terior to the precentral sulcus and perpendicular to the
interhemispheric border. Therefore, there is no clear sul-
cal demarcation between the supplementary motor area
(SMA) and the primary motor cortex (Fig. 2–3).
䉴 THE INTRAPARIETAL SULCUS
The intraparietal sulcus is divided into three parts, the
ascending postcentral, horizontal, and descending or oc-
cipital segments. The ascending segment is a vertical seg-
ment that corresponds to the inferior portion of the post-
central sulcus and may extend, especially on the right
hemisphere, to the lateral sulcus. The horizontal or true
intraparietal segment has variable relationships with the
inferior and superior postcentral sulci, but is continuous
with both the inferior and superior postcentral sulci in
almost 40% of cases. The inferior postcentral segment is
continuous with the superior postcentral sulcus in about
60% of the cases. The postcentral sulcus shows wide
variations and is frequently deeper than the central sul-
cus. Its horizontal segment is one of the deeper sulci
in the human brain (2 cm in depth). The descending
segment almost always terminates in the occipital lobe
and may even reach its pole. This segment shows a
T-shaped ending in about two-thirds of cases,13 de-
scribed as the transverse occipital sulcus. The superior
end of the postcentral sulcus terminates most frequently
on the lateral aspect of the hemisphere without exten-
sion to the medial aspect, in a Y-shaped configuration.
At this Y-shaped end, it is joined by the marginal ra-
mus of the cingulate sulcus as it extends to the lateral
aspect of the hemisphere indenting its superior border
(Fig. 2–3). This forms a useful landmark for identifying
the rolandic cortex on the interhemispheric surface.
䉴 THE SUPERIOR TEMPORAL
SULCUS
The superior temporal sulcus, one of the oldest of the
primate brain, is also called the parallel sulcus because
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
it follows closely the course of the lateral fissure (sylvian
fissure). It is a deep sulcus (2.5–3 cm) almost reaching
the level of the inferior border of the insula. Infrequently,
it divides into anterior and posterior segments, usually
below the inferior end of the central sulcus. At the level
of the central sulcus, an inconstant sulcus acousticus may
be present, which originates from the parallel sulcus and
courses toward the lateral fissure, limiting the anterior
extent of the gyrus of Heschl. The posterior part of the
parallel sulcus is the angular sulcus, which penetrates
into the inferior parietal lobule.
䉴 THE FRONTOMARGINAL SULCUS
The frontomarginal sulcus is fairly constant and deep,
found at the frontal pole parallel to the orbital margin.
It is connected posteriorly with the middle frontal sul-
cus more frequently than with the superior frontal. It
separates the transverse frontopolar gyri from the fron-
tomarginal gyrus inferiorly.
䉴 GYRI OF THE LATERAL SURFACE
OF THE CEREBRAL HEMISPHERE
The convolutions on the lateral aspect of the cerebral
hemisphere determined by these primary fissures are the
inferior, middle, and superior frontal gyri, the pre- and
postcentral gyri, and the inferior and superior parietal
convolutions, in the suprasylvian region, and the supe-
rior, middle and inferior temporal gyri, in the infrasylvian
region. The gyri of the parietal and the temporal lobes
merge posteriorly with the variable occipital gyri, which
in turn are generally delimited by a superior, lateral, and
inferior occipital sulci (Fig. 2–2).
䉴 THE FRONTAL LOBE
The frontal lobe, the largest of the hemisphere, is com-
prised of four gyri. The gyri on the lateral aspect of
the frontal lobe are the inferior, the middle, and the su-
perior frontal gyri, which follow a course that roughly
parallels the superior border of the hemisphere. Me-
dially, the frontal lobe consists of a hook-like gyrus
bounded inferiorly by the cingulate sulcus. Posteriorly,
the precentral gyrus parallels the central sulcus, which
forms the boundary between the frontal and parietal
lobes.
The inferior frontal gyrus is situated between the
inferior frontal sulcus and the lateral sulcus and includes
both horizontal and vertical rami. These rami divide the
gyrus into three parts: the pars orbitalis, the pars trian-
gularis, and the pars opercularis. The orbital component
17
Figure 2–4. Three-dimensional MR view of the brain
showing the sulcal and gyral pattern of the inferior
frontal region and the anterior speech cortical area.
1, lateral sulcus; 2, horizontal ramus of lateral sulcus;
3, ascending ramus of lateral sulcus; 4, radiate
sulcus; 5, inferior precentral sulcus; 6, diagonal
sulcus; 7, central sulcus; 8, anterior subcentral sulcus;
9, posterior subcentral sulcus; 10, precentral gyrus;
11, annectent gyrus; 12, postcentral gyrus; 13, pars
opercularis of inferior frontal gyrus; 14, pars
triangularis of inferior frontal gyrus; 15, pars orbitalis
of inferior frontal gyrus; 16, superior temporal gyrus;
17, middle frontal gyrus; 18, superior frontal gyrus;
19, frontomarginal gyrus; 20, inferior parietal lobule.
runs into the basal orbital aspect of the hemisphere. The
opercular component merges with the lower extension
of the precentral gyrus, together constituting the frontal
operculum. The inferior frontal gyrus is more devel-
oped in the dominant hemisphere, particularly the pars
triangularis and pars opercularis, which together form
Broca’s area, the cortical region that is most essential
for expressive speech. The pars triangularis is traversed
in more than one-third of cases by the radiate sulcus
(Fig. 2–4).
The middle frontal gyrus is located between the in-
ferior and the superior frontal sulci and is separated from
the precentral gyrus posteriorly by the precentral sulci.
It is connected to the precentral gyrus by a deep an-
nectent gyrus. It is traversed by an inconstant interme-
diate frontal sulcus, which usually ends as a part of the
frontomarginal sulcus.
The superior frontal gyrus is situated between the
superior frontal sulcus and the dorsal margin of the
hemisphere. It continues on the medial aspect of
the hemisphere as the medial frontal gyrus and is con-
nected posteriorly to the central gyrus. The precentral
gyrus is located between the central sulcus and the in-
ferior and superior frontal sulci. It is limited inferiorly
by the lateral sulcus and extends superiorly to reach the
18 SECTION I TECHNIQUES
superior border of the hemisphere, where it is continu-
ous with the paracentral lobule on the medial aspect of
the hemisphere (Fig. 2–2).
䉴 THE PARIETAL LOBE
The parietal lobe is located superior to the lateral fis-
sure and behind the central sulcus, extending posteri-
orly to an arbitrary line connecting the lateral extent of
the parieto-occipital sulcus to the preoccipital notch. It
extends to the medial aspect of the hemisphere as the
medial postcentral gyrus anteriorly and as the precuneus
gyrus posteriorly. Its largest portion on the lateral surface
of the hemisphere is divided into three gyri by the intra-
parietal sulcus: the inferior parietal, the superior parietal,
and the postcentral gyri.
The postcentral gyrus is found posterior to the cen-
tral sulcus, with its lower end connected to the inferior
precentral gyrus. The inferior parietal lobule is situated
between the lateral fissure inferiorly, the horizontal seg-
ment of the intraparietal sulcus superiorly, and the as-
cending postcentral segment of the intraparietal sulcus
anteriorly. It is composed from front to back as the
supramarginal gyrus arching over the terminal ascend-
ing ramus of the lateral fissure, the angular gyrus arching
over the extremity of the upturned branch of the paral-
lel sulcus, and the posterior parietal gyrus, which may
cap the posterior end of the inferior temporal sulcus.
The supramarginal and the angular arched convolutions
are separated by a short sulcus, the primary intermediate
sulcus.17 The angular gyrus may be separated from the
posterior parietal by the secondary intermediate sulcus18
(Fig. 2–5).
The superior parietal lobule is located dorsal to the
inferior parietal lobule, limited inferiorly by the intra-
parietal sulcus, anteriorly by the superior postcentral
sulcus, and extends posteriorly to the lateral extremity
of the parieto-occipital sulcus, beyond which it passes
into the occipital lobe as the arcus parieto-occipitalis
or the superior parieto-occipital “pli de passage” of
Gratiolet.19
䉴 THE TEMPORAL LOBE
Somewhat pyramidal in shape, the temporal lobe has
lateral, basal, and dorsal aspects and an anterior apex
or pole. The lateral aspect is bounded superiorly by the
lateral fissure, which separates it from the frontoparietal
lobes. Caudally, it is continuous with the inferior parietal
lobule superiorly, and with the occipital lobe, inferiorly.
Ventrally, the temporal lobe extends to the collateral sul-
cus at the basal aspect of the hemisphere, which sepa-
rates it from the limbic lobe. The lateral convolutions of
the temporal lobe, oriented anteroposteriorly, are three
Figure 2–5. Three-dimensional MR view of the lateral
aspect of the brain showing the sulcal and gyral
anatomy of the inferior temporo-parieto-occipital
region and the posterior speech cortical area. 1,
interhemispheric fissure; 2, lateral sulcus; 3, terminal
ascending ramus of lateral sulcus; 4, parallel sulcus;
5, terminal ascending branch of parallel sulcus or
angular sulcus; 6, intraparietal sulcus, horizontal
segment; 7, sulcus intermedius primus; 8, sulcus
intermedius secundus; 9, superior occipital sulcus; 10,
transverse occipital sulcus; 11, lateral occipital sulcus;
12, inferior temporal sulcus; 13, Postcentral gyrus; 14,
inferior parietal lobule; 15, superior parietal gyrus; 16,
supramarginal gyrus; 17, angular gyrus; 18, posterior
parietal gyrus; 19, superior temporal gyrus; 20, middle
temporal gyrus; 21, inferior temporal gyrus; 22,
inferior occipital gyrus; 23, superior occipital gyrus;
24, middle occipital gyrus, 25 occipital pole.
in number: the superior, middle, and inferior temporal
gyri (Fig. 2–2).
The superior temporal gyrus is located between the
lateral fissure above and the parallel superior temporal
sulcus below. Its anterior extent contributes to the for-
mation of the temporal pole, and its posterior extremity
merges with the supramarginal gyrus. The dorsal surface
of this gyrus called the operculoinsular surface is divided
into an opercular and an insular segment. The former is
located in relation to the frontal and parietal opercula
and the latter is related to the insula. One or two trans-
verse temporal gyri of Heschl,20 cross the dorsal aspect
of the superior temporal gyrus, obliquely forward, at the
depth of the lateral fissure. More frequently doubled on
the right side, these gyri are separated at least partly by
an intermediate transverse temporal sulcus. These gyri
are posteriorly separated from the planum temporale,
by the transverse supratemporal sulcus of Holl21 origi-
nating from the lateral fissure. The frontal boundary of
the Heschl gyri is marked by the anterior limiting sulcus
of Holl.
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
The middle temporal gyrus is separated from the
superior temporal gyrus by the superior temporal sulcus
and bounded inferiorly by the inferior temporal sulcus,
which is regularly interrupted. This gyrus is continuous
posteriorly with the angular gyrus superiorly, and with
the occipital lobe inferiorly.
The inferior temporal gyrus is bounded superiorly
by the inferior temporal sulcus and extends inferiorly
over the basolateral border of the cerebral hemisphere,
to the inferior surface limited by the occipitotemporal
sulcus. It is largely discontinuous extending like the oc-
cipitotemporal gyrus close to the preoccipital notch. At
this level, it is continuous posteriorly and inferiorly with
the inferior occipital gyrus.
䉴 THE OCCIPITAL LOBE
The occipital lobe occupies the posterior aspect of the
hemisphere and is the smallest of all hemispheric lobes.
It is formed by the presence of two longitudinal parieto-
occipital “plis de passage” of Gratiolet: the first occupies
the superior aspect of the hemisphere and joins the su-
perior parietal gyrus to the superior occipital gyrus, lim-
ited laterally by the occipital segment of the intraparietal
sulcus; the second joins the angular gyrus to the mid-
dle occipital gyrus. This gyrus is the largest of the lateral
aspect of the occipital lobe and may be subdivided into
superior and inferior portions by the occipital lateral sul-
cus, which may anastomose anteriorly with the parallel
sulcus. Two other temporal occipital “plis de passage,”
which are separated by an inconstant inferior occipital
sulcus that may correspond to a side branch of the in-
ferior temporal sulcus, occupy the inferior lateral aspect
of the occipital lobe. The anterior extent of the inferior
occipital gyrus is ill-defined and continuous anteriorly
with the inferior temporal gyrus (Fig. 2–5).
䉴 THE INSULA OF REIL
The insula of Reil is the smallest of the cerebral lobes
found in the depth of the lateral fissure. It is triangular
in shape with an apex directed anteriorly and inferiorly,
called the monticulus, and overhangs the falciform sul-
cus and the preinsular region. The latter is connected
to the anterior perforated substance through the limen
insulae. The insula is separated from the frontoparietal
and the temporal opercula by the circular sulcus.
The insula proper is constituted of convergent gyri
presenting a fan-like arrangement, usually separated into
three short and one or two long convolutions by the cen-
tral sulcus insulae, the deepest and longest of all insular
furrows reaching the circular sulcus. It originates from
the superior limiting sulcus and is directed obliquely to-
ward the falciform sulcus. The insular lobe covers the
19
lentiform nucleus, separated from it laterally to mesially
by the extreme capsule, the claustrum, and the external
capsule. The sulci of the insula bear a relatively constant
relationship with the overlying cortical sulci. The central
sulcus appears to be continuous with the central sulcus
of the insula, interrupted at the level of the hidden cen-
tral operculum.
䉴 TOPOGRAPHICAL AND
FUNCTIONAL ANATOMY OF THE
SENSORIMOTOR CORTEX
The primary motor and sensory cortices include the
precentral and postcentral gyri. The extent of the sen-
sorimotor complex was defined mostly on the basis of
stimulation studies performed under local anesthesia by
several workers in the field. Penfield22 defines the pre-
central gyrus as a “sensorimotor functional unit.” This
definition was later extended to the concept of a central
lobe by Rasmussen23 (Fig. 2–2).
THE PRECENTRAL GYRUS
Anatomically, the precentral gyrus can be divided into
four segments, defined by its three bends and the para-
central lobule.
The inferior segment is convex anteriorly, and it
is close to the lateral fissure, which marks the inferior
boundary of the precentral gyrus. It commonly commu-
nicates with the postcentral gyrus, forming the central
operculum. Medially, it reaches the insula and frequently
communicates with the pars opercularis of the frontal
lobe.
The middle segment is convex posteriorly. The
junction between the inferior and middle segments is
characterized by a tapering of the gyrus, which corre-
sponds to the transition area between face and thumb
representation. This segment has no clearly defined lim-
its anteriorly, as it extends into the premotor area, due
to the interruption of the precentral sulcus in this region.
Posteriorly, it is sharply bound by the central sulcus and
medially by the corona radiata.
The superior segment is convex anteriorly. In its
initial segment, it is sharply distinct from the premo-
tor cortex. Toward the interhemispheric fissure, these
boundaries become difficult to define as this gyrus
merges with the SMA. It is sharply bound posteriorly
by the central sulcus, superiorly by the interhemispheric
fissure, and medially by the corona radiata. The direction
of the superior segment assumes a less oblique course
than that of the middle segment.
The paracentral segment occupies the posterior ex-
tent of the paracentral lobule with no sharp anterior
20 SECTION I TECHNIQUES
boundaries. Posteriorly, it appears to be demarcated for
a short distance by the central sulcus. Most stimulation
studies do not, however, corroborate a functional cor-
relate to this anatomy, as primary motor and sensory
responses are not elicited in the inferior portion of the
paracentral lobule.
THE POSTCENTRAL GYRUS
The postcentral gyrus can also be divided into four seg-
ments. Its configuration closely resembles the precentral
gyrus. Inferiorly, in the opercular region, it is wider and
thicker than its motor counterpart. The middle and su-
perior segments are thinner and more sharply defined
by the postcentral sulcus. Superiorly, since the postcen-
tral sulcus terminates caudal to the marginal ramus of
the cingulate sulcus, the primary sensory area of the leg
extends beyond the paracentral lobule.
䉴 THE PREMOTOR CORTEX
The premotor cortex is a transitional area located be-
tween the frontal pole and the primary motor cortex. Its
boundaries in humans are not well defined and gyral
patterns in this region appear to vary considerably be-
tween subjects. The anterior boundary is arbitrarily de-
fined as a line joining the anterior extent of the SMA with
the frontal eye field. Posteriorly, the premotor cortex is
delimited by the precentral sulcus.
䉴 THE MOTOR AND SENSORY
REPRESENTATION IN THE
CENTRAL CORTEX
Although there is clear evidence for a functional overlap
in the representation of specific body areas,24 the pri-
mary motor and sensory cortices that straddle the central
sulcus follow a generally orderly pattern of somatotopic
organization that is well represented in the classic ho-
munculus of Penfield and Rasmussen.22 These authors
hypothesized that the motor and sensory units were ar-
ranged in horizontal strips extending from precentral to
postcentral sulci and across the central sulcus. Thus, the
sensorimotor cortex can be divided from inferior to su-
perior into four functional units:1 the face unit, extending
from the lateral sulcus (sylvian fissure) superiorly to ap-
proximately 3 cm;2 the hand–arm unit, starting with the
thumb representation corresponding to the inferior genu
and ending at the shoulder area;3 the trunk unit, border-
ing on the interhemispheric fissure;4 the leg–foot unit,
located at the mesial aspect of the hemisphere within
the paracentral lobule (Fig. 2–2).
䉴 IMAGING APPROACHES FOR
THE LOCALIZATION OF THE
CENTRAL SULCUS
Different approaches have been used for the localization
of the central sulcus. Historically, indirect approaches
have relied on skull landmarks and, more recently, on
brain reference coordinates. Two widely used indirect
methods are the Talairach method based on the AC–PC
(anterior commissure–posterior commissure) reference
plane8,25,26,27,28 and the Olivier method based on the cal-
losal reference plane.29,30,31 Direct anatomic approaches
rely on identification of the central sulcus with mod-
ern imaging modalities. Various authors have described
landmarks for localization of the central sulcus, which
are visible on axial and sagittal MR scans,12,32 ). Iden-
tification of the superior frontal sulcus and the distinct
“hand know” on axial MR image usually permits straight-
forward identification of the central sulcus. On sagittal
images, the marginal ramus of the cingulated sulcus can
usually be followed superiorly to identify the postcentral
sulcus, which lies one sulcus posterior the central sulcus.
Using oblique 2D cuts obtained parallel to the “forniceal
reference plane,” the pericentral anatomy can be eas-
ily and precisely displayed.62 All these 2D methods lack
the ability to visualize the full extent of the central sul-
cus. For this reason, 3D MR has been used as a superior
alternative. Another approach relies on direct identifica-
tion of the sensorimotor cortex using functional imaging
techniques such as positron emission tomography, mag-
netoencephalography, or functional MRI. While these
methods add additional complexity to image acquisition,
they allow identification of sensorimotor cortex in sub-
jects with aberrant anatomy, such as patients with corti-
cal dysplasia or with tumors that efface nearby gyri and
sulci.
䉴 GYRAL ANATOMY AND
IMAGING OF THE ANTERIOR
SPEECH AREA
The anterior speech region was defined by
Broca33,34,35,36 as including the posterior third of the
left inferior frontal gyrus. Rasmussen defines the speech
area as including the pars triangularis and pars opercu-
laris of the dominant frontal lobe. However, extensive
cortical stimulation studies by Penfield and Roberts,37
Penfield and Rasmussen,22 Ojemann et al.38 and Sanai
et al.90 have shown marked individual variations in the
anterior speech area. In fact, many cortical stimulation
and functional imaging studies have shown anterior
speech representation outside of the anatomically
defined Broca’s area (Fig. 2–4).
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
Broca’s anterior speech area includes the cytoar-
chitecturally defined Brodmann’s area 45. This speech
area is anatomically limited anteriorly by the horizontal
ramus of the lateral sulcus and posteriorly by the in-
ferior segment of the precentral sulcus. Inferiorly it is
limited by the posterior ramus of the lateral sulcus and
superiorly by the inferior frontal sulcus. Two gyri thus
constitute this area, the pars triangularis and the pars
opercularis of the inferior frontal lobe. The pars trian-
gularis is limited anteriorly by the horizontal ramus and
posteriorly by the vertical ramus of the lateral sulcus.
It is characteristically U-shaped in the dominant hemi-
sphere and Y-shaped in the nondominant hemisphere.
It is traversed superiorly by the incisura capitis branch
of the radiate sulcus. The pars triangularis extends deep
into the third frontal convolution, reaching the level of
the insula. The pars opercularis is located in between the
vertical ramus and the inferior precentral sulcus. It is lim-
ited inferiorly by the sylvian fissure, reaching the inferior
frontal sulcus superiorly. It communicates with the pars
triangularis superiorly and anteriorly. Posteriorly and in-
feriorly it can communicate with the precentral gyrus. It
may be divided into two parts by the shallow diagonal
sulcus.14 More frequently found on the left (72%) than
over the right (64%) side, the diagonal sulcus appears
to almost always be connected to the sylvian fissure on
the right and only infrequently on the left, according to
Ono et al.13
䉴 GYRAL ANATOMY AND
IMAGING OF THE POSTERIOR
SPEECH AREA
Because of its marked variability,37 the anatomic local-
ization and extent of the posterior speech area is diffi-
cult and can only be determined by cortical stimulation.
Functional MRI has contributed some insight into the
organization and localization of speech.
Numerous stimulation studies and cortical excisions
(Fig. 2–5) have shown that the receptive speech area is
most frequently infrasylvian and includes the posterior
extent of the first temporal convolution and the mid and
posterior second temporal gyrus. Speech appears not
to extend to the third temporal convolution (the infe-
rior temporal gyrus) and is, in some cases, exclusively
suprasylvian. Thus, it is localized to the supramarginal
and angular gyri. The inferior parietal lobule is divided
into three contiguous convolutions: the supramarginal,
the angular, and the posterior parietal gyri, which are
separated by two intermediate sulci. The primary inter-
mediate sulcus is present in 24% of cases on the right
side and in 80% on the left. The secondary intermediate
sulcus is present in 64% of cases on the right and 72% on
the left.13 Variations of the gyral pattern of the inferior
21
parietal lobule were pointed out by Naidich et al.12 who
reported the presence of accessory supernumerary gyri
in the inferior parietal lobule: a presupramarginal gyrus,
found in 16% of cases on the left and 4% on the right
side, and a preangular gyrus found in 28% on the left
and 16% on the right side.
The posterior speech area includes: Heschl’s
gyrus,20 the temporal planum, the parietal operculum,
the parietal and temporal speech related gyri.
Heschl’s gyrus is a hidden arch-like gyrus located
entirely within the lateral sulcus and assuming a poste-
rior oblique orientation within the supratemporal plane.
This relationship is seen on axial MR cuts performed in
the sylvian plane orientation, as obtained using the “CH–
PC (chiasmatico-commissural) reference plane.”40,41 Its
anatomical landmarks are: the chiasmal point (CH) an-
teriorly and the PC posteriorly, readily shown on a mid-
sagittal MR scout view.
Heschl’s gyrus is limited anteriorly and posteriorly
by transverse supratemporal sulci. According to Bailey
and von Bonin, the posterior transverse supratemporal
sulcus is the most constant sulcus and is easily visualized
on the lateral surface of the temporal lobe originating
from the sylvian fissure with a distinct anterior oblique
orientation, located in close proximity to the postcen-
tral sulcus. It separates Heschl’s gyrus from the planum
temporale. The anterior transverse supratemporal sulcus
constitutes the anterior border of Heschl’s gyrus, reach-
ing the lateral aspect of the temporal lobe at the level of
the central sulcus. The intermediate sulcus is inconstant
and does exist when two Heschl’s gyri, mainly on the
right side, are noted.42 As Duvernoy notes, the sulcus
acusticus is the furrow that originates from the parallel
sulcus and heads toward Heschl area. Heschl’s gyri are
typically larger and more obliquely oriented on the left
side and shorter on the right side (Fig. 2–1). Although
it is assumed that the entire Heschl’s gyrus corresponds
to the primary auditory cortex, stimulation studies have
elicited responses from its posteromedial extent close
to the level of the insula.43 Strainer et al.,44 using pure
tone activation, showed different tonotopic organization
within Heschl’s gyri, depending on the frequency of the
auditory stimulus: responses elicited for tones in the
lower frequencies (1000 Hz) predominated in the lat-
eral transverse temporal gyrus, whereas those of higher
frequencies (4000 Hz) appear localized in the medial
transverse temporal gyrus.
The temporal planum is a triangular cortical sur-
face, apparent as early as the 29th week of gestation,51
studied initially by von Economo and Horn45 and subse-
quently by others.27,42,46,47,48,49,50 It is limited laterally by
the lateral sulcus and anteriorly by the posterior trans-
verse supratemporal sulcus. Its posterior limit is not well
defined. Habib et al.52,53,54 and Steinmetz et al.,55,56,57
considered the terminal descending branch of the lat-
eral sulcus as the posterior limit. In the absence of
22 SECTION I TECHNIQUES
this branch, the temporal planum includes the entire
supratemporal extent of the third division of the sylvian
fissure (Fig. 2–1). Cytoarchitecturally, it corresponds to
the posterior portion of area 22 of Brodmann. In most in-
dividuals, the left temporal planum is wider than its right-
sided counterpart and is formed by several small gyri
that assume a superior oblique orientation. The right-
side planum has a smaller cortical surface and a flat
surface.54,58 Dominance of the left cerebral hemisphere
for speech was noted early in the 19th century by Marc
Dax in 1836,63 promoter of the concept of speech local-
ization in the left hemisphere followed by Paul Broca36
and Wernicke,64 according to Alajouanine.65
Imaging identification of the posterior speech area
has been carried out extensively by Salamon and
collaborators54,59,60,61 using the bicommissural AC–PC
coordinates. These authors demonstrated that the peri-
sylvian cortical speech area and the inferior parietal lob-
ule may be reliably explored using a limited number
of cuts (four slices, 5 mm thick), oriented parallel to
the bicommissural plane, and performed at 45 mm and
50 mm above the reference line, to display the posterior
part of the first and second temporal gyri, and at 60 mm
and 70 mm, to explore the supramarginal and angular
gyri.60 Using MRI, the temporal planum is best explored
in the axial plane using CH–PC coordinates and in coro-
nal plane perpendicular to the sylvian CH–PC reference
as obtained using the PC–OB (posterior commissure–
obex) reference plane. This coronal approach permits
identification of the sylvian fissure followed on more
posterior sections on the left and located higher on the
right. It allows a direct evaluation of the depth of the
planum and an easy depiction of Heschl’s gyri on both
sides. The axial cuts performed parallel to the CH–PC ref-
erence plane, which corresponds to the sylvian fissure
orientation plane,39,40,62 best evaluate the supratemporal
region displaying, from anterior to posterior, the gyral
anatomy of the planum polare, the transverse temporal
gyri, and posteriorly the temporal planum.
䉴 THE MESIAL SURFACE OF THE
CEREBRAL HEMISPHERE
The specific gyral patterns characteristic of the inter-
hemispheric area are influenced by the development of
the callosal connections. Sulci and gyri of the mesial as-
pect of the hemisphere are evident on a sagittal and
2D-parasagittal cuts of the brain (Fig. 2–6).
䉴 THE CINGULATE SULCUS AND
THE ROSTRAL SULCI
Also called the callosomarginal sulcus, the cingulate sul-
cus begins below the rostrum of the corpus callosum,
Figure 2–6. Two-dimensional MR parasagittal cut of
the brain, showing the main sulci and gyri of the
mesial aspect of the hemisphere. 1,callosal sulcus; 2,
cingulate sulcus; 3, marginal ramus of cingulate
sulcus; 4, central sulcus; 5, paracentral sulcus; 6,
parieto-occipital sulcus; 7, subparietal sulcus; 8,
superior rostral sulcus; 9, inferior rostral sulcus; 10,
calcarine sulcus, posterior segment; 11, calcarine
sulcus, anterior segment; 12, transverse parietal
sulcus; 13, cingulate gyrus; 14, medial frontal gyrus;
15, paracentral lobule; 16, postcentral gyrus; 17,
precentral gyrus; 18, subcallosal gyrus; 19,
fronto-orbital gyri; 20, isthmus cinguli; 21, cuneus; 22,
precuneus; 23, lingual gyrus; 24, parahippocampal
gyrus; 25, parietolimbic “pli de passage”; 26,
cuneolingual gyrus; 27, retrocalcarine sulcus; 28,
frontopolar gyri; 29, gyrus descendens; 30, temporal
pole.
in the subcallosal region, before it sweeps around the
genu paralleling the corpus callosum, separating the me-
dial frontal gyrus from the cingulate gyrus, ending as a
marginal ramus in the parietal lobe and separating the
precuneus from the paracentral lobule. The marginal ra-
mus has a fairly constant relationship to the central sul-
cus, ending about 10 mm posterior to it. Up to three
interruptions are frequently noted along its course lead-
ing to invaginations of the mesial frontal gyrus into the
cingulate gyrus, as the “plis de passage frontolimbiques”
of Broca (Fig. 2–6).
The superior rostral sulcus courses anteroposteri-
orly around the rostrum of the corpus callosum and ends
closely behind the frontal pole. It is roughly parallel to
the anterior cingulate sulcus and is very frequently dou-
bled by an inferior, shallower accessory rostral sulcus
(Fig. 2–6).
䉴 THE PARIETO-OCCIPITAL
SULCUS
The parieto-occipital sulcus is a deep, constant sulcus
of the primate brain, situated on the posterior mesial
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
aspect of the hemisphere, extending downward from
the dorsal margin forward to the caudal aspect of the
splenium where it joins the stem of the calcarine sulcus.
It continues as the external incisure on the lateral aspect
of the hemisphere for a short distance (about 10–12 mm)
cutting deeply into its edge. A line connecting the
parieto-occipital incisure to the preoccipital notch draws
the arbitrary boundary on the lateral surface separating
the occipital lobe from the temporal and parietal lobes.
䉴 THE CALCARINE SULCUS AND
THE STRIATE VISUAL CORTEX
The calcarine sulcus arises behind and just below the
splenium of the corpus callosum and proceeds posteri-
orly toward the occipital pole. This deep sulcus is di-
vided into two segments at the point of its junction with
the parieto-occipital sulcus. The first, cephalad to this
junction, is the anterior calcarine sulcus. The second is
the posterior calcarine sulcus, a caudal division that typ-
ically ends posteriorly in a bifurcation on the medial as-
pect of the hemisphere. One or two submerged gyri, the
anterior and the posterior cuneolingual folds of Déjerine,
may be found within the posterior calcarine segment,
and may be seen on parasagittal MR images. The up-
per and the lower lips of the posterior calcarine sulcus
and the lower lip only of the anterior calcarine sulcus,
correspond to the striate visual cortex (area 17).
The striate or primary visual cortex is limited pos-
teriorly by the lunate sulcus, when present, and may
extend beyond the occipital pole of the hemisphere for
a distance of 1–1.5 cm. This extension onto the medial
posterior aspect of the occipital pole shows important
individual variations. The cortex of the visual sensory
area identified histologically by a white line (or stria-
tion), the line of Gennari, which is a layer of myelinated
terminals of optic radiations fibers. The parieto-occipital
sulcus limits the striate cortex anteriorly. An average of
67% of the visual cortex is buried in the depth of the
calcarine fissure and its branches. The area of the striate
cortex is greater below than above the calcarine fissure,
extending about 2 cm more anteriorly. The striate cor-
tex is situated between the cuneus, a wedge-shaped area
located above the calcarine sulcus whose surface is gen-
erally indented by one or two small sulci, and the lingual
gyrus lying below, between the calcarine sulcus superi-
orly and the collateral sulcus inferiorly (Fig. 2–6). The
cuneus and lingual gyri are both part of the extrastriate
visual cortex.
Considering the functional and anatomic aspects of
the visual cortex,66 there is general agreement regarding
the following conception of cortical representation: the
upper half of each retina is retinotopically represented
in the dorsal part of the occipital striate cortex and the
23
lower half in the ventral part. Regarding the disposition
of the macular fibers, Holmes considered it to be located
on the tip of the posterior pole of the cerebral hemi-
sphere, whereas according to Polyak, a wide distribution
of these fibers along the calcarine sulcus is observed.
The striate cortex (area 17) is intimately related to
the parastriate cortex (area 18), which lies in a portion of
the occipital lobe contiguous to the latter. The Gennari
band is not found in this area. The peristriate area (area
19) is much larger than area 18, lying on the lateral as-
pect of the cerebral hemisphere and extending beyond
the medial aspect of the hemisphere to surround the
parastriate area from above and below. Most of the peri-
striate area lies in the posterior part of the parietal lobe.
It extends inferomedially to the posterior portion of the
temporal lobe (Fig. 2–5).
Considering imaging, many authors have proposed
reference planes and have tried to describe the ideal an-
gulations to use with respect to the orbitomeatal line or
to an anthropologically based line.39,40,62,67,68,69,70,71,72,73,
The best compromise would be a reference plane suit-
able for exploration of both the optic pathways and the
brain. For this reason, the neuro–ocular plane, as the
anatomophysiological and anthropological cephalic ref-
erence plane, appears to be the most suitable for study-
ing the visual pathway.68,69,71,72 It is, in our opinion,
also efficient enough for evaluation of the retrochias-
matic pathways in routine practice. In order to facilitate
the neuroanatomical approach and optimize topometric
studies of the brain and the retrochiasmal visual path-
ways, the CH–PC line, defining a CH–PC reference plane
is used.39,40,74,75
The calcarine fissures and striate cortex are shown
on the midsagittal cut of the brain, and may also be de-
picted on coronal and axial cuts. Their close relationship
to the occipital horns of the lateral ventricle may aid in
their recognition. However, there is no ideal cephalic
orientation for studying the calcarine fissures, as they
are variable in shape among individuals. Note that the
CH–PC reference line intersects posteriorly the common
stem of the parieto-occipital and calcarine sulci.
䉴 GYRI OF THE MESIAL SURFACE
OF THE CEREBRAL HEMISPHERE
Seven gyri constitute the mesial hemisphere.76 These
are described as follows, from anterior to posterior
(Fig. 2–6).
THE GYRUS RECTUS
The gyrus rectus is limited inferiorly by the floor of the
anterior cranial fossa, laterally by the olfactory sulcus,
and superiorly by the superior rostral sulcus (Fig. 2–7).
24 SECTION I TECHNIQUES
Figure 2–7. Three-dimensional MR view of the sulcal
and gyral anatomy of the basal aspect of the
hemisphere. 1, olfactory sulcus; 2, orbital sulci (“H”);
2a, medial orbital sulcus; 2b, lateral orbital sulcus; 2c,
arcuate or transverse orbital sulcus; 3,
interhemispheric fissure; 4, gyrus rectus; 5, medial
orbital gyrus; 6, lateral orbital gyrus; 7, anterior orbital
gyrus; 8, Posterior orbital gyrus; 9, superior temporal
gyrus and temporal pole; 10, middle temporal gyrus;
11, inferior temporal gyrus; 12, parallel sulcus; 13,
parahippocampal gyrus; 14, uncus; 15, optic chiasm;
16, pons; 17, medulla oblongata.
THE CINGULATE GYRUS
The cingulate gyrus is limited ventrally by the callosal
sulcus, ventrally and anteriorly by the anterior paraol-
factory sulcus, superiorly by the cingulate sulcus, su-
periorly and posteriorly by the subparietal sulcus, and
posteriorly and inferiorly by the anterior calcarine sul-
cus. It is continuous with the parahippocampal gyrus
through the isthmus. The anterior cingulate is followed
in the subcallosal region, where it abuts the subcal-
losal gyrus, which is limited anteriorly by the ante-
rior subcallosal sulcus and bounded posteriorly by the
posterior subcallosal sulcus, the latter limiting anteri-
orly the paraterminal gyrus. Together with the subcal-
losal, the isthmus hippocampi, and the parahippocampal
gyri, the cingulate gyrus forms the limbic lobe of Broca
(Fig. 2–6).
THE MEDIAL FRONTAL GYRUS AND
THE SUPPLEMENTARY MOTOR AREA
The medial frontal gyrus is limited ventrally and ante-
riorly by the gyrus rectus. Superiorly, it constitutes the
superior border of the hemisphere and posteriorly it is
limited by the paracentral sulcus. The SMA as described
by Penfield and Welch77 is of variable extent and located
in the mesial aspect of the first frontal convolution, an-
terior to the representation of the lower extremity in the
primary motor cortex and superior to the cingulate sul-
cus. It may extend superiorly onto the lateral convexity
of the hemisphere. The anatomic boundaries of the SMA
have been a subject of considerable debate.78 The an-
terior extent of the SMA was defined by Talairach and
Bancaud79 as a line perpendicular to the AC–PC line,
passing by the anterior-most extent of the genu of the
corpus callosum.
THE PARACENTRAL LOBULE
The paracentral lobule is limited superiorly by the su-
perior border of the hemisphere and anteriorly by the
paracentral sulcus. Posteriorly, the paracentral lobule is
bounded by the marginal ramus, which ends at the hemi-
spheric border and in more than two-thirds of cases
extends to the lateral surface. The paracentral lobule
proper usually extends anterior to the precentral sulcus.
The relationship of the marginal ramus to the central
area has not been adequately assessed. The marginal ra-
mus has a relatively constant relationship with the cen-
tral sulcus and ends posterior to the central sulcus. The
anterior limit of the primary motor area over the mesial
hemisphere tends to be unclear. The postcentral sulcus
extends to the mesial surface in about one-third of ex-
amined hemispheres. Most commonly, it is posterior to
the marginal ramus (Fig. 2–3). Thus, the primary sensory
leg–foot area appears to extend anatomically beyond the
limits of the paracentral lobule.
THE PRECUNEUS
The precuneus is limited anteriorly by the marginal ra-
mus, superiorly by the superior border of the hemi-
sphere, posteriorly by the parieto-occipital sulcus, and
inferiorly by the subparietal sulcus. The parieto-occipital
sulcus is a deep constant sulcus that demarcates the pre-
cuneus from the cuneus of the occipital lobe. The sub-
parietal sulcus is a variable sulcus, which may show var-
ious branching or may appear as a posterior branching
of the cingulate sulcus. It is frequently traversed by one
or two parietolimbic “plis de passage” (Fig. 2–6).
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
THE CUNEUS
Triangular in shape, the cuneus is the only occipital
gyrus that is consistently well delimited. It is bounded
anteriorly by the parieto-occipital sulcus, superiorly by
the superior border of the hemisphere, and inferiorly by
the posterior calcarine sulcus. It is continuous with the
surface of the lateral hemisphere. The calcarine sulcus
extends anteriorly and stops at the most posterior ex-
tent of the collateral sulcus. The cuneus is connected to
the posterior aspect of the cingulate gyrus by a deep
cuneolimbic “pli de passage” (Fig. 2–6).
THE LINGUAL GYRUS
The lingual gyrus constitutes the inferior mesial aspect
of the occipital lobe. It is bordered superiorly by the cal-
carine sulcus and connected to the cuneus through the
retrocalcarine sulcus by one or two cuneolingual gyri.6 It
is continuous anteriorly with the parahippocampal gyrus
(Fig. 2–6).
䉴 THE INFERIOR AND MESIAL
SURFACE OF THE CEREBRAL
HEMISPHERE
Sulci and gyri of the basal aspect of the frontotemporal
lobes are best imaged and analyzed on coronal cuts per-
formed parallel to the PC–OB brain reference line.39,40,80
Coronal anatomic correlations and cross-sectional atlas
are available.9,75 We will separate the basal surface into
an anterior basal orbitofrontal lobe and a posterior basal
temporal lobe (Fig. 2–7).
䉴 THE ANTERIOR BASAL
ORBITOFRONTAL SULCI AND
GYRI
The orbital surface of the frontal lobe includes a primary
sulcus, the olfactory sulcus, and a secondary composite
sulcus, the orbital sulci, that varies considerably between
individuals.
The olfactory sulcus originates at the anterior per-
forated substance. It courses in the posterior–anterior
plane roughly parallel to the anterior interhemispheric
fissure, and terminates about 1.5 cm posterior to the
frontal pole. It is closely related anatomically to the olfac-
tory tract. This sulcus separates the gyrus rectus medially
from the orbital gyri laterally.
The orbital sulci show numerous variations,81 with
two longitudinal sulci connected by a transverse furrows
arranged in the shape of an “H” or “X” or “K.” The longi-
25
tudinal sulci are the medial and the lateral orbital sulci,
which divide the orbital surface into medial and lateral
orbital gyri and an intermediate orbital cortex. This is
subdivided transversely into anterior and posterior mid-
dle orbital gyri by the arcuate orbital sulcus. The lateral
orbital sulcus limits the orbitofrontal lobe from the lateral
aspect of the inferior frontal gyrus (Fig. 2–7).
䉴 THE POSTERIOR BASAL
TEMPORAL SULCI AND GYRI
The basal surface of the temporal lobe extends later-
ally from the inferior lateral border of the hemisphere
to the mesial temporal border at the lateral wing of the
transverse fissure. It extends from the temporal pole to
the inferior occipital lobe without definite demarcation.
From mesial to lateral, two longitudinal sulci, the collat-
eral and the occipitotemporal divide the basal tempo-
ral lobe into three gyri, the parahippocampal gyrus, the
fusiform gyrus, and the inferior temporal gyrus, at the
junction between the lateral and the inferior aspects of
the hemisphere.
The collateral sulcus, a primary sulcus also called
the medial occipitotemporal sulcus, is a constant, elon-
gated S-shaped sulcus of the basal aspect of the temporal
lobe. It usually originates near the temporal pole and
separates the parahippocampal gyrus and the lingual
gyrus from the more laterally situated fusiform gyrus.
The lateral occipitotemporal sulcus is a secondary
sulcus that runs lateral and roughly parallel to the
collateral sulcus, near the inferolateral margin of the
hemisphere, and end near the preoccipital notch. It is
frequently interrupted by additional small sulci. It con-
stitutes the medial boundary of the occipitotemporal or
fusiform gyrus. This gyrus does not reach the temporal
pole anteriorly and its width increases from the pole to
its posterior extremity before it merges with the inferior
occipital lobe (Fig. 2–7).
䉴 THE LIMBIC LOBE AND THE
MESIAL TEMPORAL REGION
The limbic lobe, corresponding to the “grand lobe lim-
bique” of Paul Broca includes anatomical structures bor-
dering the diencephalon.85 Ontogenetically, this arch
convolution located at the inferomedial aspect of the
cerebral hemisphere is limited continuously by major
primary sulci represented mainly by the cingulate sulcus
dorsally and ventrally, the collateral sulcus posteriorly
and the rhinal sulcus anteriorly. These sulci laterally limit
the uncus and the parahippocampal gyrus, which curves
posteriorly through the narrow isthmus around the sple-
nium of the corpus callosum covering and surrounding
26 SECTION I TECHNIQUES

it completely. It is separated from the corpus callosum
by the callosal sulcus. Anteriorly, below the callosal ros-
trum, it merges with the paraterminal gyrus, which cor-
responds to the prehippocampal rudiment, immediately
in front of the lamina terminalis. Starting in the subcal-
losal region, the limbic lobe structures encircle the upper
brainstem and the corpus callosum as the subcallosal,
cingulate, parahippocampal and hippocampal, and den-
tate gyri (Fig. 2–8).
Imaging of the limbic structures has dramatically
improved with the advent of high-resolution 3D MRI.
Coronal slices performed parallel to the PC–OB refer-
ence plane are very useful for volumetric analysis of the
amygdala–hippocampal complex.
Embryologically, the fornices together with the
choroidal fissures develop along an oblique plane with
a complex arciform course. This shape is focused on
by temporalization of the brain. Imaging along the “for-
niceal plane” is therefore particularly useful.75 This plane
is defined by a line joining the lateral aspect of the fim-
bria fornix in the hippocampus with the lateral aspect
of the crus fornicis. These structures are visualized and

Figure 2–8. Two-dimensional reformation of the mesial temporal region using the
“forniceal plane” (A) to display the limbic belt medially (B) and the central lobe laterally
(C). (A) MR topogram showing the orientation of the sagittal oblique “forniceal
(fimbria-fornix)” reference plane oriented at about 45˚ to the midsagittal plane. (B) 1,
hippocampus; 2, fimbria; 3, fornix; 4, amygdala; 5, splenium of corpus callosum; 6,
collateral sulcus; 7, parahippocampal sulcus; 8, fusiform gyrus; 9, rostral sulcus; 10,
occipital lobe; 11, temporal pole; 12, interhemispheric fissure. (C) 1, central sulcus; 2,
superior precentral sulcus; 3, inferior precentral sulcus; 4, superior frontal sulcus; 5,
inferior frontal sulcus; 6, inferior postcentral sulcus; 7, superior postcentral sulcus; 8,
intraparietal sulcus; 9, lateral sulcus; 10, precentral gyrus; 11, postcentral gyrus; 12,
superior frontal gyrus; 13, middle frontal gyrus; 14, inferior frontal gyrus; 15, inferior
parietal lobule.
CHAPTER 2 STRUCTURAL IMAGING FOR IDENTIFICATION OF FUNCTIONAL BRAIN REGIONS
joined on the coronal PC–OB reference plane itself. Se-
rial oblique cuts are then acquired or reformatted parallel
to the forniceal plane to cover the entire mesial temporal
lobe and extend to the convexity. This reference plane
appears especially interesting for the study of hippocam-
pal, amygdala, and temporal polar cortex formations. We
have found the lateral slices particularly helpful for the
study of the central brain region as well. The frontal
lobe perisylvian convolutions are well depicted, facili-
tating the identification of the sulcal and gyral anatomy
of this region (Fig. 2–8).
The anatomy of the mesial temporal region is partic-
ularly complex and is composed of the temporal pole,
the amygdala, the hippocampus, the parahippocampal
gyrus, and certain cortical areas related to these struc-
tures.
The temporal polar cortex corresponds to area 38
of Brodmann. Its cytoarchitectural characteristics have
been defined by Insausti.82 The temporal pole, extend-
ing from the tip of the temporal lobe laterally and ventro-
laterally to the level of the superior or inferior temporal
gyri, is characterized by the appearance of the superior
or inferior temporal sulci. Ventromedially, the temporal
polar cortex blends with the perirhinal area and dor-
sally extends to the level of the limen insulae. The tem-
poral pole includes three surfaces: dorsal, lateral, and
mesial.
The entorhinal area occupies most of the anterior
extent of the parahippocampal gyrus and extends dor-
somedially to the periamygdaloid cortex (area 28 of
Brodmann). Caudomedially, it reaches the presubiculum
and laterally extends into the medial bank of the collat-
eral sulcus. The entorhinal area extends rostrally from
the level of the limen insulae and medially to the pe-
riamygdaloid cortex. It is separated from the amygdala
by the sulcus semiannularis. Its extension over the un-
cus includes the ambient gyrus and reaches laterally to
the level of the collateral sulcus. According to Insausti
et al.,83 the rhinal sulcus has a limited value in defining
the extent of the entorhinal area. At the level of the pos-
teromedial uncus, its extent is limited by the hippocam-
pal fissure. The perirhinal area corresponds to area 35
of Brodmann.84 It follows the collateral sulcus along its
rostrocaudal extent, occupying its fundus and its medial
bank. In addition, the perirhinal area comprises area 36.
This area is medial to area 20 of Brodmann and anteriorly
continues with area 38. The perirhinal cortex constitutes
the lateral border of the vestigial rhinal sulcus and, more
caudally, the collateral sulcus.
The amygdala, or amygdaloid nuclear complex, re-
ceived its name from its shape, which resembles that
of an almond. It constitutes, along with the hippocam-
pus, one of the two major telencephalic components
of the limbic system. The topographical relationships of
the amygdala are complex and are best appreciated and
evaluated on MR coronal sections obtained using the
27
PC–OB reference line displaying the nuclear mass dor-
sal to the hippocampal formation and rostral to the tip
of the inferior horn of the lateral ventricle. The supe-
rior aspect of the amygdala is partly continuous with the
inferior margin of the claustrum, and is separated from
the inferior aspect of the putamen and the pallidum by
fibers of the external capsule and the ventral striatum,
in close contact with the optic tract. At this level, the
amygdala fuses with the tip of the tail of the caudate nu-
cleus. The amygdala is a corticonuclear transition area
located dorsomedially in the temporal lobe and form-
ing the ventral superior and medial walls of the inferior
horn of the lateral ventricle. Numerous subdivisions of
the amygdala have been reported. According to Gloor,85
the amygdala can be divided into three large subnu-
clei: the basolateral, corticomedial, and central group of
nuclei.
Perhaps the earliest description of the hippocam-
pus was given by Arantius (1587) and J.G. Duvernoy
provided the first illustrations in 1729, according to H.
Duvernoy.86,87 Reviews of the complex terminology may
be found in Tilney88 and Klingler.89 The hippocam-
pus consists of two cortical lamina each interlocked
with the other: the Ammon’s horn or the hippocampus
proper, and the gyrus. The hippocampal formation may
be subdivided morphologically into a precommissural,
a supracommissural, and a retrocommissural portion.
The retrocommissural portion represents the hippocam-
pal formation, the other parts being vestigial anatomi-
cal structures. The precommissural portion occupies the
caudal part of the area subcallosa. The supracommis-
sural portion is represented by the indusium griseum or
supracallosal gyrus. The hippocampus is located in the
mesial temporal lobe and protrudes into the temporal
horn of the lateral ventricle after it rolls in on itself along
the hippocampal sulcus during ontogenesis. Its rostral
extremity extends ventrally to the amygdala. The major
topographical structures of hippocampal formation are
seen on coronal anatomic and MR cuts perpendicular to
the long axis of the inferior horn of the lateral ventricle as
obtained according to the PC–OB reference plane62,75,80
and/or perpendicular to the CH–PC reference plane.39,40
The shape of the hippocampus and the localization of its
constitutive structures are explained by the cortical fold-
ing, which occurs during development. The external as-
pects of the subiculum and the dentate gyrus face each
other in the depths of the hippocampal sulcus. When
opening the hippocampal sulcus, the dentate gyrus is
seen between the hippocampal sulcus, which is below,
and the fimbria, which are above. The dentate gyrus may
be followed backward accompanied by the fimbria until
it reaches the splenium of the corpus callosum. The cor-
tical zone medial to the dentate gyrus is the subiculum,
which is contiguous with the parahippocampal gyrus
or entorhinal area. Ammon’s horn, which is the third
longitudinal structure of the hippocampal formation, is
28 SECTION I TECHNIQUES
the hippocampus proper. The hippocampal formation is
covered by a lamina of whiter matter fibers, the alveus,
which converges on the medial aspect of the hippocam-
pus to form the fimbria and then the fornix.
The hippocampal formation is divided into two
parts, the hippocampus proper or the Ammon’s horn,
and the dentatus gyrus or the fascia dentata. The hip-
pocampus proper is a cylindrical structure, voluminous
anteriorly, extending as much as 4–5 cm from the tip of
the temporal horn to the splenium of the corpus callo-
sum where it becomes continuous with the fornix. Its
course assumes a strong inner concavity. It is commonly
divided into three parts: head, body, and tail. The hip-
pocampal head is characterized by several digitations
that are apparent on its ventricular surface, representing
the foldings of the hippocampal formation. At the level
of the body, the hippocampal proper is limited later-
ally by the collateral eminence, created in the temporal
horn by the collateral sulcus. Its ventricular surface, the
alveus, constitutes the output of the hippocampus, and is
continuous with the fimbria fornix. The anterior segment
of the tail resembles the body of the hippocampus. It is,
however, distinct due to a progressive thinning of the
hippocampus proper and increase in size of the fimbria
fornix. The posterior aspect of the tail has a markedly dif-
ferent geometry as two important structures, the dentate
gyrus and the fimbria fornix, assume divergent destina-
tions. The dentate gyrus courses toward a supracallosal
destination to become the indusium griseum, and the
fornix, together with the rest of the body, moves toward
an infracallosal course.
The uncus includes parts of the amygdala,
hippocampus, and piriform cortex. It is posteriorly con-
tinuous with the parahippocampal gyrus and its postero-
lateral extent is separated from this latter structure by
the uncal sulcus. The amygdala produces a characteris-
tic protrusion on the surface of the uncus, the semilunar
gyrus. The semilunar gyrus is separated from the entorhi-
nal cortex by the semiannular or amygdaloid sulcus. An-
teriorly, the amygdala or rhinal cortex blends with the
prepiriform cortex, the lateral olfactory striae and is sep-
arated from the perforated substance by the endorhinal
sulcus. Posteromedially, it is bordered by the optic tract.
The posterior aspect of the uncus is occupied by parts
of the head of the hippocampal formation.
䉴 CONCLUSION
Contemporary MR imaging is remarkably adept at iden-
tifying specific cortical and subcortical brain structures,
including regions that are well correlated with specific
clinically important functions, such as the primary mo-
tor are in the precentral gyrus. Careful imaging meth-
ods described in this chapter allow clinicians to identify
many functionally important areas with very high reli-
ability and in a manner that is practically useful in the
clinical setting. One major caveat, however, is that struc-
tural imaging cannot account for functional variability
that frequently exists across different individuals. For this
reason, functional imaging and other functional mapping
techniques must often be used to supplement anatomic
data.
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 Chapter 3
Functional MRI for Cerebral
Localization: Principles and
Methodology
Michael S. Beauchamp
Department of Neurobiology and Anatomy, University of Texas Health Science Center, Houston, Texas
䉴 INTRODUCTION
The widespread availability of magnetic resonance imag-
ing (MRI) scanners has allowed clinicians a clearer pic-
ture of brain structure and function. In addition to the
static anatomy imaged with traditional MRI, functional
MRI (fMRI) allows for the measurement of brain function.
The most widely used fMRI technique is known as blood
oxygen level dependent (BOLD) fMRI. BOLD fMRI has
become a powerful tool for studying brain function, and
has led to important advances in our understanding of
the basic neurobiology of the brain. However, there are
significant obstacles to translating these advances into
clinically useful information. In this chapter, we give a
brief overview of the techniques used to create BOLD
images and the data analysis necessary to identify ac-
tive brain areas. Finally, we examine the difficulties in
drawing clinical inferences from fMRI studies.
䉴 A BRIEF HISTORY OF fMRI
Paul Lauterbur and Peter Mansfield received the 2003
Nobel Prize for developing techniques to transform NMR
(nuclear magnetic resonance), which gives information
about a uniform sample of material, into a technique that
provides a two-dimensional (2D) image of an object.1,2
This method is now known as MRI, a considerably more
patient-friendly term than the original name, which was
“NMR Zeugmatography” (zeugma, Greek for yoke, refer-
ring to joining a magnetic field gradient to a local region
to form an image). Because of its medical importance,
it is likely that a future Nobel Prize will honor those
involved in the development of fMRI. A probable hon-
oree is Seiji Ogawa, who discovered that hemoglobin
could serve as a natural contrast agent to measure blood
oxygenation.3−5 Following Ogawa’s discovery, a num-
ber of groups realized that this BOLD MRI could be
31
used to measure changes in blood oxygen in the human
brain linked to brain activity.6−8 This new method was
termed functional MRI (fMRI) because it measured brain
function, and to distinguish it from the more traditional
anatomical or structural MRI.
䉴 A THUMBNAIL SKETCH OF fMRI
As neuronal activity in the brain fluctuates, the local
blood oxygen content varies. A particular type of MR
image, a T2*-weighted image (effective T2), is sensitive
to the blood oxygen content. What distinguishes fMRI
from MRI is that instead of collecting a single image (to
inspect brain anatomy), a whole series of brain images
is collected to find brain areas with fluctuating blood
oxygen content. When this type of image is acquired,
active brain regions become brighter. Figure 3–1 shows
a thumbnail sketch of a simple fMRI experiment. When
the patient views a blank screen, there is little activity
in visual cortex in the occipital lobe. When the patient
views a picture, neurons in visual cortex become active
and the blood oxygenation level increases, resulting in
an increase in MR signal intensity. When the picture dis-
appears, neurons in visual cortex cease firing and the
MR signal returns to baseline intensity.
In order to perform an fMRI experiment, special-
ized equipment over and above that required for typical
clinical MRI is required. Most importantly, sensory stim-
uli must be delivered to the patient, and these stimuli
must by synchronized with the MR image acquisition
(Fig. 3–2).
A thriving cottage industry exists to provide this
equipment; often the scanner manufacturers will com-
bine and resell the equipment from a combination
of vendors as part of an “fMRI package.” However,
third party vendors often offer capabilities unavailable
from the scanner manufacturer. Headphones allow the
delivery of auditory stimuli (such as single words) or
32 SECTION I TECHNIQUES

Figure 3–1. Top: visual display viewed by a subject. The subject views a blank screen,
followed by an image of a face, then a blank screen. Bottom: T2∗ MR images from the
subject’s brain collected while viewing the display. An axial slice showing visual cortex
in the occipital lobe (green arrow). When neuronal activity in visual cortex increases,
there is a concomitant brightening of the voxels in visual cortex. When the stimulus is
turned off, the brightness returns to baseline.

instructions (tap the fingers in your right hand). The
stock headphones included with MR scanners are pneu-
matic (as in old-fashioned airline headsets): sound is
generated in a speaker and transmitted through plastic
tubes to the headset. This is adequate for patient commu-
nication, but is not sufficient for an auditory fMRI experi-
ment in which the brain responses to carefully calibrated
stimuli are measured. Therefore, at least three vendors
produce high-fidelity MR compatible headphones. Visual
stimuli may be delivered using goggles (containing small

A B

D E C

Figure 3–2. Apparatus for delivering sensory stimuli and recording behavioral
responses during a functional MRI experiment. (A) Picture of the MR scanner showing
bed and head coil. (B) Close-up view with patient holding button response device,
wearing earphones, and viewing visual stimulus in mirror attached to head coil. (C)
View behind the scanner, showing screen with visual display viewed by subject via
mirror (white arrow) and video-based infrared eye tracker (ASL Inc., green arrow). (D)
Close-up view of button response device (Current Designs, Inc.). (E) Close-up view of
somatosensory stimulation device consisting of a piezoelectric bender attached to
subject’s hand with an elastic bandage.
 CHAPTER 3 FUNCTIONAL MRI FOR CEREBRAL LOCALIZATION
LCD panels) or via a mirror viewed by the subject. This
allows the patient to see visual stimuli projected onto
a screen behind or in front of the scanner. Piezoelec-
tric vibrotactile devices allow delivery of somatosensory
stimuli. Because subjects may close their eyes or fall
asleep, a useful tool for fMRI is an eye tracker, which
allows experimenters to view a video image of the sub-
ject’s eyes and monitor their behavioral state. It is also
important to monitor responses to be sure subjects are
able to perform the task. For instance, a subject might
press one button when seeing a male face and another
button when seeing a female face. This helps the sub-
ject maintain alertness and makes sure that the subject
understands the instructions and is performing the task.
䉴 MRI AND MR SCANNERS
MRI scanners can be viewed as complex computers that
can use different programs (known as pulse sequences)
to acquire many different kinds of images that depend
on different physiological properties. Because no ioniz-
ing radiation is used during MRI scanning, a typical MR
examination includes many different pulse sequences,
with the primary limit being the time that the subject
can remain in the scanner.
By far, the most common method for performing
fMRI of the brain is BOLD fMRI. To perform BOLD fMRI,
a pulse sequence must be sensitive to the amount of
blood oxygenation in the tissue, and it must acquire im-
ages quickly. A typical spoiled-GRASS pulse sequence
used for anatomical imaging of the brain takes minutes
to acquire a single brain image. As generally applied,
BOLD fMRI uses a pulse sequence with two key fea-
tures: first, it generates images with T2* contrast, a con-
trast that is sensitive to the amount of oxygenated blood
in the tissue, and second, it generates images of the
entire brain in a second or two (rather than minutes)
using echo-planar imaging. These images are referred
to as T2*, echo-planar imaging (EPI), or functional im-
ages (as opposed to purely anatomical images). Figure
3–3 shows the basic physiological mechanism of BOLD
as it is currently understood: increased neuronal activity
causes spatially localized increase in blood flow without
as large an increase in oxygen consumption, resulting in
a net increase in blood oxygenation and an increased
MR signal.
䉴 COLLECTING MRI DATA
Because the rapidly acquired T2* images used to mea-
sure BOLD activity have poor contrast and are of low
resolution, fMRI experiments nearly always acquire a
high-resolution T1-weighted anatomical brain volume to
serve as an anatomical underlay for the functional brain
33
map (Fig. 3–4A). To acquire this single anatomical vol-
ume takes about 5 minutes. Images for BOLD activity
are acquired much more quickly, usually limited by the
speed of the magnetic field gradients used for image ac-
quisition. The typical goal in an fMRI study is to collect
data from the entire brain. If a single slice of approx-
imately 3 mm thickness is acquired in 50 ms, we can
collect 40 such slices within a 2-second repetition time
or TR (the TR is the time required to collect the entire
volume of interest). This allows us to collect data from
a 12-cm-thick slab of tissue, or about the inferior to su-
perior extent of the average human brain (Fig. 3–4B).
BOLD fMRI studies generate huge amounts of data.
A 5-minute anatomical MR scan series generates a single
brain volume. The single volume is viewed as a series
of slices on a workstation or a light box, and can be
quickly read by a radiologist who examines each slice
for abnormalities. In the same 5-minute period, a typi-
cal fMRI scan series would collect brain volumes every 2
seconds, producing 150 brain volumes (Fig. 3–4C). Even
if these brain volumes were each manually examined, it
would be difficult to detect the slight changes in im-
age intensity that signal the presence of brain activity.
Therefore, we can consider BOLD fMRI data analysis as
a problem of compression, or reduction, in which the
hundreds of brain volumes acquired are reduced to one
or a few brain volumes that can be easily examined by
the scientist or clinician.
䉴 ANALYZING fMRI DATA
fMRI studies acquire data from thousands of brain loca-
tions, leading to the analysis problem of deciding which
brain locations are involved in the experimental task. To
address this problem, techniques developed to analyze
other types of time varying data have been adapted to
fMRI.
Figure 3–5 shows some sample raw data from vox-
els in the ventricle (where there is no neural response to
the visual stimulus) and from voxels in the visual cortex
(where there is a great deal of response to the visual
stimulus).
The challenge faced by fMRI analysis is to accu-
rately distinguish these two populations, differentiating
active voxels from inactive voxels. An arbitrary statisti-
cal threshold is used, which inevitably classifies some
truly active voxels as inactive, or vice versa. There is
no universally agreed upon threshold for use in creat-
ing activation maps, or even universally agreed upon
way of calculating significance; that is, a map that is la-
beled as “active voxels, p < 0.05” in one study may use
a completely different statistical test than that used in a
different study that uses the same nominal threshold.
Before fMRI, the most popular method for brain
imaging was positron emission tomography (PET). In a
34 SECTION I TECHNIQUES

Figure 3–3. Mechanism of blood oxygen level dependent functional MRI. (A) The
cerebral vasculature in a small region of auditory cortex. A precapillary arteriole (red)
gives rise to a collateral capillary (green) which divided into two terminal capillaries
(orange and cyan) before joining with other capillary loops and entering a
postcapillary venule (blue). (Adapted from Harrison RV, Harel N, Panesar J, Mount RJ.
Blood capillary distribution correlates with hemodynamic-based functional imaging in
cerebral cortex. Cereb Cortex 2002;12(3):225–233.) (B) Enlargement showing
perivascular control structures near capillary branching points that may control blood
flood. (Adapted from Harrison RV, Harel N, Panesar J, Mount RJ. Blood capillary
distribution correlates with hemodynamic-based functional imaging in cerebral cortex.
Cereb Cortex 2002;12(3):225–233.) (C) At rest, there is relatively little blood flow into
an area of cortex. Black lines show a capillary, hexagonal shapes represent red blood
cells, red color represents oxyhemoglobin, and blue color represents
deoxyhemoglobin. Most of the hemoglobin is deoxygenated, weakening the echo
from nearby protons in water molecules (black sinusoidal curve). (D) During
activation, more blood flow enters the capillary. Only some of the extra oxygen is
extracted, resulting in less deoxygenated hemoglobin and greater signal from protons
in nearby water molecules.

typical PET experiment, only a single brain image would
be collected for each condition for each subject. Then,
a subtraction was performed to show areas with differ-
ential blood flow between conditions.9
In the early days of fMRI, people would treat the
fMRI data like PET data, simply performing a t-test be-
tween task epochs (e.g., subject looking at a picture) and
rest epochs (e.g., subject looking at a blank screen). The
flaws in this approach are immediately apparent when
examining Fig. 3–5C. A t-test assumes that values collect
in task and baseline periods are similar to each other.
However, the MR time series in active voxels in visual
 CHAPTER 3 FUNCTIONAL MRI FOR CEREBRAL LOCALIZATION 35

C B

Figure 3–4. Data collected in a typical functional MRI experiment. (A) High-resolution
anatomical image (T1-weighted) showing fine detail of anatomical structures. Green
lines show location of T2∗ -weighted images pictured in (B). (B) T2∗ -weighted
echo-planar images collected in a single 2-second repetition time (TR). 33 slices are
pictured in a 3 × 11 montage, from inferior (top left) to superior (bottom right). Each
slice is 3-mm thick, with 2.75 mm × 2.75 mm in plane resolution. (C) A T2∗ -weighted
brain volume is collected every 2 seconds, leading to 150 volumes in a typical
5-minute scan series.

cortex does not resemble a square wave, but more
closely resembles a sine wave. Treating all points on
the top half of the sine wave (for task epochs) and
bottom half of the sine wave (for baseline epochs) as
equivalent is inaccurate. Therefore, the next stage in
the development of fMRI analysis techniques was to use
cross-correlation,10 which allows knowledge about the
expected shape of the MR time series to be incorporated
into the analysis. The next (and consensus) method for
analyzing fMRI data was to use multiple regression.11 In
this most common analysis method, also referred to as
the multivariate generalized linear hypothesis or general
linear model, regressors are created that correspond to
the temporal sequence of different events experienced
by the subject during scanning.12−14 Brain regions in
which the MR time series is time-locked to these events
are classified as “active.” In this section, we discuss
the methods and procedures for deciding whether any
36 SECTION I TECHNIQUES

A
B

Figure 3–5. (A) Axial slice through the brain. Grids show voxel locations (enlarged) of
voxels shown in (B) and (C). (B) A plot of the intensity in nine voxels in the red grid in
(A), located in a ventricle. Each black trace shows the intensity of that voxel in each of
150 images, collected every 2 seconds over a 5-minute scan series. No regular
variation in the intensity is apparent. (C) A plot of the intensity of the nine voxels in the
green grid shown in (A) located in visual cortex. The signal becomes brighter and
dimmer as the subject views visual stimuli.
 CHAPTER 3 FUNCTIONAL MRI FOR CEREBRAL LOCALIZATION
brain area is active in a given stimulus or behavioral
task.
To understand these statistical analyses, we use as
an example a simple visual stimulation experiment. Fig-
ure 3–5 shows a single axial slice through a brain vol-
ume, along with the time series. In a single 5-minute scan
series, we collected 150 such images. We may plot the
intensity of each voxel in a simple x–y plot, with time
along the horizontal axis and image intensity along the
vertical axis. Plotting the time series of a few neighboring
voxels gives even more information. In voxels in visual
cortex, we see a periodic variation in the image intensity,
with seven peaks over the course of the 5-minute scan.
These peaks correspond to the times at which the sub-
ject was looking at visual stimuli (in this case, a movie
entitled “Winged Migration”). The troughs correspond to
times at which the subject was viewing a blank fixation
screen.
A number of important points can be made by look-
ing at these time series. First, notice that the time series
in neighboring voxels is not identical. Even though they
are only separated by 3 mm, the voxel in the top left
has a relatively small signal change and the voxel in the
middle has a very large signal change (on the order of
10%). This demonstrates that the BOLD fMRI signal is
not “all or nothing.” The amount of BOLD signal change
in a voxel is thought to be proportional to the summed
neuronal activity of all of the neurons in that voxel (on
the order of a million neurons if the voxel contains en-
tirely gray matter). The voxel in the upper left may have
fewer neurons, or it may have neurons that do not re-
spond as strongly to the visual stimulus as the voxel
in the center of the display. Next, note that (even for
the center voxel) the height of each peak varies. Be-
cause each peak represents presentation of a different
segment of the movie, the different peaks are a measure
of how strongly the neurons in the voxel responded to
that particular segment of the movie. Note that the third
peak is the highest in the center voxel, and in the other
voxels as well, suggesting that all of the neurons in this
neighborhood preferred the third movie segment.
Next, notice that the troughs of the signal are not
identical, even though the subject viewed the exact same
visual stimulus (a blank screen) in each trough. This sug-
gests that the variation in the signal intensity is not de-
termined solely by the neuronal activity in the voxel.
This can be seen more clearly by examining the time
series from voxels in the ventricle and adjacent white
matter. No periodic variation of the signal intensity re-
lated to visual stimulation is observed. However, the sig-
nal does have peaks and dips. These variations in signal
intensity have a number of sources, including respira-
tion, which introduces changes in tissue oxygenation;
the cardiac cycle, which can introduce changes in tissue
oxygenation; gross movement of the brain because of
pulsations or subject head movements; and scanner or
37
thermal noise. Effectively, this noise in the MR time se-
ries limits the ability to detect active brain regions. If the
fluctuations in the MR signal introduced by the stimulus
are much smaller than the noise in the MR signal, active
regions cannot be detected.
Visual examination of the MR time series is a crit-
ical step in performing quality control in fMRI experi-
ments. Hardware problems, such as hardware-generated
“spikes” in the MR signal, can be easily detected. How-
ever, visual inspection of the time series in each voxel
to determine whether it is active or not is impractical.
Therefore, quantitative methods are used to generate a
measure of the degree of activity in each voxel.
We next show how the generalized linear hypoth-
esis can be used to analyze fMRI time series (Fig. 3–6).
Each voxel is fit separately, termed univariate analysis.
The model requires the analyst to generate a series of
predictions about what might be happening in the time
series in each voxel. These are known as “predictors” or
“regressors” and each must have the same length as the
time series in each voxel.
The regressors are placed into two groups: one is
the “baseline” group, which can be considered as the
“null hypothesis”: what should the time series look like
in a voxel in which there is no neural activity related
to the stimulus. In Fig. 3–6A, a single baseline regressor
is shown, consisting of a flat line. The null hypothesis
in this case is that the brightness of the voxel should
not change over time, because there is change in voxel
intensity due to blood oxygenation changes. In a real
fMRI experiment, a number of other baseline regressors
would also be used. For instance, there are often slow
fluctuations in intensity due to respiration. This can be
modeled as slow changes in voxel intensity. Or, the sub-
ject’s head movement can be estimated. This means that
an inactive voxel might be predicted to have some in-
tensity fluctuations related to head motion.
The second set of regressors represent the “exper-
imental hypothesis.” These are the predictions about
what should happen in voxels in which there is neu-
ral activity related to the stimulus or task. In Fig. 3–6B,
a single experimental regressor is shown, representing
a sine wave of the same frequency of the visual stim-
ulus (on and off 8 times over the course of 5-minute
run). Voxels containing neurons responding to the vi-
sual stimulus would be predicted to get brighter and
darker as the visual stimulus turns on and off. In a real
fMRI experiment, we might have multiple experimental
regressors. If two different types of visual stimuli were
shown (such as faces and houses), we would have two
separate regressors, each representing the amplitude of
the response to each type of stimulus.
The next step is to fit all of the baseline regressors
to the voxel time series. For a sample ventricle voxel
time series, this is shown in Figs. 3–6C and D. The
flat baseline regressor is fit to the time series, and the
38 SECTION I TECHNIQUES

0 sec 300 sec 0 sec 300 sec

A B

Baseline error - Full error

Full error

Baseline error = 134 Full error = 123

C D

Baseline error - Full error

Full error

Baseline error = 377 Full error = 0.4

E F

Figure 3–6. (A) Baseline (null-hypothesis) regressor consisting of a flat line,

equivalent to constant intensity in the voxel over time. The y-axis is arbitrary, since the
waveform fits separately to each voxel. (B) Experimental regressor consisting of a
sinusoidal waveform. Black lines under x-axis show the time when each visual
stimulus is on screen. The voxel intensity is expected to increase when the stimulus is
on screen and decrease when it is not. (C) The black line shows the actual MR time
series from a voxel in a ventricle over the course of a 5-minute MR scan series. The
red line shows the best-fit baseline regressor from (A). The baseline error is the
difference between the black and red lines. (D) The red line shows the best-fit
combination of the baseline regressor in (A) and the experimental regressor in (B) (full
statistical model). The full error is the difference between the black and red lines. (E)
The black line shows the actual MR time series from a voxel in visual cortex over the
course of a 5-minute MR scan series. The red line shows the best-fit baseline
regressor from (A). The baseline error is the difference between the black and red
lines (large error). (F) The red line shows the best-fit combination of the baseline
regressor in (A) and the experimental regressor in (B) (full statistical model). There is
a good match between the lines, resulting in low error.

error (difference between best fit and actual data) is cal-
culated. Next, the combination of baseline regressors
and experimental regressors are fit to the voxel time
series and error is again calculated. This error will al-
ways be less, because fitting additional curves always
fits better. To determine if the experimental hypothesis
is correct, the key question is how much extra variance
is accounted for by the experimental regressors. To do
this, we calculate an F -ratio, the ratio of the explained
variance to unexplained variance. In this case, the
explained variance is the extra variance accounted for
by the experimental regressors (full error – baseline
 CHAPTER 3 FUNCTIONAL MRI FOR CEREBRAL LOCALIZATION
error) divided by the total error. In Figs. 3–6C and D,
this extra variance is very small, leading to a small F -
ratio (0.14). To calculate statistical significance, we can
examine a table that requires two values, the numerator
and denominator degrees of freedom. The numerator
degrees of freedom specifies how many experimental
regressors are used (as more regressors are used, more
variance is accounted for by chance) and the denomina-
tor degrees of freedom is approximately the number of
points in the MR time series (as this number increases,
power increases as well, meaning that it is important to
always collect as much fMRI data as possible).
The same process for an active voxel is shown in
Figs. 3–6E and F. The baseline error is large because the
stimulus-evoked fluctuations in the MR signal are not
well fit by the baseline straight-line function. In contrast,
the full model error is low, because the sinusoidal ex-
perimental regressor fits the MR intensity very well. This
results in a very large F -statistic.
This process of model fitting is repeated for every
voxel in the brain.
䉴 CREATING ACTIVATION MAPS
To construct an activation map, the range of F -values is
mapped to a color scale. In the Fig. 3–7, low F -values
are assigned a green color, and higher F -values are as-
signed yellow to red colors. Then, each voxel is colored
in according the F -value calculated for it. Figure 3–7B
shows the result of this process. Most of the brain is
green (meaning low F -rations) except for voxels in oc-
cipital lobe, which have yellow to red colors. In order
to make the binary judgement of which voxels are “ac-
tive” or not, a statistical threshold must be chosen. In this
example, an F -statistic of ten corresponds to a chance
probability of p < 10–7 . If there are 105 voxels in the
brain volume, this means the odds of a single voxel be-
ing active by chance is p < 0.01 using the conservative
Bonferroni correction for multiple comparisons. If we
display only voxels that have an F -value greater than
15, we see mainly voxels in the occipital lobe.
In order to be more sensitive to weak activations,
other processing steps are often performed before the
F -ratio is calculated for every voxel. An important pre-
processing step is motion correction. Gross head motion
can occur as the head settles into the foam padding of
the MR head coil, or the body gradually relaxes, over
the course of the scan session. By comparing each vol-
ume to the initial volume (or the mean of all volumes),
these slow motions can be corrected fairly well. Quick
motions, such as those that occur during a sneeze are
difficult to correct. Therefore, it is important to explain
to the patient the necessity of holding the head still and
attempt to restrict head motion with padding or commer-
cial products (such as foam beads) while still maintaining
patient comfort.
39
Another popular preprocessing step is spatial
smoothing. If each voxel contains noise from physio-
logical or scanner sources, averaging data across sev-
eral voxels can reduce the noise. The averaging is usu-
ally performed only within images acquired at the same
time (spatial smoothing) as opposed to images acquired
across time (temporal smoothing).
Both motion correction and spatial smoothing re-
duce the error in the full model fit, increasing the re-
sulting F -statistic and meaning that more voxels pass
the significance threshold. There is no single statistical
threshold that is correct for all patients and experiments.
It is important to examine fMRI data using a range of
statistical thresholds, or completely unthresholded, as in
the Fig. 3–7, in order to get a clear understanding of the
data.
fMRI activations can be considered as a virtual
“mountain range.” At a very high threshold, only the
very tops of the highest mountain peaks will be visible.
As the threshold is lowered, the peaks will enlarge
as the flanks of the tall mountains emerge above the
threshold, and the tops of smaller activation mountains
will also be visible.
This effect is shown in Fig. 3–7. At very high thresh-
olds, only voxels in early visual cortex (V1/V2) are ac-
tive; as the threshold is lower, voxels in other regions of
extrastriate cortex become active. In order to determine
whether activations are “real,” or represent false posi-
tives, it is important to examine the time series from the
voxels in question.
In this example, we focussed only on a simple two-
condition experiment, in which the subject alternately
views a moving visual stimulus and a blank fixation
screen. However, the exact same analysis procedures
can be used with much more complex designs. For
instance, we could alternate between viewing a visual
stimulus, hearing an auditory stimulus, and viewing a
blank screen (and hearing nothing). In this experiment,
the full model would contain two different predictor
functions, one for the visual stimulus and one for the
auditory stimulus. Activation maps could then be cre-
ated for both functions, either functions, or the contrast
between auditory and visual functions. This process can
be repeated indefinitely, for instance, ten different types
of visual stimuli. A predictor function is created for each
predictor functions, and the full model fit to each voxel’s
time series. Activation maps can be created to show vox-
els responding to any stimulus (full-F ) or any combina-
tion of individual stimuli.
䉴 VISUALIZATION OF ACTIVATION
ON THE CORTICAL SURFACE
Because the T2* EPI images used to create fMRI acti-
vation maps are relatively low resolution, they are not
40 SECTION I TECHNIQUES

A C
B

D E

F G

Figure 3–7. Visualization of active brain areas. (A) Original T2∗ brain image. (B) Brain
image with each voxel colored by the significance of the activation (calculated as in
Fig. 3–6). Green is low significance and red is high significance (F-values shown by
color scale). (C) Combination of (A) and (B): active voxels above a certain threshold
(F > 10) are colored; all other values are from original brain image. (D) Map created
with a more liberal threshold (F > 5). (E) Map created with a stricter threshold
(F > 15). (F) Thresholded voxels (F > 10) interpolated and overlaid on a high-resolution
T1 image from the same subject. (G) Enlargement of visual cortex region in (F).
Colored voxels are made transparent to allow visualization of anatomical structure
and functional activation. Notice correspondence between gray matter in T1 image
and significant (colored) voxels.
 CHAPTER 3 FUNCTIONAL MRI FOR CEREBRAL LOCALIZATION
ideal for clinical decision-making. The typical strategy is
to collect a high-resolution T1 anatomy in the same pa-
tient during the same scanning session. Then, the active
voxels calculated from the EPI images are overlaid on
this high-resolution T1 anatomy (see Fig. 3–8).
There are two problems inherent in this approach.
First, the subject may move between collection of the
T1 anatomy and the functional EPI images. By aligning
(motion correcting) the EPIs relative to the T1, this can
be compensated for. Second, EPI images are distorted
relative to the true brain anatomy pictured in T1 images
because of magnetic susceptibility and other artifacts.
This means that even without any patient motion, there
can be shifts of many millimeters between the EPI and
the T1.
Therefore, even if activations maps are viewed over-
laid on a T1, it is critical to also visualize them overlaid
on the original EPI to ascertain the true location of acti-
vation.
Additional processing steps are often performed to
make the T1 anatomy more visualization friendly. These
include skull stripping (removing the skull) and normal-
izing the brain so that it is in a standard space. This
means that regardless of the patient’s position in the
scanner, the brain will have a consistent alignment with a
template. If the template has labels attached, for instance
the location of Brodmann areas or anatomical structures,
these labels can be applied to the individual subject brain
to make identification of different anatomical structures
easier.
Another useful tool for visualizing MRI data are
three-dimensional (3D) models of the cortical surface.
As shown in the Fig. 3–8, computerized tools are avail-
able to automatically segment the MR image into con-
tours tracing the boundary between gray and white mat-
ter and the boundary between gray matter and CSF
(pial surface of the brain). After creation of these con-
tours, a surface tessellation is created consisting of a
mesh of thousands of triangles (middle panel and en-
largement). This tessellation is physically equivalent to
the cortical surface, which also consists of a single
sheet of tissue, folded to fit within the confines of the
skull.
When viewed in 2D slices, it can be difficult to iden-
tify specific sulci or gyri. When viewed as a whole, it is
easy to identify a specific sulcus, such as the superior
temporal sulcus, at any location along its anterior to pos-
terior extent. Most of the cortex is buried in the sulcal
folds. With a cortical surface model, the links between
nodes can be relaxed, allowing the surface to inflate like
a balloon. This reveals tissue previously hidden in the
sulci. fMRI activations can be visualized on the cortical
surface (with the same caveat as overlaying them on the
T1). This has the enormous advantage of allowing view-
ing of all active regions in the brain in a single glance,
instead of sorting through stacks of images.
41
The surface model can also be rotated to get dif-
ferent views of how it would look like in various clini-
cal situations, for instance when exposed during a cra-
niotomy.
Because of the many complex steps required to
analyze and visualize fMRI data, analysis is typically
conducted with specialized software packages. Many
of these packages, including AFNI15 and SPM,9 are
freely available and include sample datasets, providing
an easily accessible way to become familiar with fMRI
data.
䉴 DRAWING CLINICAL
INFERENCES FROM fMRI
STUDIES
In order to draw clinical inferences from fMRI studies, we
must make a number of inferences from our fMRI activa-
tion maps. The first inference is that active voxels reflect
activity in neurons located inside the voxel. How justified
is this assumption? There is good evidence from experi-
ments in animal models that changes in blood oxygena-
tion are tightly coupled to local neuronal activity.16,17
This coupling is made possible because of the dense
network of capillaries in cortex (see Fig. 3–3).18 Individ-
ual capillaries appear to open and close with metabolic
demand, producing a spatially localized fMRI BOLD sig-
nal. This is seen in fMRI studies, which image cortical
ocular dominance columns (on the order of ∼1 mm
in size) in human primary visual cortex. These maps
are reproducible within the same scanning session and
across different scanning sessions on different days.19 In
diseases in which the vasculature is impaired, such as
stroke or tumor, the spatial localization of the BOLD sig-
nal may also be impaired. In general, it is important to
obtain converging evidence for neural organization ob-
served with fMRI. An example of converging evidence
is shown in Fig. 3–9.
With high-resolution fMRI, it was shown that re-
gions of human superior temporal sulcus contains segre-
gated, patchy regions that respond to auditory stimula-
tion, such as speech, and visual stimulation, such as face
movements, or both. However, this conclusion is tem-
pered by the knowledge that fMRI is an indirect measure
of neural activity. Therefore, critical additional evidence
is provided by two additional methods, anatomical in-
formation from tracer injections in macaque monkeys;20
and direct recordings of neural responses using pene-
trating microelectrodes in monkeys.21 Both of these very
different techniques showed similar evidence of patchy
organization, suggesting that the organization observed
with fMRI is real, and not an artifact of differential vascu-
larization, experimental design, stimulus set, or analysis
method.
42 SECTION I TECHNIQUES

A B C

F
D E

G H

I J

Figure 3–8. Structural MRI analysis stream for functional MRI. (A) Midsagittal section
of T1-weighted anatomical scan. (B) Skull-stripped and intensity normalized brain. (C)
Automated tracing of cortical gray matter and CSF boundary (pink line) and cortical
gray matter and white matter boundary (yellow line). Enlargement of blue area shown
in (A). (D) Cortical surface model, rendered as surface. (E) Cortical surface model
rendered to show individual mesh elements. (F) Enlargement showing individual
triangular elements (face sets) of cortical surface mesh. (G) Functional activation
(thresholdF> 15) mapped to cortical surface as colored regions. (H) Lateral view of
cortical surface with activation. (I) Inflated cortical surface model (medial view). (J)
Inflated cortical surface model (lateral view).
 CHAPTER 3 FUNCTIONAL MRI FOR CEREBRAL LOCALIZATION 43

B
A C

Figure 3–9. Converging evidence on neural organization from functional MRI (fMRI)
and other methods. (A) Anatomical data set showing the superior temporal sulcus
(STS) of the macaque monkey. (Adapted from Seltzer B, Cola MG, Gutierrez C,
Massee M, Weldon C, Cusick CG. Overlapping and nonoverlapping cortical
projections to cortex of the superior temporal sulcus in the rhesus monkey: double
anterograde tracer studies. J Comp Neurol 1996;370(2):173–190.) Tracer injection of
anterograde tracer into macaque monkey auditory cortex and visual cortex. Blue
regions of STS receive input from auditory cortex. Orange regions receive input form
visual cortex. Note the patchy organization, with some regions receiving auditory
input, some regions receiving visual input. (B) fMRI data demonstrating patchy
organization of human STS, with interleaved regions responding to auditory
stimulation (blue), visual stimulation (orange), or both (green). (Adapted from
Beauchamp MS, Argall BD, Bodurka J, Duyn JH, Martin A. Unraveling multisensory
integration: patchy organization within human STS multisensory cortex. Nat Neurosci
2004;7(11):1190–1192.) (C) Single-unit recording from macaque STS showing uneven
patchy distribution of neurons responding to auditory stimulation (blue), visual
stimulation (orange), or both (green). (Adapted from Dahl CD, Logothetis NK, Kayser
C. Spatial organization of multisensory responses in temporal association cortex. J
Neurosci 2009;29(38):11924–11932.)

A second inference is that the region of activity
is necessary for the cognitive function being studied.
This problem is particularly acute in studies of language,
memory, and other complex cognitive functions. In a
typical cognitive study (such as picture naming) in which
subjects are presented with stimuli, make cognitive de-
cisions about them, and then produce a motor response,
activations would be expected in unisensory regions re-
sponding to the sensory stimulus, multisensory regions
that integrate across modalities, cognitive regions that
are important for decision-making, and response selec-
tion and motor regions that produce the behavioral out-
put. Even without an explicit behavioral task, (such as
viewing, but not naming, pictures) subjects may perform
language and memory operations when presented with
a stimulus (and without a task there is no measure of
subjects’ alertness or attention, or the amount of pro-
cessing performed on each stimulus). With or without
a task, fMRI experiments typically find activity in many
brain regions. Statistical criteria or a priori criterion are
applied to the fMRI data in order to classify a subset
of these active regions as being specifically involved in
particular elements of the cognitive task. For instance,
if the subjects’ task is to press a button in response
to an auditory tone, activations on the superior tem-
poral gyrus would be classified as due to the auditory
tone, whereas activations along the central sulcus would
be attributed to the motor response and associated so-
matosensory feedback.22 However, even in this simple
task, other brain activations are not so clear cut: sec-
ondary somatosensory cortex in the parietal operculum,
which might be active in response to somatosensory
feedback from the button press, is adjacent to auditory
association areas, which might also be active depending
on the nature of the auditory tone, with no clear bound-
ary between them. A further complicating factor is brain
reorganization or anatomical distortion due to injury or
tumor.23
44 SECTION I TECHNIQUES
Finally, BOLD fMRI depends on patient compliance.
For instance, normal volunteers will reliably tap their fin-
gers and keep their head still when instructed to, result-
ing in excellent maps of motor cortex. Patients who do
not understand instructions, or are unwilling to comply,
will produce poor quality or uninterpretable activation
maps. This is one reason that it is important to collect be-
havioral data from subjects while they are in the scanner.
For instance, if there is little activation in motor cortex
during a finger-tapping task, is it because motor cortex
is impaired? Or, because the subject was asleep in the
scanner and was not performing the task? If an objective
measure, such as the number of finger taps per minute,
is available, this can answer the question.
In summary, fMRI provides the most powerful tech-
nique currently available to measure human brain func-
tion. Rapid advances continue more than 20 years after
the basic principles were first demonstrated, suggesting
a bright future for the technique.
REFERENCES
1. Lauterbur PC. Image formation by induced local interac-
tions: examples employing nuclear magnetic resonance.
Nature 1973;242:190-191.
2. Lauterbur PC. Progress in n.m.r. zeugmatography imaging.
Philos Trans R Soc Lond B Biol Sci 1980;289(1037):483-
487.
3. Ogawa S, Lee TM. Magnetic resonance imaging of blood
vessels at high fields: in vivo and in vitro measurements
and image simulation. Magn Reson Med 1990;16(1):9-18.
4. Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic res-
onance imaging with contrast dependent on blood oxy-
genation. Proc Natl Acad Sci USA 1990;87(24):9868-9872.
5. Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-
sensitive contrast in magnetic resonance image of ro-
dent brain at high magnetic fields. Magn Reson Med
1990;14(1):68-78.
6. Bandettini PA, Wong EC, Hinks RS, Tikofsky RS, Hyde JS.
Time course EPI of human brain function during task acti-
vation. Magn Reson Med 1992;25(2):390-397.
7. Kwong KK, Belliveau JW, Chesler DA, et al. Dynamic
magnetic resonance imaging of human brain activity dur-
ing primary sensory stimulation. Proc Natl Acad Sci USA
1992;89(12):5675-5679.
8. Ogawa S, Tank DW, Menon R, et al. Intrinsic signal changes
accompanying sensory stimulation: functional brain map-
ping with magnetic resonance imaging. Proc Natl Acad Sci
USA 1992;89(13):5951-5955.
9. Friston KJ, Frith CD, Liddle PF, Frackowiak RS. Compar-
ing functional (PET) images: the assessment of significant
change. J Cereb Blood Flow Metab 1991;11(4):690-699.
10. Bandettini PA, Jesmanowicz A, Wong EC, Hyde JS. Process-
ing strategies for time-course data sets in functional MRI of
the human brain. Magn Reson Med 1993;30(2):161-173.
11. Worsley KJ, Friston KJ. Analysis of fMRI time-series
revisited–again. Neuroimage 1995;2(3):173-181.
12. Bowerman BL, O’Connell RT. Linear Statistical Models: An
Applied Approach. Boston: PWS-Kent Pub. Co., 1990, pp.
xvi-1024.
13. Neter J, Wasserman W, Kutner MH. Applied Linear Statis-
tical Models: Regression, Analysis of Variance, and Experi-
mental Designs. Homewood, IL: Irwin, 1990, pp. xvi-1181.
14. Rencher AC. Methods of Multivariate Analysis. New York:
Wiley, 1995.
15. Cox RW. AFNI: software for analysis and visualization
of functional magnetic resonance neuroimages. Comput
Biomed Res 1996;29:162-173.
16. Logothetis NK. The neural basis of the blood-oxygen-level-
dependent functional magnetic resonance imaging signal.
Philos Trans R Soc Lond B Biol Sci 2002;357(1424):1003-
1037.
17. Lee JH, Durand R, Gradinaru V, et al. Global and local fMRI
signals driven by neurons defined optogenetically by type
and wiring. Nature 2010;465(7299):788-792.
18. Harrison RV, Harel N, Panesar J, Mount RJ. Blood capillary
distribution correlates with hemodynamic-based functional
imaging in cerebral cortex. Cereb Cortex 2002;12(3):225-
233.
19. Cheng K, Waggoner RA, Tanaka K. Human ocular domi-
nance columns as revealed by high-field functional mag-
netic resonance imaging. Neuron 2001;32(2):359-374.
20. Seltzer B, Cola MG, Gutierrez C, Massee M, Weldon C, Cu-
sick CG. Overlapping and nonoverlapping cortical projec-
tions to cortex of the superior temporal sulcus in the rhesus
monkey: double anterograde tracer studies. J Comp Neurol
1996;370(2):173-190.
21. Dahl CD, Logothetis NK, Kayser C. Spatial organization of
multisensory responses in temporal association cortex. J
Neurosci 2009;29(38):11924-11932.
22. Beauchamp MS, Lee KE, Argall BD, Martin A. Integration of
auditory and visual information about objects in superior
temporal sulcus. Neuron 2004;41(5):809-823.
23. Ulmer JL, Hacein-Bey L, Mathews VP, et al. Lesion-induced
pseudo-dominance at functional magnetic resonance imag-
ing: implications for preoperative assessments. Neuro-
surgery 2004;55(3):569-579; discussion 580-581.
 Chapter 4
Functional MRI: Application to
Clinical Practice in Surgical Planning
and Intraoperative Guidance
Michael Schulder 1 and Robin Wellington 2
1
Department of Neurosurgery, North Shore-Long Island Jewish Health System, Manhasset, New York
2
Department of Psychology, St. John’s University, Flushing, New York
䉴 INTRODUCTION
Since functional magnetic resonance imaging (fMRI) was
described in 1991 by Belliveau et al.,1 this noninvasive
method of mapping the brain has generated a veritable
industry of research and clinical applications. A PubMed
search for fMRI yields many thousands of references. The
majority of this work has been done by cognitive neu-
roscientists and psychologists using fMRI to learn more
about how memories, emotions, and behaviors are pro-
cessed and generated by the brain.2−5 It has also become
a valuable method of assessing patients with movement
disorders, especially Parkinson’s disease.6,7
Neurosurgeons’ interest in fMRI has been mainly in
its use for surgical planning and intraoperative guidance,
which will be the subject of this chapter.
䉴 TECHNIQUE OF fMRI
Clinicians seeking to use fMRI must remember that
the activation maps generated by this modality are not
“images” per se, but rather statistical maps. These maps
are generated by statistical analyses that compare “rest”
and “activity” states. Practically speaking, patient coop-
eration is needed to acquire the data for these analyses.
The subjects need to perform the appropriate task and
to lie still for what can be a relatively prolonged time
in the closed MRI bore.8 It may be possible to give sen-
sory and visual stimuli to anesthetized patients but this
would not work for other areas of functionally important
cortex.
Since described by Ogawa, blood oxygen level de-
pendent (BOLD) fMRI has been most commonly ac-
quired because of its completely noninvasive nature.9
Most often, fMRI data are processed after acquisition in
a laboratory separate from the site of data acquisition.
45
This step includes motion correction, statistical analysis,
and registration of the analyzed data to anatomical im-
ages. The aim is to identify voxels with activation levels
that are (statistically) significant in activity versus rest
states. The ultimate appearance of the maps will de-
pend to a large part on statistical thresholding. Clinicians
who plan on using the data must appreciate this, and
should be prepared to take an active role in the analysis.
For instance, they may accept a significance level greater
than 0.05 if the result is a useful visual presentation of
a particular functional volume; conversely, the clinician
may insist on a lower threshold in order to eliminate
irrelevant areas of activation.
fMRI can be viewed for surgical planning as a stand-
alone image, on hard copy or on a picture archiving
and communication system. This is adequate for surgical
planning, but ideally for intraoperative use, fMRI should
be registered for neuronavigation (see later).10
䉴 PARADIGMS IN fMRI
When requesting an fMRI study, the clinician should
understand the tasks, or paradigms, that patients per-
form for data acquisition. A “robust” paradigm is one
that reliably supplies an accurate activation map that is
easy to interpret. The tasks are relatively simple and easy
for the patient to accomplish. Thus, mapping of the pri-
mary motor cortex via finger tapping, or of the visual
cortex by presentation of patterns, usually provide large
areas of activation at a high significance threshold.11,12
Light touch sensation can be used to identify primary
sensory cortex, although this area’s location can be in-
ferred from that of the motor cortex immediately across
the central sulcus.13,14 It is somewhat intuitive that these
functions would and do yield the most robust fMRI
results. Moving beyond these, the complexity of data
46 SECTION I TECHNIQUES

A B

Figure 4–1. Diffusion-weighted images of language functional magnetic resonance

imaging in a 42-year-old woman with a right parietal high-grade glioma. (A) Silent
word generation to map expressive language area in left hemisphere. (B) Text
comprehension to identify receptive language showing activation in both
hemispheres.

acquisition and the reliability of the data become increas-
ingly questionable.
A specific and sensitive means of noninvasively
mapping language areas is highly desirable. Paradigms
for assessment of expressive and receptive language
continue to be modified.15,16 fMRI is a reliable means
of identifying the hemisphere dominant for language, at
least in right-handed patients who clearly have left-sided
language activation (Fig. 4–1).17,18 Still, any question at
all regarding dominance in patients whose impending
surgery may put language function at risk should be
evaluated with a Wada test (see Chapter 6) or have their
surgery performed with an awake language mapping.19
The use of fMRI to identify areas of memory, cogni-
tive function, emotion, and so forth remains primarily in
the domain of neuroscientific investigation.20,21 If preop-
erative patients will tolerate a prolonged fMRI acquisi-
tion session, it may be worthwhile to attempt imaging of
these functions, but surgical planning decisions cannot
be made on their basis at this stage of fMRI understand-
ing (see Chapter 18).
sections of lesions that on anatomical images appear to
be in or near eloquent areas may be changed to less
invasive treatments. Conversely, surgery thought to be
prohibitively dangerous can be planned with reasonable
assurance if functional areas are seen with fMRI to be at
a safe distance from the lesion. Stereotactic approaches
likewise can be planned to avoid eloquent areas (Fig.
4–2). While fMRI has played an important role in defin-
ing targets for surgical treatment of movement disorders
or psychiatric disorders,22,23 these data do not have the
spatial precision required for targeting based on the ac-
tivation itself. As noted above, if language areas are at
risk in surgery, then awake mapping should be done to
avoid new deficits.
If fMRI is to be used for surgical decision-making,
the surgeon should have at least a basic understanding
of acquisition and analysis. The surgeon should be in-
volved with image interpretation and should confirm that
the visible activation maps are based on valid statistical
analysis.

SURGICAL NAVIGATION
䉴 NEUROSURGICAL APPLICATIONS
OF fMRI To fully take advantage of fMRI as an adjunct to intracra-
nial surgery, the data should be available in the operating
SURGICAL PLANNING room in an interactive fashion. Studies have confirmed
the possibility of registering fMRI on a surgical naviga-
fMRI data are most often used in neurosurgical planning tion platform, and by so doing confirming the stereotac-
as a means of assessing the likely risks of surgery. Re- tic accuracy of the data. Schulder et al. registered motor
 CHAPTER 4 FUNCTIONAL MRI 47

Figure 4–2. Motor functional magnetic resonance imaging (fMRI) in a 46-year-old

woman with a right frontal ganglioglioma. Activation was posterior to the tumor,
allowing for complete resection. Surgery was done with intraoperative MRI guidance,
and based on the fMRI, an anterior to posterior approach was used to reach the
tumor.

fMRI from a finger tapping paradigm and compared the
predicted center of activation with the location of hand
motion by bipolar cortical stimulation or phase reversal
of somatosensory evoked potentials.10
Other studies have compared the accuracy of fMRI
to positron emission tomography24,25 and magnetic
source imaging26 and shown a high concordance be-
tween the various methods. These reports have estab-
lished that fMRI, if properly registered to a stereotactic
anatomical image, can be relied upon to indicate the
location of eloquent cortex. Like all navigation based
on preoperative datasets, however, the surgeon must
remain alert to the reality of brain shift. Loss of cere-
brospinal fluid after dural opening, and lesion removal it-
self, may quickly render navigation inaccurate.27,28 fMRI
can be registered to intraoperative MRI (iMRI) for naviga-
tional use (Fig. 4–3). Anatomical images can be updated
with iMRI, but, of course, this in itself will not compen-
sate for brain shift affecting fMRI-based navigation.
BRAIN TUMORS
The goal of brain tumor surgery is to maximize resec-
tion while preserving function. fMRI can play a vital
role toward this end. This is most obvious for patients
with gliomas. These intraaxial tumors may infiltrate ar-
eas of eloquent cortex even while function is preserved,
especially in patients with low-grade tumors.29 fMRI
may steer the surgeon away from resection as a result
48 SECTION I TECHNIQUES

Figure 4–3. A 64-year-old woman with recurrent parasagittal meningiomas. (A)

Image fusion of preoperative motor functional magnetic resonance imaging (fMRI)
and anatomical contrast-enhanced anatomical image acquired in the operating room
with intaroperative MRI. (B) Surgical navigation with registered fMRI. (continued)

(Fig. 4–4). At the same time, by confirming that the tu-
mor is separate from critical function, fMRI can provide
the basis for a planned gross resection (Fig. 4–2). Hall
and colleagues’ use of fMRI allowed for complete resec-
tion, with minimal morbidity, in two-thirds of patients
with tumors in or near the motor cortex.30
fMRI need not be restricted to use in patients with
gliomas. Metastatic tumors displace brain but may often
be adjacent or deep to eloquent cortex, making fMRI
a useful adjunct for surgical planning and navigation.
Likewise, meningiomas are extra-axial tumors, and as
long as the surgeon respects the border between tumor
capsule and brain, no deficit will occur. However, in
practice, even histologically benign meningiomas may
invade the adjacent pia, and knowing the relationship
between tumor and eloquent brain will aid in surgical
planning (Fig. 4–5).
ARTERIOVENOUS MALFORMATIONS
fMRI in patients with arteriovenous malformations
(AVMs) poses a special challenge. The BOLD method is
based on minute differences in blood flow between task
and rest states. Changes in regional perfusion because of
the AVM can, therefore, interfere with fMRI acquisition.31
EPILEPSY
Resection of epileptic foci in the temporal lobe and else-
where may involve removal of functionally viable brain.
Surgery in the dominant temporal lobe in particular
has been studied in patients who underwent resections
for medically refractory seizures.32 fMRI may be useful
in certain patients as a way of establishing language
 CHAPTER 4 FUNCTIONAL MRI 49

Figure 4–3. (Continued)

Figure 4–4. Motor functional magnetic resonance Figure 4–5. Motor functional magnetic resonance
imaging in a 49-year-old woman with a low-grade imaging in a 25-year-old woman with a left
glioma, seen as gyral fullness just anterior to the main parasagittal meningiomas, seen here to be just
site of activation in the right frontal lobe. anteromedial to the left primary motor cortex.
50 SECTION I TECHNIQUES
dominance in the hemisphere contralateral to the
planned resection, but as noted, is not adequate, at
present, for precise spatial localization of the main areas
controlling expressive and receptive speech. If language
fMRI is acquired in such patients, it should be supple-
mented with intraoperative cortical mapping
STEREOTACTIC RADIOSURGERY
fMRI offers the possibility of more precisely defining
the safe limits of stereotactic radiosurgery (SRS) when
applied to targets in or near cerebral cortex.33 Given
the location of many SRS targets that may be within
the cerebellar hemispheres or elsewhere in the poste-
rior fossa, fMRI of brainstem nuclei may be of use in
certain patients.34 Identification of “eloquent” areas can
be used to direct excess dose toward less critical lo-
cations. If routinely used, fMRI for SRS could provide
useful information about the tolerance of functionally
important brain to various dose levels of irradiation given
in single or several sessions. These limits are fairly well
understood for most cranial nerves, but we are still in
the early stages of understanding the dose limits of SRS
for specific areas of brain function.35,36 Figure 4–6 is a
radiosurgical dose plan in a 64-year-old woman with a
Figure 4–6. Radiosurgical dose plan. The
prescription dose is delivered to the meningiomas
target (yellow). Functional magnetic resonance
imaging activation of the left primary motor cortex is
shaded blue, and isodose lines indicate that a
relatively small dose of radiation is received by that
area.
recurrent parasagittal meningiomas, showing how fMRI
can be used to identify the motor cortex and measure
the amount of radiation it receives.
䉴 PITFALLS OF fMRI
The accuracy and reliability of fMRI may be adversely
affected by various factors. Among these are patient
movement, inadequate cooperation in task performance
and alternating rest cycles, and statistical manipulation
(Fig. 4–7). Increasing or decreasing the threshold of sta-
tistical significance may result in under- or overestimat-
ing the volume of functional cortex, respectively. Like-
wise, the presence of adjacent tumor mass or edema may
decrease the BOLD signal changes, presumably because
of impaired regional blood flow.37 As with any other pre-
operative dataset, brain shift will invalidate the spatial
accuracy of fMRI, making reliance on surgical naviga-
tion potentially hazardous.27 Of course, as a task-based
method, fMRI cannot be done if the patient has a rele-
vant deficit (e.g., aphasia not allowing for language map-
ping). This does not necessarily mean that the function
is irretrievably lost, so surgical plans should not rely on
the absence of activation in such patients.
fMRI is a method for identifying areas of functionally
important gray matter. Lack of attention to the relevant
white matter tracts can lead to new neurological deficits
despite the most careful imaging and avoidance of cortex
or nuclei. Use of diffusion tensor imaging tractography,
possibly in conjunction with subcortical mapping, can
help to avoid such complications.38,39
There is often a certain circularity of reasoning ap-
plied to fMRI. For instance, motor area activation looks
accurate “because that’s where the motor cortex is sup-
posed to be.” The surgeon should avoid being caught
up in this dubious logic and if any question remains re-
garding the safety of relying on fMRI alone, the surgeon
should be prepared to perform intraoperative cortical
mapping.40,41
䉴 FUTURE DIRECTIONS
fMRI has not quite fulfilled its promise as a routine clin-
ical tool. Acquisition and analysis still requires some
degree of specialized expertise. This should change
with the availability of standardized paradigms and
systems that record patient activity, in conjunction
with services that will perform the statistical analysis
(http://www.neurognostics.com/). The goal of such sys-
tems is to make fMRI as routine as anatomical imaging.
One obstacle to further acceptance of fMRI is the
delay between scanning and the availability of the acti-
vation maps. For patients who live some distance from
imaging facilities, and/or are having surgery too soon to
 CHAPTER 4 FUNCTIONAL MRI 51

Figure 4–7. Attempted motor functional magnetic resonance imaging, registered for
surgical navigation, in a 56-year-old man with a single metastatic tumor adjacent to
the right primary motor cortex. Scattered random areas of activation resulted from
suboptimal patient task performance.

allow for imaging and data analysis, fMRI is impractical.
The ability to acquire valid real-time fMRI will avoid this
problem. Preliminary results indicate that data so gener-
ated are as accurate as those done with “conventional”
methods.42,43
It may be possible to bring fMRI into the operat-
ing room. Despite concerns regarding chemical shifts
and other sources of decreased signal, the feasibility of
acquiring fMRI even with a low-field strength (0.15 T)
intraoperative magnet has been demonstrated.44 Other
studies have described intraoperative fMRI with high-
field strength magnets45,46 The main obstacle to prac-
tical implementation of this technique is the need for
activity and rest states—that is, as noted above, for most
paradigms, the patient has to be awake and cooperative
for the acquisition (assuming that true real-time analy-
sis will be a reality, another requirement for fMRI in the
operating room). Exceptions to this might be sensory or
visual stimulation, which can be presented to patients
under anesthesia. Benefits of intraoperative fMRI could
include compensation for brain shift and avoidance of
prolonged preoperative data acquisitions.47,48 Still, in-
vestigators pursuing this option will have to prove a clear
advantage to it over other means of updating informa-
tion during surgery.
With fMRI, as with other technological advances in
neurosurgery, the question arises: how much is really
necessary? And how much does it benefit the patient
in terms of improved outcome or at least greater ease,
lower cost, and so forth? Data that definitively establish
fMRI, even for robust paradigms, as superior to cortical
stimulation are hard to come by. But we are still relatively
52 SECTION I TECHNIQUES
early in the fMRI era. As the speed of data processing im-
proves and we get closer to reliable real-time fMRI that
can be acquired in nonspecialized settings, this technol-
ogy truly will move out of its purely scientific phase and
become a routine clinical tool in neurosurgery.
䉴 CONCLUSIONS
Ongoing refinements and acceptance of fMRI will con-
tinue to make it a regular part of 21st century intracranial
neurosurgery. In the near future, it will be as routine as
acquiring an anatomical study. Noninvasive functional
mapping of the brain with fMRI will be seen as an indis-
pensable neurosurgical tool.
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for neuropsychology from functional MRI in patients with
epilepsy. Epilepsy Behav 2004;5(Suppl 1):S81-S89.
16. Harrington GS, Buonocore MH, Farias ST. Intrasubject re-
producibility of functional MR imaging activation in lan-
guage tasks. AJNR Am J Neuroradiol 2006;27(4):938-944.
17. Balsamo LM, Gaillard WD. The utility of functional mag-
netic resonance imaging in epilepsy and language. Curr
Neurol Neurosci Rep 2002;2(2):142-149.
18. Sabbah P, Chassoux F, Leveque C, et al. Functional MR
imaging in assessment of language dominance in epileptic
patients. Neuroimage 2003;18(2):460-467.
19. Danks RA, Rogers M, Aglio LS, Gugino LD, Black PM. Pa-
tient tolerance of craniotomy performed with the patient
under local anesthesia and monitored conscious sedation.
Neurosurgery 1998;42(1):28-34; discussion 34-36.
20. Meyer M, Zysset S, von Cramon DY, Alter K. Distinct fMRI
responses to laughter, speech, and sounds along the hu-
man peri-sylvian cortex. Brain Res 2005;24(2):291-306.
21. Powell HW, Duncan JS. Functional magnetic resonance
imaging for assessment of language and memory in clinical
practice. Curr Opin Neurol 2005;18(2):161-166.
22. Keightley ML, Winocur G, Graham SJ, Mayberg HS,
Hevenor SJ, Grady CL. An fMRI study investigating cog-
nitive modulation of brain regions associated with emo-
tional processing of visual stimuli. Neuropsychologia
2003;41(5):585-596.
23. Zrinzo L. The role of imaging in the surgical treat-
ment of movement disorders. Neuroimaging Clin N Am
2010;20(1):125-140.
24. Baumann SB, Noll DC, Kondziolka DS, et al. Comparison of
functional magnetic resonance imaging with positron emis-
sion tomography and magnetoencephalography to iden-
tify the motor cortex in a patient with an arteriovenous
malformation. J Image Guid Surg 1995;1(4):191-197.
25. Joliot M, Papathanassiou D, Mellet E, et al. FMRI and PET
of self-paced finger movement: comparison of intersubject
stereotaxic averaged data. Neuroimage 1999;10(4):430-447.
26. McDonald JD, Chong BW, Lewine JD, et al. Integration of
preoperative and intraoperative functional brain mapping
in a frameless stereotactic environment for lesions near elo-
quent cortex. Technical note. J Neurosurg 1999;90(3):591-
598.
27. Dorward N, Alberti O, Velani B, et al. Postimaging
brain distortion: magnitude, correlates, and impact on
neuronavigation. J Neurosurg 1998;88(4):656-662.
28. Nabavi A, Black PM, Gering DT, et al. Serial intraoperative
magnetic resonance imaging of brain shift. Neurosurgery
2001;48(4):787-797; discussion 97-98.
29. Atlas S, Howard RI, Maldjian J, et al. Functional MRI of re-
gional brain activity in patients with intracerebral gliomas:
findings and implications for clinical management. Neuro-
surgery 1996;38:329-338.
30. Hall WA, Liu H, Truwit CL. Functional magnetic resonance
imaging-guided resection of low-grade gliomas. Surg Neu-
rol 2005;64(1):20-27; discussion 27.

31. Maldjian J, Atlas SW, Howard RS II, et al. Functional
magnetic resonance imaging of regional brain activity
in patients with intracerebral arteriovenous malforma-
tions before surgical or endovascular therapy. J Neurosurg
1996;84:477-483.
32. Ojemann G, Ojemann J, Lettich E, Berger M. Cortical lan-
guage localization in left, dominant hemisphere. An elec-
trical stimulation mapping investigation in 117 patients.
J Neurosurg 1989;71(3):316-326.
33. Schulder M, Vega J, Narra V, et al. Functional magnetic reso-
nance imaging and radiosurgical dose planning. Stereotact
Funct Neurosurg 1999;73(1-4):38-44.
34. Komisaruk BR, Mosier KM, Liu WC, et al. Functional lo-
calization of brainstem and cervical spinal cord nuclei in
humans with fMRI. Am J Neuroradiol 2002;23(4):609-617.
35. Maruyama K, Kamada K, Shin M, et al. Optic radia-
tion tractography integrated into simulated treatment plan-
ning for Gamma Knife surgery. J Neurosurg 2007;107(4):
721-726.
36. Aoyama H, Kamada K, Shirato H, et al. Integration of func-
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ment planning using magnetoencephalography and mag-
netic resonance axonography. Int J Radiat Oncol Biol Phys
2004;58(4):1177-1183.
37. Liu WC, Feldman SC, Schulder M, et al. The effect of tu-
mour type and distance on activation in the motor cortex.
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38. Nimsky C, Ganslandt O, Fahlbusch R. Implementation
of fiber tract navigation. Neurosurgery 2006;58(4 Suppl
2):ONS292-ONS303; discussion ONS303-ONS304.
39. Berman JI, Berger MS, Chung SW, Nagarajan SS, Henry RG.
Accuracy of diffusion tensor magnetic resonance imaging
tractography assessed using intraoperative subcortical stim-
ulation mapping and magnetic source imaging. J Neurosurg
2007;107(3):488-494.
CHAPTER 4 FUNCTIONAL MRI 53
40. Duffau H, Lopes M, Arthuis F, et al. Contribution of intra-
operative electrical stimulations in surgery of low grade
gliomas: a comparative study between two series with-
out (1985–96) and with (1996–2003) functional mapping
in the same institution. J Neurol Neurosurg Psychiatry
2005;76(6):845-851.
41. Krishnan R, Raabe A, Hattingen E, et al. Functional
magnetic resonance imaging-integrated neuronavigation:
correlation between lesion-to-motor cortex distance and
outcome. Neurosurgery 2004;55(4):904-914; discusssion
914-915.
42. Feigl GC, Safavi-Abbasi S, Gharabaghi A, et al. Real-time
3T fMRI data of brain tumour patients for intra-operative
localization of primary motor areas. Eur J Surg Oncol
2008;34(6):708-715.
43. Kesavadas C, Thomas B, Sujesh S, et al. Real-time func-
tional MR imaging (fMRI) for presurgical evaluation of pae-
diatric epilepsy. Pediatr Radiol 2007;37(10):964-974.
44. Azmi H, Biswal B, Salas S, Schulder M. Functional
imaging in a low-field, mobile intraoperative magnetic
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2007;60(1):143-148; discussion 148-149.
45. Hall WA, Liu H, Martin AJ, Pozza CH, Maxwell RE,
Truwit CL. Safety, efficacy, and functionality of high-
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cussion 641-642.
46. Nimsky C, Ganslandt O, von Keller B, Fahlbusch R. Intraop-
erative high-field MRI: anatomical and functional imaging.
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47. Nabavi A, Gering DT, Kacher DF, et al. Surgical navigation
in the open MRI. Acta Neurochir Suppl 2003;85:121-125.
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nance imaging in a low-field intraoperative scanner. Stereo-
tact Funct Neurosurg 2003;80(1-4):125-131.
This page intentionally left blank
 Chapter 5
Neuropsychological Testing:
Understanding Brain–behavior
Relationships
Mario F. Dulay1 , Corwin Boake 2 , Daniel Yoshor 3 , and Harvey S. Levin4
1
Department of Neurosurgery, The Methodist Hospital Neurological Institute,
Houston, Texas
2
Department of Physical Medicine and Rehabilitation, The University of Texas
Medical School, Houston, Texas
3
Department of Neurosurgery, Baylor College of Medicine, and Neuroscience Center, St. Luke’s
Episcopal Hospital, Houston, Texas
4
Departments of Physical Medicine and Rehabilitation, Pediatrics, Neurosurgery and Neurology,
Baylor College of Medicine, Houston, Texas

䉴 INTRODUCTION AND neuropsychological tests are often designed or validated

HISTORICAL PERSPECTIVE
Neuropsychology is a field of science focused on
the study of the neuroanatomical correlates of overt
cognitive, behavioral, or emotional processes.1 Neu-
ropsychological tests are noninvasive, psychometrically
validated measures of cognition. Subspecialties that use
neuropsychological tests to understand brain–behavior
relationships include cognitive neuroscience, experi-
mental neuropsychology, cognitive neuropsychology,
psycholinguistics, neuropsychiatry, and clinical neu-
ropsychology. Clinical neuropsychology applies the
knowledge of human brain–behavior relationships to
clinical problems thereby bridging the gap between the
laboratory and the clinic.
Historically, a primary goal of a neuropsychological
evaluation was to quantify behavior in order to local-
ize structural lesions.2 Today, neuropsychologists are no
longer asked to localize brain lesions based on testing
given that structural imaging techniques such as comput-
erized tomography (CT) or magnetic resonance imaging
(MRI) are effective at identifying neuroanatomical ab-
normalities. Though neuropsychological assessment is
not generally used for localizing brain lesions, validity of
neuropsychological testing techniques is often based on
whether or not there is concordance of test results with
focal abnormalities or neurologic dysfunction.3,4 That is,
to quantify the impact of general or focal brain damage
on neurobehavioral functioning.
There are many types of referral questions that can
be addressed in different medical settings with a neu-
ropsychological assessment including (1) what are the
cognitive profiles associated with different disease states,
(2) what is the severity of a specific disease, (3) what is
the baseline cognitive status of a patient with an acute
brain injury and what is the prognosis for cognitive re-
covery compared to how others have recovered after
injury, (4) what is the functional impact of brain damage
on academic or vocational functioning, (5) what spe-
cific recommendations can be made for treatment of
identified cognitive deficits, and (6) how can we match
patients’ cognitive limitations to rehabilitation services?
When addressing these questions, clinical neuropsychol-
ogists are less concerned with localization and more in-
terested in determining diagnosis, prognosis, and treat-
ment planning.
However, there are medical settings where refer-
ral questions directly relate to understanding brain–
behavior relationships, for example in settings when
the goal is the neurosurgical treatment of medically in-
tractable epilepsy or a brain tumor. In these settings, re-
ferral questions might include (1) what is the functional
status of an area where a lesion is identified by CT or
MRI, (2) what is the functional status of an area identified

55
56 SECTION I TECHNIQUES
by electroencephalography (EEG) as a seizure focus in
the absence of an MRI identified lesion, (3) is there a pat-
tern of cognitive test performance indicating lateralized
hemispheric dysfunction that is consistent with EEG and
imaging findings, (4) what is the risk of cognitive impair-
ment associated with removal of neural tissue, and (5)
what is the longitudinal impact of an identified growing
or changing focal lesion on behavior? To address these
questions, it is assumed that distinct cognitive abilities
either map on to specific brain regions or represent an
interaction of specific brain regions.
䉴 HISTORY
Relationships of brain pathology to cognitive and par-
ticularly language disorders have been discussed since
the ancient medical literature.5 A critical insight into
the relationship between cognitive disorders and brain
pathology was prompted by case reports by Broca
and others during the late 1800s, demonstrating that
speech production was impaired selectively by stroke
and trauma affecting the frontal region of the left cere-
bral hemisphere.6 Following this discovery, numerous
cognitive disorders associated with focal brain pathology
were described. For example, the major syndromes of
aphasia were identified more than a century ago, mostly
on the basis of case reports of stroke or brain trauma
in which damage could be visualized during surgery
or postmortem. Advances in neurosurgery during the
early 1900s created opportunities for the study of be-
havioral consequences of penetrating brain injuries and
ablative surgery. This research clarified the sensory and
cognitive functions of the temporal, parietal, and occip-
ital lobes. The paradoxical results of pathology in the
prefrontal area, producing minimal change on conven-
tional cognitive testing, were also demonstrated.7 During
the later 1900s, rapid progress in neuropsychology was
due to combined advances in neuroimaging and cog-
nitive assessment. Cognitive tests were developed with
greater sensitivity and specificity to selective cognitive
disorders (e.g., amnesia, visual neglect). For example,
based on observations that patients with dysfunction of
the right cerebral hemisphere had relatively more dif-
ficulty performing visual perception tasks, studies us-
ing refined tests to compare patients with different le-
sion locations discovered that abnormality in the right
temporal–parietal area produced a selective impairment
in perceiving spatial relationships.8 The measurement
of brain abnormalities was revolutionized by comput-
erized structural neuroimaging. A major consequence
of this technology was to facilitate the investigation of
cognitive disorders associated with diffuse brain pathol-
ogy. For example, patterns of cerebral atrophy in pa-
tients with degenerative dementia were compared quan-
titatively to impairments in memory. In addition, de-
tailed neuroimaging findings made it possible to study
the cognitive effects of focal lesions affecting subcorti-
cal structures (e.g., amnesia resulting from fornix and
thalamic lesions). Until recently, knowledge of human
brain–behavior relationships was based largely on re-
search with neurologic patients. The cognitive functions
of a given brain structure could be studied indirectly, to
the extent that neurologic disorders affecting that struc-
ture led to changes in the function of interest. Interpre-
tation of these findings was complicated by many con-
founding influences, such as recovery of function caused
by compensatory strategies or functional brain reorgani-
zation. The advent of functional neuroimaging has re-
moved this major barrier by allowing direct observation
of cerebral activation while engaged in cognitive tasks.
䉴 UNDERLYING PRINCIPLES
PHILOSOPHICAL CONSIDERATIONS IN
CLINICAL MAPPING
A major assumption underlying clinical mapping is that
there are quantifiable behaviors that are associated with
brain neuroanatomy and physiology. Different perspec-
tives exist in neuropsychology regarding the extent to
which there are localized functions in the brain. Tradi-
tional localizationists assume that several distinct brain
regions are involved in the processing of specific be-
havioral functions and interact through associative path-
ways. This is supported by data that show that focal le-
sions lead to a predictable pattern of motor, emotional,
and cognitive impairments. This perspective is similar
to the concept of neurologic specificity and anatomic
modularity.9,10 Traditional generalists assume parallel
and/or hierarchical processing of cognitions/behaviors
that do not solely map onto one brain region and do not
work in isolation, but rather are produced as a result of
an interaction of the parts or of the whole unit.11 The
idea of equipotentiality, or the proposal that a different
region will resume functions of a damaged or excised
region of the brain, provides support for the generalist
approach and is supported by research that shows that
larger lesions lead to greater impairment.12 Traditional
connectionists assume that there are both specialized re-
gions of functioning in the brain that are interrupted with
focal damage, as well as areas away from the damaged
region that are interrupted due to a disruption of neural
interconnectivity.13,14
Which approach would we support? This is an em-
pirical question open to debate. However, while the
basic orientation in some subspecialties within neu-
ropsychology is to assume localization of function, a
strict localization of function view is unsupported. That
is, behaviors, emotions, and cognitions do not consis-
tently map on to specific brain regions and there is
 CHAPTER 5 NEUROPSYCHOLOGICAL TESTING 57

increasing evidence for the role of distributed neural net-

works mediating complex cognitive functions. Even so, X
neuropsychological tests are often developed and val-
idated to measure specific cognitive constructs that are Y
tied to specific brain processes and regions. That is, there Association
are robust associations that have been found when using
neuropsychological tests to lateralize and localize cogni-
tive functions when focal damage is known to exist (dis-
cussed later in this chapter). An important point to note
is that an identified lesion may not result in complete
loss of functions, but rather a degree of loss.15 Thus, A Task A Task B

the prominent sign of brain impairment may be the de-

gree of inefficiency of processing instead of total loss of
functioning. In some patient populations, neuropsycho- X
logical tests have data supporting their sensitivity to focal
brain dysfunction, for example, in patients with com-
plex partial seizures. In other patient populations such Y Dissociation
as traumatic brain injury due to closed head trauma, the
effects of multifocal or diffuse neuropathology often pre-
dominate and assessment of cognitive deficit associated
with a focal lesion is of less importance.
B Task A Task B

THE LESION METHOD,

ASSOCIATIONS, AND DISSOCIATIONS
Y
The efficacy of neuropsychological assessment in clin-
ical mapping to quantify the functional status of the
Double dissociation
brain is its use in conjunction with structural imaging X

techniques. The lesion method is an approach to under-

standing brain–behavior relationships based on the de-
gree to which brain damage or selective removal of neu-
ral tissue impairs some cognitive abilities while sparing
other abilities. The approach is guided by the assump- C Task A Task B

tion that if a specific brain region contributes to ade-
quate performance on a neuropsychological task, then
structural damage to that region should lead to func-
tional impairment.7 The approach also assumes that cog-
nitive domains can be damaged separately from each
other. The material or domain specificity hypothesis, a
concept routinely discussed in the context of memory,
refers to the belief that specific tests and procedures can
be constructed that are sensitive to impairments in spe-
cific regions of the brain.16 For example, verbal memory
impairment is associated with language dominant uni-
lateral hippocampal damage and nonverbal memory
impairment is associated with nonlanguage dominant
unilateral hippocampal damage. 17
Within the lesion method, three main approaches
are used to evaluate the relationship between neuropsy-
chological data and lesion locations Fig. 5–1: (1) associa-
tion of deficits, (2) single dissociation of deficits, and (3)
double dissociation.9 Association of deficits refers to the
study of the correlation between two cognitive impair-
ments that occur together, for example, poor attention
(Task A in Fig. 5–1A for patients X and Y) and verbal
Figure 5–1. Association, dissociation, and double
dissociation. (Adapted from Bauer RM, Leritz E,
Bowers D. Research methods in neuropsychology. In
Comprehensive Handbook of Psychology, vol. 2,
edited by JA Schinka and WF Velicer. New York: John
Wiley & Sons, 2003, pp. 282–322.)
memory (Task B in Fig. 5–1A) difficulties often co-occur.
Association of deficits might occur because the process-
ing of abilities is anatomically close in the brain (even
though the systems might be functionally distinct) or be-
cause a deficit in one ability leads to impairment in the
other ability. For example, a patient should be able to at-
tend to episodic information to be remembered in order
for the information to be encoded and later retrieved.
A single dissociation occurs when a patient with a focal
lesion is impaired on one task (Task B in Fig. 5–1B for
patient X is impaired (higher is poorer), but performs
normally on another task (Task A is intact for patient X
and patient Y, and patient Y performs within normal lim-
its for Task B). For example, nonverbal memory is intact
58 SECTION I TECHNIQUES
but there is impaired verbal memory associated with lan-
guage dominant (often left) hippocampal damage in a
single patient. A double dissociation occurs when a focal
lesion impairs a specific ability while other abilities are
left intact in one person (Task A is impaired but Task B is
intact for patient X in Fig. 5–1C), and a focal lesion in an-
other area in another person impairs a different specific
ability while leaving other abilities intact (Task B is im-
paired but Task A is intact for patient Y in Fig. 5–1C). For
example, the dissociation noted previously with a single
case would become a double dissociation when another
patient is found to have the opposite cognitive presen-
tation. That is, verbal memory may be intact but there
is impaired nonverbal memory associated with nonlan-
guage dominant (often right) hippocampal damage in a
separate patient.
䉴 METHODS
Clinical neuropsychologists use a variety of validated
tests to evaluate brain functions. There are several books
that provide extensive readings on the different types of
neuropsychological tests that are available.18−20 A thor-
ough neuropsychological evaluation is routinely based
on at least four types of information: (1) medical history,
(2) clinical interview, (3) behavioral observations during
the interview and testing, and (4) the test battery.19 An
effective neuropsychological assessment begins with ob-
taining relevant medical history including imaging and
neurologic exam results. These data, along with the
referral question and patient complaints, often guide
which neuropsychological tests will be chosen for the
assessment. A clinical interview with the patient and
family members is conducted to obtain relevant demo-
graphic, social, educational, language learning, occupa-
tional, and psychiatric history, as well as to obtain a
patient’s level of activities of daily living in order to bet-
ter interpret neuropsychological test results. Also, these
data provide ecologically valid clues to real world dys-
function that may be correlated with neuropsychologi-
cal impairments. Information obtained in the interview
is also useful for modifying the selection or administra-
tion of neuropsychological tests to accommodate spe-
cific disabilities, other limitations, and to gauge fluency
in English for patients who primarily speak a foreign lan-
guage. Behavioral observations are an important part of
gathering qualitative data during a neuropsychological
assessment that can provide evidence for or disconfirm
impressions garnered from the objective testing.
In this section, we describe neuropsychological
tests that represent different cognitive domains. A neu-
ropsychological assessment should evaluate multiple
functional domains. Evaluating multiple domains allows
a clinician to determine the pattern of cognitive strengths
and weaknesses, and often helps to clarify the reason
for impairment. Evaluating multiple domains also serves
to address the concern that a single neuropsychologi-
cal test does not solely measure one cognitive function,
but rather a single test often involves multiple cognitive
abilities. For example, adequate performance on a neu-
ropsychological test requiring one to remember a story
involves the ability to attend to the story, understand in-
structions, strategically encode the information, and re-
trieve the story. Poor performance revealed by an inabil-
ity to retrieve the story may result from a breakdown of
any of these independent cognitive abilities. This issue
is akin to the problem in functional MRI (fMRI) research
of finding adequate control or baseline tasks for a block
design to negate the behaviors that are not of interest,
or why event-related designs usually identify a network
of brain regions activated during performance on a task.
Testing multiple cognitive domains may also help to ex-
plain why a person performs within normal limits on a
task when imaging data suggests that the person should
be impaired on the particular ability. For example, a per-
son may be able to compensate for a weakness such as
verbal memory difficulties related to identified left hip-
pocampal sclerosis because of good working memory
and visual memory strategies that he or she uses to help
compensate for the structural damage.
There are several strategic approaches that a clinical
neuropsychologist may take when evaluating cognitive
functions. One approach is the use of a fixed battery
of neuropsychological tests that covers most cognitive
domains of interest. The approach could be used to cal-
culate both individual and global scores in a multivari-
ate approach to determining a patient’s strengths and
weaknesses. Given that multiple domains are assessed
representing different brain regions, this approach lends
itself well to evaluating lateralized and localized relative
weaknesses associated with focal brain damage. This ap-
proach also provides a uniform database that could be
used to study patterns of findings in relation to patient
variables, surgery, or pharmacologic treatment. Another
approach is to use a flexible battery where a core bat-
tery of neuropsychological tests is used to screen for
impairment and then the assessment is refocused on the
identified cognitive problems. In this approach, empha-
sis on test selection is often strongly guided by the dis-
ease state or type of neurologic impairment, or to ac-
commodate individual differences such as educational
level or disabilities. However, in each approach, tests
may be chosen to measure previously identified seque-
lae associated with the specific disease state based on
clinical and research literature. Finally, a common ap-
proach is to begin with a fixed battery and add additional
tests when deficits in one domain are determined, or add
tests to help confirm impressions (e.g., the multiple fixed
battery approach,13 ). Regardless of the approach, the
chosen tests should have known normal standard values
and known psychometric properties in order to improve
 CHAPTER 5
the validly and reliability of testing. Qualitative methods
are also useful. The process approach involves the iden-
tification and quantification of qualitative behaviors rep-
resentative of possible brain dysfunction. The approach
involves testing the limits21 to help explain how a per-
son performed poorly on a particular test and is usually
conducted after giving the standardized version of the
test.
SUBJECT PREPARATION
Several factors should be controlled for prior to and dur-
ing an evaluation to maintain the validity and reliability
of the testing session. First, a testing session should be
conducted in an environment free of distractions (e.g.,
noise). Second, it should be determined whether or not
a patient has visual or auditory acuity problems that will
affect cognitive testing. Third, a standard introduction
to testing should be provided to the patient that ex-
plains what to expect. The introduction partly serves to
minimize patient anxiety, as too much anxiety can af-
fect neuropsychological test performance.22 Fourth, as a
part of behavioral observations and during testing, eval-
uate whether or not there are other patient issues such
as poor comprehension level, difficulty with attention,
poor motivation, patient response style, and poor mood
state that can affect the validity of testing. Instructions
should be simplified or repeated if it appears through
behavioral observation or testing that a patient has dif-
ficulty comprehending instructions or difficulty attend-
ing long enough to encode instructions. Poor effort, low
motivation or malingering can be evaluated through the
use of validated tests of malingering. Behavioral obser-
vations may also suggest that a patient is giving poor
effort (e.g., statements such as “I quit because I cannot
do it”), although it is often difficult to differentiate frus-
tration with an inability to perform a task due to brain
dysfunction from poor effort due to low self-esteem or
depressed mood. Taking these factors into account will
help to create a testing environment that promotes op-
timal performance. Noting these patient limitations will
also help clarify the nature of true cognitive impairments
that reflect neuroanatomical degradation from misinter-
pretation of poor test scores due to confounding factors.
TOOLS OF INVESTIGATION
Neuropsychological tests should be chosen that have
known psychometric properties. The validity and reli-
ability of the most commonly used neuropsychological
tools of assessment are published.18−20 Tests are given
either by standard pencil and paper or computer ad-
ministration. Giving tests in a standardized fashion im-
proves the reliability of the testing session. Comparing
NEUROPSYCHOLOGICAL TESTING 59
performance to known chronologic age, gender and/or
education-based norms improves the likelihood that the
interpretation of scores identified as impaired will be a
valid indicator of brain dysfunction. We now define the
different cognitive constructs that compose a neuropsy-
chological assessment.
Intelligence
Intelligence is a global composite of different mental
abilities mental, such as the capacities to solve prob-
lems, plan, comprehend ideas and language, remember
and learn. An intelligence quotient (IQ) below 70 is a
criterion of mental retardation. One of the most widely
used measures of intelligence is the Wechsler Adult In-
telligence Scale.23 The WAIS-IV has a composite score
that is an indicator of general overall intellectual func-
tioning (Full scale IQ), as well as subscales that estimate
verbal intelligence (known as verbal IQ (VIQ); e.g., fund
of knowledge, vocabulary level) and nonverbal intelli-
gence (known as performance IQ (PIQ); e.g., visual con-
struction, spatial reasoning). The WAIS-IV manual pro-
vides standard score values that indicate the significant
difference that exists between a VIQ-PIQ split suggest-
ing lateralized impairment with left hemisphere damage
more likely to lead to lower VIQ scores and right hemi-
sphere damage more likely to lead to lower PIQ scores.23
Memory
Figure 5–2 shows a taxonomy of the different types of
memories that may exist.3 A wide variety of tests exist
that measure the explicit memory domain. Episodic ver-
bal memory tests commonly involve verbally presenting
a story or a list of words to a patient and then have the
patient repeat the story or list in a short duration (e.g.,
within 30–45 seconds) or a longer duration (typically
over 25–30 minutes). The most commonly used episodic
verbal memory tests include the California Verbal Learn-
ing Test, subtests of the Wechsler Memory Scales, the Rey
Auditory Verbal Learning test, and Warrington’s Recog-
nition Memory Test for words.24−27 Episodic nonver-
bal memory tests commonly involve visually present-
ing faces, spatial locations or an abstract design to a
patient and then have the patient draw what she saw,
point to the location of the objects, or match the objects
in a forced-choice paradigm. The most commonly used
episodic nonverbal memory tests include the Warrington
Recognition Memory Test for faces, the Rey-Osterrieth
Complex Figures test, and the Brief Visual-Spatial Mem-
ory Test.26,28−30 Comparison of results on verbal versus
nonverbal memory tests may point to lateralization of
brain pathology. Implicit memory refers to unintentional
learning of material that someone was exposed to and is
measured with tests of perceptual priming (e.g., word-
stem completion or lexical decision tasks), procedural
60 SECTION I TECHNIQUES
Long-term
memory
Explicit
(declarative)
Episodic Semantic (factual
(events) knowledge)
CC and operant
conditioning
Figure 5–2. Model of long-term memory. (Adapted from Squire LR. Memory systems
of the brain: A brief history and current perspective. Neurobiol Learn Mem 2004;82:
171-177.)
memory (e.g., learning to ride a bike), and nonasso-
ciative learning (e.g., learning unrelated and irrelevant
information in the process of learning a target task).
Language
Language is broadly defined by many different abilities
including comprehension, repetition, naming, fluency,
reading, writing, and prosody. Confrontation naming, or
a verbal response to visually presented objects or pic-
tures, is one of the most commonly tested domains using
measures such as the Boston Naming Test.31 Standard-
ized batteries such as the Multilingual Aphasia Examina-
tion and Boston Diagnostic Aphasia Examination have
been created that sample the wide range of language
abilities.32,33
Attention and Working Memory
Attention refers to our ability to process certain informa-
tion selectively and continuously while ignoring other
information and is often evaluated by timed tests that
emphasize both speed and accuracy of performance.
Standardized measures of different aspects of attention
(e.g., selective attention, focused attention and divided
attention) include the Digit Span subtest of the WAIS-IV,
the Ruff 2 and 7 Selective Attention Test and the Paced
Auditory Serial Attention Test.23,34−36 Working memory
refers to the ability to mentally manipulate and store in-
formation received either from visual or auditory sensory
inputs or from long-term memory stores.20 Commonly
used standardized measures of working memory include
Implicit
(nondeclarative)
Procedural (motor, Perceptual
cognitive skills) priming
Nonassociative
learning
the Digit Span Backwards/Sequencing and Spatial Span
subtests of the Wechsler Memory Scale.27
Visual Perception
Visual perception refers to identification of stimuli and
localizing them in space. Measures of visual perception
involve a variety of abilities including copying an object,
recognizing faces in a forced choice format, and judging
line orientations. Common measures include the copy
portion of the Clock Drawing Test, Benton’s Face Recog-
nition Test, and Benton’s Judgment of Line Orientation
Test.37,38
Cognitive Speed
Cognitive speed has been measured by many types
of tasks. The most common measures require visual-
motor tracking as a person quickly connects numbers
(e.g., Trails A; Army Individual Test,39 quickly naming
words (e.g., Stroop Word),40 or orally names numbers
that match abstract geometric designs (e.g., Symbol Digit
Modalities Test).41 The main idea of these types of tasks
is to quantify how fast individuals are able to process
information and exert cognitive control as in the Stroop
task, which involves suppressing a well-established
response (reading) while performing a more effortful re-
sponse (naming the color of print that conflicts with a
color word such as “blue” appearing in red print). Cog-
nitive control and cognitive speed are less related to lat-
eralized and localized dysfunction and more sensitive
to generalized white matter injury or disease and other
neuropathology that results in motor or visual-motor
 CHAPTER 5
tracking impairments. Cognitive control also pertains to
executive functions as described in the following sec-
tion.
Executive Functions
Executive functions refer to complex behavioral pro-
cesses that involve initiation, planning, problem solv-
ing and adaptation, purposive action and goal seeking,
the ability to inhibit responses, self-monitoring of be-
havior, and avolition.42 As such, there are diverse sets
of tools that can be used. Several neuropsychological
tests thought to be symptomatic of problems with ex-
ecutive functions have been validated that quantify the
extent of loss in different types of executive function-
type behaviors.43 The most common tasks include the
Ruff Figural Fluency Test (RFFT; a measure of the abil-
ity to generate spatial designs; sustained attention, self-
monitoring to avoid repetition, regulation of responses,
cognitive processing speed),36 the Stroop Color-Word
task (ability to inhibit a response, selective attention,
cognitive processing speed),40 the Trail Making Test part
B (visual conceptual and visuomotor tracking, set shift-
ing, ability to inhibit responses; Army Individual Test),39
Wisconsin Card Sorting Test (assess abstract behavior,
ability to use feedback, ability to shift sets),44 and FAS
Letter Fluency (word knowledge base, organization of
verbal retrieval, cognitive flexibility, ability to inhibit a
response).37 Newer standardized measures of executive
functioning include the Iowa gambling task45 and the
Delis–Kaplan Executive Function System.46
DATA ANALYSIS AND
INTERPRETATION
Data analysis is straightforward and begins by scoring
information (e.g., response accuracy, response speed)
using standard criteria and using the raw scores to deter-
mine the z-score or percentile rank compared to norma-
tive data from samples of nonbrain injured controls. The
goal of using normative data is to understand whether
or not poor performance on a test is actually impaired
or if performance is expected compared to others with
similar demographic characteristics. For example, two
individuals of the same age may differ in their abil-
ity to name pictures of objects if their education lev-
els differ, reflecting experiential differences rather than
functional brain impairment. There are several sources
that provide normative data for the most commonly
used and well-validated measures of neuropsycholog-
ical functioning.18,19,20 Data are routinely adjusted for
chronological age since expected performance on many
neurocognitive tasks change with age.47 There are also
normative data for some tests that adjust for race, sex,
and level of education.48
NEUROPSYCHOLOGICAL TESTING 61
Once the data are scored, there are several meth-
ods to interpret neuropsychological test scores that re-
quire clinical judgment. These methods include (1) in-
terpreting the level of performance (normal/abnormal,
below average above average) on a particular test, (2)
analyzing the pattern of performance on test scores,
(3) comparison of tests that purportedly measure op-
posite sides of the hemispheres and (4) the evalu-
ation of pathognomonic signs indicative of localized
impairment.49 Analysis of level of performance involves
interpreting how poorly someone performs on a test (or
a group of tests in the same domain) in comparison
to a standard, usually normative data from a sample of
the general population. Impaired performance is often
defined by cut-off scores or percentile rank. Percentile
ranks below a certain threshold (e.g., 10%, 5%) are used
to define impairment based on the referral context. An-
alyzing the pattern of test scores helps to determine
patient strengths and weaknesses and helps provide par-
allel support for functional impairment when an identi-
fied lesion exists. Use of continuous data also helps to
determine impairment on a continuum if the cognitive
function relies on several brain regions since, as previ-
ously mentioned, impairments are not usually absolute
but rather relative. Comparing how someone performs
on tests representing the left or right hemisphere is
a standard tool in neurologic exams. Neuropsycholo-
gists can use the evaluation of sensory, motor, memory,
language, and perceptual-motor skills to discuss the rel-
ative efficiency of the two hemispheres. Finally, use
of pathognomonic signs can help to interpret data by
identifying specific types of behaviors characteristic of
specific brain dysfunction. Classic examples include
paraphasic errors (indicative of language dominant
hemisphere impairment), as well as perserverative re-
sponses and confabulations (indicative of probable
frontal lobe impairment).
Interpretation of neuropsychological data should be
approached with caution given that several factors can
contribute to the misclassification of functional impair-
ment. Individual differences in level of comprehension,
visual and auditory acuity, IQ, sedative medications, and
severe depression are examples of factors that can lead
to false lateralizing and localizing information that mis-
lead conclusions drawn from neuropsychological test-
ing and therefore need to be taken into account to
increase the likelihood of validly assessing neuropsy-
chological results. Also, patients for whom English is a
second language may perform below expectation on
tests that involve processing complex language. Another
issue, which is a limit of the lesion method and any
clinical mapping approach, is that the same lesion in
the same place does not always equate to the same
observable behavior due to individual factors such as
chronologic age, education, sex, culture, and other fac-
tors. Also, disease characteristics may lead to functional
62 SECTION I TECHNIQUES
reorganization of abilities.50 Normative data help to par-
tially address this concern by providing a definition of
typical performance. Thus, a goal of much neuropsy-
chological research has been to determine what factors
account for individual differences.
䉴 APPLICATION
The following section mainly focuses on research re-
garding frontal or temporal lobe epilepsy/surgery pa-
tients given that the bulk of studies have reported data
on these groups, and we only briefly discuss the litera-
ture regarding patients with parietal and occipital lobe
epilepsy. We present these data with particular focus
on the neuroanatomical correlates of neuropsychologi-
cal tests. There is an extensive history of the study of the
neuroanatomical correlates of neuropsychological test
performance with pre- and posttemporal lobectomy pa-
tients with intractable epilepsy as neuropsychological as-
sessment methods play a valuable role in the evaluation
of patients presenting at epilepsy treatment centers.51
Surgical candidates provide the closest approximation of
lesion studies in animal models given that pre- to post-
surgical evaluations can be conducted on patients that
receive similar excision of structures, mostly anterior
temporal lobe, which helps minimize a criticism of the
lesion method by increasing the similarity among patient
lesions.
LATERALIZATION OF FUNCTION: LEFT
VERSUS RIGHT HEMISPHERE
Verbal Versus Performance IQ
The lateralizing value of material specific IQ indices has
been studied in patients with epilepsy. Double disso-
ciations have been reported such that left hemisphere
damage is more likely to lead to lower VIQ scores, and
right hemisphere damage is more likely to lead to poorer
PIQ scores.52−56 For example, using the mean score dif-
ference between the VIQ and PIQ, Akanuma et al.52
found that patients with video-EEG defined left-sided
temporal lobe epilepsy (TLE) were more likely to have
poorer VIQ scores compared to individuals with right-
sided TLE attributable to difficulties with language pro-
cesses. In nonepilepsy patient populations, the VIQ–PIQ
split is more prominent in males57 as lateralization of
cerebral specialization (i.e., into verbal and visuo-spatial)
is less characteristic of females than males. Larrabee58
suggested that the lateralizing utility of the VIQ–PIQ
split may be diminished by language impairments that
affect performance on the supposed “nonverbal” PIQ
subtests.58
Global Versus Local Processing
of Information
Previous research suggests that the two hemispheres are
specialized in the perceptual organization of visual in-
formation with the right hemisphere integrating many
features of an object or scene as a whole (called global
processing, also known as holistic or contextual or con-
figurational gestalt) and the left hemisphere processing
local (fine details of a whole object, a.k.a. analytic or
featural) features of an object or scene in healthy hu-
man subjects.59 Presenting information to both visual
fields, Doyon and Milner60 found faster processing of
local information for patients who had undergone right
anterior temporal lobectomy (ATL) compared to subjects
post left-ATL. The authors interpreted this finding as re-
flecting the damaged right temporal lobe’s minimized
focus on the processing of global characteristics of vi-
sual information. Other researchers have used complex
visual information with responses quantified using free-
hand drawing when stimuli were presented to full vi-
sual fields in either presurgical or postsurgical patients
with epileptic seizures. The results of these studies are
equivocal with two studies providing some evidence for
global processing impairments in individuals with right
TLE,61,62 but another study not finding evidence for dis-
sociation between hemispheres.63 Finally, applied to the
processing of unfamiliar faces, research suggests that the
right hemisphere processes features of a face as a whole
and the left hemisphere relies on a parts-based decoding
of faces.64,65
LOCALIZATION OF FUNCTION: THE
TEMPORAL LOBE
Episodic Verbal Memory
The largest amount of neuropsychological research on
individuals with epilepsy has focused on the study of
memory. Modern theories of medial temporal lobe func-
tioning agree that the hippocampus and parahippocam-
pal gyrus are important for memory of factual knowledge
and episodic events.3,66 Evidence supporting the role
of the language-dominant hippocampus in the encod-
ing, short-term storage and retrieval of verbal material
is well validated. Verbal recall and recognition memory
impairments have been found in patients with video-
EEG defined left-TLE on measures of declarative mem-
ory tested with story recall, verbal paired associates,
and list-learning formats (see Bell and Giovagnoli for
a review).67 Further, the presence of imaging abnor-
malities suggestive of left-hippocampal mesial temporal
sclerosis (MTS) is associated with poorer performance
on measures of verbal memory compared to individuals
without left-MTS or patients with right-MTS.68−70 Further,
decreased left lateral temporal lobe hypometabolism,
 CHAPTER 5 NEUROPSYCHOLOGICAL TESTING 63

based on positron emission tomography (PET), is asso-
ciated with impaired verbal memory in individuals with
left-TLE.71 Recently, Pauli et al.72 found that neuronal
cell loss within the internal limb of the dentate gyrus
of the hippocampus was the strongest predictor of the
ability of a patient to acquire new verbal memories.
Other evidence supporting the role of the left lan-
guage dominant temporal lobe in the processing of ver-
bal memories comes from research in patients who un-
derwent unilateral ATL. Left-ATL leads to a precipitous
drop in verbal recall and learning ability.73−80 Figure
5–3A shows the rate of impaired verbal learning across
trials for left-ATL patients compared to better perfor-
mance for right-ATL patients on the Buschke Verbal Se-
lective Reminding Test from data from our series of pa-
tients at the Baylor College of Medicine.81 Figure 5–3B
shows the magnitude of impaired performance for the
sum across trials between the two groups. The decline
in verbal memory abilities after surgery is especially ap-
parent in patients without presurgical imaging abnor-
malities or hippocampal sclerosis,75,82−85 in patients with
greater presurgical left medial temporal lobe activation
12 Left-sided
Number of words recalled
based on fMRI,86 and in patients with higher presurgi-
cal verbal memory ability,74,87−89 which all are hypothe-
sized to reflect functional (e.g., nonimpaired) tissue that
was ultimately resected. There is also evidence that re-
sults of Wada testing (intracarotid injection of amobar-
bital to test for language and memory) indicating poor
memory ability in the contralateral temporal lobe pre-
dicts postsurgical verbal memory impairment because
the contralateral hemisphere is not able to compen-
sate for the ipsilateral removal of functional tissue.90
Other factors found to account for individual differ-
ences in the extent of decline in verbal memory after a
language dominant/left-temporal lobe resection include
more extensive left-ATL,74 older age at ATL surgery,91,92
poor seizure control after surgery,93,94 male gender, as
women have a more bilateral representation of verbal
memory,95 and depressed mood state either before96 or
after surgery.97,98
Episodic Nonverbal Memory
Material specific nonverbal memory impairments have
been associated with nonlanguage dominant temporal
lobectomy. Table 5–1 shows the extant evidence be-
tween studies that assessed nonverbal memory for ab-

11 Right-sided
10
stract designs, faces and spatial locations after right-ATL
9 compared to patients who underwent left-ATL. For tests
8 of memory for abstract designs, there are many stud-
7 ies that show both impairments and no impairments
6
after right-ATL compared to left-ATL. Data are more con-
5
4 vincing using memory for faces with all studies show-
3 ing impaired performance in individuals who underwent
2 right-ATL. Moran et al.105 was the only study that found
1 that the impairment was not greater for right-ATL pa-
0
A 0 1 2 3 4 5 6 7 8 9 10 11 12 tients compared to left-ATL patients because both groups
Trial showed impaired performance on face memory after
surgery. Spatial learning tests also provide some evi-
120 dence for a role in the nonlanguage dominant hemi-
Total number of words recalled

p < .001 sphere in nonverbal memory functioning, but there are

110 still several studies that show no post-ATL impairments.
The lack of evidence relating the right temporal lobe
100 to nonverbal memory tasks from some studies has been
attributed to several reasons including (1) visual informa-
90 tion to be remembered is often not complex enough to
elicit the deficit, (2) visual information can sometimes be
80
easily verbalized so more abstract and less familiar infor-
mation should be used to elicit anterior right-hemisphere
functions, and (3) the contralateral hemisphere is able to
70
B Left Right compensate effectively for deficiencies when the visual
information is presented to both visual fields.
Surgery side
Nonverbal visual memory impairments are more
Figure 5–3. (A) Shows the rate of verbal learning
likely to occur in patients with right-MTS or smaller
across trials by side of anterior temporal lobectomy right-sided hippocampal volumes.82,133 New postsurgi-
(ATL). (B) Bar graph shows the total recall of words cal nonverbal memory impairments are predicted by re-
from 12 trials divided by side of ATL. section of a relatively large right hippocampus,85 better
64 SECTION I TECHNIQUES

䉴 TABLE 5–1. STUDIES OF VISUAL MEMORY WITH POSTSURGICAL GROUP DATA COMPARING
RIGHT TO LEFT-ANTERIOR TEMPORAL LOBECTOMY

Type of Nonverbal Memory Significantly Poorer Performance vs. Left-ATL No Significant Difference vs. Left-ATL

Abstract design memory Abrahams et al.99 Gleissner et al.a100

Doyon and Milner60 Chelune et al.87
Goldstein and Polkey101 Dulay et al.102
Graydon et al.103 Katz et al.76
Ivnik et al.104 Moran et al.a105
Jones-Gotman106 Nunn et al.107 (wnl)
Jones-Gotman et al.108 Rausch et al.109
Helmstaedter et al.110 Selwa et al.111
Kimura112 Spiers et al.113
Rausch and Babb114
Face memory Chiaravalloti and Glosser115 Moran et al.a105
Chiaravalloti et al.116
Doss et al.117
Dulay et al.102
Milner118,119
Morris et al.120
Spiers et al.113
Spatial learning and memory Abrahams et al.99 Chiaravalloti and Glosser115 (wnl)
Corkin121 Feigenbaumb and Morris122 (wnl)
Dulay et al.102 Goldstein et al.a,c123
Milner16 Maguire et al.a124
Nunn et al.107,125 Owen et al.a126
Parslow et al.127
Petrides128
Pigott and Milner129
Pillon et al.130
Smith and Milner131
Spiers et al.113
Worsley et al.132
a
Indicates memory test performance was impaired for both left and right ATL compared to normative data or significantly poorer than a
normal control group.
b
There was no significant difference between left/right or controls when using an egocentric spatial memory task, but the right-ATL
group performed significantly poorer than controls using an allocentric spatial memory task.
c
Goldstein et al.123 found no significant difference among between left/right or controls when using an egocentric spatial memory task,
but the right- and left-ATL group performed significantly poorer than controls using an allocentric spatial memory task.
Wnl, indicates within normal limits compared to normative data or a normal control group.

presurgical nonverbal memory ability,100 right sided
presurgical fMRI activation during a nonverbal task,86,134
larger right-lateral neocortex and mesial temporal
excision,106,119 and later age at onset of seizures,101
which all suggest the removal of functional right hip-
pocampal tissue. Later age at onset is a predictor because
individuals who have seizures that begin in adulthood
have a greater likelihood of developing adequate non-
verbal memory abilities that are at risk for loss when
functional hippocampus is resected.
Implicit Memory
Relatively few studies have evaluated the biologic basis
of implicit memory tests (measures of unintended or in-
direct learning) in patients with epileptic seizures135 (see
for a review). In almost every case, the focus has been on
patients with TLE or post-ATL. Anatomical distinctions
between explicit/episodic memory and implicit memory
originally came from research with patient H.M. who
had a bilateral temporal lobectomy. He was found to
have impaired explicit memory with the ability to learn
new information implicitly suggesting that mesial tempo-
ral lobe structures are not essential in the processing of
implicit memories.78 In research with other patient pop-
ulations, implicit memory impairments have been tied to
basal ganglia, cerebellum, occipital lobe, and association
cortex damage depending on the characteristics of the
implicit memory task.136,137 However, implicit memory
impairments have been demonstrated in individuals with
a unilateral TLE or post-ATL138−141 though there is also
research that has not found impairment.142 To address
this discordance, Leritz et al.135 hypothesized that hip-
pocampus is important for the formation of new memo-
ries regardless of the explicit/implicit nature of the task
 CHAPTER 5
because the important factor in explaining the variability
is the degree to which the tests that were used required
effort or intention. Thus, implicit memory tasks that re-
quire more effort for remembering (even though it is
unintended learning) will be more dependent on mesial
temporal lobe functioning. There is also debate regard-
ing lateralized processing of material-specific verbal im-
plicit memory tasks as some have found no differences
between left- and right-TLE patients,140 whereas others
have found differences.138,139 Interestingly Zaidel DW,
et al.,141 found a significant association between poorer
performance on a verbal implicit memory task and re-
duced left-CA1 hippocampal cell densities.
Language
Different types of naming tasks are impaired in individu-
als with left-TLE compared to individuals with right-TLE.
Confrontation naming tasks, or the ability to provide a
one or two word verbal label for a picture, has been
the most commonly studied type of naming task. Con-
frontation naming impairments in individuals with left-
TLE is associated with the presence of left hippocampal
atrophy or sclerosis,143,144 reduced left hippocampal cell
density,145 postictal language disturbance,146 and more
lateral lesions (vs. mesial).147 Research also demonstrates
a precipitous drop in confrontation naming ability after
surgical resection of the left temporal lobe that is pre-
dicted by more extensive resection of lateral temporal
cortex,148 better presurgical naming ability,149 absence
of hippocampal sclerosis144,150,151 and later age at onset
of seizures,149,150,152−154 which are indicative of a func-
tional left hemisphere. Further, Bell et al.155 found that
object names learned later in childhood are more likely
to be lost after left ATL.
Other test material-specific language difficulties
have been associated with the language-dominant left
temporal lobe. For example, Hermann et al.156 reported
that left-TLE patients performed significantly poorer on
tests of sentence repetition, listening comprehension and
reading comprehension compared to right-TLE patients.
Further, left-ATL patients have greater difficulty nam-
ing living things (e.g., animals) versus naming nonliving
things (e.g., tools) after surgery compared to right-ATL
patients157,158 providing support for the idea that there
exists focal and lateralized category specific naming re-
gions of the brain. In addition, Glosser and Donofrio159
found that left-ATL patients had a selective deficit for
naming “pictured objects,” but not “pictured actions”
compared to right-ATL patients, which provided evi-
dence of specialization of left temporal lobe structures
for processing nouns but not verbs. Auditory naming
tasks that assess the ability to provide definitions of
common animals and objects (without visual stimuli, but
rather a cued verbal label) have also been shown to be
sensitive to left temporal lobe impairment, and may be
NEUROPSYCHOLOGICAL TESTING 65
more sensitive to left temporal lobe damage than con-
frontation naming.160−162 Finally, the presence of phone-
mic paraphasias, but not semantic paraphasias, occurs
at a greater rate in left TLE146,163,164 suggesting an un-
derlying phonological deficit (vs. a semantic deficit) to
identified naming difficulties.
Processing of Faces
Previous research with pre- and postsurgical epilepsy pa-
tients indicates greater impairments in face recognition
memory ability for unfamiliar faces,115,165 face recogni-
tion memory for famous faces,166 and identification of
fearful facial expressions167,168,169 for right-TLE patients
compared to left-TLE patients or normal controls. The
amygdala likely plays a primary role in the emotional la-
beling of faces,170 though the effects of recurrent seizures
in patients with right-TLE or the effects of right-ATL are
not specific enough to be able to differentiate the differ-
ent roles of mesial temporal lobe structures (e.g., amyg-
dala vs. hippocampus, hippocampus vs. entorhinal cor-
tex). A role of both the left and right hemispheres has
been hypothesized to exist for the processing of face
stimuli when task instructions require the lexical or se-
mantic naming of familiar or famous faces with simulta-
neous visual processing of the face.166,171,172−175
Olfaction
In the field of epilepsy research, olfactory loss has been
consistently found with seizure focus and damage.176
Table 5–2 displays studies that assessed olfactory func-
tioning in patients with epilepsy, the olfaction-cognition
tasks employed, and the region implicated in loss of abil-
ity. These studies indicate poor performance on mea-
sures of olfactory function as a result of temporal lobe
disruption, damage, or surgery. Previous research has
found conflicting results regarding lateralization when
assessing odor discrimination (ability to discriminate be-
tween two or more odors) and odor recognition memory
performance (the ability to remember and discriminate
an odor among a group of other odors after a delay) in
patients with epilepsy. The right temporal lobe is con-
sistently implicated in all of the studies; nonetheless, the
left temporal lobe is also implicated in several studies
(see West and Doty for a review).189 On the other hand,
most of the studies that have assessed odor identifica-
tion ability (the ability to discriminate between odors
and retrieval of an odor label) indicated deficits with im-
pairment to either the left or right temporal lobe. Other
researchers have found odor identification deficits in
patients with orbitofrontal resection and frontal lobec-
tomies that impinged on orbitofrontal cortex.176,185,188
66 SECTION I TECHNIQUES

䉴 TABLE 5–2. STUDIES THAT REPORT DEFICITS ON OLFACTORY MEASURES OF COGNITIVE

FUNCTIONING IN PATIENTS WITH EPILEPSY AS A FUNCTION OF SIDE OF SURGERY

Task Number of Patients with Impairment and Location of Seizures or Surgery

Odor recognition memory impairment

Right-sided impairment only:
Eskenazi et al.177 16 anterior right temporal lobe resection
Jones-Gotman and Zatorre178 36 right temporal lobe and 8 right orbitofrontal/frontal lobectomy (ipsilateral)a
Martinez et al.179 11 right medial temporal lobe resection (ipsilateral)a
Rausch and Serfetinides180 1 patient with right temporal lobe resection
Left or right-sided impairment:
Henkin et al.181 4 left and 7 right temporal lobectomy
Rausch et al.182 7 left and 7 left anterior temporal lobectomy
Eskenazi et al.183 7 language dominant and 10 nonlanguage dominant side temporal lobectomy
Odor identification impairment
Right-sided impairment only:
Eskenazi et al.177 16 anterior right temporal lobe resection
Martinez et al.179 11 right medial temporal lobe resection (ipsilateral)a
Left or right-sided impairment:
Eichenbaum et al.184 Patient H.M., bilateral temporal lobe resection
Eskenazi et al.183 7 language dominant and 10 nonlanguage dominant side temporal lobectomy
Jones-Gotman and Zatorre185 36 left and 35 right temporal lobe lobectomy
8 left frontal-orbital, 12 right frontotemporal, and 8 right lobectomy
Jones-Gotman et al.108 11 left and 14 right amygdalohippocampectomy (ipsilateral)a ;
11 left and 12 right anterior temporal lobe resection (ipsilateral)a ;
12 left and 10 right temporal neocorticectomy (ipsilateral)a
Lehrner et al.186 Case study on a patient with amygdalohippocampectomy
Odor discrimination impairment
Right-sided impairment only:
Abraham and Mathai187 14 right temporal lobectomy
Martinez et al.179 11 right medial temporal lobe resection (ipsilateral)a
Left or right-sided impairment:
Eichenbaum et al.184 Patient H.M., bilateral temporal lobe resection
Eskenazi et al.183 7 language dominant and 10-nonlanguage dominant side temporal lobectomy
Zatorre and Gotman188 31 left temporal and 31 right temporal lobectomy
9 left frontal (ipsilateral),a 10 right orbitofrontal, and 10 right frontal lobectomy
a
Ipsilateral refers to the finding that there was olfactory impairment only for the nostril ipsilateral to the side of the seizure focus or
surgery.

LOCALIZATION OF FUNCTION: THE
FRONTAL LOBE
Attention and Working Memory
Previous research indicates that attention and working
memory are impaired in individuals with frontal lobe
seizure foci, or post unilateral frontal lobe resection;190
(see Helmstaedter et al. for reviews).191,192 For example,
Helmstaedter et al.192 found that patients with frontal
lobe epilepsy (FLE) performed poorer on a measure of
sustained attention compared to patients with TLE (see
also Auclair et al.).193 Further, McDonald et al.194 found
that FLE patients performed below controls or patients
with TLE on a measure of selective attention. Within the
frontal lobe, damage to dorsolateral prefrontal cortex has
been specifically associated with impaired performance
on measures of attention and working memory.195 Oth-
ers have found greater material specific impairment on
spatial working memory tasks (vs. verbal working mem-
ory) after right frontal lobectomy compared to left frontal
lobectomy,196,197 but this laterality effect of spatial work-
ing memory tasks has not been seen in nonsurgical
epilepsy candidates with a unilateral seizure focus.125
Design and Verbal Fluency
The ability to generate words (phonemic or semantic
fluency) and create novel designs (design fluency) is
associated with frontal lobe functioning.198−203 For ex-
ample, Jones-Gotman and Milner200 originally found a
double dissociation with poorer performance on a mea-
sure of design fluency for individuals with right-TLE
compared with left-TLE patients, and greater verbal flu-
ency impairments for left-TLE patients compared to
right-TLE patients. In a follow-up study with postsur-
gical data, Jones-Gotman204 found that centrally located
 CHAPTER 5
right frontal resections (vs. right frontal lateral resections)
were more likely to lead to the design fluency impair-
ment. Others have reported that verbal and design flu-
ency tasks were sensitive in differentiating individuals
with FLE from individuals with TLE.202,203 Left frontal
lobectomy is associated with declines in phonemic flu-
ency ability after surgery and design fluency after right
frontal lobectomy when the resection was large (e.g.,
including frontal pole and orbitofrontal cortex).201
Not all of the data is consistent concerning the later-
ality of phonemic versus design fluency.153,205 McDonald
et al.206 found that design fluency impairments could be
demonstrated in patients with left frontal lobe lesions.
Further, Davidson et al.207 found the presence of ver-
bal fluency deficits after right frontal resection. Davidson
et al.207 suggested that executive dysfunction explains
the presence of the verbal fluency impairments after
right-sided surgery while both linguistic and executive
impairments may explain the verbal fluency deficits after
left-sided surgery. Of note, Helmstaedter et al.191 found
phonemic fluency impairments after left frontal lobec-
tomy only when transient expressive aphasia difficulties
occurred when surgery included left frontal premotor/
supplemental motor areas.
Executive Functioning
Performance on different aspects of executive func-
tioning is diminished in individuals with FLE or af-
ter unilateral frontal lobectomy. Specifically, impair-
ments have been found on cognitive tests designed
to measure response inhibition,16,191,192,203,208,209 mental
flexibility,190,207,210,211 concept formation,190 estimation
of abilities,212 humor appreciation,213 proverb interpreta-
tion214 and motor programming and coordination192
compared to individuals with TLE or normal con-
trols. Individuals with FLE are also more likely to
demonstrate memory difficulties due to poor en-
coding strategies215,216 or difficulties with proactive
interference,217 have loss of set when performing a
task,210 and demonstrate perseverative responding.211,218
In an interesting study, McDonald et al.216 recently found
that patients with left-FLE benefit the most from struc-
tured encoding of verbal information while right-FLE
patients do not.
Several factors are associated with greater extent of
executive dysfunction in individuals with frontal lobe
epilepsy. For example, executive dysfunction is associ-
ated with depressed mood110,219,220 possibly reflecting
frontostriatal dysfunction. In addition, larger frontal lobe
resections have been associated with difficulties in in-
hibiting responses and a perseverative response style201
compared to smaller resections. Further, Helmstaedter
et al.191 found distinct impairments in initiation of ac-
tions when frontal lobe resection included supplemen-
tal motor areas. Finally, earlier age at onset of seizures
NEUROPSYCHOLOGICAL TESTING 67
is associated with poorer executive functioning221 pos-
sibly reflecting greater chronicity of disease or possible
re organization of these behavioral functions.
There is also literature demonstrating executive dys-
function in individuals with TLE compared to healthy
controls Table 5–3. Most of the research to date has
focused on performance on the Wisconsin Card Sort-
ing Test (WCST), a measure of abstraction, sorting
strategy, attention shifting, indicating impaired per-
formance compared to normal controls or normative
data.221,222,224,227,230 Others have found impaired perfor-
mance on tests of mental flexibility222 in patients with
TLE. Laterality differences have been found on measures
of executive functioning such that individuals with left-
TLE performed more poorly on the WCST compared
with individuals with right-TLE208,221 or left-TLE com-
pared with healthy controls.226
Several theories have been proposed that attempt
to explain why executive functions would be dimin-
ished in individuals with TLE. For example, research has
provided support for the hypothesis that electrical dis-
charges propagate to the frontal lobe thereby interfer-
ing with frontal-type functions.226,229,235 Other research
has provided support for the idea that hippocampal
dysfunction impairs the registration or retrieval of in-
formation important for adequate performance on tests
of executive function.208,223 For instance, poorer perfor-
mance on measures of executive functioning is asso-
ciated with hippocampal sclerosis compared to those
without sclerosis.208,222 Corcoran and Upton223 found
that performance on a measure of concept formation
if poorer for TLE patients with hippocampal sclerosis
compared to patients with FLE.
LOCALIZATION OF FUNCTION: THE
PARIETAL AND OCCIPITAL LOBES
Relatively few studies have been published evaluating
neuropsychological performance associated with pari-
etal lobe epilepsy.236 On the basis of case studies and/or
behavioral observation without formal neuropsycholog-
ical testing, several studies report that parietal lobe
lesions are associated with visual perception and con-
structional difficulties, as well as disturbances of body
image (e.g., asomatognosia or a lack of awareness of the
condition of part of one’s body) and visual illusions.237
Salanova et al.238 reported that 9 of 30 presurgical pari-
etal lobe epilepsy patients showed impaired visuocon-
struction and spatial impairments, and 7 of 27 had new
onset apraxia and face recognition problems after resec-
tion of parietal lobe seizure foci. Djordjevic and Jones-
Gotman239 describe a series of patients with right parietal
lobe focal damage who had poor or distorted copying
of a complex figure, and they found left parietal seizure
68 SECTION I TECHNIQUES

䉴 TABLE 5–3. STUDIES THAT ASSESS COMMON MEASURES OF EXECUTIVE FUNCTIONS IN

INDIVIDUALS WITH EPILEPSY

Study Sample Measures Results

Allegri et al.222 TLE WCST, Trails B TLE poorer than NC

TLE with sclerosis poorer vs.
w/out
Corcoran and Upton223 FLE, TLE WCST TLE with sclerosis worse than
FLE
LTLE poorer than RTLE
Drake et al.224 TLE and GE WCST categories Larger percentage of poor EF
with TLE
Giovagnoli208 LTLE, RTLE, LF, RF WCST LF and TLE with sclerosis
perform poorest
Giovagnoli and Avanzini225 LTLE and RTLE WCST categories, No between-group differences
perseverations Phonemic Fluency, Trails B
Helmstaedter et al.191 L/RFLE, L/RTLE Letter fluency, FLE worse on all vs. TLE
Maze test (response No LTLE vs. RTLE
inhibition) differences
Hermann et al.226 LTLE, RTLE, GTC WCST RTLE more PEs vs. GTC
LTLE more PEs vs. GTC
RTLE poorer than LTLE
Hermann et al.219 LTLE and RTLE WCST Depression and WCST
performance related in LTLE
Horner et al.227 LTLE and RTLE WCST Both groups perform poorly on
WCST
Klein et al.228 epilepsy with gliomas Stroop Color-Word Poorer performance vs. NC
Concept Shifting Test EF related to seizure severity
and AED
Martin et al.229 CPS WCST Comorbid GE with CPS worse
than
CPS alone
Martin et al.230 LTLE vs. RTLE WCST category, PE No between-group differences.
Trails B, COWAT 40% RTLE impaired on WCST,
38%
LTLE; COWA similarly impaired.
Martin et al.231 TLE letter fluency LTLE worse than RTLE, RTLE
poorer than NC
Moore and Baker232 LTLE and RTLE Stroop Color-Word No lateralized differences
Paradiso et al.220 LTLE, RTLE WCST, Trails B, COWAT Depressed with TLE have
poorer
COWAT and TMT
Prevey et al.233 CPS vs. GTC vs. NC Stroop Color-Word, COWAT GTC worse on both vs. CPS
and NC
Strauss et al.221 LTLE vs. RTLE WCST Interaction between side of
focus and
Age of seizure onset with LTLE
and younger age poorest
Suchy et al.202 LTLE, RTLE FAS, Figural Fluency No lateralization; no between
group FAS
LFLE, RFLE, FLE poorer on Figural vs. TLE
Upton and Corcoran234 RLTE WCST Poor sorting performance vs.
NC

TLE, temporal lobe epilepsy; WCST, Wisconsin Card Sorting Test; NC, normal controls; FLE, frontal lobe epilepsy; GE, generalized
epilepsy; CPS, complex partial seizures, LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; EF, executive function;
RFLE, right frontal lobe epilepsy; GTC, generalized tonic-clonic epilepsy; PE, perseverative errors; AED, antiepileptic drugs; TMT, trail
making test, FAS, letter fluency for letters FAS.
 CHAPTER 5
foci to be associated with inefficient reading abilities. Fi-
nally, Djordjevic and Jones-Gotman239 reported impaired
tactile discrimination ability for the hand contralateral to
the parietal lobe seizure focus.
Few studies have also been published describing
the cognitive sequelae associated with occipital lobe
epilepsy. Visual agnosia has been consistently reported
in case studies of individuals with occipitotemporal lobe
seizure foci.240−242 Seizure semiology consisting of vi-
sual hallucinations (e.g., unfamiliar faces or scenes), vi-
sual illusions, blindness, seeing colored dots, and field
defects have also been reported.243,244 In a sample
of 11 individuals with occipital lobe epilepsy, Chilosi
et al.245 found that 8 of the 11 had poorer PQ abili-
ties compared to VIQ abilities (laterality of seizures were
not reported), partly attributable to difficulties in com-
petently completing the highly loaded visual-perceptual
subtests that make up PQ.246 They also found impaired
performance on the Judgment of Line Orientation test
and Benton Face Recognition task in a subgroup of the
occipital lobe epilepsy patients. In a sample of 28 teens
and adults with “posterior cortex” lesions (5 parietal, 5
occipital, 14 temporal-occipital and 2 temporal-parietal
occipital), Luerding et al.247 found that PIQ showed a
small but significant decline after posterior cortex focal
resection while VIQ showed significant improvement. In
a sample of 21 children with occipital lobe epilepsy (side
of focus not identified), Gulgonen et al.246 found signif-
icant impairments compared to a normal control group
on tests of PIQ, visual memory, and visual planning and
problem solving. They also unexpectedly found poorer
performance on measures of VIQ and verbal memory
leading the authors to suggest that the impact of oc-
cipital lobe epilepsy in children (or the treatment for the
seizures) leads to generalized deficits and does not read-
ily dissociate into verbal versus visual domains. Finally,
Fleischman et al.136 revealed a dissociation on a test of
implicit visual memory with intact explicit visual mem-
ory in a 30-year-old right handed male who underwent
right occipital lobectomy of Brodmann’s areas 17, 18 and
a portion of 19 suggesting that the right occipital lobe
may be intricately involved in the processing of visual
implicit memories.
䉴 RELATIVE STRENGTHS AND
WEAKNESSES COMPARED TO
OTHER MAPPING TECHNIQUES
There are several strengths to the use of neuropsycho-
logical assessment in a clinical setting when evaluat-
ing the neuroanatomical correlates of cognition. First,
correlating structural damage with neuropsychological
deficits shows that the brain region is required to per-
form the task.248 This is in contrast to techniques such
NEUROPSYCHOLOGICAL TESTING 69
as PET, magnetoencephalography (MEG) and fMRI that
identify the brain regions involved in a cognitive task,
but do not indicate if the region is vital to competent
performance on a task. That is, many brain regions are
implicated during performance of a task using functional
neuroimaging techniques even though the regions may
not be required. Transcranial magnetic stimulation (TMS)
and electrical stimulation (ES) also show that a brain re-
gion is required to perform a task by creating a transient
lesion, but ES is very invasive and only used on select
samples, and TMS can both excite and inhibit cognitive
functions leading to interpretation difficulties.
Second, neuropsychological assessment allows re-
searchers to hypothesize about how impairment occurs
because multiple domains are evaluated to create a cog-
nitive profile of strengths and weaknesses. This is a ben-
efit in clinical settings versus neuroimaging techniques
because the profile may be used to separate cognitive
impairment correlated with structural lesions from im-
pairments associated with individual disease-related and
demographic differences. For example, a right-handed
patient with identified right hippocampal sclerosis may
perform poorly both on measures of verbal and nonver-
bal memory, and a neuropsychological assessment can
suggest that the verbal memory impairment may be as-
sociated with severe attentional difficulties (e.g., associ-
ated with poly anti-epileptic medication use). Neuropsy-
chological assessment can also be advantageous versus
neuroimaging techniques in a clinical setting because
rehabilitation, vocational, and academic recommenda-
tions can be made based on a cognitive profile. A closely
related third strength is that neuropsychological assess-
ment is the best approximation of how individuals act in
real world settings. Neuroimaging experimental design
is naturally limited by the setting (e.g., scanner noise)
and requires many different assumptions when analyz-
ing the data that make the techniques further removed
from real world situations. Among the different mapping
techniques in this book, only the ecological validity of
neuropsychological functioning in predicting level of ac-
tivities of daily living, academic achievement and every
day attentional and memory abilities in individuals with
focal brain damage has been well studied.249,250
A fourth strength of neuropsychological assessment
compared to other techniques in a clinical setting is
that the normal range of test scores is known, and can
be statistically verified (e.g., impaired performance be-
low fifth percentile rank), for the most commonly used
tests compared to age, education, and/or sex-based nor-
mative data. Functional imaging uses control groups,
but methods vary from center to center, demographic-
equated control groups do not minimize problems with
individual variability when sample sizes are small, and
normative data are not yet routinely available, mak-
ing clinical utility limited when trying to define func-
tional impairment. In addition, the quantitative nature of
70 SECTION I TECHNIQUES
neuropsychological test results facilitates longitudinal
testing (e.g., pre- and postsurgical testing).
Finally, we argue that neuropsychological testing is
a different way of looking at certain aspects of the brain–
behavior relationship that may be helpful to physicians.
The power of mapping in a clinical setting lies in the
ability of clinicians to use multiple mapping techniques
that provide converging validity to explicate the role of
a region of the brain. For example, for a single patient,
the efficacy of neuropsychological assessment may be
demonstrated when neuropsychological impairment in
a specific domain is correlated with a structural lesion,
hypometabolism with PET, MEG reduction and/or de-
creased fMRI BOLD signal. For research purposes across
patients, evidence for the neuroanatomical substrates of
a cognitive function may be demonstrated by concurrent
evidence of neuropsychological impairment, increased
functional activity in healthy patients (MEG, PET, fMRI),
and deficits induced by TMS or electrical stimulation.
There are also several limitations of neuropsy-
chological assessment as a tool to understand brain–
behavior relationships. First, replication of a relationship
between structural damage and cognitive impairment is
limited by the inherent variability in the extent of an MRI
identified lesion or the extent of surgical resection of the
patient population. This creates a problem because mul-
tiple structural areas tied to multiple functional domains
may be impaired simultaneously. Other issues that in-
troduce variability include: a lesion in the same location
does not always lead to the same functional deficits be-
tween individual subjects, a lesion in the same location
can cause multiple deficits, and lesions in different brain
regions can lead to a similar cognitive impairment. These
are also limitations of other lesion methods such as
TMS and electrical stimulation. Understanding structure/
function relations with any mapping technique is con-
founded by the variables of individual differences (hand-
edness, demographics, poor motivation, poor attention
level, low IQ, depression), and there are always excep-
tions to robust structure/function relationships due to
reorganization of function or plasticity after injury.
An additional limitation is that neuropsychological
assessment does not determine what cognitive function
is supported by the lesioned area, but rather it estimates
how the system processes information when the area is
damaged or excised. Therefore, we cannot differentiate
whether a brain region is the primary source involved in
a specific function from whether or not the region serves
as a pathway that, when damaged, leads to a disconnec-
tion from other regions that are intricately involved in a
specific function. We can only demonstrate that the area
is required because, when damaged, task performance
is impaired.
Additionally, the validity of a neuropsychological
assessment is limited by the ability of the patient to par-
ticipate in testing. This is contrast to neuroimaging tech-
niques that can require the patient to passively view im-
ages or scenes to determine brain function. However, all
clinical mapping techniques are limited by the patient’s
comprehension of instructions, motivation to perform
at an optimal level, and visuomotor abilities to execute
necessary movements.
A final limitation is that interpretation of neuropsy-
chological test results is more complex when applied to
patients from different language, learning, and educa-
tional backgrounds. Neuropsychological test normative
data and standardized instructions are lacking in many
developing countries.
䉴 CASE EXAMPLE
We now present data from a surgical candidate with
intractable epileptic seizures to demonstrate the prin-
ciples discussed in this chapter. The patient is a
30-year-old right-handed female with 12 years of edu-
cation, referred for neuropsychological assessment as
part of a diagnostic work-up for possible surgical in-
tervention for medically intractable seizures. Prolonged
video-EEG scalp with scalp electrodes revealed electro-
graphic seizure activity originating over the left temporal
lobe with nearly immediate spread to the right tempo-
ral lobe. Seizure semiology consisted of staring, chew-
ing movements, loss of awareness and responsiveness
for 1–2 minutes, picking at her arm, and increased agi-
tation or violent behavior after the event. The postictal
behavior led to animosity among family members. In-
tracarotid sodium amobarbital testing indicated mixed
language dominance, and her right hemisphere was
found to support memory functions. Structural MRI sug-
gested left hippocampal sclerosis. Neurologic exam was
normal. Medical history was negative for other neuro-
logic disorders or other medical conditions. She was be-
ing treated for major depression. Her complex partial
seizure disorder began at the age of 6-years-old, and at
the time of her evaluation, seizures were occurring at a
rate of 1–2 per week at the time of the evaluation. She
graduated from high school with average grades, and
never attended special education services. She stopped
working as a manager at a store in the year prior to
the evaluation because of difficulties with transportation
to work, interpersonal difficulties associated with anger
management, and on the job memory difficulties.
As part of her neuropsychological assessment, there
were no noted irregular behavioral observations during
the clinical interview or during testing other than notice-
able word finding difficulties and the presence of para-
phasic errors during conversational speech. Neuropsy-
chological testing was conducted covering all major
cognitive areas. Testing revealed average overall intel-
lectual functioning with a significantly poorer VIQ com-
pared to her non-VIQ (12 point difference). There were
 CHAPTER 5
mild defects in recent memory, verbal recall and recog-
nition memory, letter and category fluency, confronta-
tion naming with paraphasic errors, and auditory nam-
ing suggesting left temporal lobe involvement. She had
relative strengths for perceptual constructional skills,
cognitive speed, sustained attention, and visual reten-
tive memory. Planning and problem solving were intact,
except that she would lose set when performing dif-
ferent tasks. Given the already existing impairments in
the processing of verbal information, the patient was
considered to be at minimal risk for sustaining addi-
tional memory and language impairments after standard
left-ATL (consisting of resection of lateral temporal neo-
cortex from superior or middle temporal gyrus to the
collateral fissure, as well as anterior hippocampal for-
mation, subiculum, parahippocampal gyrus, and infe-
rior amygadala). The patient underwent left-ATL and
was seizure-free thereafter. She noticed some additional
memory difficulties immediately after surgery with re-
turn to baseline after several months. Language abilities
improved to the point that paraphasic errors were no
longer apparent. She was able to resume driving, but
did not return to work because of her verbal memory
difficulties. She was referred for rehabilitation services in
order to help her to compensate for the continued verbal
memory difficulties and to help her learn to more fully
exploit her cognitive strengths in non-VIQ, nonverbal
memory, processing speed, and planning and problem
solving.
䉴 CONCLUSION
Our review shows that complex relationships exist
among multiple factors that combine to influence per-
formance on any neuropsychological test. The main
strength of neuropsychological assessment in a clinical
setting for brain mapping is its use in conjunction with
other mapping methods to provide converging validity
about the role of a region of the brain in overt behav-
ior. Testing methods are also useful for creating a risk–
benefit profile when estimating the possible postsurgical
decrements associated with excision of eloquent areas
of the brain. We believe that neuropsychological assess-
ment provides an important contribution to multidisci-
plinary teams because unique information is provided
about how focal damage relates to a patient’s level of
functioning in their everyday lives.
䉴 ACKNOWLEDGEMENT
The authors would like to acknowledge the generous
support of The Moody Foundation for a grant on
epilepsy research.
NEUROPSYCHOLOGICAL TESTING 71
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 Chapter 6
The Wada Test: Intracarotid Injection
of Sodium Amobarbital to Evaluate
Language and Memory
Brian D. Bell 1,2 , Bruce P. Hermann1 , and Paul Rutecki 1,2
1
Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
2
Department of Neurology, W.S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
䉴 INTRODUCTION, HISTORICAL
PERSPECTIVE AND,
UNDERLYING PRINCIPLES
The Wada test or the procedure of intracarotid injection
of sodium amobarbital to evaluate language and mem-
ory is used most often with patients being considered
for epilepsy surgery, especially unilateral anterior tem-
poral lobectomy (ATL) for the treatment of intractable
mesial temporal lobe epilepsy (TLE).1 TLE is among the
most common forms of epilepsy and the one of the most
pharmacoresistant. ATL is a well-established surgery that
reportedly eliminates disabling seizures in about 70%
of TLE patients and reduces seizure frequency in an-
other 15%.2–4 The success of ATL in terms of seizure
outcome and neuropsychological morbidity is depen-
dent on careful selection of surgery candidates. Mem-
ory and object naming are the cognitive abilities most
vulnerable to ATL, especially when the surgery is per-
formed on the dominant temporal lobe.5 The Wada test
typically is a component of a comprehensive preopera-
tive work up that also includes electroencephalographic
(EEG)-video monitoring, structural and functional imag-
ing, and a clinical neuropsychological assessment.6 Ide-
ally, these techniques provide concordant evidence of a
focal seizure locus and rule out risk factors that would
preclude surgery.7–9
The Wada test is a means of studying brain func-
tion unilaterally. Amobarbital (sodium amytal) injection
into the right or left internal carotid artery (ICA) creates
a temporary “pharmacological lesion” or “chemical
lobectomy”10 in the anterior two-thirds of one hemi-
sphere. This permits a presurgical evaluation of the rel-
ative contribution of each temporal lobe to vital lan-
guage and memory functions, with the goal of predicting
level of risk of aphasia and, especially, amnesia, should
surgery be performed.
79
The Wada procedure has a fascinating history.
While working in his native Japan in the late 1940s, Juhn
A. Wada, MD, saw patients treated with unilateral elec-
tric shock therapy for psychiatric disorders. Striving to
prevent cognitive deficits that could result from bilateral
convulsions, he arrived at the idea of injecting amobar-
bital into the common carotid artery to anesthetize the
dominant hemisphere and thereby prevent the spread
of the seizure from the contralateral hemisphere. How-
ever, before unilateral amobarbital injection was first im-
plemented for this purpose, Wada was presented with a
boy in status epilepticus unresponsive to medication. He
made a left common carotid amobarbital injection that
arrested the seizure and had only transitory neurological
side effects. Intracarotid amobarbital injection for cessa-
tion of unremitting status epilepticus soon was used else-
where with success and, in fact, its routine use in such
cases was recommended.11 But most importantly, this
early success with unilateral amobarbital injection led
Wada to consider the potential of the procedure for iden-
tification of the speech dominant hemisphere in brain
surgery candidates.12,13
In 1955, during sabbatical years in North America,
Wada introduced what became known as the Wada test
to the Montreal Neurological Institute (MNI) and soon
published the results of amobarbital injections in mon-
keys and in 20 human surgical candidates.14 The latter
were tested because their handedness or seizure pat-
tern raised questions about the speech dominant hemi-
sphere. This early research clearly demonstrated that
(1) unilateral amobarbital injection resulted in a con-
tralateral flaccid paralysis and hemianopsia, as well as
other neurological and EEG changes, and (2) dominant
hemisphere injection typically also resulted in speech ar-
rest and then the production of dysphasic errors as lan-
guage functions gradually returned over the course of a
few minutes.13,14 The Wada test added to knowledge
80 SECTION I TECHNIQUES
of localization of speech functions acquired from
postmortem findings and provided complementary in-
formation to intraoperative speech mapping data.15,16
Examination of language dominance via the Wada
test quickly spread to other countries.17–22 Wada and
Rasmussen14 concluded their 1960 paper by recom-
mending the amobarbital injection technique “. . . as a
preliminary to operations in the vicinity of the Syl-
vian area in left-handed and ambidextrous patients, and
in right-handed patients in whom any doubt exists as
to which cerebral hemisphere is dominant for speech”
(p. 282).
However, clinicians became well aware that lan-
guage was not the only cognitive function that could be
disrupted permanently by temporal lobe surgery. For ex-
ample, during the 1950s, bilateral temporal lobe surgery
resulted in global amnesia in the well-known case of
H.M.
In addition, in the absence of imaging techniques to
determine the integrity of the contralateral mesial tempo-
ral region,23,24 it became readily apparent that, if the con-
tralateral temporal lobe was damaged already, patients
undergoing unilateral ATL could become amnestic;25–27
defined as memory loss for events and other informa-
tion that is disproportionate to other cognitive deficits,
present across modalities, evident in assessment of re-
call and recognition, and quite apparent clinically.28
Theodore Rasmussen, suggested in 1959 that the Wada
test might be successfully extended to the assessment
of memory in order to identify patients who would
be at risk for amnesia.27 Brenda Milner, the eminent
Canadian neuropsychologist and Rasmussen’s colleague,
then developed a memory component for the Wada
test. She soon determined that failure on free recall
testing was common during the Wada test, even when
the hemisphere ipsilateral to the lesion was injected.
Thereafter, recognition memory results became the pri-
ority for the procedure.29 Milner, Rasmussen, and col-
leagues (Wada had begun a career at the University of
British Columbia by this time) quickly made the im-
portant observation that memory and language perfor-
mance were dissociable during the Wada test. Aphasia
did not necessarily cause poor recognition memory and
memory could be impaired even after nondominant
hemisphere injection.26,27 Thus, with selection of ap-
propriate stimuli, memory assessment during the Wada
procedure is “designed to anticipate and cope with dys-
phasia” (p. 813).30
In the first series of MNI patients who were admin-
istered the Wada recognition memory protocol, tempo-
rary memory impairment was unexpectedly rare (22%)
after injections contralateral to the lesion and there were
other question marks about memory functioning during
the test.31 These issues led to further Wada test research
and refinements at MNI and elsewhere.10,17,27,30,32–34
This work resulted, for example, in the discovery that
the occurrence of memory impairment during the Wada
test was not dependent on filling of the posterior cere-
bral artery (PCA). To better control and understand the
distribution of the drug, further developments included
femoral catheterization to replace the common carotid
injection, the pre-Wada test control angiogram, estab-
lishing an optimal range for the amobarbital dose, and
a slower rate of injection.27,35,36 After the institution of
the memory procedure, no cases of postoperative global
amnesia were encountered in its early years of use at
MNI.26,27 In 1962, Milner and colleagues26 concluded
from their preliminary findings that “. . . the amytal tech-
nique may be of value in reducing the incidence of
memory loss after temporal lobectomy in patients with
bilateral EEG abnormality.” Its purpose expanded and
great variation developed across institutions in the ad-
ministration and interpretation of both the language and
memory tasks. But the test continues to be an integral
part of the pre-ATL work up and to bear Wada’s name,
in recognition of his pioneering work.37
䉴 METHODS
SUBJECT PREPARATION
The Wada test procedures are explained to the patient
hours or days in advance. The safety of the procedure
and the range and temporary nature of the amobarbital’s
neurological effects should be highlighted to minimize
the patient’s anxiety.37–39 Clinicians also may administer
tasks at this introduction to acquire baseline language
and memory data and for the purpose of assessing ret-
rograde memory during the Wada test. Alternatively, the
baseline data without anesthetization can be acquired
hours after the Wada test has been completed.40 The
patient fasts the night before the test. It has been rec-
ommended that, if a generalized seizure occurs within
the 24 hours preceding the test, the procedure should
be postponed, although there is no consensus about
this issue.6,16 See Rausch and Risinger,16 and Dodrill41
for additional clinical guidelines. The Wada test session
may be videotaped for the purpose of later review and
precise scoring.42
On the day of the test, the patient is brought to
the radiological suite, bilaterally symmetric EEG scalp
electrodes are placed, and several minutes of baseline
EEG data are obtained before the procedure begins.
With the patient supine, the right femoral artery is punc-
tured after local anesthesia and a guide wire and catheter
are advanced under fluoroscopic guidance through the
femoral artery and aorta to final placement just distal to
the origin of the ICA. Angiography is carried out for ex-
amination of the vascular anatomy. After ruling out prob-
lematic vascular anomalies and determining whether
there is any excessive interhemispheric cross-flow or

filling of the posterior cerebral artery via the posterior
communicating artery, the patient is prepared for the
amobarbital injections. At different centers, the hemi-
sphere with the epileptic focus or the one without the
focus is injected first in all cases, the left or right hemi-
sphere is injected first, or the order of injection side is
alternated across patients.37,43–45 Most centers perform
both injections on the same day, 30–60 minutes apart.
Others recommend carrying out the two injections on
consecutive days,,15,46,47 but this recommendation has
been questioned.41,43,48,49
Before the amobarbital is injected and while still
supine, of course, the patient is asked to raise his or
her arms in the air with elbows flexed, with palms
turned rostrally and fingers spread, and to count out
loud. Hemiplegia or hemiparesis quickly becomes ev-
ident in the contralateral arm, which falls to the bedside.
The patient often keeps the arm ipsilateral to injection in
the air and it may be guided to the bedside.50 The patient
is instructed to count because the overlearned nature of
this sequence is easier to resume when speech suddenly
stops immediately after injection. If normal counting
quickly resumes after a prompt, this suggests language
disruption has not occurred. A potential drawback of the
counting instruction is that after a nondominant hemi-
sphere injection, the patient may perseverate on count-
ing despite instructions to discontinue. An alternative is
to begin conversing with the patient before the injec-
tion. With a nondominant injection, the conversation is
expected to continue, although the patient’s speech is
likely to be dysarthric and there may be some garru-
lousness. Within seconds after a dominant hemisphere
injection, speech arrest and a period of global apha-
sia is typical. For cases with mixed dominance, where
both hemispheres contribute to speech, variations in the
prototypical language changes may occur.51 Amobarbital
induced deficits are “transient and in continuous resolu-
tion” (p. viii).37 The nature and resolution of the domi-
nant hemisphere language changes are described more
fully later in this chapter.
When the contralateral hemiparesis and expected
EEG changes (see later) are confirmed and it is estab-
lished that the patient is demonstrating an appropri-
ate level of alertness and visual attention, the memory
stimuli are presented to the ipsilateral visual field, be-
cause presentation of the target stimuli must take into
account gaze deviation and hemianopsia caused by the
amobarbital.17,30,37 In some cases, it may be necessary
to hold open the patient’s eyelids.50
To avoid the possibility of a false-negative result,
memory testing should be conducted during the height
of the drug effect. It is not necessary to wait for speech
to return before presenting the memory stimuli, as it
has been demonstrated that registration in memory can
occur even when aphasia is present.29,37,43,44,50,52 On
the other hand, obtundation can lead to a false-positive
CHAPTER 6 THE WADA TEST 81
memory failure, and so the timing of test administration
is a subjective but critical matter.10 A patient is said to be
confused or obtunded when “unable to maintain atten-
tion on a single object or person, except transiently.”50
This state may pass relatively quickly, allowing the test
to proceed.
The majority of patients do not show depression or
euphoria after an amobarbital injection. When such a re-
action does occur, depressive reactions are more likely
after left hemisphere injection, whereas euphoria or dis-
inhibition is more likely after injection on the right. But
not all investigators report observing a clear lateraliza-
tion effect.37
Extreme and prolonged emotional reactions that
seriously disrupt the Wada assessment appear to oc-
cur in less than or equal to 6% of patients undergo-
ing the test.38,39 There are no clear predictor variables
for extreme emotional reactions, but partial restraint,
manipulation of the inguinal region for the femoral
catheterization, a predominantly male staff, and
amobarbital-induced disinhibition of emotions may all
be factors in some cases with a history of sexual
trauma.39 In one case, such behavior began or esca-
lated after an initial period of adequate cooperation.38
It has been suggested that continuous cognitive testing
during the entire period of recovery from the drug may
help suppress strong emotional reactions.53 See O’Shea
et al.54 for a novel use of the Wada test in studying disin-
hibited behavior and predicting response to frontal lobe
surgery in patients with frontal lobe injury.
INSTRUMENTATION
The sodium salt of amobarbital is very lipid soluble
and so it crosses the blood–brain barrier easily and has
a rapid anesthetic effect.45 Injection into the ICA via
a catheter placed with a transfemoral artery approach
causes inactivation of areas in the distribution of the ip-
silateral anterior and middle cerebral arteries and the
anterior choroidal artery. Thus, the amobarbital perfuses
frontal and temporal lobe language areas and the ante-
rior one-third of the hippocampus, modeling to a degree
the effects of surgery on the injected hemisphere.45,55
The carotid angiography preceding the Wada test
confirms catheter placement in the ICA rather than the
external carotid or vertebral artery, in addition to deter-
mining whether there is cross-flow of amobarbital into
the contralateral hemisphere, usually via the anterior
communicating artery, perfusion of the posterior cere-
bral artery, or atypical neurovascular architecture that
might result in a dangerous distribution of the drug.56 In
regard to the latter issue, a vascular variation in which
there is a persistent trigeminal artery precludes the Wada
test because of the risk of anesthetizing the brain stem.57
82 SECTION I TECHNIQUES

It should be noted that the distributions of the con-
trast medium during angiography and the amobarbi-
tal may differ due to differences in injection methods,
with amobarbital usually less extensively distributed.6,28
On the other hand, angiography may underestimate the
extent of bilateral perfusion of the drug when com-
pared to single-photon emission computed tomography
(SPECT).58
The dosage and concentration of amobarbital, the
volume of the drug and saline mixture, and the rate
and method (manual vs. automated injection) of deliv-
ery vary widely.6 A faster rate or a greater volume of
injection may perfuse a larger area with widespread ef-
fects on cognition, whereas a slower rate or smaller vol-
ume of injection can lead to a more intense or persistent
drug effect.6,45 Generally speaking, the amount of the
medication used appears to have been reduced over the
past few decades.29 Most centers administer the drug in
a single bolus, but others use incremental injections as
necessary.29,59 On the basis of a survey of epilepsy cen-
ters, Rausch et al.6 reported that 125 mg was the most
frequently reported dosage, with a range of 3–5 cc of so-
lution and a 1–2 cc/s manual injection speed being most
common. But individual patient variation in pharmaco-
dynamics and arterial anatomy are quite important.59
Centers vary in setting criteria for a sufficient anestheti-
zation effect based on tone and grip strength changes
and EEG slowing.6
Most epilepsy centers use surface EEG during the
Wada test to monitor the strength and lateralization of
the drug effect.6 There are a few different advantages
to simultaneous EEG monitoring.16,60 The EEG can (1)
identify possible seizure activity, (2) reveal bilateral EEG
abnormalities that may coincide with an obtunded state
resulting from bilateral perfusion, and (3) establish the
duration of the amobarbital effect and the window for
testing. Unilateral injection of the amobarbital results in
a brief period of bilateral EEG delta waves (Fig. 6–1),
but afterward the delta activity becomes predomi-
nantly ipsilateral.28,30 The EEG effects typically last for
7–8 minutes.29,30,61 Amobarbital may also result in an
increase in spike discharges, as revealed by depth

Figure 6–1. (A) Electroencephalographic (EEG) obtained following left intracarotid

injection with 100 mg of sodium amobarbital. The injection started approximately
7 seconds before the start of the EEG record shown in the figure. Note the asymmetry
of fast activity and the development of rhythmic delta activity over the left hemisphere
leads. Delta slowing is also noted in the right frontal central regions. The angiogram
showed minimal cross-filling. Associated with the injection was a flaccid right arm
weakness and global aphasia. The annotation regarding the left arm down refers to
the examiner guiding the arm down. Visual stimuli were presented during the patient’s
aphasia, which showed partial recovery approximately 3.5 minutes after the injection.
Difficulty repeating sentences was present until 6.5 minutes after the injection. At
10 minutes after the injection, full strength and language function had returned. At that
time, the patient recalled 7 of the 8 objects presented without any false-positive
responses for a net score of 7.0.
 CHAPTER 6 THE WADA TEST 83

Figure 6–1 (Continued ). (B) EEG obtained 10 seconds following injection of right
internal carotid artery with 100 mg of sodium amobarbital. As with the other injection,
there is increased fast activity and development of rhythmic delta activity over right
hemisphere leads and left frontal regions. Left arm weakness occurred and no
language dysfunction was identified. During the period of weakness, eight different
target objects were presented visually and the patient could name them. At 10
minutes following the injection, the patient identified all eight objects presented and
mistakenly chose one of the sixteen foils as a target object, so that the net score was
7.5. Thus, the EEG during the Wada test documented focal slowing with some
contralateral frontal slowing typically observed following unilateral injection. This Wada
study demonstrated intact memory function of both left and right hemispheres as well
as left hemisphere language dominance. These findings were expected in this
right-handed patient with a cavernous angioma near the left angular gyrus. The
patient has been seizure free for 14 months since a left temporal lobe lesionectomy
performed after intraoperative language mapping.

electrode recordings.62 As implied previously, attention
to the EEG helps distinguish global aphasia due to a uni-
lateral amytal effect from obtundation that might be due
to a temporary bilateral effect and it also helps avoid
false-negative data by assuring that language and mem-
ory stimuli are being presented while the amobarbital is
still active.30
RECORDING TECHNIQUES
“Protocols vary widely in almost every detail.”56 This
statement holds true for both the language and memory
aspects of the Wada test. In fact, protocol changes some-
times are made over time even within epilepsy centers.
For example, the type of stimuli, the timing of their pre-
sentation, and the assessment technique all vary.6 Wada
memory assessment can involve continuous testing or
discrete item presentation. Continuous testing involves
assessing memory after presentation of the stimuli and a
distracter task, all while the patient still is under the ef-
fect of the drug. With discrete item presentation, target
items are presented during the drug effect and memory
is then assessed about 10–15 minutes later or when the
amobarbital effect has dissipated.
Loring and colleagues37 developed the following
protocol that uses discrete presentation of real objects
followed by a language assessment and subsequent
measurement of recognition memory for the target ob-
jects. Real objects are presented rather than drawings or
verbal items so that the stimuli are minimally biased to-
ward either hemisphere and easily encoded. The Loring
et al. procedure, initiated at the Medical College of Geor-
gia, now is used with some variations in a number of
other epilepsy centers. Prior to the procedure, the patient
is informed of its purpose, and is instructed to remem-
ber a sentence and line drawings of two common ob-
jects. After the preparatory work of the neuroradiologists
84 SECTION I TECHNIQUES
is completed, the procedure starts with a single bo-
lus injection of 100 mg amobarbital (5% solution) by
hand over about a 4-second interval. As the injection is
made, the patient holds his or her hands raised in the air
with fingers spread and counts repeatedly from 1 to 20.
Following evaluation for hemiplegia and eye gaze devi-
ation, a simple motor command is given. The neuropsy-
chologist then presents eight common objects (utensils,
plastic animals, etc.) to the eye field ipsilateral to the in-
jection, and the patient’s eyelids are held open when
necessary. After the eight memory stimuli have been
presented, language tasks are administered: a modified
token test or comprehension test,63 object naming,
sentence repetition, and reading. A nonverbal discrimi-
nation task is also presented. The language and discrim-
ination tasks serve as “late memory items,” in contrast to
the objects, which are “early memory items” presented
during maximal amobarbital effect.
The counting, comprehension, naming, and read-
ing performances are scored on a 0 to 2, 0 to 3, or 0
to 4 scale, with zero representing normal function. Free
recall and recognition memory are tested after the amo-
barbital effect has cleared, as demonstrated by further
brief motor and language testing and EEG normaliza-
tion. A yes/no recognition memory test for the target
objects is the primary memory measure. It involves pre-
sentation of the eight objects randomly interspersed with
sixteen foils. A correct recognition of a target receives a
score of 1.0. Any false-positive errors are multiplied by
0.5 and that number is subtracted from the total num-
ber correct. False-positive errors are rare. The maximum
and minimum scores are 8.0 and -8.0, respectively, with
consistent guessing expected to achieve a score of 0.0.
Different target objects and foils are used after each in-
jection. If less than two target objects are recognized
after the injection ipsilateral to the planned surgery,
the test may be repeated for that side. Memory testing
for the “late memory items” follows the object mem-
ory assessment and the data is used to help determine
whether or not an injection is repeated on one side. See
Loring et al. (1992)37 for more procedural and scoring
details.
Over the course of the past two decades, Loring,
Meador, Lee, and colleagues have published a wide
range of reports based on their procedure that have ex-
tended knowledge of lateralized cerebral function and
helped secure the Wada test as a standard compo-
nent of the pre-ATL work up. Their Wada test reports
have covered topics that include optimizing amobarbi-
tal dosage and stimulus presentation timing, retrograde
memory, false-positive recognition memory errors, com-
parison of Wada language findings with cortical stim-
ulation mapping, prediction of post-ATL amnesia, and
hemispheric specialization for language representation,
memory, emotional expression, eye gaze mechanisms,
tactile attention, and motor organization.
DATA ACQUISITION AND
DATA ANALYSIS
Language
“The dominant hemisphere can be distinguished from
the nondominant . . . by the appearance of language
disturbances that in the space of 5–7 minutes repro-
duce all the known varieties of receptive and expres-
sive aphasia . . . ”22 The systematic assessment of object
naming and the gradual recovery from dysnomia dur-
ing the Wada test was described decades ago by Fedio
and Weinberg53 for left hemisphere speech dominant pa-
tients. No significant naming errors occurred after right-
side injection. After left injection, dysnomia persisted
after vocalization ability returned. Complete recovery
from dysnomia generally occurred within 5 minutes, al-
though some patients had persisting dysnomia for 6–
7 minutes. Errors of substitution and omission were
equally common, whereas perseverative errors were
much rarer. Rausch et al.64 also examined language func-
tioning after each injection in small groups of left and
right TLE patients, all of whom had left hemisphere lan-
guage dominance. In this study, the time elapsed until
naming and reading abilities returned to baseline was
not reported, but it was established that the time to
the first correct response for each of these abilities was
more prolonged for left-side injections. Any deficits af-
ter the right hemisphere injection resolved quickly. An-
other finding was a consistent interaction between side
of injection and side of seizure focus. After left injection,
delay to naming and reading lasted longer in right TLE
patients. The reverse was true for right-side injection,
but to a lesser degree. Similarly, EEG slowing in the
hemisphere ipsilateral to the injection was more pro-
longed when the epileptic focus was in the contralat-
eral hemisphere. Thus, dysfunction in the epileptogenic
hemisphere interfered with behavioral and physiologi-
cal recovery of the contralateral, injected hemisphere. In
fact, Fedio and Weinberg53 cautioned that an injection
contralateral to a hemisphere with diffuse cortical injury
can result in several minutes of unresponsiveness.
More recently, Ravdin et al.65 provided a compre-
hensive description of the gradual recovery from global
aphasia following dominant hemisphere injection of
either 100 mg or 125 mg of amobarbital, with some pa-
tients receiving additional incremental injections if nec-
essary to maintain hemiplegia. All 41 patients in this
study were judged to be either left hemisphere (95%)
or right hemisphere dominant, with no mixed domi-
nance cases present. After memory test items were pre-
sented, the authors tested language functions serially at
increasing levels of difficulty. For example, the naming
items included visual confrontation naming and naming
to definition, and the range of difficulty for the latter
included “color of the sky” versus “hard outside part

of bread.” Comprehension was tested with basic com-
mands such as “touch your nose” as well as syntacti-
cally complex questions that included, “If the lion was
eaten by the tiger, which animal died?” Items requiring
repetition were interspersed with the naming and com-
prehension items and ranged from the patient’s name
to “the phantom soared across the foggy heath.” Para-
phasic and dysnomic errors were monitored. Baseline
testing prior to the Wada procedure determined the high-
est levels of difficulty that would be employed during
the procedure. Recovery was defined as a successful re-
sponse to the most difficult item administered to a par-
ticular patient. It is notable that linguistic errors persisted
after the return of motor functions, consistent with other
reports.43,66 In almost 75% of patients, the pattern of lan-
guage recovery was described as a stereotypical progres-
sion, in which return of vocalization was followed in turn
by naming, comprehension, and then repetition. Thus,
muteness typically occurred and was followed by intel-
ligible vocalizations at an average of 3.5 minutes postin-
jection, although paraphasic errors invariably remained
at that point. The return of imperfect vocalizations was
followed by full return of naming at 8.5 minutes, com-
prehension at 10 minutes, and repetition at 12.5 minutes.
Ravdin et al.65 noted that anomia often is the most persis-
tent deficit in aphasia due to stroke, whereas a repetition
deficit or conduction aphasia was most persistent until
full recovery from the amobarbital. They hypothesized
that the latter may represent a specific amobarbital effect
on complex polysynaptic neuronal networks integrating
verbal comprehension and verbal expression. Finally, it
is worth noting that two left TLE patients in this study
demonstrated speech arrest after a right hemisphere in-
jection but in these cases this effect was not considered
evidence of right hemisphere language. One patient was
lethargic, abulic, and akinetic as well as mute, the other
initially was obtunded, and both showed rapid recovery
of all language functions upon return of vocalizations.
It was concluded that (1) “patterns representative of the
classic acquired aphasias are usually present following
dominant hemisphere injection and typically show an
evolution from a global aphasic syndrome to a longer
lasting conduction aphasia,” and (2) “recovery of lan-
guage functions uncomplicated by linguistic errors is
suggestive of nonlinguistic (i.e., motor, attentional) me-
diated aspects of vocal production.”
Meador67 discussed some of the considerations in
interpreting Wada language testing. For example, he
pointed out that agitation or obtundation may compli-
cate or preclude language assessment and absence of
aphasia after both injections can be due to either inade-
quate amobarbital effects or bilateral language represen-
tation. When language is in fact bilaterally represented,
there can be dissociations among various speech func-
tions, but the exact contribution of each hemisphere may
be difficult to determine.42,51 It should be noted that the
CHAPTER 6 THE WADA TEST 85
operational definition of bilateral speech varies among
epilepsy centers.68 In addition, the possible contribution
to language of the posterior temporal lobe(s), which is
not perfused by the amobarbital, cannot be determined
by Wada testing. This is an issue because early damage
to the anterior temporal lobe may result in either an in-
trahemispheric or interhemispheric transfer of language.
Memory
Initially, Wada memory testing emphasized the perfor-
mance of the hemisphere contralateral to the side of
the proposed lobectomy and evaluation of this hemi-
sphere remains vital.7,17,30,69–73 Failed memory test-
ing after amobarbital injection ipsilateral to the seizure
focus suggests the contralateral temporal lobe is dys-
functional and that surgery might result in amnesia. Such
contralateral temporal lobe dysfunction could be the re-
sult of a diffuse or multifocal initial precipitating injury
that caused not only a seizure focus in one temporal lobe
but also dysfunction in the other. Meningitis, encephali-
tis, and traumatic brain injuries are examples of this type
of injury. Another possible explanation of contralateral
memory impairment is the deleterious effect of seizures
across time.40,74
A false-negative Wada test memory result, in which
a patient passes memory testing after ipsilateral injection
and then develops severe amnesia after ATL, is rare.6,28
However, some patients who show adequate contralat-
eral Wada memory may show significant post-ATL de-
cline in memory functioning, as opposed to global
amnesia.75 The possible association between extent of
hippocampal resection and postoperative memory de-
cline received a good deal of early attention. But poor
outcome has more to do with the integrity of the ipsilat-
eral hippocampus.76–80 The ideal result from Wada mem-
ory testing is an intact score for the side contralateral to
the epileptogenic temporal lobe and a relatively low ip-
silateral score, in other words, a memory asymmetry. A
poor score for the ipsilateral, epileptogenic hemisphere
after an injection contralateral to it indicates a probable
abnormality of the hippocampus planned for resection.
This likelihood is, of course, preferable to resection of
a well-functioning hippocampus.37,70 Loring et al.81 re-
ported that left ATL patients who declined greater than
one standard deviation pre- to postsurgery on a verbal
selective reminding test or story memory test had a sig-
nificantly smaller mean Wada memory asymmetry score
(left injection score minus right injection score) com-
pared to patients who did not decline postsurgically. The
authors also applied a memory asymmetry cutoff score
of 2.5, where the score for each hemisphere ranges from
−8.0 to 8.0, to predict decline at the individual level.
Patients who had an asymmetry at least this large experi-
enced significantly less decline on the two verbal mem-
ory measures administered postsurgically compared to
86 SECTION I TECHNIQUES
those who had an asymmetry score less than or equal
to 2.0.
In this study then, neither left nor right hemisphere
memory scores in isolation were significantly related to
postsurgical memory outcome. It was the combination
of functional reserve in the contralateral mesial tempo-
ral lobe and the functional adequacy of the ipsilateral
side that predicted outcome. Thus, when hippocampal
sclerosis is present in the epileptogenic hemisphere, the
Wada memory score after the contralateral injection is
likely to be relatively low.27,49 This finding in combi-
nation with an intact contralateral Wada memory score
suggests a relatively low risk of significant postsurgery
decline on clinical memory testing and a greater likeli-
hood of seizure freedom.49,51,77,81–83 Significant memory
decline after surgery now often is defined by reliable
change index data, which are derived from assessing
nonsurgical patients on two different occasions.84
䉴 APPLICATION
HEALTHY SUBJECTS
Because it is an invasive procedure, the Wada test is not
carried out on healthy subjects.
DISEASE STATES
As noted, the Wada test is used most often in individuals
with TLE who are candidates for ATL.56 There contin-
ues to be variation among centers as to whether the test
is administered to all candidates or only a select group
of patients.6,14,15,23,30,37,41,56,85,86 Some institutions apply
it only in cases where cerebral dominance is uncertain
(e.g., left-handers or early left hemisphere damage), clin-
ical neuropsychological test results bring into question
the laterality or possible bilateralism of memory impair-
ment, or there is a discrepancy between other measures
such as EEG and imaging.51
䉴 VALIDATION OF THE TECHNIQUE
There has been very little systematic research on the
relative contribution of the Wada test to clinical decision-
making in the neurosurgical referral process.8,9 How-
ever, the validity of the Wada is supported by studies
that have revealed a correlation between Wada mem-
ory results and lateralization of the seizure focus, lateral
versus mesial temporal lobe localization of the epilepto-
genic zone, hippocampal volume and pathology, mesial
temporal glucose metabolism, age of seizure onset, and
post-ATL seizure outcome.23,49,74,77,87–93 For example,
Rausch et al.90 reported that 63% of TLE patients demon-
strated poor memory after amobarbital injection con-
tralateral to the side of proposed surgery. Hamberger
et al.87 reported that a group of patients with lat-
eral TLE had a significantly smaller memory asymmetry
score compared to a group with mesial TLE, consistent
with the expectation that a neocortical temporal seizure
focus would interfere less with new learning than a
mesial temporal focus. On the other hand, Spencer
et al.86 reported that five of seven patients with mesial
frontal lobe epilepsy demonstrated bilateral Wada mem-
ory impairment. They suggested that bilateral failure
should raise suspicion of mesial frontal epilepsy in pa-
tients who perform normally on clinical memory tests
and are thought to have mesial TLE.
In a unique criterion validity study, two patients
with global amnesia unrelated to epilepsy were admin-
istered a Wada recognition memory procedure without
injection of amobarbital.94 They failed the test by scor-
ing near or below the chance level, supporting the idea
that Wada memory failure in ATL candidates is capable
of identifying patients who are at risk for a post-ATL
global amnesia. In another study, the Wada test was ad-
ministered to three patients before they underwent an
amygdalohippocampectomy (2 left, 1 right) and then
a second time before resection of more tissue on the
same side by ATL.95 As would be predicted, all three
patients showed at least a slight decline in Wada mem-
ory performance when the contralateral hemisphere was
injected after the initial surgery.
Some patients are refused surgery or undergo a tem-
poral lobe surgery in which the hippocampus is spared
because they failed memory testing after an ipsilateral
Wada test injection. It cannot be determined how many
of such cases are actually false positives.51,59 That is,
while the Wada test can prevent post-ATL amnesia by
identifying patients who should not have surgery, it also
probably mistakenly excludes some patients with in-
tractable epilepsy from surgery.27,37,51,94 See Simkins-
Bullock29 for an extended discussion of this issue. To
avoid the scenario where a patient could be unnecessar-
ily excluded from surgery, Loring et al.37 recommended,
“We suggest that the Wada memory results not be con-
sidered as absolute and should be interpreted within the
entire clinical context of preoperative epilepsy surgery
evaluation.” In some cases where the Wada test results in
prolonged obtundation, anomalous data, or some other
question about its reliability, the test is repeated, possi-
bly with a smaller dose.6,29,96 An alternative is to carry
out a selective or superselective Wada test in which a
vessel that supplies a more limited cerebral territory is in-
jected. However, this type of injection is associated with
greater risks.28,37,97 For a discussion of selective Wada
procedures, see Weissenborn et al.98 and Wieser et al.99
A false-positive memory finding could result from
procedures in which verbal stimuli such as written words
predominate among the memory test items.40,100–102 This

approach conflates language and memory, so that a
left hemisphere injection in a patient with left TLE and
left hemisphere language dominance may result in an
apparent poor contralateral hemisphere memory score.
In fact, the contralateral score may be worse than the
ipsilateral memory score, which constitutes a reverse
asymmetry or “wrong-way Wada.” In one study, more
than one-third of the left TLE patients showed this re-
verse asymmetry.101 However, the failure to recognize
the verbal stimuli after the drug effect has worn off could
represent left hemisphere aphasia rather than right hemi-
sphere amnesia, which would explain the absence of
a relationship between Wada data and postoperative
memory outcome.101,102 For a memory Wada procedure
that employed dually encodable objects, the wrong-way
Wada occurred less frequently and was associated with
poor memory outcome, as would be expected.103
Because the amobarbital does not typically per-
fuse the posterior hippocampus, the exact effect of in-
tracarotid injection on memory functioning has been a
matter of debate.26,28,30 Some SPECT and depth elec-
trode recordings have led to the conclusion that the
amobarbital effect on a large part of the temporal lobe
produces a functional deafferentation of the posterior
hippocampus.61,104,105 Moreover, a number of studies re-
ported no relationship between posterior cerebral artery
(PCA) filling and memory performance.44,106,107 One
study found a limited relationship between the presence
of PCA filling and Wada memory performance, but the
authors concluded that lack of PCA filling does not inval-
idate the procedure.108 On the basis of the relationship
between Wada memory findings and hippocampal imag-
ing and pathology data, Jones-Gotman51 concluded,
“. . . we are succeeding in testing hippocampal function
with amobarbital memory tests. We infer further that re-
sults from the tests do allow us to predict postoperative
memory loss, although this remains difficult or impossi-
ble to prove.”
䉴 RELATIVE STRENGTHS AND
WEAKNESS COMPARED TO
OTHER MAPPING TECHNIQUES
Morbidity is low with the Wada test and its associated
arteriogram.6,14,15,30,41,57 But it is invasive, uncomfort-
able for the patient, and difficult to apply to children,
and interpretation can be complicated by issues such as
agitation, chronic cognitive impairments, or incomplete
sedation.109 In rare cases, it is necessary to physically re-
strain a patient for a brief period due to disinhibition or
agitation.38 It has been predicted, even by Wada himself,
that the test eventually will be replaced by less invasive
procedures.12,29 Some of these techniques can provide
localization as well as lateralization of functions, but they
CHAPTER 6 THE WADA TEST 87
are not without drawbacks themselves.57 For example,
functional MRI (fMRI) allows observation of changes re-
lated to regional blood flow during the performance of
cognitive tasks. It uses widely available technology, has
received the most research attention, can provide both
lateralization and localization information, and is the
leading candidate to replace the Wada test. But it is an
expensive procedure that requires a lengthy period of re-
stricted movement in a confined space on the part of the
patient and a great deal of data processing.57,109 Magne-
toencephalography directly measures neurophysiologi-
cal activation and is noninvasive, relatively fast, and free
of risk. But it has not yet been thoroughly tested as a
replacement for the Wada and is not widely available.57
䉴 EXAMPLES IN CLINICAL
PRACTICE
Andelman et al.7 described a relatively complex left TLE
case for which Wada data were useful. A 30-year-old,
left-handed man with a high school education had a his-
tory of early childhood febrile seizures and onset of com-
plex partial seizures at age 22. His seizures were resistant
to polytherapy with antiepilepsy drugs. Video-EEG, ictal
SPECT, and MRI were consistent with left TLE. How-
ever, clinical neuropsychological testing revealed both
verbal and visual memory impairment, which could in-
dicate bilateral dysfunction, as well as a deficit in visual-
perceptual ability. The Wada test (125 mg injections)
was consistent with right hemisphere language domi-
nance, impaired left temporal lobe memory (0/10 cor-
rect), and intact right temporal lobe memory (10/10).
After a left ATL, the patient was seizure-free except for
auras of déjà vu and showed no postoperative cogni-
tive decline. The authors concluded that language and
memory functions had transferred early in life to the
right hemisphere and in so doing created a “crowding”
effect, with visual-perceptual abilities suffering as a re-
sult. The authors observed, “The critical contribution of
the Wada test results to neurosurgical decision-making
was in its ability to demonstrate intact memory function
in the hemisphere contralateral to surgery. Demonstrated
right hemisphere language and memory functioning al-
lowed a more liberal left hemisphere resection . . . ”
䉴 PEARLS AND PITFALLS
Because there is no standardized Wada test, all of its
aspects vary from center to center, including the num-
ber and type of stimuli presented and the strategies for
interpreting the data.6,17,29,60 Almost four decades after
the memory component of the Wada test was initiated,
Milner27 wrote “. . . the question of how we define failure
88 SECTION I TECHNIQUES
on these tests remains to be satisfactorily resolved.” This
is in line with the cautionary note by Loring et al.37 that
Wada test memory results should not be considered in
isolation.
It recently has been reported that carbonic an-
hydrase inhibitors, which include topiramate and
zonisamide, can reduce the amobarbital effect.110 Barbi-
turate compounds such as phenobarbital also may affect
the cellular uptake of amobarbital.16,59 Because of past
shortages of amobarbital, other drugs have been used
as a replacement.111 These include etomidate, propofol,
and methohexital, all of which have half-lives shorter
than amobarbital.57 Etomidate is a nonbarbiturate with a
short duration of action that is administered by bolus and
subsequent infusion to maintain the drug effects. How-
ever, this medication was associated with adrenal insuf-
ficiency in critically ill patients (not Wada test patients)
who received a dose when they required tracheal intuba-
tion. In one Wada study,112 , about one-third of patients
experienced side effects from propofol that included in-
creased muscle tone and twitching and rhythmic move-
ments or tonic posturing. These were more likely to
occur in older patients who received a higher than aver-
age dose. Methohexital commonly is used for the Wada
test in France and South America and has been used suc-
cessfully in the United States.113 This drug is associated
with a shorter duration of action and less sedation than
amobarbital and so two or more successive injections are
made, with language tested after the first and memory af-
ter the second.113 Methohexital does have epileptogenic
potential with high doses45,113 and has been in short sup-
ply itself at times.111 In addition, it recently was reported
that methohexital resulted in a higher memory score af-
ter the second, contralateral hemisphere injection in one
group of patients compared to a second group that re-
ceived amobarbital.114
The future of the Wada test has been discussed for
many years. It is possible that advances in structural
and functional imaging, as well as our understanding of
the relationship between a range of epilepsy variables
and prognosis,73,85,115 , will make the test obsolete rel-
atively soon.57,97,109,111,116–118 One advantage the Wada
test maintains over most other approaches is its ability
to directly assess each hemisphere unilaterally.67,116,119
And, of course, both its strengths and limitations now
are well understood. But its future does indeed appear
to be growing shorter because of the promise shown
by fMRI and other noninvasive techniques.109,120–124 The
Wada test will remain widely used until it is established
that the noninvasive techniques have the ability to pre-
dict postsurgical language and memory outcome at the
individual level.57,102 The development of these nonin-
vasive tests could be hastened by multicenter collabo-
rative research.57,94 Although its future is uncertain, it
is clear that for more than five decades the Wada test
has made a unique and invaluable contribution to the
study of language, memory, and other neuropsycholog-
ical functions and the careful selection of candidates for
epilepsy surgery.
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65. Ravdin LD, Perrine K, Santschi Haywood C, et al. Serial
recovery of language during the intracarotid amobarbital
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66. Rausch R, Fedio P, Ary CM, et al. Resumption of behavior
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67. Meador KJ. Ambiguous language in Wada evaluations.
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68. Loring DW, Meador KJ, Lee GP, et al. Cerebral language
lateralization: evidence from intracarotid amobarbital test-
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69. Bell BD, Davies KG, Haltiner AM, et al. Intracarotid amo-
barbital procedure and prediction of postoperative mem-
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70. Chelune G. Hippocampal adequacy versus functional re-
serve: predicting memory functions following temporal
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71. Chiaravalloti ND, Glosser G. Material-specific memory
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72. Grunwald T, Lehnertz K, Helmstaedter C, et al. Limbic
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73. Jokeit H, Ebner A, Holthausen H, et al. Individual predic-
tion of change in delayed recall of prose passages after
left-sided anterior temporal lobectomy. Neurol 1997;49:
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74. Jokeit H, Ebner A, Arnold S, et al. Bilateral reduc-
tions of hippocampal volume, glucose metabolism, and
Wada hemispheric memory performance are related to
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76. Andelman F, Kipervasser S, Neufeld MY, et al. Predictive
value of Wada memory scores on postoperative learning
and memory abilities in patients with intractable epilepsy.
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77. Davies KG, Hermann BP, Foley KT. Relation between
intracarotid amobarbital memory asymmetry scores and
hippocampal sclerosis in patients undergoing anterior
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outcome from left anterior temporal lobectomy. Neuro-
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80. Stroup E, Langfitt J, Berg M, et al. Predicting verbal mem-
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81. Loring DW, Meador KJ, Lee GP, et al. Wada memory
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lobectomy. Neurol 1995;45:1329.
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83. Sass KJ, Lencz T, Westerveld M, et al. The neural substrate
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84. Martin R, Sawrie S, Gilliam F, et al. Determining reliable
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85. Helmstaedter C. Neuropsychological aspects of epilepsy
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86. Spencer DC, Morrell MJ, Risinger MW. The role of the in-
tracarotid amobarbital procedure in evaluation of patients
for epilepsy surgery. Epilepsia 2000;41:320.
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90. Rausch R, Babb TL, Engel J Jr, et al. Memory following
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93. Wyllie E, Naugle R, Chelune G, et al. Intracarotid amo-
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95. Brahman J, Morris RG. Pre- and postoperative intracarotid
amytal procedure: an assessment of validity. Epilepsy
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96. Blum DE, Bortz JJ, Ehsan T. Factors affecting degree
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98. Weissenborn K, Ruckert N, Brassel F, et al. A proposed
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99. Wieser H-G, Muller S, Schiess R, et al. The anterior
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way” Wada: the Wada test for language and memory lat-
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103. Sabsevitz DS, Swanson SJ, Morris GL, et al. Memory out-
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104. McMackin D, Dubeau F, Jones-Gotman M, et al. Assess-
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105. Urbach H, Kurthen M, Klemm E, et al. Amobarbital ef-
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107. Smith IM, McGlone J, Fox AJ. Intracarotid amobarbital
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114. Andelman F, Kipervasser S, Reider-Groswasser II, et al.
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 Chapter 7
Extraoperative Brain Mapping Using
Chronically Implanted Subdural
Electrodes
David E. Friedman1 and James J. Riviello, Jr.2
1
Department of Neurosciences, Winthrop-University Hospital,
Mineola, New York
2
Division of Pediatric Neurology, Department of Neurology and NYU Comprehensive Epilepsy Center,
New York University, New York, New York
䉴 INTRODUCTION
Epilepsy is the most common chronic neurological dis-
order and affects more than two million people in the
United States.1 Though newer medications for treat-
ment of epilepsy have been introduced over the past
two decades, many patients still do not attain seizure
control2 with medical therapy and other nonpharmaco-
logical forms of treatment may be necessary, including
resective surgery. In recent years, neuroimaging tech-
niques have advanced, and many patients who undergo
resective epilepsy surgery do not require invasive elec-
troencephalographic (EEG) recording studies. However,
for some patients, particularly those without a lesion on
magnetic resonance imagining (MRI) (nonlesional cases)
or when the noninvasive diagnostic evaluation reveals
undefined or discordant results, monitoring with inva-
sive EEG is necessary and potentially advantageous.3−6
Invasive studies not only allow for a more detailed anal-
ysis with intracranial EEG that is unfiltered by scalp and
skull, but also serve to permit functional localization,
or the mapping of cortical function, prior to cortical re-
sections. Chronically placed invasive electrodes offer the
possibility of extraoperative testing at the bedside, as op-
posed to intraoperative testing in which time limitations
and anesthesiology considerations are factors that may
limit the functional mapping. This chapter reviews the
role of extraoperative cortical functional localization, its
benefits, and limitations.
䉴 HISTORICAL PERSPECTIVE
Intracranial recording and adjunctive brain electrical
stimulation offer information regarding epileptogenic
localization and preresection assessment of eloquent
93
cortex; in other words, what to resect and what not
to resect. Historically, the observations of clinical semi-
ology associated with epileptic seizures first by John
Hughlings Jackson7 then by Sir William Richard Gowers8
provided the initial clues in functional localization. For
instance, the “Jacksonian march” is a classic term de-
scribing the spread of involuntary muscle movements
associated with progressive focal motor seizures, and in-
dicates cortical involvement of the motor cortex.
Stimulation studies have provided much of our
knowledge on brain functioning. Animal studies were
first performed in the 19th century by Fritsch and Hitzig,9
in which frontal cortical stimulation produced contralat-
eral forelimb movement and resection resulted in fore-
limb weakness in the dog. Roberts Bartholow’s 1874
study of the patient Mary Rafferty is widely cited as the
first demonstration of the motor excitability of the human
cerebral cortex, although some question its priority.10
Functional localization of human motor, sensory, and
language-related cortex was initially determined from di-
rect observations made in the operating room with elec-
trical stimulation during the diagnosis and treatment of
epilepsy.3 Intraoperative electrical stimulation eventually
led to the development of a topographic map of mo-
tor and somatosensory function of the respective pre-
and postcentral gyri, better known as the motor and
somatosensory homunculi.11 The homunculi were intro-
duced by Wilder Penfield and Theodore Rasmussen as
a means of summarizing the functional organization of
the primary motor and sensory cortices.11 This allowed
the identification of eloquent cortex prior to surgery
for the treatment of epilepsy, and helped the neurosur-
geon avoid areas that could lead to functional neurolog-
ical deficits if resected.
Penfield described the first case of intracranial EEG
monitoring for surgical treatment of epilepsy in 1939.12
94 SECTION I TECHNIQUES
Over the last several decades, centers around the world
have utilized a technique of implanting various arrays of
electrodes in different portions of the subdural or epidu-
ral space in patients with medication-resistant epilepsy
for both epileptogenic and functional localization in
adults13−26 and children.27−29 These techniques help
clinicians pursue proper surgical management, while de-
creasing the risk of adverse affects of normally function-
ing cortical areas with resection.
䉴 METHODOLOGY
Chronic intracranial EEG recording is indicated for
selective patients with intractable, pharmacoresistant
epilepsy who are undergoing evaluation for epilepsy
surgery. Specific indications for indwelling EEG elec-
trodes must be met before pursuing this invasive proce-
dure. Localization of the epileptogenic zone starts with
noninvasive methods including inpatient noninvasive
video-EEG monitoring, MRI, positron emission tomogra-
phy, and single photon emission computed tomography.
If the area of interest is not localized after this evalua-
tion, or if the results of the diagnostic assessment are
discordant, intracranial EEG by way of subdural strips,
grids, and depth electrodes may be employed to iden-
tify or further delineate epileptogenic regions.4,30 How-
ever, placement of the electrodes should only be per-
formed after the evaluation guides the epileptologist to
a reasonable hypothesis as to the location of the area of
epileptogenicity. The hypothesis should be based on not
only the results of the aforementioned studies, but also
supplemented with the clinical history and neurologi-
cal examination. The strength of this hypothesis is pro-
portional to the likelihood of success with the invasive
evaluation.31
䉴 SUBJECT PREPARATION
Once a patient is considered for intracranial EEG mon-
itoring, that patient is taken to the operating room and
electrodes are placed. Subdural strip and grid electrodes
and depth electrodes are most commonly used.31−33
Subdural electrodes are embedded in thin sheets or strips
of flexible biocompatible material, such as polyurethane,
and implanted in the subdural space (Fig. 7–1). Subdu-
ral grids are typically placed over the cortical surface
through a craniotomy. Grid arrays contain disc elec-
trodes made of stainless steel or platinum alloy that
measure 2–4 mm in diameter spaced at 1 cm fixed
intervals. Grids are commercially available in a vari-
ety of sizes and shapes, with varying number of elec-
trodes in rows and columns, and may contain up to 64
contacts points. Their placement requires a craniotomy.
Figure 7–1. Subdural electrode array placed over the
cortical surface in preparation for chronic extra-
operative recording.
Subdural strips are made of similar material and contain
similar electrodes with the electrode array in a single
row of varying number and length. The strips may be
inserted through burr holes or the edges of the cran-
iotomy and slipped into the subdural space providing
coverage beyond the “window” of the craniotomy. Strips
provide EEG coverage to areas that may not be easily
accessed with a craniotomy, such as the orbitofrontal,
occipital, and basal surface of the temporal regions.19,34
Once placed, it is imperative to test the electrodes in
the operating room with electrocorticography to ex-
clude technical malfunction and ensure satisfactory ex-
traoperative recording. It is suboptimal care to discover
that the invasive electrodes, not tested in the operating
room, are not working afterward when the patient is
in postoperative care or the epilepsy monitoring unit.
The craniotomy is then closed and the patient is eventu-
ally transferred to a video-EEG monitoring unit for con-
tinuous EEG to assist in determining the epileptogenic
area(s).
In addition to localization of areas of epileptogenic-
ity, the chronic indwelling intracranial electrodes allow
for functional localization studies that could be per-
formed in the video-EEG monitoring unit at the bed-
side. Functional localization techniques with subdural
electrodes include cortical stimulation. Cortical stimu-
lation involves introducing small currents of electricity
through individual electrodes with simultaneous obser-
vation for clinical symptoms or signs of either the acti-
vation or interference with cortical functioning.35 For in-
stance, applying electrical stimulation over the patient’s
motor cortex would produce contralateral motor signs,
manifesting with involuntary movements. This is referred
to as brain mapping.
 CHAPTER 7 EXTRAOPERATIVE BRAIN MAPPING 95

䉴 BACKGROUND ELECTRONIC
PRINCIPLES
Ohm’s law states that voltage (V ) = current (I ) × re-
sistance (R). The current intensity, measured in mil-
liamperes (mA), is determined by the height of each
square wave pulse. The rate of stimulation is inversely
related to the pulse interval, which represents the in-
terval of time between the onset of each consecutive
pulse. The charge (coulombs, C) of each square wave
pulse is obtained by multiplying the current intensity by
the pulse duration. With biphasic stimulation, the charge
correlates with the area under each phase of the pulse.
The charge density represents the charge per unit cross-
sectional area stimulated.
The area of cortical tissue stimulated depends on
both the distance from the stimulating electrode to the
cortex and the amount of current applied. The area stim-
ulated decreases by the square of the distance from the
stimulating electrode. Therefore, only a relatively small
area is stimulated.36
Current density rapidly diminishes with increas-
ing distance from the tissue underlying the stimulat-
ing electrodes.37 Also, significant shunting could occur
through cerebrospinal fluid (CSF) so that the maximum
current density could be reduced as much as tenfold
when traveling from the CSF to the gray matter.38 Elec- Figure 7–2. Example of a constant current stimulator
trode shape also plays a role in the current distribution, device. (Nicolet Cortical Stimulator, CareFusion.)
as a smooth drop off occurs when currents move from
the center of a circular contact, and the drop off is not 1 cm center-to-center distances. Pulse width is set to ei-
smooth when current distributions were estimated at the ther 300 or 500 microsecond (␮s), and the pulse fre-
edges of the circular disk.37 These effects cause theoret- quency ranges from 20 to 50 Hz. An alternating current
ical issues when trying to estimate the amount of cortex is administered for anywhere between 3 and 10 sec-
affected by electrical stimulation. onds, with a subsequent stepwise advancement in cur-
rent. Initial current setting may be as low as 1 mA and
䉴 INSTRUMENTATION, RECORDING gradually increased to the maximum of 15–17.5 mA or
afterdischarge (AD) thresholds, whichever is lower. A
TECHNIQUES, AND DATA
summary of the typical parameters can be found in Ta-
ACQUISITION AND ANALYSIS ble 7–1. The duration of electrical stimulation (train dura-
tion) may vary based on the cortical region or the cortical
Electrical current is delivered to the intracranial elec- function being tested. For instance, when testing motor
trodes with a constant current stimulator device, such as
the Grass S12 stimulator (Grass Technologies, West War-
䉴 TABLE 7–1. TYPICAL STARTING
wick, RI, USA), Nicolet Cortical Stimulator (CareFusion
PARAMETERS FOR EXTRAOPERATIVE
Middleton, WI) (Fig. 7–2) or other commercially avail-
FUNCTIONAL CORTICAL MAPPING
able stimulators. Bipolar stimulation, defined by using
two adjacent electrodes rather than monopolar electrode Pulse Pulse Train
stimulation is typically employed. Monopolar stimula- Current Width Frequency Duration
tion was previously described,39 and involves testing a (mA) (␮s) (Hz) (seconds)
contact of interest by pairing the active electrode to a 1.0a 300 50 3b
distant reference electrode in a silent area. Bipolar stim-
a
ulation offers the advantage of theoretically producing Current is gradually increased to the maximum of 17.5 mA or
afterdischarge threshold, whichever is lower.
a higher current density in a more restricted area than b
Train duration can be administered between 3 and 10 seconds,
monopolar stimulation.39−41 Brief pulses of stimulation depending on the region stimulated, with longer periods of
are applied to indwelling electrodes that are spaced by stimulation typically required for language mapping.
96 SECTION I TECHNIQUES
functioning, relatively shorter periods of stimulation de-
livery (short train) may be necessary. Longer periods of
electrical stimulation (long train) may be required for
more advanced testing, such as when mapping different
aspects of language function. Larger amounts of current,
the energy, (an increase stimulation intensity, pulse du-
ration, or both), may be needed to obtain responses in
children as the amount of current needed is dependent
upon the degree of myelination.42
Symptoms during stimulation may include positive
motor phenomena (tonic or clonic contraction of a mus-
cle group), negative motor phenomena (inhibition of
voluntary movements of the tongue, fingers, or toes),
somatosensory phenomena (tingling or numbness of
a part of the body), or language impairment (speech
hesitation or arrest, anomia, or difficulties with com-
prehension by either sentence completion or simple
commands).29,31 Language tasks may include having the
patient recite a well-known phrase or poem, or read in
order to assess for speech hesitation or arrest. The pa-
tient may also be asked to name an object or picture
during stimulation to test for dysnomia. To assess recep-
tive language functioning, the patient could be asked
to complete simple phrases or follow commands during
stimulation. Signs or symptoms during electrode stimu-
lation indicate that the cortex underlying the contacts is
involved in that particular affected function. A summary
of the possible responses can be found in Table 7–2.
Clinical syndromes and specific areas have been demon-
䉴 TABLE 7–2. RESPONSES INDUCED BY CORTICAL STIMULATION
Cortical Regions
Positive Responses:
Induce function (excitation)
Motor cortex
Somatosensory cortex
Auditory cortex
Visual cortex
Negative Responses:
Inhibit function (depolarization,
inhibition)
Primary negative motor area
(lateral convexity)
Supplementary negative motor
area (mesial interhemispheric
surface)
Language areas (Broca’s,
Wernicke’s)
SMA, supplementary motor area; PMA, primary motor area.
strated with cortical stimulation, and include frontal
eye fields,43 supplementary motor area,21,44 supplemen-
tary negative motor areas,45 cingulate gyrus,46 Broca’s
aphasia,20,47 Wernicke’s aphasia,48 conduction aphasia,49
Gerstmann’s syndrome,50 basal temporal language,51
basal temporal vision and alexia,25 auditory naming
cortex,52 writing,53 and verbal memory.22
During extraoperative functional mapping studies,
simultaneous video-EEG is recorded. The continuous
display of EEG allows the clinician to determine whether
stimulation induced an electrographic seizure causing
the patient’s symptoms or signs. It also permits the neu-
rologist to view for ADs.
One of the complications of direct cortical stimu-
lation is the occurrence of ADs, which are repetitive
epileptiform potentials or rhythmic waveforms that fol-
low the precipitating electrical stimulus (Fig. 7–3). The
presence of ADs, defined as spikes, sharp waves, or
rhythmic discharges following cortical stimulation or the
induction of an actual habitual seizure may help to local-
ize the area of epileptogenicity.54 In addition, the pres-
ence of ADs during cortical stimulation indicates the
local convulsive threshold.55 However, these findings
should be viewed with caution, as the induction of a
habitual seizure following cortical stimulation does not
absolutely guarantee that the seizure did originate from
that stimulated source (the actual electrodes stimulated),
nor does it guarantee that the area stimulated repre-
sents the epileptogenic zone.56 In addition, there is not a
Responses Comments
Movements SMA: primarily proximal and
tonic contralateral upper
extremity movements
PMA: primarily distal and
clonic contralateral
extremity movements
Dysesthesias
Buzzing sensation
Phosphenes
Inhibilion of voluntory
movements
Speech hesitation, or
arrest, anomia,
alexia, difficulties with
comprehension
 CHAPTER 7
Figure 7–3. Afterdischarges following direct cortical stimulation.
consistent relationship with the elicitation of ADs from
a given site and the site of origin of habitual seizures.57
The AD threshold is determined in each stimulated
location, if possible. The AD threshold is obtained by
sequentially increasing the amount of current applied
and monitoring the electrocorticogram for ADs. The AD
threshold varies in different cortical regions, and may
not occur in every stimulated area.58 In adults, func-
tional testing is usually done at subthreshold AD stimula-
tion levels, as the clinical response stimulation intensity
threshold is lower than the AD stimulation intensity
threshold level and ADs may interfere with function.
However, the clinical response threshold is higher than
the AD threshold level in children younger than 4–6
years.42
䉴 SAFTEY AND POTENTIAL
ADVERSE EFFECTS
Established safety parameters are necessary for cortical
stimulation in humans. Animal studies have indicated
that predictable damage to the cortex can occur when
specific stimulation parameters are exceeded.59 Mecha-
nisms of stimulation-induced tissue injury include accu-
mulation of a negative charge at the cathode, production
of metal ions from the anode, and tissue heat produced
by hydrolysis.60 However, most animal models typically
employ continuous stimulation over prolonged periods
of time, for example, 0.5 hours,61 205 hours,62 and 9
hours/day for 4 days.63 In contrast, cortical stimulation
in humans for functional mapping occurs over a brief
period of time, typically lasting no more than 10 sec-
onds. Extraoperative individual sessions of testing may
EXTRAOPERATIVE BRAIN MAPPING 97
last from one to several hours, and sessions may recur
over several days.16 Furthermore, the testing involves
intermittent brief pulses of stimulation, rather than
continuous stimulation. Prior studies have shown that
intermittent stimulation is associated with less cortical
damage than occurs with continuous stimulation, even
when the intermittent periods of stimulation are far
longer than what typically occurs during extraoperative
functional mapping.63,64 Gordon and colleagues evalu-
ated the possibility of stimulation-related tissue damage
in three patients who had undergone subdural electrode
stimulation. The histopathology on all three patients re-
vealed no evidence that electrical stimulation caused
cortical changes.38 Girvin reported a patient who had
received occipital cortical stimulation via subdural elec-
trodes for a period of 10 years for the purpose of artifi-
cial vision production. No reports of pathologic changes
were seen after removal of the electrodes.65
A more practical consideration regarding safety and
extraoperative cortical electrical stimulation is the possi-
bility of infection. With indwelling subdural electrodes,
the potential for infection exists, as the wires from the
electrodes exit through the dura, skull, and scalp. Most
centers attempt to minimize the risk with strict anti-
septic preventative techniques both in and out of the
operating room. In addition, tunneling the wires for dis-
tances through the scalp, and vigorous use of prophylac-
tic antibiotics also help lower the potential for infection.
The incidence of infection was reported to be between
5% and 15%66,67 over a decade ago, but has decreased
over the years to 1% to 5%, with the low end of that
range being applicable to most recent years.68−70 Infec-
tion may be less frequent with subdural strips than with
grids.42
98 SECTION I TECHNIQUES

Patients generally tolerate the actual stimulation 䉴 EXTRAOPERATIVE VERSUS

without difficulties. However, ipsilateral painful sensa- INTRAOPERATIVE FUNCTIONAL
tions can be induced with either epidural stimulation or
MAPPING
by stimulation of trigeminal nerve fibers accompanying
pia-arachnoid vessels.71 Epidural stimulation may oc-
One of the major advantages of mapping with extra-
cur with reoperation, when scar tissue may preclude
operative subdural arrays is the fact that functional lo-
only subdural positioning. Subthreshold AD stimulation
calization studies can be performed after the patient is
is also done to prevent the induction of a seizure during
transferred from the operating room eventually to the
cortical stimulation, since this often halts the stimulation
epilepsy monitoring unit. This allows for a less restricted
session due to lack of cooperation.
time limit, given that recording time of the intraoperative
Hemorrhage, namely subdural hematoma with sub-
technique is often limited to no more than a few hours.
dural electrodes, is one of the more feared complica-
Extraopertative testing may be repeated if information is
tions of indwelling electrodes. The incidence of life-
not obtained or if the patient has seizures that preclude
threatening hemorrhage has been reduced by using
further testing during a session. Also, the patient should
preoperative angiography to define vascular anatomy
be fully awake during extraoperative testing, allowing
and directly visualizing the cortex through use of a
the examiner to carefully gauge for clinical changes in a
craniectomy rather than a burr hole for electrode place-
relatively stress free environment.
ment. Preoperative evaluation of coagulation and clot-
The disadvantages of extraoperative placement in-
ting parameters is essential, as well as counseling pa-
clude the potential for a direct infection. One study
tients to avoid drugs that inhibit platelet functioning in
found an overall rate of infection of 7.9% and a 5.7% rate
the week before surgery.72 Caution should be used with
per craniotomy.75 Inflammatory responses have been
valproate, since it may interfere with hemostasis and pro-
seen on histopathology to the invasive electrodes. Multi-
mote bleeding.
focal septic meningitis and hypersensitivity meningoen-
Another major, yet rare, risk is edema underneath
cephalitis occurs, more with subdural electrodes rather
the grid electrodes. Herniation has been reported, usu-
than depth electrodes76 ; this may raise the question
ally in the first few days after electrode implantation,
of chronic encephalitis as the cause of the refractory
though the incidence is well less than 1% with modern
epilepsy. Intraoperative testing lengthens the operating
electrodes.72 Because of this potentially life-threatening
time, but otherwise imparts no added risk to the patient.
adverse effect, patients who undergo intracranial moni-
In addition, intraoperative testing allows better anatomic
toring require regular, careful neurological assessments,
resolution since there is direct observation of electrode
as emergent removal of the electrodes might be neces-
position and the recording electrodes can be moved, de-
sary. A recent epilepsy center reported complications
pending on the responses.77
during invasive video-EEG monitoring with subdural
An example of a map created from extraoperative
grid electrodes.73 Complications were encountered in
monitoring and cortical mapping in a patient with a prior
less than 20% of patients. Most were transient and did
resection is presented in Fig. 7–4. It is not possible to
not require treatment. A summary of these complications
obtain all this information from a shorter period of in-
can be found in Table 7–3. Complications were associ-
traoperative monitoring alone: ictal onset and spread of
ated with greater number of electrodes, longer duration
electrographic seizure activity, interictal activity, and cor-
of monitoring, older patient age, left-sided grid insertion,
tical mapping obtained from cortical stimulation (face
and burr holes in addition to the craniotomy. Prophylac-
motor, receptive language, Gertsmann’s syndrome, pic-
tic administration of steroids during monitoring is effica-
ture naming) and visual evoked potential data (courtesy
cious in reducing cerebral swelling and may reduce the
of Masanori Takeoka, Children’s Hospital, Boston). This
risk of potential complications.74
would require an awake craniotomy, which requires

䉴 TABLE 7–3. SUMMARY OF COMPLICATIONS DURING 198 EPISODES OF INVASIVE

VIDEO-ELECTROENCEPHALOGRAPHIC MONITORING WITH SUBDURAL GRID ELECTRODES∗

Complication Frequency n (%) Treatment Required n (%) Permanent Deficit n (%) Death n (%)

Neurological deficit 25 (12.6) 9 (4.6) 3 (1.5)

Infection 24 (12.1) 18 (9.1) 6 (3.0)
Bleeding 6 (3.0) 5 (2.5) 1 (0.5)
Decreased consciousness 5 (2.5) 1 (0.5)
Delirium 1 (0.5) 1 (0.5)

Values are expressed as n or (%).

∗
Modified from Hamer HM, Morris HH, Mascha EJ, et al., (73).
 CHAPTER 7 EXTRAOPERATIVE BRAIN MAPPING 99

41
42 33
43 34 PP
1 44 35
2 45 6
FP 3 6 73
4
5 56 474 83
6 6 8 3
55 4 4 0 39
Face motor
7 PO
8 63 4
Receptive language
546
53 2 32 31 30 29 28 27 26 25
61 24 23 22 21 20 19 18 17
5
AT 2 60
51
5
50 9 16 15 14 13
12 11 10 9
58 8 7 6 5
49 4 3 2 1
57
Gerstmann
syndrome TO

8
8

7
6
7
ST

5
Picture

4
naming

3
3

2
MT
2
1
1
VEP max

Figure 7–4. Example of a map of chronically implanted subdural electrodes for

extraoperative monitoring. AT, anterior temporal; MT, mesial temporal; FP, frontal
partial; PP, posterior partial; PO, partial occipital; TO, temporal occipital; ST, superior
temporal; VEP, visual evoked potential.

different anesthetic techniques and is also not suitable
for many patients, especially younger children.78
䉴 CONCLUSIONS
Across the world, epilepsy surgery centers have been us-
ing intracranial EEG monitoring for patients with phar-
macoresistant epilepsy. Decisions to use this form of
monitoring are not systematic, and are based on results
of extensive diagnostic evaluation for the individual pa-
tient, which includes extracranial video-EEG monitoring,
structural and functional neuroimaging, and neuropsy-
chological evaluation. Invasive monitoring allows for
functional cortical mapping, which provides the treat-
ing neurologist and neurosurgeon information regarding
eloquent cortex, which, in turn, may play a substantial
role in surgical planning.
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 Chapter 8
Brain Mapping in the Operating Room
Sepehr Sani 1 , Edward F. Chang 2 , and Nicholas M. Barbaro 3
1
Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois
2
Department of Neurological Surgery, University of California, San Francisco, California
3
Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana
䉴 INTRODUCTION AND HISTORY
Classic anatomic descriptions of cortical language and
motor locations are not sufficient for localizing elo-
quent cortices. Language organization in the dominant
hemisphere is highly variable in the setting of normal
anatomy.1–5 Furthermore, reorganization and plasticity
of language and primary motor cortices due to tumors,
epilepsy, or vascular lesions is common.6–8 Although
uses of neuronavigation and functional neuroimaging
have improved localization, these techniques only reveal
areas that are involved in language or motor function,
but not critical to it. Intraoperative cortical mapping is a
method to identify essential cortical areas for language
or motor functions, which provides the neurosurgeon
with a more precise intraoperative understanding of ac-
ceptable resection borders.
Originally described by Penfield and Boldrey9 for
identification of the central sulcus, the technique of di-
rect cortical stimulation mapping involves 50- or 60-Hz
frequency intermittent stimulation of small cortical
patches while observing motor or language responses
in the patient. Stimulation mapping of eloquent cor-
tex continues to remain the gold standard for providing
in vivo representation of motor and language areas.
䉴 UNDERLYING PRINCIPLES
Intraoperative mapping of a hemisphere for localizing
language function is performed after lateralization has
been determined preoperatively by the amobarbital test.
Traditionally, in order to ensure the lowest possible risk
of postoperative neurological deficit, the planned cran-
iotomy included the area of proposed lesion resection as
well as the central sulcus, pre- and postcentral gyri, an-
gular gyrus, and the anterior superior temporal/inferior
prefrontal Broca’s areas. This technique relies on positive
identification of cortical areas responsible for language
or motor function, as well as negative areas that can be
safely resected. However, the large craniotomy size and
103
extensive mapping time are often time-consuming and
uncomfortable for the patient. More recently, it has been
shown by Sanai et al.10 that a tailored craniotomy includ-
ing the cortical margins of lesion with negative mapping
of language areas can be used as effectively in tumor
resections with morbidity comparable to more extensive
craniotomies and positive mapping.
Cortical electrical stimulation involves both excita-
tion and inhibition of input/output fibers, local interneu-
rons, and passing fibers affecting distant sites.11 With mo-
tor cortex stimulation, a “positive response” is elicited:
movement of a body region detected either visually or
with electromyography electrodes. Conversely, language
mapping involves a “negative response” with cessation
of language or induction of errors in naming. Motor map-
ping appears to cause direct excitatory depolarization
of the corticospinal tract, whereas speech mapping ap-
pears to result from local interference in the language
network. Electrical spread of current across the cortex is
dependent on duration and amplitude of stimulation but
is typically 1 cm or less.
䉴 METHODS
The anesthetic technique varies greatly depending on
which cortical functions are to be mapped and whether
intraoperative electroencephalography (EEG) will be uti-
lized. If language mapping is desired, awake craniotomy
with local anesthesia and sedation is required. For motor
mapping alone, the operation may be performed under
general anesthesia. If EEG will be used as in determin-
ing a seizure focus, then preanesthetic sedative medi-
cations and intraoperative anesthetic agents should be
avoided. In fact, even brief use of certain inhalational
agents can interfere with EEG for several hours. Resec-
tions involving the premotor region and/or primary sen-
sory cortex should be performed in the awake setting.
Baseline dysphasia or aphasia, significant language bar-
rier, confusion, or decreased level of consciousness are
contraindications to awake craniotomy. Development of
104 SECTION I TECHNIQUES
patient rapport and review of steps of operations be-
forehand are very helpful in reducing anxiety in awake
patients. For picture naming, it is important to have
the person who will perform the intraoperative testing,
review the material with the patient the day prior to be
sure that instructions are understood and that the pa-
tient can name all objects to be used in the operating
room.
POSITIONING
The patient is positioned on the operating table accord-
ing to the usual routine and monitors are attached, an
indwelling urinary catheter is inserted, and oxygen deliv-
ery via nasal cannula is provided. Usually, the semilateral
position is preferred using a padded roll for back sup-
port. Pressure points are padded. Medications such as
mannitol and dexamethasone, as well as antibiotics are
given prior to making the incision based on individual
surgeon preference. If frameless stereotactic techniques
are needed, the patient will typically be placed in pins.
Otherwise, a foam headrest is sufficient and avoids po-
tential injury if the patient has a seizure during the pro-
cedure.
ANESTHESIA
For general anesthesia, routine cranial neuroanesthe-
sia protocol is followed. Pharmacological paralysis and
high concentrations of inhalation anesthetic agents are
avoided. In awake craniotomy cases, the following reg-
imen is employed:
Before incision, midazolam (2 mg; avoided if EEG
to be recorded) and fentanyl (50–100 ␮g) are adminis-
tered. During surgery, either propofol (50–100 ␮g/kg of
body weight per minute; avoided if EEG to be recorded)
or dexmedetomidine (0.7–2 ␮g/kg/h) and remifentanil
(0.05–0.2 ␮g/kg/min) are given. Local anesthesia is given
along the Mayfield pin sites as well as a circumferential
scalp field block. A mixture of 0.5% lidocaine, 0.25%
Marcaine (bupivacaine hydrochloride), and epinephrine
(1/200,000) are used. Once the craniotomy is performed,
intradural injections along either side of the middle
meningeal artery are given. Anesthetic agents are discon-
tinued at this time until mapping is completed. Painful
portions of the operation, such as early portions of the
exposure and dural opening are managed by patient
reassurance and transient increase in propofol infusion
rate. In cases of insufficient sedation, supplementary bo-
luses of propofol (0.5 mg/kg) are given and the infu-
sion rate may be increased to 125 ␮g/kg/min. Nausea or
vomiting can be controlled with intravenous droperidol
(1.2–2.5 mg) or metoclopramide (5–10 mg). The patient
is asked to hyperventilate before dural opening. Once
mapping is complete, sedatives are restarted.
Intraoperative seizures due to cortical stimulation
have been reported in up to 24% of cases.12,13 Epilepsy
patients are at particularly increased risk of intraop-
erative seizures due to decreased anticonvulsant lev-
els. These seizures, whether focal or general, are usu-
ally transient and can be suppressed by application of
local ice-cold Ringer’s solution and a bolus of intra-
venous propofol (1 mg/kg).14 If seizures are prolonged,
they should be controlled with intravenous methohexi-
tal, 0.5–1 mg/kg. If airway control is of concern, tracheal
intubation may be necessary.
CRANIOTOMY
The draping is performed accordingly to allow the anes-
thesiologist and examiner the full view of the patients
face as well as contralateral arm and leg for intraoper-
ative monitoring. A frontotemporal craniotomy is per-
formed using standard neurosurgical technique with the
assistance of neuronavigation. A tailored craniotomy is
preferred, including the underlying lesion or seizure
focus, along with exposure of surrounding posterior
frontal and superior temporal lobes. After the durotomy,
neuronavigation is used to identify the cortical margins
of the lesion. Expected locations of central sulcus and
sylvian fissure are also identified. All margins and land-
marks are labeled on the cortical surface.
SOMATOSENSORY EVOKED
POTENTIAL RECORDING
Evoked potential recording is used to localize the central
sulcus.15,16 This is particularly helpful in cases in which
underlying lesions have distorted normal anatomy. The
technique is performed by placing an electrode strip per-
pendicular across the proposed location of central sul-
cus. A contralateral suprathreshold median nerve stimu-
lation is made, an N20 wave is recorded over the hand
somatosensory cortex, and a phase reversal is observed
across the fissure. This process is performed several
times as the strip is moved along the sensory-motor strip.
Recording is usually begun 3 cm above sylvian fissure
and repeated a few times as the strip is moved more
medial. Two or three recordings are usually needed to
localize the central sulcus. The hand region is the most
readily identifiable area and is generally localized to
4–6 cm above the sylvian fissure. Once identified, the
sulcus is labeled accordingly and the strip is removed.
Evoked potential recording can be performed in the
awake patient or under general anesthesia.
 CHAPTER 8
ELECTROCORTICOGRAPHY
In patients with intractable epilepsy, electrocorticogra-
phy may be used in order to identify the abnormal in-
terictal spikes. The technique requires the presence of a
neurophysiologists or epileptologist with neurophysiol-
ogy expertise in the operating room for recording inter-
pretation. An electrode grid is laid over the cortical area
of interest and several minutes of electrocortical activity
are recorded. Areas with abnormal interictal spikes are
marked.17,18 Surgical resection of these areas depends
on their functional importance based on motor or lan-
guage mapping. Electrocorticography is also employed
in monitoring of afterdischarges during sensorimotor
or language mapping as described in the succeeding
section.
SENSORIMOTOR STIMULATION
The localization of pre- and postcentral gyri is con-
firmed by direct cortical stimulation after identification
with evoked potentials. Detailed somatotopic mapping
is also possible with cortical stimulation. This technique
is used when the lesion or seizure focus is close to or
involves sensorimotor locations.
Stimulation is performed using an Ojemann Cortical
Stimulator (Radionics Corp., Burlington, MA). Primary
sensory cortex is mapped with the patient awake. Stim-
ulation parameters of 1–2 mA total, with a frequency
of 60 Hz and a pulse duration of 1 ms are used. Corti-
cal patches of 1 cc are stimulated sequentially with rest
periods between stimulations. The probe is applied to
the cortex for short 1–2 seconds duration and the pa-
tient is asked to report the onset and location of any
perceived paresthesias. Stimulation starts in the supra-
sylvian portion of the sensory gyrus and advanced su-
periorly, thereby sequentially identifying the tongue, lip,
and hand sensory areas.
If the operation is being performed under general
anesthesia, only motor mapping is possible.17 Stimula-
tion parameters remain the same, but usually a higher
threshold of initial stimulation is used (3 mA). Stimula-
tion intensity increases until contralateral movement is
observed by the anesthesiologist or the examiner. Am-
plitudes greater than 18 mA are not recommended in
motor cortex stimulation. Congruent with sensory map-
ping, stimulation is initiated in the suprasylvian region in
1 cc patches and moves superiorly along the gyrus un-
til somatotopic mapping of tongue, lips, thumb, hand,
and arm are obtained sequentially. If mapping of motor
leg region is needed, stimulation is given through a strip
electrode that is inserted in the interhemispheric fissure.
Seizures, focal and general, can occur during mo-
tor mapping and have been reported in up to 24% of
BRAIN MAPPING IN THE OPERATING ROOM 105
cases.12,13 They are usually transient. Application of ice-
cold Ringer’s solution for 5–10 seconds is often effective
at breaking the seizures. A bolus of intravenous propo-
fol (1 mg/kg)14 can also be given as adjunct to stop
the seizure. If a prolonged refractory seizure occurs,
it should be controlled with intravenous methohexital,
0.5–1 mg/kg and intubation may be considered if air-
way is of concern.
LANGUAGE MAPPING
Language mapping is done in the awake patient when
the lesion involves the dominant perisylvian frontotem-
poral region. Preoperatively, the patient is extensively
counseled on the nature of intraoperative testing and
undergoes a baseline language evaluation as follows:
The patient is asked to count numbers from 1 to 50,
name objects seen on a computer-generated slide show,
read single words projected on a computer screen se-
quentially, repeat complex sentences, and write words
and sentences on paper. Language deficits are classified
as anomia when the patient is unable to name an ob-
ject but able to repeat sentences and has fluent speech.
Alexia is defined as the retention of the ability to write
and spell, but with reading errors. Aphasias may be
expressive, receptive, or mixed. Mild language errors
such as paraphasic errors are not considered in resec-
tion planning. Intraoperative language mapping is con-
traindicated in patients with significant language deficits.
Intraoperatively, Broca’s area is identified by
stimulation-induced speech arrest. Mapping is initiated
at stimulation parameters of 1.5–6 mA, frequency of
60 Hz, and a pulse duration of 1 ms. Once identified,
cortical patches of 5 mm are stimulated sequentially with
rest periods between stimulations. The probe is applied
to the cortex for 1–2 seconds and the patient is moni-
tored. Each cortical patch is tested three times.
Electrocorticography is monitored to determine the
threshold for afterdischarges. It is important to keep
all stimulation below this threshold and meticulously
monitor for afterdischarges as they can produce false
localizing results during mapping. For each site, the
patient is tested for counting errors, object naming er-
rors, and word reading errors as they are presented
on a computer-generated slide show. A cortical patch
is considered positive for language function if the pa-
tient is unable to count, name objects, or read words
two out of three stimulation times.8 Positive sites are la-
beled by sterile numbers on the cortex and marked us-
ing neuronavigation. Usually, no more than 25–30 sites
are tested around the intended resection site to delin-
eate the positive language areas. All positive language
areas must be preserved during resection with a margin
of 1 cm. In anterior temporal resections of the dominant
106 SECTION I TECHNIQUES
hemisphere, resections within 2 cm of a positive lan-
guage area, particularly stimulation-induced anomia, will
produce a mild but identifiable general language deficit
observed on an aphasia battery administered 1 month
after the operation.19
If all tested areas are negative for language errors,
wider cortical exposure is not necessary and the resec-
tion can be carried out based on delineated margins of
the lesion or seizure focus. The cortical incision is made
in a “silent” area first and resection is carried out. Subcor-
tical stimulation may be performed to preserve essential
fibers. Once mapping is completed, additional anesthetic
agent may be given for patient comfort.
It may be difficult to distinguish the mechanism
of speech arrest during stimulation of the inferior pre-
frontal cortex as this area is intimately involved in both
language and motor function. Speech arrest can be
attributed to a stimulus disturbance of language func-
tion or arrest of motor activity.20 Indeed, a combined
language and motor function in these cortical areas has
been suggested.21–23 These areas, when encountered,
should be marked as eloquent cortex and preserved,
as their resection will lead to postoperative language
deficits.
䉴 POSTOPERATIVE OUTCOME
After the operation, the patient is maintained on high
normal levels of anticonvulsants. Steroids are used in
cases of tumor resections for control of vasogenic
edema. In cases involving resection around the language
areas, approximately 25%24 of patients exhibit temporary
worsening of speech function at 1 week after surgery.
This is particularly seen in anterior temporal lobe resec-
tion cases where seizure focus or lesion resections are
carried up to 1 cm away from the positively identified
language areas. In longer term follow-ups, however, in
review of 250 patients with language area glioma resec-
tion at 6 months, only 1.6% of surviving patients exhib-
ited a persistent language deficit.10,24
Resection of lesions involving the supplementary
motor cortex results in a contralateral hemiparesis in
80–85% of cases in the immediate postoperative period.
If the primary motor area and underlying corticospinal
white matter tracts are preserved, however, the hemi-
paresis recovers fully in 2–4 weeks.17 Resections involv-
ing the premotor upper or lower extremity areas should
be performed with the patient awake. In our experi-
ence, with repeated contralateral motor examinations,
premotor region resections can be carried out until the
motor strength is diminished to no less than three-fifths
in the contralateral extremity. This paresis resolves in
several weeks to months with aggressive postoperative
therapy.
Figure 8–1. Speech and motor mapping during
awake craniotomy for epilepsy surgery. Left lateral
hemisphere with labels (1, chin tingling; 2, lip tingling;
3, lower lip movement; 4, lower lip and jaw
movement; 5 and 6, tongue tingling; 7, speech
arrest). Syl = sylvian fissure.
䉴 EXAMPLE IN CLINICAL PRACTICE
A 54-year-old woman presented with a long history
of intractable complex partial seizures. Over the last 2
years, her seizures increased in frequency and resulted
in word finding difficulties, anomia, and alexia dur-
ing a prolonged postictal period resulting in significant
functional disability. Her MRI revealed atrophy of the
left mesial temporal lobe structures, and positron emis-
sion tomography imaging demonstrated left temporal
hypometabolism. Her intracarotid injection of amobarbi-
tal test (Wada examination) showed left language domi-
nance. She was therefore a good candidate for left tem-
poral lobectomy. In order to protect language function,
an awake craniotomy was performed with speech and
motor mapping with electrical cortical stimulation. Fig-
ure 8–1 shows the left lateral exposure with frontal,
temporal, and parietal exposure. Numbers 1–6 were
placed over the sensorimotor strip. Speech mapping re-
vealed a speech arrest site in the posterior frontal op-
erculum. No anomia sites were found in the temporal
lobe cortex. Intraoperative electrocorticography showed
epileptiform activity in the amygdala and hippocampal
depth electrodes, with spread to the lateral cortical sur-
face. Therefore, a standard anatomic resection was car-
ried out. Postoperatively, she had completely preserved
language function and had excellent long-term seizure
control.
REFERENCES
1. Mogilner A, Grossman JA, Ribary U, et al. Somatosen-
sory cortical plasticity in adult humans revealed by
 CHAPTER 8
magnetoencephalography. Proc Natl Acad Sci USA 1993;90:
3593-3597.
2. Buonomano DV, Merzenich MM. Cortical plasticity: from
synapses to maps. Annu Rev Neurosci 1998;21:149-
186.
3. Sanes JN, Donoghue JP. Plasticity and primary motor cor-
tex. Annu Rev Neurosci 2000;23:393-415.
4. Feldman DE, Brecht M. Map plasticity in somatosensory
cortex. Science 2005;310:810-815.
5. Lee HW, Shin JS, Webber WRS, et al. Reorganisation of
cortical motor and language distribution in human brain. J
Neurol Neurosurg Psychiatry 2009;80:285-290.
6. Wunderlich G, Knorr U, Herzog H, et al. Precentral glioma
location determines the displacement of cortical hand rep-
resentation. Neurosurgery 1998;42:18-26.
7. Duffau H, Denvil D, Capelle L. Long term reshaping of lan-
guage, sensory, and motor maps after glioma resection: a
new parameter to integrate in the surgical strategy. J Neurol
Neurosurg Psychiatry 2002;72:511-516.
8. Ojemann G, Ojemann J, Lettich E, et al. Cortical language
localization in left dominant hemisphere. An electrical stim-
ulation mapping investigation in 117 patients. J Neurosurg
1989;71:316-326.
9. Penfield W, Roberts L. Speech and Brain Mechanisms.
Princeton, NJ: Princeton University Press, 1959.
10. Sanai N, Mirzadeh Z, Berger MS. Functional outcome af-
ter language mapping for glioma resection. N Engl J Med
2008;358:18-27.
11. Ranck JB. Which elements are excited in electrical stimula-
tion of mammalian central nervous system: a review. Brain
Res 1975;98:417-440.
12. Sartorius CJ, Wright G. Intraoperative brain mapping in a
community setting: technical considerations. Surg Neurol
1997;47:380-388.
13. Yingling CD, Ojemann S, Dodson B, et al. Identification
of motor pathways during tumor surgery facilitated by
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multichannel electromyographic recording. J Neurosurg
1999;91:922-927.
14. Sartorius CJ, Berger MS. Rapid termination of intraopera-
tive stimulation-evoked seizures with application of cold
Ringer’s lactate to the cortex: technical note. J Neurosurg
1998;88:349-351.
15. Lueders H, Lesser RP, Hahn J, et al. Cortical somatosen-
sory evoked potentials in response to hand stimulation. J
Neurosurg 1983;58:885-894.
16. Wood CC, Spencer DD, Alison T. Localization of human
sensorimotor cortex during surgery by cortical surface
recording of somatosensory evoked potentials. J Neuro-
surg 1988;68:99-111.
17. Berger MS. Lesions in functional cortex and subcortical
white matter. Clin Neurosurg 1994;41:444-463.
18. Plicher WH, Silbergel DL, Berger MS, et al. Intraopera-
tive electrocorticography during tumor resection: impact
on seizure outcome in patients with gangliogliomas. J Neu-
rosurg 1993;78:891-902.
19. Ojemann GA, Dodrill CB. Verbal memory deficits after left
temporal lobectomy for epilepsy. Mechanism and intraop-
erative prediction. J Neurosurg 1985;62:101-107.
20. Lueders H, Lesser RP, Dinner DS, et al. Inhibition of mo-
tor activity by elicited electrical stimulation of the human
cortex. Epilepsia 1983;24:519.
21. Kimura D. Left-hemisphere control of oral and brachial
movements and their relation to communication. Philos
Trans R Soc Lond (Biol) 1982;298:135-149.
22. Liberman AM, Cooper FS, Shankweiler DP, et al. Perception
of the speech code. Psychol Rev 1967;74:431-461.
23. Ojemann GA. Brain organization for language from the per-
spective of electrical stimulation mapping. Behav Brain Sci
1983;6:189-206.
24. Haglund MM, Berger MS, Shamseldin M, et al. Cortical lo-
calization of temporal lobe language sites in patients with
gliomas. Neurosurgery 1994;34:567-576.
This page intentionally left blank
 Chapter 9
Anesthesia for Brain
Mapping Surgery
Nicholas P. Carling1 , Chris D. Glover 1 , Daryn H. Moller 2 , and Ira J. Rampil 2
1
Department of Pediatrics (Anesthesiology), Texas Children’s Hospital, and Baylor College of Medicine,
Houston, Texas
2
Department of Anesthesiology, University at Stony Brook, Stony Brook, New York
䉴 INTRODUCTION
Brain mapping techniques are utilized during neurosur-
gical procedures to precisely identify pathological tissue
while trying to preserve viable functional cortex. Proce-
dures include surgical resections of lesions lying close to
or within eloquent tissue such as motor, sensory, or vi-
sual cortex. They also include resection of epileptogenic
foci and placement of electrodes to treat dyskinesias and
Parkinsonism via deep brain stimulation. Currently no
prospective randomized trials have determined an op-
timal anesthetic for brain mapping procedures, and the
ever-burgeoning retrospective analyses have created in-
stitutionally developed protocols without consensus. In
fact, the anesthetic maintenance choice has little bear-
ing on neurosurgical outcomes when given properly.1
While each has advantages and drawbacks, the one cho-
sen depends on a variety of factors including familiarity
of the anesthesia provider with a particular technique,
individual patient characteristics such as difficulty of air-
way management or ability to tolerate an awake proce-
dure, the location and type of lesion to be resected, and
the type of electrophysiological monitoring to be used
intraoperatively.
Communication is paramount and a comprehensive
plan should be developed prior to the day of surgery
if possible. For instance, if speech or sensory mapping
is required, the expectation is that the patient will be
awake during electrocorticography (ECoG) and exci-
sion. A comprehensive preoperative visit with the pa-
tient to discuss the anesthetic plan and its implications
will allay many of the fears associated with undergoing
an awake procedure. Surveys of these patients postoper-
atively demonstrate that they tolerate awake craniotomy
well both physically and psychologically.2,3
There are two electrophysiological issues with re-
gard to anesthesia (1) alteration of the seizure threshold
and loss or significant change in the character and lo-
cation of interictal spiking (IIS), and (2) increase in the
109
stimulation threshold for somatic motor mapping. Suc-
cessful mapping requires the anesthesiologist be aware
of the aforementioned intraoperative plan, and cog-
nizant of the electrophysiological and behavioral ef-
fects of anesthetic agents in the context of neurosurgical
mapping. Epilepsy surgery on the dominant hemisphere
using intraoperative mapping to identify seizure foci
and speech areas has the most stringent requirements
for anesthetic management, whereas motor area map-
ping has the least. The evolution of techniques such as
magnetoencephalography and functional magnetic res-
onance imaging for preoperative evaluation and local-
ization of seizure foci and eloquent cortex has, at some
institutions, reduced the reliance on pristine neural ac-
tivity and allow a wider range of anesthetic agents in the
management of these patients. This chapter will discuss
the pharmacology of commonly used anesthetic agents,
their effects on neural electrophysiological monitoring,
and their administration during anesthetic protocols that
may be utilized when intraoperative brain mapping or
neurocognitive testing are performed.
䉴 EFFECT OF ANESTHETICS AND
SEDATIVES ON NEURAL
EXCITABILITY: GENERAL
PRINCIPLES
Most anesthetic and sedative agents produce a dose-
related synchronization and suppression of cortical ac-
tivity as illustrated in Fig. 9–1. Small doses may produce
a disinhibition and clinical excitement phase and large
doses may lead to burst suppression or even electrocor-
tical silence (flat electroencephalography (EEG)).4 Also,
it is important to note that the GABAA -mimetic effect of
many anesthetics places them squarely in the antiepilep-
tic family of drug actions. Thiopental,5,6 propofol,7,8 and
potent inhaled anesthetics9,10 have all been used to
treat status epilepticus. By definition, these anesthetics
110 SECTION I TECHNIQUES

Fast Halothane

ICV
EEG Therapeutic
Activity General anesthetic effect
drugs Desflurane

Propofol
N2O/Opioid
Slow Opioids
St Hy In M M
er pe du an ain
Flat oi rv ct ni t.
ds -P to An
en ro l
t po es
Awake Excitement Sedation Surgical Anesth Deep th
fo
Behavioral State l

Figure 9–1. Dose response of electroencephalo-
graphy (EEG) to general anesthetics. True anesthetic
agents will, at sufficient dose create a state of
surgical immobility and amnesia, and at high doses
lead to burst suppression and electrocortical silence.
The effect of opioids plateau at delta range slows
wave activity. (Modified from Whittle IR, Midgley S,
Georges H, Pringle AM, Taylor R. Patient perceptions
of “awake” brain tumour surgery. Acta Neurochir
(Wien) 2005;147(3):275–277; discussion 277.)
increase the seizure threshold and negatively modulate
the IIS activity, which defines a seizure focus.
䉴 LOCAL ANESTHETICS
Local anesthetics were first used by Harvey Cushing for
brain tumor excision during the 1920s. Their use persists
today. Local anesthetics play a vital role in awake pro-
cedures or in those that require minimal sedation. Ade-
quate scalp analgesia decreases dependence on sedative
and narcotic agents that may interfere with neurophysi-
ological monitoring and patient compliance. In addition,
local infiltration can decrease the tachycardia and hyper-
tension during head pinning as well as postoperatively
due to improved pain control.11,12 A poorly performed
block may lead to intravascular injection, respiratory de-
pression, nausea, and disinhibition.
A commonly employed technique for providing
scalp analgesia involves placing a field block with a
long lasting local anesthetic agent. However, circumfer-
ential infiltration requires a large volume of local anes-
thetic and increases the likelihood of local anesthetic
toxicity. A more precise technique involves infiltration
around the sensory branches of the trigeminal nerve
including the supraorbital, supratrochlear, auriculotem-
poral, zygomaticotemporal, lesser occipital, and greater
occipital nerves (see Fig. 9–2). Blockade at each of these
nerves requires less total anesthetic than a field block
and has been shown to provide effective scalp analge-
sia with better hemodynamic control when compared to
the field block technique.13 Local anesthetic infiltration
Figure 9–2. Innervation of the scalp and face.
(Adapted from Lalwani AK. Current Diagnosis &
Treatment in Otolarnyngology-Head and Neck
Surgery, 2nd edition. http://www.access
medicine.com.)
of pin holder sites and the surgical incision site should
also be performed to ensure adequate analgesia.
To provide for adequate duration of analgesia,
longer acting anesthetic agents such as ropivacaine,
levobupivacaine, and bupivacaine should be used. Al-
though local anesthetic toxicity is possible with any
agent, ropivacaine and levobupivacaine have a better
safety profile than bupivacaine with regards to car-
diotoxicity and neurotoxicity.14 Epinephrine 1:200,000
(5 ␮g/cc) is often added to the local anesthetic solu-
tion to provide both hemostasis as well as reduce the
systemic uptake of local anesthetic. Doses of up to 4.5
mg/kg ropivacaine and 2.5 mg/kg levobupivacaine have
been proven safe.15,16
䉴 BENZODIAZEPINES
Benzodiazepines are very popular anesthetic adjuvants.
Their mechanism of action appears to include binding
to and activation of the native ligand site on the GABAA
family of ionophores.17 These drugs reduce anxiety and
sympathetic tone, reduce the likelihood of patient move-
ment, and also reduce the probability of disturbing recall
of intraoperative events. If intraoperative localization of
an epileptic focus is part of the operative plan, midazo-
lam should not be given because in clinical doses it may
suppress IIS for many hours despite its short duration of
action. The routine use of benzodiazepines is not war-
ranted in cases in which mapping is indicated or when
resection is planned given its potential interference with
ECoG.
䉴 BARBITURATES
Barbiturates have been used for decades as both intra-
venous general anesthetics and as antiepileptic drugs.
 CHAPTER 9
Pentobarbital and phenobarbital are barbiturates that are
entirely antiepileptic in their effect. There are, however,
other members in this subgroup whose effects are pro-
convulsant. Methohexital and thiopental are both ultra-
short acting induction agents that have the expected
barbiturate depressive effects (progression to isoelectric
EEG). In small doses, however, excitement and an in-
crease in IIS activity may be seen. This observation has
been used clinically to enhance IIS when needed during
epilepsy surgery.18–21 In a mouse model of seizures
induced by pentylenetetrazol, methohexital, and
thiopental exhibited only an antiepileptic action on
(presumably) normal tissue.22 However, some studies
fail to confirm that the enhanced IIS activity comes
solely from the targeted seizure focus23,24 or that the
drugs reliably increase IIS.25,26 In somewhat larger
doses, these barbiturates will stop the generalization of
focal seizures that are occasionally induced by the cor-
tical electrical stimulation used in motor mapping. The
rapid redistribution of methohexital or thiopental from
the brain to other tissue allows this antiepileptic effect to
disappear quickly and allow further mapping after a few
minutes. While thiopental is ultra-short acting for the
first few hundred milligrams delivered, it is only slowly
metabolized and excreted, so redistribution will slow
with continued dosing. Methohexital is metabolized
and cleared much faster than thiopental, so it retains
its ultra-short kinetic profile despite repetitive dosing.
Methohexital has been used to elicit or activate seizure
foci when quiescence is encountered intraoperatively.27
With the popularity of propofol and the increasing
use of dexmedetomidine, the use of barbiturates has
declined substantially in neuroanesthesia.
䉴 KETAMINE
Ketamine is another parenteral anesthetic agent whose
use in neurosurgical cases is quite controversial and still
evolving. While considered a general anesthetic in doses
ranging from 1–4 mg/kg intravenous bolus followed by
0.1–0.5 mg/min infusion, this drug produces an anal-
gesic state in which the patient is dissociated from their
surroundings. EEG activity increases, particularly in the
theta band,28 as does cerebral blood flow (CBF) and
cerebral metabolic rate. Ketamine, at significantly lower
doses, has been used as an analgesic adjuvant and can
be used in combination with low-dose opioids to allow
patients to tolerate painful parts of the procedures. Data
supporting the use of ketamine in traumatic brain in-
jury may soon be available; however, its use in epilepsy
surgery is relatively contraindicated due to dissociated
sedation precluding cooperation, activation of the EEG,
and general lack of a need for postoperative analgesia
following craniotomy.
ANESTHESIA FOR BRAIN MAPPING SURGERY 111
䉴 OPIATES
Opiates are a mainstay of anesthesia for all forms of brain
mapping surgery. Currently available agents are highly
selective agonists of the ␮-class of endogenous opiate
receptors. While poor sedatives themselves, the analge-
sia they provide allows the patient to remain relatively
comfortable during surgery. Within the usual range of
dosing, opiates do not usually alter seizure threshold or
IIS activity. Moderate doses may result in opioid-induced
muscle rigidity without EEG spiking. At extremely high
doses, many opiates will induce seizures.29–31 Interest-
ingly, in patients with partial complex epilepsy, mod-
erate doses of opioids like fentanyl may have induced
increases in IIS, and in these cases IIS was not con-
fined to the previously identified seizure foci.32 Alfen-
tanil, an opioid half-life than fentanyl, has been used
in boluses similar to methohexital to increase IIS activ-
ity for mapping foci.33 Remifentanil has a similar effect
on IIS but its duration of action is much shorter mak-
ing it a safer choice during awake craniotomy when
ventilation cannot be mechanically controlled.34 Patients
who receive remifentanil generally require supplemen-
tal postoperative analgesia. This has been posited as
creation of an acute tolerance state of the ␮-receptors
by remifentanil.35,36 Opiate overdose will, via depressed
ventilatory drive, result in chest wall rigidity or soft tissue
airway obstruction. This can lead to hypercapnia lead-
ing in turn to cerebral vasodilation and swelling, or even
herniation. Even brief periods of hypercapnia can result
in contusion of the cerebral cortex by the bony edges of
the craniotomy. Adjuvant agents of the sedative classes
listed later are usually given during the case to reduce
the amount of opiate required and the impact of hyper-
capnic brain swelling.
䉴 ETOMIDATE
Etomidate, a carboxylated imidazole derivative, is a
GABAA -ergic agent that acts at a different site than the
benzodiazepines. This drug is frequently used to induce
anesthesia in hypovolemic patients, or those with se-
vere heart failure since it does not significantly depress
myocardial function. Etomidate also leads to less res-
piratory depression than thiopental, but is associated
with significant pain on injection and with myoclonic
movements.37 The use of etomidate is controversial in
neurosurgery since there is conflicting data on its bal-
ance of cerebroprotective38,39 versus neutral or even
harmful cerebral effects.40–42 It is clear, however, that
etomidate should be avoided in patients undergoing
surgery for epilepsy since it may activate the EEG of
epileptic patients43 and may confound seizure focus
mapping.44
112 SECTION I TECHNIQUES
䉴 PROPOFOL
Propofol is an intravenous anesthetic with a strong
GABAA -ergic effect. It is a very versatile agent, easily
titratable to behavioral endpoints ranging from light se-
dation to coma. It has relatively minimal effects on the
cardiovascular or respiratory system when given as an
infusion, but can cause significant hypotension with bo-
lus or induction dosing. Signs of upper airway obstruc-
tion should be sought and treated if needed with an
oral or nasal airway. In low-dose regimens, propofol
causes activation of EEG activity,45,46 occasionally to the
point of creating background activity, which may resem-
ble epileptiform spiking.47 Larger doses lead to slowing
and synchronization, followed by burst suppression and
isoelectricity.
The use of propofol for both awake and anes-
thetized mapping procedures has become common-
place. Propofol does, however, have an impact on
seizure foci and IIS activity, probably due to action
as a GABA A agonist.48 Propofol shortens seizure dura-
tion following electroconvulsant therapy compared to
methohexital.49,50 Herrick found that the EEG effects
of propofol sedation on ECoG could be minimized by
allowing 15 minutes recovery after terminating propo-
fol infusion before recording.47 Soriano further demon-
strated this in children with ECoG readings, obtained
when propofol was discontinued 30 minutes prior to
ECoG.51 It is therefore imperative that communication
and vigilance be maintained throughout to ensure that
optimal conditions are present for ECoG monitoring and
recording.
䉴 DEXMEDETOMIDINE
Dexmedetomidine is a relativity new anesthetic agent
that has seen increasing popularity in the field of neu-
roanesthesia. This highly specific alpha-2 receptor ag-
onist provides anxiolysis, analgesia without depression
of respiratory drive, and what has been termed “co-
operative sedation,” making it an ideal agent for use
during awake craniotomy procedures.52 Dexmedetomi-
dine has been shown to have minimal effect on neu-
rophysiological monitoring. The anxiolytic and sedative
properties of dexmedetomidine are from activation of
alpha-2 receptors located in the locus ceruleus. With
the lack of respiratory depression, dexmedetomidine
has a favorable neurophysiological profile as it does
not cause carbon dioxide retention or hypoxemia,
which can lead to cerebral edema during neurosurgical
procedures.53
Patients can be adequately sedated and will toler-
ate an oral or nasopharyngeal airway if upper airway
obstruction occurs during infusion. This helps to avoid
airway obstruction or hypoventilation in the sedated pa-
tient. Typical dexmedetomidine doses include a loading
dose of 0.7–1 ␮g/kg over 10 minutes followed by infu-
sion rates of 0.2–0.7 ␮g/kg/h. Doses as low as 0.2–0.3
␮g/kg/h have been used throughout the “asleep-awake-
asleep” (AAA) technique.
In addition to its minimal effects on ventilation,
dexmedetomidine also provides hemodynamic stability
during neurosurgical procedures.54 Via alpha-2 medi-
ated adrenoreceptor activity, we see modest reduction
in blood pressure and heart rate. We also see reduction
of circulating catecholamines effectively resulting in a
decreased incidence of tachycardia and/or hypertension
during the perioperative period.55
Transient hypertension caused by peripheral vaso-
constriction of vascular smooth muscle can occur initially
during bolus infusion of dexmedetomidine.56 However,
through alpha-2 mediated sympatholysis, dexmedeto-
midine infusion will increase vagal activity result-
ing in a corresponding bradycardia and hypotension.
Dexmedetomidine has not been shown to increase in-
tracranial pressure (ICP). CBF is usually decreased while
autoregulation and CMRO2 are preserved.
Perhaps most important in its role in brain map-
ping, dexmedetomidine has been shown to have
minimal effects on intraoperative neurophysiological
monitoring techniques. Animal and human studies have
shown dexmedetomidine preserves cortical somatosen-
sory evoked potentials and does not decrease cortical
responses.57 Multiple studies show dexmedetomidine
use in epilepsy surgery results in minimal to no sup-
pression of epileptiform activity and one patient had a
subclinical seizure detected while receiving dexmedeto-
midine infusion.58,59
Dexmedetomidine has minimal effects on intraoper-
ative ECoG. Dexmedetomidine infusion can be used not
only for the asleep portion of an AAA anesthetic tech-
nique, but also during the awake period of language
mapping and ECoG.58
Dexmedetomidine has many properties, which
make it an ideal anesthetic agent for awake craniotomy
and intraoperative brain mapping. Its provides a sta-
ble hemodynamic profile, no respiratory depression, and
a cooperative patient who can be promptly awakened
from anesthesia for neurocognitive testing, while also
having a minimal effect on neurophysiological parame-
ters monitored during brain mapping.
䉴 NITROUS OXIDE
Nitrous oxide (N2 O) is an odorless, colorless gas with
low solubility and potency. It does not affect interic-
tal spikes and can be used in neurosurgery. N2 O has
been noted to attenuate spike frequency on EcoG, but
did not seem to affect the extent of the areas affected.60
 CHAPTER 9
There are certain drawbacks to its use however. N2 O
is a cerebral vasodilator, which can increase CBF and
subsequently increase ICP. N2 O has the potential to in-
crease closed air spaces in noncompliant areas and can
rapidly increase pressure and volume in compliant ones,
which can lead to potentially devastating complications
like tension pneumocephalus and air embolus. Postop-
erative nausea and vomiting has not been consistently
linked to this agent but is still of concern in this pa-
tient population. With the advent of newer intravenous
agents, we suggest avoiding N2 O during brain mapping
and seizure surgery.
䉴 VOLATILE ANESTHETIC
NEUROPHARMACOLOGY
The neurophysiological effects of the commonly used
volatile anesthetics are summarized in Table 9–1. Of the
commonly used volatile anesthetics, isoflurane, sevoflu-
rane, and desflurane all increase CBF via a direct va-
sodilatory effect. This effect on the CBF is dose-related
and biphasic. At 0.5 MAC, the vasodilatation that occurs
is largely compensated by suppression in the CMR such
that the changes in CBF are minimal. At increased doses
(greater than 1 MAC), vasodilation occurs on a larger
scale compared to CMR depression, resulting in uncou-
pling of the two, and an overall increase in CBF. This
can lead to substantial increases in ICP as 60–70% of the
cerebral blood volume resides in the sinuses and veins.
All decrease cerebral vascular resistance with suppres-
sion of the CMR. This suppression is not uniform, as the
neocortex seems more vulnerable to suppression than
deep structures like the hippocampus.
The volatile anesthetics have similar effects on EEG
monitoring. At doses greater than 1.5 MAC, burst sup-
pression occurs on the EEG. Differences have been
noted in their propensity to elicit epileptiform activ-
ity. Epileptiform activity (spike activity) with sevoflu-
rane during single breath induction techniques or with
high-concentration exposure have been reported. This
is similar to what was seen historically with enflurance
and occurs as we proceed from burst suppression to
isoelectricity. This epileptogenic potential is completely
abolished when N2 O is administered. The volatile agents
isoflurane or desflurane seem to not have this epilep-
togenic potential. The volatile anesthetics can be used
䉴 TABLE 9–1. NEUROPHARMACOLOGY OF VOLATILE ANESTHETICS
Drug Effect on CBF Effect on EEG
Isoflurane ↔at 0.5 MAC,↑ >1 MAC ↓, burst suppression >1.5 MAC
Sevoflurane ↔at 0.5 MAC,↑ >1 MAC ↓, burst suppression >1.5 MAC
Desflurane ↔at 0.5 MAC,↑ >1 MAC ↓, burst suppression >1.5 MAC
CBF, cerebral blood flow; EEG, electroencephalography; ECoG, electrocorticography.
ANESTHESIA FOR BRAIN MAPPING SURGERY 113
for maintenance during craniotomy and mapping proce-
dures. Usually, levels below 0.5 MAC have had minimal
effect on ECoG and EEG recordings.61,62
䉴 ANESTHETIC TECHNIQUE FOR
BRAIN MAPPING WITH AWAKE
CRANIOTOMY
Anesthesia for brain mapping procedures and awake
craniotomy presents many clinical challenges to the
anesthesiologist. The patient’s specific pathology often
dictates the nature of the intraoperative neuromonitor-
ing and therefore the most appropriate anesthetic to be
used (see Table 9–2). Goals during an awake craniotomy
include maintaining patient comfort and safety, ensuring
patient cooperation while keeping the patient immobile,
and ensuring adequate ventilation and circulatory sup-
port. Anesthetic agents commonly used by anesthesia
providers work well, but usually confound electrophysi-
ological monitoring and neurocognitive testing for brain
mapping. Multiple techniques have been developed to
accomplish these tasks ranging from local anesthesia as
the sole adjunct to general anesthesia with or without
airway instrumentation.63 Palese64 reported that roughly
half of patients described craniotomy as the worst ex-
perience encountered during surgery. This finding, cou-
pled with the deleterious effects of anxiolytics on elec-
trophysiological monitoring, has led to the widespread
practice of performing AAA techniques when an awake
patient is needed intraoperatively. Here we will discuss
various techniques for performing an AAA anesthetic;
however, certain topics such as adequate analgesia from
local anesthetic infiltration (see Section on Local Anes-
thetics), preoperative patient planning, and preparation
for the possibility of intraoperative seizure activity also
go hand in hand with any anesthetic technique used for
these procedures.
PREOPERATIVE CARE
For epilepsy surgery, antiepileptic drugs should be re-
duced or discontinued for 12–24 hours prior to surgery
for maximal IIS. Some centers trade-off accuracy of focus
mapping for increased safety of the patient related to
the lower risk of seizure in the operating room (OR) by
Epileptogenicity ECoG
None ↔<0.5 MAC, ↓>0.5 MAC
Yes ↔<0.5 MAC, ↓>0.5 MAC
None ↔<0.5 MAC, ↓>0.5 MAC
114 SECTION I TECHNIQUES

䉴 TABLE 9–2. NEUROSURGICAL PROCEDURES AND ANESTHETIC CONSIDERATIONS

Surgical Procedure Anesthetic Technique Agents Used Considerations

Corpus callosotomy Any tAny t

Hemorrhage as this is near
sagittal sinus
t
Lethargy postoperation
Intracranial grid placement Asleep t
Low dose volatile + opioid t
Avoid N2 O until dura open
t
TIVA + dexmedetomidine t
VAE risk
(0.2–0.7 ␮g/kg/h) t
Testing of grids requires
minimal anesthetics
t
Propofol off 30 min prior to
EEG/ECoG
Tumors near eloquent areas Awake for language mapping t
TIVA + dexmedetomidine t
Proper patient selection If
(speech, language) or asleep-awake-asleep infusion 0.3–0.7 ␮g/kg/h cortical stimulation—avoid
t
Local and MAC NMBs
t
gropofol off 30 min prior to
EEG/ECoG
t t
Deep brain stimulation Awake Local and MAC Avoidance of GABA
t
Dexmedetomidine agonists
0.3–0.7 ␮g/kg/h

EEG, electroencephalography; ECoG, electrocorticography, VAE, venous air embolism; TIVA, total intravenous anesthesia; NMB,
neuromuscular blockade.

continuing antiepileptic drugs until surgery. No anxi-
olytic premedications should be given; the practitioner
should remember that the best anxiolytic is a good pre-
operative visit. An antisialagogue such as glycopyrrolate
(0.1–0.2 mg) may be useful in patients who smoke. As
prophylaxis against nausea and vomiting, antiemetic
agents such as ondansetron and dexamethasone should
be considered preoperatively. This is especially impor-
tant if the patient is to be awake for any part of the
procedure.
Preoperative teaching is usually performed by the
team neurologist or psychologist regarding mapping
procedures and what to expect in terms of the OR ex-
perience and should be verified in the chart or with the
patient. It is wise to counsel the patient regarding the
rare possibility of postoperative recall following a gen-
eral anesthetic planned for a mapping case. Emphasis on
aggressive pain control and minimal discomfort should
be the goal.
On call to the OR the patient should void. A pe-
ripheral IV greater than 18 gauge should be placed. On
the basis of the possibility of focal ischemic injury during
brain retraction, dextrose-containing solutions should be
avoided. Finally, consider a three-way stopcock at the
hub of IV for continuous drug infusion while allowing
maintenance fluids to infuse at a minimal rate.
INTRAOPERATIVE MONITORING
Standard ASA monitors are appropriate for mapping
craniotomies, that is, oscillometric (noninvasive) blood
pressure, electrocardiogram, and pulse oximeter. If the
patient is to remain awake no temperature probe is re-
quired. If opiates or sedatives are given, a sidestream
sample of exhaled gas should be sampled for end-tidal
CO2 assessment. A Foley catheter may be inserted into
the bladder in awake or sedated cases if the case is pro-
jected to last beyond 4–5 hours (which is typical), or if
mannitol is being used (not typical). Crystalloid infusion
should be minimal in these cases to reduce postsurgi-
cal edema. Surgical blood loss rarely exceeds 500 mL
and if volume replacement is deemed necessary either
blood or albumin are the recommended choices. Inva-
sive monitoring is not generally indicated in these cases
except possibly for the management of serious concur-
rent cardiopulmonary disease.
ANESTHETIC MANAGEMENT
AAA technique has been described both with and with-
out airway instrumentation. Before continuing, it is im-
portant to reiterate the crucial role of adequate analge-
sia from a well-performed scalp block to help maximize
patient comfort. If airway instrumentation is to be used,
taping the endotracheal tube or supraglottic airway de-
vice requires considering security and the need to vi-
sualize muscles of facial expression during mapping. A
soft bite block must be used in light of the potential for
seizure activity during surgery. Obviously, during motor
mapping neuromuscular blockade must be avoided.
During an AAA technique, the patient is placed un-
der general anesthesia for the rigid fixation if used, fol-
lowed by scalp incision, dissection of temporalis muscle,
drilling and sawing (not so much painful as disturbingly
loud), and dural opening. One of the primary con-
cerns for this technique involves airway management.
 CHAPTER 9 ANESTHESIA FOR BRAIN MAPPING SURGERY 115

Induction of general anesthesia and endotracheal 䉴 TABLE 9–3. ANESTHETIC AGENTS USED TO
intubation mandates airway topicalization with local ELICIT SPIKE WAVE ACTIVITY
anesthetics to minimize straining or coughing upon ex- Agents and Dosages
tubation as well as facilitate re-intubation after mapping
is complete. Lidocaine 5% in water-soluble ointment has Methohexital 0.3–0.5 mg/kg
been quite effective in this role. Modifications of the AAA Etomidate 0.1–0.2 mg/kg
technique involve propofol as the sole sedative agent for Alfentanil 50 ␮g/kg
Remifentanil 2.5 ␮g/kg
sedation with spontaneous respiration with or without
a laryngeal mask airway (LMA). The propofol infusion
(typically 75–250 ␮g/kg/min) is discontinued approxi-
continued mapping and prevented the conversion to
mately 15–30 minutes prior to ECoG. As noted previ-
general anesthesia.72 Doses in this latter report were
ously, propofol has a significant effect on IIS48 that may
even lower infusion rates (0.15 ␮g/kg/hr) yet still pro-
be mitigated by allowing sufficient time to pass between
viding adequate patient comfort and cooperation and
stopping the infusion and beginning ECoG.47 The transi-
good cortical mapping conditions.72 If no airway instru-
tion from asleep to awake is the most difficult aspect of
mentation is desired, dexmedetomidine is an ideal agent
this anesthetic plan secondary to issues related to airway
because, as described previously, it has minimal effect
complications with the brain exposed. Nausea and vom-
on ventilatory drive, systemic or cerebral hemodynam-
iting during this period may lead to aspiration as well as
ics, and provides for a comfortable, cooperative patient.
dramatic increases in ICP. The complication rate during
There is limited experience with dexmedetomidine in
this period is difficult to discern and variable given there
children and adolescents but several case reports have
are no prospective trials, but retrospective analysis by
demonstrated its use.73 Dexmedetomidine is frequently
Skucas and Artu showed the airway complication rate to
used as an anesthetic adjuvant during the “asleep” com-
be 2% in a review of 332 cases. Other studies point to
ponent of a craniotomy and in many hands does not
an average complication rate of 9.5%.65 The highest in-
appear to interfere significantly with neurocognitive test-
cidence of complications during this technique is based
ing. Its infusion is typically terminated 20 minutes prior
on airway management with 17% of patients experienc-
to testing and the patient allowed to be awaken to a Ram-
ing moderate desaturation (91–95%)66 and respiratory
sey Sedation score of 2 to 3.74 Obviously its use should
depression (respiratory rate <8 breaths per minute),67
be discussed preoperatively with the neurologist or psy-
which was commonly managed with LMA placement.
chologist who will be doing the intraoperative testing.
Once ECoG has finished, propofol may be reinstituted
Despite the use of anesthetic agents with minimal
for the resection and closure.68
effect on electrophysiological monitoring, sometimes
Additional modifications of the AAA technique have
there is still a lack of spike wave activity. Intravenous
involved infusion or bolus administration of short acting
medications that can be used to induce spike wave activ-
narcotics.69 At present, the most commonly used nar-
ity include methohexital, etomidate, and alfentanil (see
cotic appears to be remifentanil, most likely because
Table 9–3).
of its short half-life and titratability. Remifentanil use
The AAA technique is well tolerated by patients
has been advocated to ensure adequate analgesia dur-
and generally reported to have high satisfaction rates.
ing bone flap removal. Using the propofol–remifentanil
Approximately one-third of patients’ post-procedure re-
technique infusion rates are 100–150 ␮g/kg/min for
ported complaints about rigid head fixation being too
propofol and 0.02–0.09 ␮g/kg/min for remifentanil. With
tight and painful scalp incision.2,3 Additional complaints
this technique the time from discontinuation of infusion
were noted regarding bladder distension and pressure
to the time of “emergence,” defined as opening eyes and
on the dependent limb during lateral position. Of note,
following commands, ranged between 6 and 13 min-
no patients had recall of pain upon dural incision.3
utes following an average asleep craniotomy time of 48
minutes.70 This technique can be used either with or
without airway instrumentation, as it provides adequate
sedation for patients to tolerate either an LMA or endo- 䉴 ANESTHETIC TECHNIQUE FOR
tracheal tube. If no airway is used, the rapid titratability BRAIN MAPPING WITH GENERAL
of remifentanil allows for return of ventilatory drive if ANESTHESIA
respiratory depression were to occur.
Dexmedetomidine has become a popular adjuvant Not all patients are suitable candidates for an awake
to sedation or analgesia for the AAA technique based craniotomy. This may be because of lack of patient co-
upon its lack of respiratory depression. At low infu- operation such as occurs in the pediatric population or
sion rates (0.2 ␮g/kg/hr) there appears to be little ef- because of other factors such as a difficult airway, severe
fect on epileptiform activity and satisfactory spike and obstructive sleep apnea, or coexisting cardiopulmonary
wave discharges.71 Moore, et al. reported the use of disease. These factors may necessitate general anesthe-
dexmedetomidine as a rescue medication to allow for sia throughout the entire procedure. However, despite
116 SECTION I TECHNIQUES
presenting different challenges, general anesthesia is still
compatible with intraoperative motor mapping as long
as attention is paid to how anesthetic agents can affect
the various electrophysiological techniques being used
during the procedure.
As discussed previously, all volatile anesthetics,
benzodiazepines, and hypnotic agents can suppress
spike wave activity. When volatile anesthetic agents are
being used, they should be discontinued and eliminated
prior to performing ECoG. This can be accomplished
by having a balanced anesthetic consisting of low-dose
volatile agent combined with N2 O and opioid infusion.
When the volatile agent has been eliminated, N2 O and
opioid infusion can be maintained to ensure an adequate
anesthetic depth.
Since N2 O is not an ideal agent for craniotomies
owing to its increase in CBF and the inherent risk of
venous air embolism during craniotomy, dexmedetomi-
dine may be substituted either for maintenance through-
out the anesthetic or instituted during the time that brain
mapping is being performed. If used, dexmedetomidine
should be run at low infusion rates of 0.2–0.7 ␮g/kg/h to
ensure there is no interference with brain mapping. All
narcotic agents have been used successfully during brain
mapping, and while studies have shown various effects
on spike wave activity, any may be used as long as they
are kept at normal clinical dosages. While it is tempt-
ing to administer benzodiazepines during this period
without volatile anesthetic in the effort to prevent pa-
tient recall or awareness, one must remember that these
agents have been shown to suppress spike wave activ-
ity and should be avoided while brain mapping is be-
ing performed. Despite these maneuvers, the period of
brain mapping and lack of volatile anesthetic represents
a time when the patient is at the highest risk for lightened
anesthesia and therefore bucking or movement. Increas-
ing doses of remifentanil or fentanyl should decrease the
risk for this potential complication. If no motor mapping
is being performed, adequate paralysis should be main-
tained. Once the brain mapping has been completed,
volatile anesthetic agents may be restarted for the re-
mainder of the procedure.
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fect of etomidate on the electroencephalogram of patients
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troencephalogram. Anesth Analg 1993;76(5):976-978.
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dation may disrupt interictal epileptiform activity from a
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49. Simpson KH, Halsall PJ, Carr CM, Stewart KG. Propofol
reduces seizure duration in patients having anaesthesia
for electroconvulsive therapy. Br J Anaesth 1988;61(3):343-
344.
50. Rampton AJ, Griffin RM, Stuart CS, Durcan JJ, Huddy
NC, Abbott MA. Comparison of methohexital and propo-
fol for electroconvulsive therapy: effects on hemody-
namic responses and seizure duration. Anesthesiology
1989;70(3):412-417.
51. Soriano SG, Eldredge EA, Wang FK, et al. The effect
of propofol on intraoperative electrocorticography and
cortical stimulation during awake craniotomies in children.
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52. Frost EA, Booij LH. Anesthesia in the patient for awake
craniotomy. Curr Opin Anaesthesiol 2007;20:331-335.
53. Ramsey MA, Luterman DL. Dexmedetomidine as a total in-
travenous anesthetic agent. Anesthesiology 2004;101:787-
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surgery. Neurosurgery 2005;57:1-10.
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118 SECTION I TECHNIQUES
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during awake craniotomy for seizure resection: effects on
electrocorticography. J Neurosurg Anesthesiol 2007;19:38-
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evoked responses. Br J Anaesth 1999;83:381-386.
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for epilepsy. Can J Anaesth 1993;40(5 Pt 1):421-424.
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AH, Borel CO. A retrospective analysis of a remifen-
tanil/propofol general anesthetic for craniotomy before
awake functional brain mapping. Anesth Analg 2005;
101(2):502-508.
71. Souter MJ, Rozet I, Ojemann JG, et al. Dexmedetomidine
sedation during awake craniotomy for seizure resection:
effects on electrocorticography. J Neurosurg Anesthesiol
2007;19(1):38-44.
72. Moore TA 2nd, Markert JM, Knowlton RC. Dexmedeto-
midine as rescue drug during awake craniotomy for cor-
tical motor mapping and tumor resection. Anesth Analg
2006;102(5):1556-1558.
73. Ard J, Doyle W, Bekker A. Awake craniotomy with
dexmedetomidine in pediatric patients. J Neurosurg Anes-
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74. Mack PF, Perrine K, Kobylarz E, Schwartz TH, Lien
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20-25.
 Chapter 10
Clinical Applications of
Magnetoencephalography in
Neurology and Neurosurgery
Panagiotis G. Simos 1 , Eduardo M. Castillo2 , and Andrew C. Papanicolaou2
1
Department of Psychology, University of Crete, Rethymno, Greece
2
Department of Pediatrics, Center for Clinical Neurosciences; Departments of Neurosurgery and Neurology.
University of Texas – Health Science Center at Houston, Houston, Texas
䉴 INTRODUCTION TO
MAGNETOENCEPHALOGRAPHY
TECHNIQUES
Magnetoencephalography (MEG) is a noninvasive brain
imaging method that detects minute changes in the dis-
tribution of magnetic flux at the surface of the head.
Recordings are performed either at rest (targeting spon-
taneous abnormal activity associated with brain dam-
age, e.g., in epilepsy) or during the performance of
specific motor, language, or memory tasks. In the lat-
ter case recordings and subsequent analyses of the
magnetic signals aim to reveal the anatomic outline
of the brain mechanisms responsible for the motor,
cognitive, or linguistic function(s) engaged during task
performance. While the anatomical resolution of MEG
techniques appears to be adequate for most clinical ap-
plications, a conclusion supported by several normative
and clinical studies investigating reproducibility and con-
current validity, it is the temporal resolution of MEG
that clearly distinguishes this method among noninva-
sive brain imaging modalities that rely on hemodynamic
measures such as positron emission tomography and
functional magnetic resonance imaging (fMRI). The tem-
poral and spatial resolution of MEG, as well as its demon-
strated reliability and external validity, have led to its
routine use in many neurosurgery centers around the
world. In this chapter we review the primary clinical ap-
plications of MEG, namely the identification of epilep-
togenic foci in candidates for epilepsy surgery and the
mapping of function-specific cortex prior to resection,
following a brief description of MEG methodology.
MEG involves the measurement of neuromagnetic
signals emanating from the brain (for detailed discussion
see Papanicolaou).1 These signals reflect instantaneous
changes in intracellular dendritic (primary) electrical cur-
119
rents that take place within populations of pyramidal
cells in neo- and archeocortical brain structures. While
electroencephalography (EEG) primarily measures the
secondary currents, which spread through the extracel-
lular space and structures, reaching the head surface
with significant distortion, the magnetic flux produced
by primary currents penetrates the brain and other tis-
sues that surround the populations of active neurons
without significant distortion.
The instrument used to measure these signals is
the neuromagnetometer that is equipped with an ar-
ray of sensors (either magnetometers or gradiometers)
each coupled to a special, low noise amplifier. State-
of-the-art systems feature are equipped with 150–250 or
more sensors that cover the entire head. Recording takes
place inside a magnetically shielded room designed to
reduce extraneous magnetic fields. Special postacquisi-
tion signal-processing software is required in order to
distinguish the minute magnetic signals produced by the
brain from extraneous magnetic fields (mechanical and
biological noise).
The instantaneous surface distribution of the mag-
netic flux measured by the entire array of sensors is
represented by a contour map. Special algorithms are
applied to this distribution, which is typically registered
at every 1–4 millisecond during the recording session, in
order to estimate the position and strength of neurophys-
iological events (sources) that produced the recorded
magnetic activity. The most commonly used source esti-
mation algorithm in clinical MEG applications considers
the intracranial activity sources as equivalent to electri-
cal current dipoles. Once estimates of the coordinates
of such sources are made, in the MEG coordinate sys-
tem, they are co-registered with a set of structural im-
ages of the patient’s brain (MRI), in order to determine
the anatomical location of each source.
120 SECTION I TECHNIQUES
The capacity to identify relatively small cortical
patches that show transient increases in neurophysio-
logical activity (i.e, signaling between neuronal popula-
tions) renders MEG suitable for a variety of clinical appli-
cations, which can be classified in two broad categories:
those that involve recording and subsequent localiza-
tion of the intracranial sources of spontaneous, abnormal
neurophysiological activity, and those that target stim-
ulus evoked activity, either during passive stimulation
conditions or while the patient is performing a cognitive
or linguistic task.
䉴 SPONTANEOUS MAGNETIC
ACTIVITY
Among the clinical applications of MEG that target spon-
taneous, abnormal brain activity, the localization of the
sources of interictal transients (spikes) is the most es-
tablished one world-wide. At different epilepsy centers
MEG is part of either the Phase I or Phase II evalu-
ation procedure, as an adjunct to noninvasive (video-
EEG monitoring (VEEG)) or invasive (intracranial VEEG)
techniques, respectively. In this context, MEG studies
may contribute to the consensus decision of whether a
particular patient is a surgical candidate and help guide
subdural grid placement. The clinical utility of MEG data
has a number of prerequisite conditions. First, that the
MEG procedures and algorithms used for the localization
of abnormal magnetic activity are sufficiently accurate
in identifying the location and extent of the cortical
patches that give rise to transient increases in mag-
netic flux recorded at the surface of the head (magnetic
spikes). Second, that a sufficient quantity of spikes is de-
tected during the MEG recording session (which rarely
exceeds 1 or 2 hours in duration). And third, that the
cortical patches where generators of magnetic spikes are
localized coincide with the epileptogenic zone(s). It is
essential that the MEG study identifies at least a por-
tion of the epileptogenic zone (sensitivity) and that the
abnormally active cortical patch(es) identified by MEG
cause seizures (selectivity). The degree to which MEG
procedures meet these requirements depend faces both
practical and physiological limitations. With respect to
the first requirement, several studies concur that the
equivalent current model is sufficient in order to ac-
curately localize the origin of interictal spikes.2–4 As-
sessment of the reliability of source localization across
several spikes and, potentially, obtaining a second
recording session with the same patient may help im-
prove the accuracyof identification of abnormally active
cortical patches.
A second practical problem faced by clinicians us-
ing MEG for presurgical epilepsy planning is the rarity of
usable, abnormal epileptiform activity during the, typi-
cally brief, recording session. To optimize the yield of
magnetic spikes some clinicians have sought to evoke
epileptiform activity with the use of proconvulsant drugs
such as methohexital or clonidine.2,5 The effectiveness
of such techniques however, to increase the diagnos-
tic yield of MEG is still uncertain. Moreover, while the
preponderance of MEG applications in epilepsy have re-
lied on spike-like activity, the localization of generators
of focal slow activity, in the delta and theta frequency
range, has also been found to be useful for localization
of epileptic areas.6–10
The third prerequisite for the clinical utility of MEG
has been addressed in two ways. First, in studies that
record and attempt to localize the intracranial origin of
ictal magnetic activity.11–16 These studies can be per-
formed during nonconvulsive seizures, because mag-
netic artifacts associated with electrical muscle activity
and movement render abnormal brain activity unusable.
Alternatively, brief samples of magnetic activity at at
the very onset of a convulsive seizure can be fortu-
itously obtained. In those studies where magnetic ac-
tivity of adequate quality was obtained (for instance at
the very onset of a seizure) epileptogenic zone local-
izations were in good agreement with subsequent in-
vasive recordings14,17,18 or localizations that appear to
be more accurate than those based surface VEEG (see
Fig. 10–1).19
A fruitful approach to determine the importance of
interictal source localizations obtained by MEG in rela-
tion to the epileptogenic zone(s) is to conduct studies
that directly compare the results of interictal MEG stud-
ies with those of VEEG and invasive VEEG having, to the
degree possible, ensured that the former two prerequi-
sites are met (localization accuracy and yield). Examples
of two such studies are described in more detail later.
In the first study MEG recordings were compared
with both ictal and interictal noninvasive video EEG
(VEEG or Phase I EEG) in order to assess the rela-
tive sensitivity and selectivity of each method (Pataraia
et al.).3 The data set included 82 successive patients with
medically refractory epilepsy who underwent surgery.
The epileptogenic region identified by interictal and ictal
VEEG and MEG was defined in relation to the resected
area as either (1) perfectly overlapping with the resected
area, (2) partially overlapping, or (3) nonoverlapping.
The sensitivity of the 30-minute interictal MEG record-
ing session for detecting clinically significant epilepti-
form activity was 79.2%, while in the remaining patients
no interictal MEG events were detected. The proportion
of extra-temporal lobe epilepsy patients for whom in-
terictal events were registered was slightly higher than
the proportion of patients with temporal lobe epilepsy
(86.7% vs. 75%, respectively).
On the basis of the MEG data alone, the correct lo-
calization of the resected region would have been possi-
ble in 72.3% of the patients for whom at least five inter-
ictal spikes of similar morphology were registered. This
 CHAPTER 10 CLINICAL APPLICATIONS OF MEG IN NEUROLOGY AND NEUROSURGERY 121

Figure 10–1. Localization of epileptiform activity using magnetoencephalography

(MEG). Ictal electroencephalography/MEG tracing (left) recorded during right body
(distal arm) epilepsia partialis continua with time-locked discharges with each twitch.
The topographic distribution of the magnetic fields (center) associated with each
epileptiform discharge was used to select the MEG sensors used for source
modeling. After co-registration with the patient’s MRI (right), MEG revealed overlap of
ictal sources (triangles) with the sensorimotor areas (green square representing S1).
(Image reproduced with permission from Wheless JW, Castillo EM, Maggio V, et al.
Magnetoencephalography (MEG) and Magnetic Source Imaging (MSI). Neurologist
2004;10(3):1–16.)

figure was significantly higher than the proportion of
correct localizations made on the basis of the surface
VEEG results alone (40%). In addition, MEG contributed
to the localization of the resected region in 58.8% of the
patients in whom VEEG recordings did not provide lo-
calization information and in 72.8% of the patients for
whom VEEG identified only part of the resected zone.
Overall, MEG and VEEG results were equivalent in 32.3%
of the cases, and additional localization information was
obtained using MEG in 40% of the patients. These results
clearly suggest that MEG can be useful for presurgical
planning in patients who have either partially localizing
or nonlocalizing VEEG results. Findings from this study
concur with subsequent reports that resecting the region
demonstrating dense sources of interictal spikes would
lead to a favorable surgical outcome (see Table 10–1).21
For a subset of 41 patients (29 with temporal and 12
with extra-temporal epilepsy) it was possible to assess
the relative efficacy of interictal MEG studies and inva-
sive electrophysiological procedures (both ictal and in-
terictal, invasive VEEG) in predicting seizure outcome.22
All patients had positive interictal findings in MEG. The
epileptogenic zone was defined separately on the basis
of MEG and invasive VEEG, each in relation to post-
operative seizure outcome. The results of each method
were separately classified as (1) correct, if the identified
epileptogenic area overlapped with the area resected
and the patient was seizure-free postoperatively, (2) in-
correct if the identified area was the same as resected
area, but the patient was not seizure-free postopera-
tively, or if the localized area they identified was different
from the resected area but the patient was seizure-free
postoperatively, and (3) indeterminate if the identified
zone differed from the resected one and the patient was
not seizure-free postoperatively. With respect to post-
operative outcome, MEG localization was correct in 23
of the 41 patients and invasive VEEG localization was
correct in 22 of the 41 patients. The MEG predictions
were incorrect for 12 patients and the invasive VEEG
predictions in 16 patients. Finally, there were six and
three indeterminate cases for Invasive VEEG and MEG,
respectively. No significant differences between the two
methods were found in terms of their ability to pre-
dict the localization of the epileptic zone and, conse-
quently, seizure outcome in individual patients. There-
fore, at present, both methods can be considered to have
the same degree of accuracy for identifying the epilep-
togenic zones.
These results are in agreement with other reports
demonstrating good agreement of interictal MEG local-
izations with that of invasive recordings.2,4,14,18,19,23–28,30
For instance, Knowlton and colleagues (2006)31 reached
122 SECTION I TECHNIQUES
䉴 TABLE 10–1. CONTRIBUTION OF MEG DATA TO THE IDENTIFICATION OF THE RESECTED REGION
Noninvasive VEEG (interictal and ictal) Improvement
Perfect overlap – 21 (80.8)
Partial overlapa 16 (72.8)
Nonlocalizable 10 (58.8)
Total 26 (40.0)
Source: With permission, Pataraia et al., 2004.
EEG, electroencephalography; MEG, magnetoencephalography.
a
p <0.01.
Values are n (%).
Note: Out of 22 patients for whom the scalp video-EEG (VEEG) ictal and interictal data would have resulted in the partial delineation of
the resected area, the MEG data would have contributed to a more accurate determination of that zone in 16 patients (72.8%). In this
series, MEG data would have made a significant contribution to the delineation of the resected region in 58.8% of the patients for
whom the VEEG results failed to provide any localization information.
a similar conclusion in their study of 49 patients who
underwent both MEG and invasive VEEG.
Efficiency of MEG has been demonstrated for both
temporal3,7,32,33 and nontemporal lobe epilepsy,34–37 al-
though in general, interictal magnetic spikes can be
recorded more readily in neocortical epilepsy than in
mesial temporal lobe epilepsy.2,38
MEG studies have been successfully employed in
helping to determine or confirm targets for surgical re-
section in a variety of epileptic syndromes, such as focal
cortical dysplasia,39–47 tuberous sclerosis complex,48–52
pediatric epilepsy,23,27,35,53–58 and conditions that of-
ten cause seizures such as cavernomas,59 and mass
lesions.23,60,61 For surgical treatment, MEG localizations
have been successfully combined with neuronaviga-
tional systems.62–64
Finally, exploratory MEG studies have been con-
ducted in search of biological markers of focal brain
damage associated with traumatic brain injury,65 brain
lesions,66 cerebrovascular disease6,67–69 and tumors,70
as well as progressive degenerative disease. For in-
stance, enhanced power of slow-wave activity (in the
theta and delta bands) has been reported in patients
with Alzheimer’s disease.71,72 More recent results pro-
vided promising results highlighting the potential utility
of MEG, in conjunction with magnetic resonance spec-
troscopic as an adjunct in the evaluation for dementia.73
䉴 EVOKED MAGNETIC ACTIVITY:
PRESURGICAL MAPPING OF
ELOQUENT CORTEX
MEG recordings performed for the purpose of determin-
ing the location and extent of cortex mediating visual,
auditory, somatosensory, motor, and language functions
MEG
No Change Misidentification Total
5 (19.2) 26 (40)
3 (13.6) 3 (13.6) 22 (34)
7 (41.2) 17 (26)
31 (47.7) 8 (12.3) 65 (100)
differ from those that aim at the identification of epilep-
togenic zones in that the phenomenon that exemplifies
the function under investigation is repeated several times
while the magnetic flux around the head is sampled at
regular intervals. An external stimulus is invariably pre-
sented at each instance in order either to induce the phe-
nomenon (in the case of somatosensory and receptive
language functions) or to act as a time cue (in the case of
expressive language and motor functions). Each segment
of recorded activity, beginning a few milliseconds before
and extending up to approximately 1000 milliseconds (in
the case of language-specific cortex mapping) and up to
200 milliseconds (in the case of visual, auditory, and
somatosensory cortex mapping) after each repetition of
the stimulus, is stored separately as a MEG epoch. The
resulting averaged event-related field (ERF) consists of
early components (50–200 milliseconds poststimulus on-
set) that correspond to activation of the sensory cortex
specific to the stimulus modality, and late components
(200 – ∼800 milliseconds poststimulus onset), reflecting
activation of the association cortex or higher functions.
The intracranial sources that give rise to the recorded
ERFs at each point in time can be estimated and super-
imposed on an MRI of the patient’s brain by applying
the same algorithms and procedures used for localizing
the sources of abnormal spontaneous activity, described
previously.
䉴 SOMATOSENSORY EVOKED
MAGNETIC FIELDS (SEFs)
The spatial resolution of MEG is adequate to reveal
the somatotopic organization of primary somatosensory
cortex and the technique is used clinically for pre-
surgical planning.74–78 The sources of the early and
 CHAPTER 10 CLINICAL APPLICATIONS OF MEG IN NEUROLOGY AND NEUROSURGERY
middle-latency components of magnetic responses (oc-
curring <60 milliseconds after stimulus onset) obtained
through separate mechanical stimulation of each finger,
toe, and of the perioral area (usually the corner of the
lower lip) and modeled as successive, single equivalent
current dipoles (ECDs), originate from the contralateral
primary sensory cortex within the central sulcus (mostly
area 3b). Independent confirmation of the accuracy of
localization of the primary somatosensory area (and con-
sequently of the central sulcus) has been obtained in
several studies through direct comparisons with the re-
sults of intra- or extraoperative corticography.77,78,80–82
Moreover, MEG has proven sensitive to alterations of
the typical anatomical organization of the somatosen-
sory cortex in patients with mass lesions in the vicinity
of the central sulcus.77,83–88
䉴 MOVEMENT-RELATED
MAGNETIC FIELDS (MRFs)
Activation protocols permitting identification of motor
cortex have also been developed.89–90 Movement-related
magnetic fields (MRFs) preceding voluntary movement
are generated by neurons oriented tangential to the scalp
in motor cortex contra lateral to the movement, and are
recorded much more clearly than EEG.91–96 Typically,
somatosensory and motor mapping are performed in
separate sessions although, recently, a procedure for
mapping both somatosensory and motor functions in
the same session has been developed.76 According to
this protocol mechanical tactile stimulation is applied to
the subject’s index finger and serves as a cue for the
individual to perform a full wrist extension. Tactile stim-
ulation activates initially the contralateral primary so-
matosensory cortex followed by activation of the sec-
ondary somatosensory cortex, lasting for approximately
150 milliseconds. Activity in the contralateral precentral
gyrus is seen next immediately preceding the onset of
electromyographic activity marking the onset of finger
movement. Finally, somatosensory activity is again ob-
served during the movement presumably the result of
proprioceptive input. The location estimates of the mo-
tor cortex were subsequently verified in six patients with
perirolandic lesions through intraoperative electrocorti-
cal stimulation (see Fig. 10–2).
䉴 VISUAL EVOKED MAGNETIC
FIELDS (VEFs)
Mapping the precise location of the primary visual cor-
tex is often required prior to resecting mass lesions
in the vicinity of the calcarine fissure. The intracranial
123
sources that give rise to the early component of the
magnetic waveform evoked by rapidly changing pat-
terned stimulation are used as markers of the primary
visual area.97–102 Hemifield or single quadrant stimula-
tion has been successfully used to localize visual cortex
in patients with organic brain diseases before surgical
interventions such as craniotomy,74,103 and stereotactic
procedures.104
䉴 AUDITORY EVOKED MAGNETIC
FIELDS (AEFs)
Determining the precise location of the primary auditory
cortex may be useful for planning resections of mass le-
sions that encroach on the supratemporal plane.105,106 In
many cases application of AEFs can be evoked by bin-
aural stimulation with meaningful stimuli in the context
of language mapping.
䉴 LANGUAGE-RELATED BRAIN
MAGNETIC FIELDS (LRFs)
Recording of language-related brain magnetic fields
has two main clinical indications: (1) to establish the
profile of hemispheric involvement in the mechanism
that supports basic language functions (hemispheric
dominance107–109 ) and (2) to identify the location and
extent of functionally intact cortex involved in language
functions in relation to the area to be resected (epilep-
togenic zone or mass lesion103,110–112 ).
ESTABLISHING HEMISPHERIC
DOMINANCE FOR LANGUAGE
With the advent of functional imaging methods, there is
great potential for replacing the Wada with a less inva-
sive procedure.113–116 Validation studies of the accuracy
of fMRI, which is currently the most commonly used
hemodynamic imaging technique for mapping eloquent
cortex, have shown good concordance with the Wada
procedure and with intraoperative electrocortical stimu-
lation mapping (ioESM), under particular conditions and
with some exceptions (for recent reviews see Billingsley
and Simos,117 Papanicolaou,108 Bookheimer,118 Pelletier
et al.119 ).
Using MEG as a method of functional imaging, oth-
ers and we have verified that MEG assessments of hemi-
spheric dominance for language are concordant with
those based on the Wada procedure.107,109,120 Szyman-
ski and colleagues109 showed that the duration of late
components of event-related magnetic fields elicited by
124 SECTION I TECHNIQUES

A B

CS
LH

M
S

anterior

Les-

posterior
C D

Figure 10–2. Intraoperative verification of magnetoencephalography (MEG)-derived

estimates for primary somatosensory (S) and motor (M) cortex. (A) Axial view of
patient’s magnetic resonance imaging (MRI) were the MEG-derived estimates for
sensory (black dot) and motor (black square) are projected in proximity to the
patient’s lesion (cavernous angioma). (B) Intraoperative photograph showing the
placement of a strip of electrodes for sensory and motor mapping. (C) Schematic
diagram representing the spatial relation between the lesion (Les.), the estimated
dipoles, and the positive areas for sensory (S) and motor (M) function as were derived
from the invasive recordings. (D) Photograph taken after ressecting the cavernous
angioma showing the identified sensory (S) and motor (M) areas. CS, central sulcus;
LH, left hemisphere. (Image reproduced with permission from Castillo EM, Simos PG,
Wheless JW, et al. Integrating sensory and motor mapping in a comprehensive MEG
protocol: clinical validity and replicability. Neuroimage 2004;21(3):973–983).

vowel stimuli demonstrated hemispheric asymmetries
concordant with hemispheric dominance patterns de-
rived from the Wada procedure. Studies using a 148-
channel whole-head MEG system and a continuous
word recognition task to elicit brain activity, have also
found excellent concordance between the MEG lateral-
ity estimates and the results of the Wada procedure in
children, adolescents, and adults.107 Using identical stim-
ulation and analysis procedures, Maestú et al.120 repli-
cated these results independently for Spanish-speaking
patients.
Most recently the sensitivity and selectivity of our
noninvasive language mapping procedure for determin-
ing hemispheric dominance was assessed in a series of
100 surgical candidates aged 8–56 years with intractable
epilepsy.108 The degree of language-specific activity was
indexed by the number of consecutive sources (modeled
as single, ECDs, or ECDs) in perisylvian brain areas, as
in the aforementioned studies. Only late-component ac-
tivity sources that were observed with a high degree
of spatial and temporal overlap in two “split-half” data
sets were used to compute the MEG laterality index.
 CHAPTER 10 CLINICAL APPLICATIONS OF MEG IN NEUROLOGY AND NEUROSURGERY
Independently, all patients had Wada testing performed
for the determination of hemispheric language domi-
nance. There was a high degree of concordance (87%)
between independent clinical judgments based on MEG
and Wada data. MEG laterality judgments had an overall
sensitivity of .98 and a lower selectivity of .83, due to the
fact that MEG detected more activity in the nondominant
hemisphere than would be predicted on the basis of the
results of the Wada procedure. The same activation pro-
tocol yields reliable estimates of the location of receptive
language-specific cortex (Wernicke’s area), and the ac-
curacy of these estimates have been verified against the
results of invasive intro- or extraoperative electrocortical
stimulation mapping.111,112 Kober et al.121 and Bowyer
et al.122 have also reported success in obtaining estimates
of hemispheric laterality during performance of expres-
sive language tasks, which will be discussed in more
detail later.
FUNCTIONAL MAPPING OF THE
EXPRESSIVE LANGUAGE-SPECIFIC
CORTEX
Although mapping of receptive language cortex was
found to be sufficient for the purpose of assessing hemi-
spheric dominance for language, it is often necessary
to determine the location of expressive language cor-
tex in relation to diseased cortex. Several groups have
thus far reported success in eliciting prefrontal magnetic
activity in the vicinity of Broca’s area, associated with
the performance of a variety of expressive language
tasks.
Castillo et al.123 used a picture naming task and
MEG analysis procedures identical to those employed
earlier in the context of receptive language mapping to
derive maps of activation related to expressive language
function. The results for seven normal volunteers and
nine patients with epilepsy can be summarized as fol-
lows: (1) The task resulted in activation of the expressive
language-specific cortex (Broca’s area) in only a fraction
of the cases (in 3 of the 9 patients and 3 of the 7 neuro-
logically intact participants). Consequently, it cannot be
used alone for routine identification of Broca’s area. (2)
When prefrontal activity sources were identified, their
location matched very closely with estimates of the loca-
tion of Broca’s area based on electrocortical stimulation
mapping.123
Using a different task (word generation to phone-
mic or semantic cues) and identical analysis procedures,
Billingsley et al.124 reported consistent activity in the
vicinity of Broca’s area in neurologically intact partic-
ipants. The duration of this activity was consistently
greater in the left as compared to the right hemisphere
and this hemispheric asymmetry was larger when partic-
ipants were asked to generate a word that started with
125
a particular sound (phonemic cue condition). Although
this study provided new insights into the timing of corti-
cal interactions during expressive speech tasks, the num-
ber of activity sources in Broca’s area was not as abun-
dant as we have previously found in posterior speech
regions during the performance of receptive language
tasks, thereby rendering this task, if used alone, insuffi-
cient for routine presurgical patient mapping. We plan
to determine whether combining the verbal fluency and
the naming tasks is sufficient to fulfill that stringent re-
quirement.
Kober et al.121 have also reported success in elic-
iting inferior frontal activity using a picture naming
task, using spatial filtering rather than the single ECD
method.107,111,112,123 Kober et al.’s spatial localization and
time course results were consistent with the Wernicke-
Geschwind model of language organization. Moreover,
they showed a high degree of concordance between
results from spatial filtering and single ECD modeling,
which has been externally validated.107,112 As currently
utilized, the single ECD approach permits localization of
up to three simultaneous activity sources in each hemi-
sphere, provided that they are located at least 3–4 cm
apart and the orientation of each dipolar source results
in visually distinguishable surface isofield maps.
More recently, Bowyer et al.122 using yet another
mathematical procedure for estimating the underlying
cortical sources of magnetic fields, namely multires-
olution focal underdetermined system solution (MR-
FOCUSS), showed in a group of 24 epileptic patients and
18 control subjects that this current density imaging tech-
nique can provide reasonable localization of language
cortex. Using this technique, all participants showed ac-
tivation of the left superior temporal gyrus during a word
generation task and the left inferior frontal gyrus during
a picture naming task. Although the spatial filtering and
current source density methods have not been externally
validated for language mapping against the Wada or
electrocortical stimulation mapping, they hold promise
for detecting multiple, simultaneous sources contribut-
ing to late components of ERFs during expressive and
receptive. Promising results in the same direction have
also been reported by Hirata et al.125 using a different
algorithm for source estimation. Oscillatory activity as-
sociated with reading was recorded in 20 patients ob-
taining good agreement with the results of the Wada
test.
Clearly, future developments will decide on the
most efficient method for assessing laterality as well as
precise location of the cortical circuitry subserving ex-
pressive and receptive language as well as other cog-
nitive functions. At present, however, the ECD model
appears to be the safest to use for all types of presur-
gical evaluation, from determination of epileptogenic
zones to localization of the sensory, motor and language
cortex.
126 SECTION I TECHNIQUES
䉴 ACKNOWLEDGMENT
The research presented in this chapter was partly
supported by NIH Grant RO1 NS46588 to the last
author.
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87. Papanicolaou AC, Simos PG, Breier JI, et al. Brain plastic-
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finger movements in humans: steady-state movement-
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94. Nagamine T, Toro C, Balish M, et al. Cortical magnetic
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130 SECTION I TECHNIQUES
121. Kober H, Moller M, Nimsky C, Vieth J, Fahlbusch R,
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46-53.
 Chapter 11
Optical Spectroscopic Imaging of the
Human Brain—Clinical Applications
Hongtao Ma, Minah Suh, Mingrui Zhao, Challon Perry, Andrew Geneslaw,
and Theodore H. Schwartz
Department of Neurosurgery, Weill Medical College of Cornell University, New York, New York
Clinical neuroscience relies on a variety of human brain
mapping techniques to aid in the diagnosis and manage-
ment of patients with neurological illnesses. Anatomic
imaging techniques such as computed tomography (CT),
ultrasound, and magnetic resonance imaging (MRI) pro-
vide static renderings of brain parenchyma and vascular
anatomy at a precise moment in time. These techniques
can also be adapted to provide physiological information
about cerebral blood flow (CBF) (xenon CT, Doppler
and perfusion MRI, respectively). Functional mapping
techniques, on the other hand, provide information
about the brain’s electrical activity, whether it be normal
cortical processing or abnormal activity such as epilepsy.
These can be divided into techniques that map neuronal
activity directly and those that map it indirectly. Elec-
troencephalography (EEG) and magnetoencephalogra-
phy measure the electrical or magnetic fields resulting
from the synchronized population activity of neuronal
tissue. While the temporal resolution of these techniques
is on the order of milliseconds, spatial resolution is of-
ten measured in centimeters and sampling is limited to
cortex adjacent to the electrodes. Indirect brain mapping
techniques, on the other hand, such as functional MRI
(fMRI), positron emission tomography (PET) and single-
photon emission tomography (SPECT) measure nonelec-
trical physiological events that correlate with neuronal
activity such as metabolism, perfusion, and oxygenation.
Although these techniques can sample the brain widely,
both on the surface and at a depth, they have limited
spatial and temporal resolution, on the order of millime-
ters and seconds. In addition, correct interpretation of
these methods requires a comprehensive understanding
of neurovascular coupling during both normal and ab-
normal brain activity, which is dynamic and complex.
Optical spectroscopic imaging is based on measur-
ing changes in the absorption of light in the brain and
its blood vessels associated with neuronal activity. The
sources of this intrinsic signal include several optically
active events,1 which correlate indirectly with neuronal
activity. Characteristic physiological parameters affect
131
the degree to which incident light is reflected by the
active cortex. These are: (1) blood volume changes;
(2) changes in hemoglobin oxygenation; and (3) light
scattering. Each optical imaging method measures these
hemodynamic changes with different wavelengths. Optical
recording of intrinsic signal (ORIS) works on the visi-
ble wavelength (450–700 nm), while near infrared spec-
troscopy (NIRS) and diffuse optical tomography (DOT)
use higher wavelengths (700–1100 nm). Depending on
the optical window (i.e., intact skull vs. exposed cortex),
these techniques can measure perfusion, oxygenation,
and light scatter with a spatial resolution of approxi-
mately 200 ␮m and a temporal resolution that is limited
by the onset of the signal (tens to hundreds of mil-
liseconds). By measuring light at multiple wavelengths
(i.e., spectroscopy), these techniques can quantify
hemoglobin in its oxygenated and deoxygenated states.
䉴 NEUROVASCULAR COUPLING
The basis of functional imaging using intrinsic signals
is the coupling between neuronal activity, metabolism,
oxygen utilization and perfusion. The idea that neu-
ronal activity, which causes an increase in local cerebral
metabolic rate (CMRO2 ), would lead to a focal in-
crease in perfusion is based on the work of Roy and
Sherrington.2 They hypothesized that techniques which
measure perfusion could be used to map neuronal ac-
tivity. More recently, Fox and Raichle demonstrated that
increases in CBF, which occur 1–2 seconds after the
neurons become active, were far greater than increases
CMRO2 .3 This mismatch, or uncoupling of metabolism
and blood flow, leads to a local increase in oxygenated
hemoglobin (HbO2 ), which also forms a significant com-
ponent of the BOLD signal used for brain mapping with
fMRI, since differences in the paramagnetic properties
of oxygenated and deoxygenated hemoglobin can be
measured with high magnetic fields.4 In more recent
years, it has become clear that before the increase in
132 SECTION I TECHNIQUES

CBF occurs, the focal increase in CMRO2 elicits an early
decrease in hemoglobin oxygenation (or increase in de-
oxygenated hemoglobin (Hbr)) called the “initial dip,”
which is spatially and temporally more focally related to
the populations of active neurons than the later increase
in CBF and cerebral blood volume (CBV). This early dip
can be measured with ORIS,5,6 imaging spectroscopy,7,8
oxygen-dependent phosphorescence quenching,9 and
even high-tesla fMRI.10,11 However, the initial dip can
be very difficult to measure in rodents during normal
sensory processing and is quite sensitive to anesthe-
sia, systemic oxygenation, and blood pressure.12−14 Di-
rect measurements of tissue oxygenation with oxygen-
sensitive electrodes, however, have shown that the dip
clearly exists.15−18 During epileptiform events, on the
other hand, in which a large population of neurons are
synchronously active and metabolism is dramatically in-
creased, the dip in hemoglobin oxygenation is longer
and more profound.19−25
The existence of this “initial dip” in hemoglobin
oxygenation is of critical importance. As a mapping sig-
nal, the early CMRO2 -related increase in Hbr appears
to have more precise spatial correlation with the popu-
lation of active neurons than the later CBF-related in-
crease in HbO2 that forms a large part of the BOLD
mapping signal.5,7,9 Hence, fMRI studies may need to fo-
cus more attention on the earlier inverted BOLD signal
to increase its localization potential. In addition, using
ORIS, the CBV signal has also been shown to provide
a high-resolution mapping signal, if imaged early in its
evolution before it overperfuses the population of active
neurons,6,26,27 especially if one can separate the signal
arising from the microvasculature from that arising from
the macrovasculature.28
䉴 OPTICAL IMAGING TECHNIQUES
OPTICAL RECORDING OF
INTRINSIC SIGNAL
ORIS measures small changes in light absorption (or re-
flection) associated with neuronal activity. The brain is
exposed and either illuminated with visible light (400–
650 nm) or light at a specific wavelength. If illuminated
with visible light, then emission filters are needed to se-
lect the wavelength of interest for recording. The im-
ages are then acquired with a CCD camera while the
brain is activated, either by normal activity or patholog-
ical events. While a variety of intrinsic chromophores
exist in normal brain tissue, the majority of the signal in
the visible range is absorbed by hemoglobin. At higher
wavelengths, light scattering becomes a larger percent-
age of the signal. Because of the different absorption rate
of Hbr and HbO2 (Fig. 11–1), one can use the intrinsic
signal to quantitate hemoglobin oxygenation. At isos-
bestic wavelengths of hemoglobin where Hbr and HbO2
reflect light equally well (525 nm, 545 nm, 570.5 nm,
and 583 nm; corrected for path length),6 ORIS measures
total hemoglobin (Hbt), which is directly proportional

Hbt Hbr
HbO2
Hbr
Absorbance
increasing

450 500 550 600 650 700

Wavelength (nm)

Figure 11–1. The absorption curve of oxyhemoglobin (HbO2 ) and deoxyhemoglobin

(Hbr). Note that at the wavelength of 525 nm, 545 nm, 570.5 nm, and 583 nm,
(indicated with solid rectangle) Hbr and HbO2 absorb light equally and optical
recording of intrinsic signal (ORIS) signal mainly shows changes in total hemoglobin
concentration. At wavelength 600–650 nm, the ORIS signal mainly shows changes in
Hbr concentration.
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS
to CBV and CBF assuming that the concentration of
red blood cells remains constant.26,29 At higher wave-
lengths (600–650 nm), the majority of the signal arises
from the oxygenation state of hemoglobin, since Hbr
absorbs light with three times the absorption coefficient
of HbO2 .7,30 Hence, a decrease in light reflection indi-
cates an increase in Hbr. When intrinsic signals of mul-
tiple wavelengths are recorded simultaneously from the
same preparation, spectrum analysis can be performed
with the Beer-Lambert law to quantify relative changes
in Hbr, HbO2 , and Hbt. Because the reflectance changes
are small, usually approximately 0.1% of the illumina-
tion, they are not directly visible. In order to visualize
activated brain regions, images must be acquired when
the brain is active and inactive for a relative compar-
ison. The most straightforward way is to subtract im-
ages recorded during nonactive conditions from those
recorded during active conditions. Other methods, based
on frequency-dependent stimulus presentation and anal-
ysis, have also been successful.31 Although ORIS only
records functional changes occurring near the cortical
surface in the supragranular levels, due to the short pen-
etration distance of visible light, ORIS offers a superior
combination of spatial sampling (as wide a field as can
be imaged), spatial resolution (∼200 ␮m) and temporal
resolution (∼100 milliseconds, based on the relatively
slow temporal evolution of the signal, although faster
frame rates can be acquired).
NEAR INFRARED SPECTROSCOPY
AND DIFFUSE OPTICAL
TOMOGRAPHY
Visible light penetrates tissue only short distances, thus
little information is available about the activity in deep
tissue. In the NIR spectrum (700–1100 nm), however,
photons can penetrate deeper into tissue (∼3 cm), even
through bone. Within this spectral region, light absorp-
tion is also sensitive to the oxygenation of hemoglobin
(Fig. 11–1). While Hbr has a peak absorption at 760 nm,
HbO2 has a peak absorption at 920 nm. The cortex is
generally illuminated via fiberoptic bundles directed ver-
tically at the cortical surface. Since photons do not travel
in a straight line through tissue, they will be reflected and
scattered. Each photon entering the tissue will follow a
different path with only a small fraction reaching each
detector simultaneously. These paths are generally mod-
eled as banana-shaped (Fig. 11–2). The recorded signal
will only contain information within the banana-shaped
region, which results in a lower spatial resolution from
which only two-dimensional topographic imaging can
be generated.
DOT uses the same illumination wavelengths as
NIRS to monitor cerebral hemodynamics and oxygena-
tion. However, DOT techniques process the scattered
light in more detail to obtain spatial information about
133
Illumination
Detector 1 3
Signal
source
2 4
Figure 11–2. Illustration of the path of light traveling
through a scattering media. When nearly infrared light
was shined into a scattering media, the light will be
absorbed and scattered by the media. Each detector
will receive light traveling through a banana-shaped
pathway. Detectors at different locations will receive
light from different pathways. When a signal source is
located in the pathway, the light change will be
detected by the relative detector. For example, the
signal source on the right could be detected by
Detector 4 and the signal source on the left can be
detected by Detector 2.
its spatial origin. DOT images contain three-dimensional
information about the origin of Hbt, Hbr, and HbO2 aris-
ing from a large volume of tissue (or the whole brain)
with high temporal resolution.32−38 Compared to other
optical imaging modalities, DOT has a number of promi-
nent advantages such as portability, long recording time,
and an insensitivity to mechanical movement. Both tech-
niques work better when less skin and skull lies between
the light emission source and the detector. For this rea-
son, studies in infants are common.
䉴 IMAGING NORMAL
ARCHITECTURE IN ANIMALS
AND HUMANS
The application of optical imaging to the study of
normal brain architecture has lead to several major
breakthroughs in our understanding of the functional
architecture based on its ability to sample large areas
of the cortex simultaneously. Since the intrinsic signal
represents hemodynamic surrogates of neuronal activity,
areas of activation are more widespread than the pop-
ulation of cells firing action potentials, corresponding
more closely with the area of subthreshold activation.
Hence, mapping functional architecture often requires a
detailed understanding of the variety of behaviors that
in combination will activate the entire cortex, in order to
134 SECTION I TECHNIQUES

perform the appropriate subtractions that will individu- and guinea pig auditory cortex and Hess and Scheich70
ally identify the cortical region associated with a partic- analyzed frequency- and intensity- dependent spatial-
ular behavior. For this reason, maps of primary cortex temporal activity in primary auditory cortex AE of awake
are more robust than maps of association cortex since Mongolian gerbils. Later on, Harel et al.71 defined three
the range of behaviors that activate association cortex separate auditory area, AI, AII, and AAF in chinchilla.
are not as clearly understood (i.e., all five fingers can be They showed a cochleotopic or tonotopic organization
stimulated individually to map the hand sensory area but based on the differences in intrinsic signal areas evoked
generating maps of every possible phonemic, semiotic, by pure tones at octave-spaced frequencies from 500 Hz
and grammatical unit in a particular language would not to 16 KHz. The maps in AI and AII are arranged orthog-
be possible). onal to each other. In a recent study, Mrsic-Flogel et al.72
use ORIS to study the maturation of functional maps in
primary auditory cortex (A1) after the onset of sensory
VISUAL CORTEX
experience and they found that neither the tonotopic or-
ganization nor the representation of inputs from each ear
ORIS was used initially to study the functional archi-
reach maturity until approximately 1 month after hearing
tecture of visual cortex, which lead to major discov-
onset.
eries such as the pinwheel organization of orientation
columns and relative locations of the ocular dominance
columns and spatiotemporal frequency domains within SOMATOSENSORY CORTEX
area 17 and 18 (Fig. 11–3).5,39−48 Subsequently, ORIS was
ORIS has been used to map the functional organization
used to map direction of motion preference,49,50 color
of the whisker barrel cortex in rodents39,73−76 as well as
selective neuronal clusters in V1,51 distribution of hue
forepaw and hindpaw representation in somatosensory
maps in macaque striate cortex (V1), thin cytochrome
cortex of rodents and cats.6,77−81 A recent study using
oxidase stripes of V252−54 as well as form processing
voltage-sensitive dye (VSD) and ORIS in the same animal
modules in V455 and complex object representation in
showed good correlation between the centers of the two
infratemporal cortex.56 With chronically implanted cham-
maps, with differences in spatial extent82 ).
bers and artificial dura, ORIS can be applied to study
The somatotopic hand representation in macaque
the stability of visual architecture in awake behaving
and squirrel monkey primary somatosensory cortex
monkeys57−59 and the role of experience in the devel-
(area S-I) has also been studied with ORIS.83,84 The ac-
opment of the columnar organization of the cortex.60,62
tivation evoked by stimulation of a single finger was
While ORIS requires a craniotomy and exposed cor-
strongest in a narrow transverse band across the postcen-
tex, NIRS and DOT can be performed though the in-
tral gyrus and a sequential organization of these bands
tact skull making studies of visual processing in humans
was observed (Fig. 11–4). In addition to finger-specific
more practical. Kato et al.63 first use NIRS to monitor hu-
bands, activation areas common to all animals were
man visual cortical function during photic stimulation.
identified as well as specific areas sensitive to flutter,
Both increases in CBV and Hbr were recorded. Soon
pressure, and vibratory stimuli.83,84
after, Meek et al.,64 Sakatani et al.,65 Takahashi et al.,66
In humans, Toga et al.85 analyzed the spatiotem-
and Wilcox et al.67 also showed that NIRS can record
poral evolution of hemodynamic changes in sensorimo-
hemodynamic changes from the visual cortex in adults
tor cortex in response to peripheral somesthetic stimu-
and in infants.
lation. The somatosensory cortex of seven anesthetized
DOT imaging has also been used for study of
patients was mapped in response to transcutaneous elec-
visual processing and can provide additional three-
trical median and ulnar nerve stimulation using optical
dimensional spatial information about the activated
reflectance imaging. The ORIS maps colocalized with
cortical regions. Taga et al.68 used DOT to image the
the largest evoked potentials in both motor and sen-
hemodynamic responses in occipital and frontal cor-
sory regions. Cannestra et al.86 mapped the cortical rep-
tex of newborn infants during visual stimulation. They
resentation of different fingers with ORIS. They found
found that visual stimulation induced statistically signifi-
that the peak ORIS response to the stimulation of dif-
cant increases in oxyhemoglobin not only in the occipital
ferent fingers did not overlap, but the nonpeak optical
cortex but also in the prefrontal cortex. These results
signals were more widespread with significant overlap.
suggest that the neurovascular coupling is already func-
Co-localization between peak ORIS responses and sites
tioning in the newborn’s brain.
where direct cortical stimulation induced finger move-
ment was also observed. Sato et al.87 used intraop-
AUDITORY CORTEX erative ORIS to study the representation of different
fingers in somatosensory cortex. Biphasic optical
In 1996, ORIS was first employed to study the functional changes were recorded with ORIS during the stimula-
architecture of auditory cortex. Bakin et al.69 investi- tion of the first and fifth digits. Near the central sulcus,
gated the suprathreshold tonotopic organization of rat the cortical response area to the first and fifth digit was
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS 135

M L

B C

D E

F G

Figure 11–3. Optical imaging of intrinsic signals reveals the functional architecture in
ferret visual cortex. (A) Blood vessel pattern of the surface of the visual cortex.
(B) Differential map produced by dividing images obtained with 0◦ and 90◦ stimulation.
(C) Differential map produced by dividing images obtained with 45◦ and 135◦
stimulation. The size of the 45◦ and 135◦ iso-orientation domains is smaller than that of
the 0◦ and 90◦ domains. (D) The angle map is generated by color-coded vectorial
summation of each single condition map on a pixel-by-pixel basis. (E) Fracture map
generated from the two-dimensional derivative of the angle map demonstrates rapid
changes in orientation preference at pinwheel centers. (F) Ocular dominance map in
the ferret has a seemingly disorganized structure and column diameters vary widely
both between and within animals. The V1/V2 border correlates with the margin
between the caudal contralateral and rostral ipsilateral eye bands. (G) Spatial
frequency maps demonstrate high spatial frequency preference caudally and
low-spatial frequency preference rostrally. The spatial frequency border is roughly
parallel to the ocular dominance border but shifted caudally. R, rostral; C, caudal; L,
lateral; M, medial. Scale bar = 1 mm. From, Schwartz TH: Optical imaging of
epileptiform events in visual cortex in response to patterned photic stimulation. Cereb
Cortex 2003;13:1287-1298.

spatially distinct, whereas in the postcentral sulcus, the
two fingers were represented in the same region. Their
results suggested a hierarchical organization of the pri-
mary somatosensory cortex.
NIRS has also been used to map the representation
of both painful and tactile stimulation in somatosensory
cortex in the preterm newborn brain.88 Different hemo-
dynamic responses in the somatosensory cortex were
observed. Painful stimulation induced a significant de-
crease in oxygen saturation ( p < 0.0001), whereas tactile
stimulation produced no changes in oxygen saturation.
Both tactile and painful stimulation induced an increase
in HbO2 bilaterally regardless of which hand was stimu-
lated. Pain-induced HbO2 increases in the contralateral
somatosensory cortex ( p < 0.05) were not mirrored in
the occipital cortex ( p > 0.1).
136 SECTION I TECHNIQUES

som
atos
ens
ory
motor

5 mm

5 mm

Figure 11–4. Somatosensory organization of hand area in monkey. (A) Time course of
optical response to mechanical stimulation of a single finger. The first figure is the
image of the cortical surface (left hemisphere, monkey M3). The somatosensory and
motor areas are marked. The anterior part of the somatosensory strip is Brodmann’s
area 1, and the posterior part is area 2. An image series of the left hemisphere in
monkey M3 showing the temporal development of the optical response to a weak
mechanical indentation stimulation of finger 3 of the right hand. Each frame
represents 500 milliseconds of summation of collected video frames. The finger was
stimulated at the distal phalanx using pneumatic air pressure pulses (10 milliseconds)
delivered for 2 seconds at a rate of 10 Hz. The stimulus started concurrently with the
acquisition of the second frame (stimulus duration is marked by a black horizontal
bar). The full gray scale corresponds to a fractional change of 1 × 10−3 . The images
from 45 repetitions of the stimulus (and blank) presentations were averaged. (B)
Somatotopic organization of the hand area in monkey M5. Left hemisphere finger
maps for right-hand stimulation are summarized here in two formats. Left, The
images show contour maps from the three monkeys. Contour lines at the level of 30%
of peak activation for each finger are superimposed on the surface vasculature image
(imaged with green light). The thin contour lines were computed from a smoothed
version of the maps (low-pass filtered with a Gaussian filter, = 120 ␮). The contour for
each finger is colored according to the color code shown in the hand drawing below
the maps. To facilitate a comparison with the second type of analysis shown on the
right, the WTA patches are also superimposed. Right, The images show WTA maps
calculated from the same data. The information from the individual finger maps is
integrated here using a winner-takes-all rule. The color of each pixel is determined by
the finger that gave the strongest response, using the same color codes used for the
contours. The intensity encodes the amplitude of the response to the “winning” finger.
Only pixels in which this response was >30% of the peak activation were colored. The
other pixels show the underlying vascular pattern.
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS 137

GLM
d d
coefficient

c r

coronal sagittal

GLM
d
d coefficient

c r

coronal sagitt

Figure 11–5. Diffuse optical tomography imaging of functional brain activity during
front paw stimulation. The hemodynamic change maps (color ) were overlaid onto
anatomical cross-sections of the rat brain. Top: HbO2 , bottom: deoxyhemoglobin
(Hbr). v, ventral; c, caudal; r, rostral; GLM, generalized linear mode.

DOT imaging has also been successfully used in
the imaging of functional brain responses to paw stimu-
lation in rats.36 The spatial distribution and quantitative
changes in different hemodynamic components could be
clearly mapped in both superficially, in the somatosen-
sory cortex and at a depth, in the thalamus (Fig. 11–5).
LANGUAGE CORTEX
ORIS was also applied in humans to detect cortical lan-
guage areas in awake patients undergoing neurosur-
gical procedures. Haglund et al.89 first demonstrated
cognitively evoked activity in a language area. Significant
activation was seen in essential language areas that cor-
related with areas where stimulation mapping induced
errors. Intrinsic signal changes were more widespread,
indication that the area of cortex participating in lan-
guage processing was larger than the area essential for
language. Cannestra et al. 200090 also used ORIS to
study the cortical response to different language tasks
in awake patients. They found that different tasks and
performance can induce distinct spatial and temporal
response patterns in Broca’s and Wernicke’s area (Fig.
11–6). Pouratian et al.91 also reported that cortical lan-
guage representation in bilinguals may consist of both
overlapping and distinct areas.
NIRS and DOT imaging have also been used to
study the prefrontal hypo-oxygenation during language
processing and the cortical representation of sound
and language through an intact skull. Fallgatter et al.92
found that during language processing, Hbr increases
and HbO2 decreases were significant but no hemispheric
differences were found. Minagawa-Kawai et al.93 used
NIRS to assess the cerebral representation of Japanese
short- and long-vowel categories. Their results showed
that NIRS could capture phoneme-specific information
and confirmed the left dominance in phoneme process-
ing. Taga and Asakawa94 used DOT to localize the corti-
cal response to auditory and visual stimulation in awake
infants aged 2 to 4 months. They found that auditory
stimulation could induce focal increases in HbO2 and
decreases in Hbr in both hemispheres, but visual stim-
ulation did not induce significant change is HbO2 and
Figure 11–6. Optical recording of intrinsic signal (ORIS) response over Wernicke’s
area demonstrates that topographic specificity depends on the language task. ORIS
was performed over the temporal/parietal junction during an awake neurosurgical
procedure. Images were acquired in a block paradigm scheme (10 sec rest, 20 sec
activation), and averaged across blocks to obtain reflectance changes. Overall,
regions 3 and 5 were activated by all paradigms (region WAc in lower right
schematic). When comparing object naming (upper left) and word discrimination
(upper right), object naming selectively activated anterior and inferior cortices (region
WAa in lower right schematic) while word discrimination activated more superior and
anterior anatomy (superior to ESM site 3; region WAs in lower right schematic).
Auditory responsive naming (lower right) tasks activated all of the regions
corresponding to both the object naming and the word discrimination paradigms, and
was more intense centrally (in WAc). In addition, the auditory responsive naming
discrimination paradigm also selectively activated more posterior cortex (near ESM
site 4; WAp in lower right schematic). The magnitude contours demarcate these
differences. Baseline activity is observed in the lower left. ESM mapping revealed
anomia for cortical regions 3, 4, 5, and 6. ESM mapping at site 1 (at upper left cranial
margin) reveal hand and arm movement, thereby localizing motor cortex. In this
patient (patient 8), angular gyrus and superior temporal gyrus were noted to be
shifted anterior and inferior due to the presence of an arteriovenous malformation
superior and deep to angular gyrus. Magnitude contours (in yellow ) indicate
increasing intensity. Magnitude contours were obtained after applying a 5-pixel
Gaussian blur. Images are averages of eight scans in one patient. A, anterior;
S, superior; CS, central sulcus; SF, superior frontal. The color bar is reflectance
change 10−4 for all paradigms. Scale bar: 1 cm.

138
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS
Hbr, indicating staggered development of neurovascular
coupling mechanisms.
SUMMARY
Overall, optical imaging techniques have had a dramatic
impact in our understanding of the topographic rep-
resentation of function in primary cortex such as vi-
sual, auditory, and somatosensory cortex. This work has
been most clear in animal models in the laboratory. Hu-
man studies of primary cortex are feasible but to date
have been mostly derivative of the laboratory studies
and lack the spatial resolution of the laboratory stud-
ies due to large sources of noise, primarily from brain
pulsation and vasomotor fluctuations. Imaging the initial
dip, which would increase the spatial resolution, is chal-
lenging compared with the less spatially restricted BOLD
signal (i.e., hyperperfusion and hyperoxygenation over-
shoot). The operating room environment is also not con-
ducive to these sensitive optical experiments based on
time constraints. However, great promise exists for future
work. In association cortex, the sources of the intrinsic
signal changes and the correlations between the signals
and behavior is less well-understood but still a fertile
ground for future research. Chronic experiments with
implanted optical arrays or skull mounted DOT helmets
may hold scientific promise for future breakthroughs.
䉴 IMAGING PATHOLOGY IN
ANIMALS AND HUMANS
Many brain diseases, such as epilepsy, stroke, intracra-
nial hemorrhage, and trauma, can significantly influence
CBF and hemoglobin oxygenation. Optical spectro-
scopic imaging can be a powerful tool for identifying
and understanding these pathophysiological processes.
EPILEPSY
Epilepsy is a clinical term referring to a disease which ef-
fects between 1% and 2% of the population of the United
States involving recurrent seizures.95 Seizures consist of
the paroxysmal, synchronous, rhythmic firing of a popu-
lation of pathologically interconnected neurons capable
of demonstrating high-frequency oscillatory activity.96
These events are caused by an imbalance in excitatory
and inhibitory mechanisms leading to both hypersyn-
chrony and hyperexcitability.97
Most studies in epilepsy have been done using elec-
trophysiological recording from surface field and ex-
tracellular single-unit electrodes. The current method
of identifying epileptogenic cortex in humans is also
139
with chronically implanted grids of electrodes. How-
ever, these methods have limitations in their ability to
identify ictal onset zones, areas of propagation, and in-
terictal spikes because of low spatial sampling. ORIS
has been employed to study epilepsy in various ani-
mal models98−102 as well as in humans in the operating
room.89,103
Schwartz and Bonhoeffer101 showed in an animal
model that ORIS is an excellent method for in vivo map-
ping of clinically relevant epileptiform events, such as
interictal spikes, ictal onsets, ictal propagation, and sec-
ondary homotopic foci. Using optical spectroscopy, Suh
et al.20 and Bahar et al.23 have shown that interictal
and ictal events cause a rapid focal increase in Hbt as
well as an increase in Hbr (Fig. 11–7). The increase in
Hbr, or “epileptic dip” lasts longer than the initial dip
reported after normal sensory processing and implies
that for a period of time, the reactive increase in CBF
is not able to compensate for the metabolic demands
of both ictal and interictal events. However, both the
Hbt and Hbr signals are useful for mapping either in-
terictal or ictal events. The later decrease in Hbr, which
comprises much of the BOLD signal demonstrated with
fMRI, however, was much less focal and spread to larger
areas of cortex. Comparing the Hbr/Hbt maps with VSD
maps reveals that although there was a linear relation-
ship between the amplitude of the hemodynamic and
voltage signals, both Hbr and Hbt spatially overshoot
the extent of the excitatory VSD signal by approximately
2×.24 Overall, ORIS has been shown in animal models
to be an excellent tool for mapping epilepsy, and as
shown by Schwartz et al.19,104 can be used to simulta-
neously derive maps of both epileptic and functional
architecture.
Experience with optical mapping of epilepsy in hu-
mans is limited since seizures do not routinely occur
during surgery and cannot be reliably induced. Electri-
cally triggered afterdischarges have been imaged in hu-
man patients during craniotomies.89,105 Haglund et al.89
reported that the optical changes increased in magni-
tude as the intensity and duration of the afterdischarges
increased. Spontaneous seizures have been recorded in
two reports. Haglund et al.106 localized a seizure using
the Hbt signal and Zhao et al.103 used both Hbr and Hbt
signals. In the latter publication, the authors confirmed
the presence of the epileptic dip in unanesthetized hu-
man cortex during spontaneous seizures and also re-
ported focal changes in light reflection, which preceded
the onset of seizures by approximately 20 seconds (Fig.
11–8). This finding mirrors similar data reported in the
rat107 and may offer new possibilities not only for seizure
localization but prediction.
Another method of optical imaging, NIRS, is cur-
rently being explored in experimental trials in the
clinic as a method for presurgical seizure localization
and is attractive because of its noninvasiveness. The
140 SECTION I TECHNIQUES

1 mV

50 ms

Hbr
0.2%
0.1%
0 ms 408.8 817.6 1226.4 1635.2 2044 2452.8
0

Hbt

0.1%
0 ms 408.8 817.6 1226.4 1635.2 2044 2452.8 0
A
–0.1%
4 mm

1 mv

10 s

Hbr

0.6
−1.4 s 0 0.8 1.2 2.0 5.0 8.1
0
–0.6
20.1 30.0 40.1 50.2 60.1 70.2 80.1

Hbt

0.6
−1.4 s 0 0.8 1.2 2.0 5.0 8.1
0

20.1 30.0 40.1 50.2 60.1 70.2 80.1 –0.6

B
4 mm

Figure 11–7. Optical recording of intrinsic signal of interictal and ictal events. (A) Time
course of optical response to interictal events. The top trace is the average signal
recorded from the local field potential of multiple interictal spikes. Below is the
evolution and propagation of the deoxyhemoglobin (Hbr) and total hemoglobin (Hbt)
signals. (B) Ictal events last for a longer period of time. Field potential above indicates
the duration of the seizure corresponding with the development of the Hbr and Hbt
signals shown in the figure.

first NIRS study on epileptic patients was performed
by Villringer and his colleague.108 They used NIRS
to continuously monitor hemodynamic changes during
spontaneous complex-partial seizures. They found that
extremely large increases in CBV and HbO2 concentra-
tion were measured during seizure, which were larger
than during other cognitive functions such as calcu-
lations and visual processing. NIRS was subsequently
used to monitor the hemodynamic responses to
epilepsy,109−111 render a diagnosis of epilepsy,112 distin-
guish seizure types,113 and in the management of status
epilepticus in infants.114 Although the spatial resolution
of NIRS is low, technical advances may overcome this
limitation. As a presurgical tool NIRS cannot yet replace
the EEG but may provide complementary information to
aid in the decision-making process.
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS 141

LFP (mV)
2

0
0.1
–2
−40 −20 0 20 40 0.05

0
0.06
-0.05

0.03 -0.1

-0.03
A −40 −20 0 20 40

2
LFP (mV)

–2
−40 −20 0 20 40
0.2

0.1
0.2
0.15 0

0.1 -0.1

0.05 -0.2
0
-0.05
−40 −20 0 20 40
B

Figure 11–8. Hemodynamic change during spontaneous seizure in a human. The

electrocorticographic recording and optical signal (A, 610 nm, B, 570 nm) 40 seconds
before and after the onset of the seizure are presented above. Optical signals from a
linear region of interest (60 × 6 pixels (height × width); 2.3 × 0.23 cm) over the crest
of the gyrus from which the seizures arise are presented below. Six pixels in width
were averaged and each pixel was divided from the baseline, taken from an average
of 150 frames (4.5 sec) at the onset of each trial. The pixel changes in comparison to
the baseline pixels were color coded (see color bar: the increase in red and the
decrease in blue) and plotted as a function of time. The image on the right shows the
optical recording of intrinsic signal maps for each of the two seizures at the time of
maximum increase. Each image is divided by the baseline image. Scale bar: 1 cm

STROKE tical imaging techniques can provide real-time measure-

Stroke is the clinical designation for a rapidly devel-
oping loss of brain function due to an interruption in
the blood supply to all or parts of the brain. This phe-
nomenon can be caused by thrombosis, embolism, or
hemorrhage. Traditional functional brain imaging meth-
ods such as fMRI, PET, and SPECT have provided insight
into the functional changes associated with stroke. How-
ever, these techniques have some common drawbacks
such as the immobilization of the subject’s head and
lack of real-time or long-term monitoring capability. Op-
ments of perfusion and oxygenation in large areas of the
cortex.
In an animal model, Wolf et al.115 first used NIRS in
the monitoring of regional cerebral blood oxygenation
(CBO) during peri-infarct depolarization in a model of
focal cerebral ischemia in the rat. Their work proved
that NIRS is a powerful tool to detect typical peri-infarct
depolarization-associated changes in blood oxygena-
tion. Chen et al.,116 further confirmed that in ischemic rat
brain, the geometric shape and infarct area measured by
NIRS matched well with those measured with fMRI and
142 SECTION I TECHNIQUES

A B C D E

Figure 11–9. Orientation/Retinotopic map reorganization after an ischemic lesion.

(A) Blood vessel pattern. (B) Iso-orientation maps in response to gratings of 0◦ (C)
Retinotopic map in response to a 1◦ wide stimulus oriented at 0◦ . (D) Retinotopic map
in response to 1◦ wide stimulus oriented at 0◦ , adjacent to the stimulus presented in C.
(E) Overlap between responses in C and D: light gray domains correspond to active
zones in C, dark gray domains correspond to active zones in D, and black zones
correspond to active areas in both C and D, the “overlap.” Note that the overlapping
area fully recovers after 5wPL. Orientation of the imaged cortical area is shown. A,
anterior; P, posterior; M, medial; L, lateral.

postmortem histology. NIRS can monitor the hemody-
namic change in real-time and may be a practical tool for
identifying the onset of stroke in high-risk patients. ORIS
has also been applied to study the effects of ischemic
events on functional cortical maps. Zepeda et al. (2003)117
induced a focal photochemical lesion in V1 of kittens
and analyzed the subsequent reorganization of the cor-
tical maps using ORIS. They found that the retinotopic
and orientation preference maps reorganize around the
lesion over a period of 5 weeks correlating with dendritic
spouting and biochemical changes (Fig. 11–9).118
Several studies in humans have examined the utility
of NIRS to monitor various aspects of a stroke in evolu-
tion, such as the hemodynamic response patterns, and
recovery or rehabilitation after stroke. Benaron et al.119
used NIRS to study hemoglobin oxygenation in neonates
after acute stroke, and areas of decreased oxygenation
were found to spatially overlap with the region of is-
chemia as measured by CT scan. In chronic stroke pa-
tients, however, conflicting data about CBO have been
reported. Kato et al.120 found that chronic stroke patients
exhibit a similar CBO response as do normal subjects
in the sensorimotor cortex during hand movement. In
contrast, Sakatani et al.121 reported an atypical evoked
CBO change the left prefrontal cortex of a group of
stroke patients during language tasks. Murata et al.122
also observed similar atypical evoked CBO changes in
the primary sensorimotor cortex during contralateral mo-
tor tasks. A further study by Murata et al.123 on patients
with a variety of cerebral circulatory conditions showed
that the affect of cerebral ischemia on the evoked CBO
response patterns varies depending on the level of is-
chemia. That is, moderate cerebral ischemia caused no
changes in the evoked CBO response pattern, whereas
severe cerebral ischemia caused an increase in Hbr con-
centration.
The first NIRS study of stroke rehabilitation was
by Saitou et al.124 They investigated the CBV and cere-
bral oxygen volume (COV) in 44 hemiplegic patients
and 24 normal control subjects. Each subject performed
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS
specific rehabilitation tasks, including head-up tilt, cal-
culation, an ergometer task, facilitation, stand-up task,
and gait. They found both increases and decreases in
CBV and COV during different tasks in all the sub-
jects. Their work clearly showed that NIRS is a useful
tool for monitoring changes in regional cerebral hemo-
dynamics and oxygenation during rehabilitation. Miyai
et al.125 also used NIRS to study the rehabilitation of
gait following stroke. Six nonambulatory patients with
severe stroke were monitored during a treadmill test
approximately 3 months after stroke. Each patient per-
formed the tasks (0.2 km/hr) for 30 seconds followed
by a 30-second rest period. The researchers found in-
creased activity in the premotor and presupplementary
motor cortex in the affected hemisphere during rehabili-
tation training. They also found that a therapist-facilitated
swing induced greater activation than did mechanical
assistance. Their finding suggested that multiple motor
areas, including the premotor cortex and presupplemen-
tary motor area might play important roles in restora-
tion of gait in patients with hemiplegia following severe
stroke.
Kato et al.31 performed a study of hand grasp on
six chronic stroke patients with minimal hemiparesis and
five similar age-matched control subjects. Both NIRS and
fMRI were used to evaluate the compensatory motor ac-
tivation of cortical regions in patients who recovered
from hemiparesis after cortical cerebral infarction. They
found very similar data from NIRS and fMRI, although
NIRS measurements seemed to be more sensitive than
the fMRI. However, NIRS only measures superficial acti-
vation, whereas fMRI can measure from the entire vol-
ume of the brain.
Miyai et al.126 used NIRS in longitudinal studies of
recovery after stroke (Fig. 11–10). A total of eight pa-
tients with stroke were investigated during hemiparetic
gait training on the treadmill. They found that ambulat-
ing was associated with increased levels of HbO2 in the
medial primary sensorimotor cortex, premotor cortex,
and supplementary motor area, and that the activity was
greater in the unaffected hemisphere than in the affected
hemisphere. On the second examination, the asymmetry
in sensorimotor activation was significantly diminished,
and there was enhanced premotor cortex activation in
the affected hemispheres. This improvement in asym-
metry significantly correlated with an improvement in
gait.
TRAUMATIC BRAIN INJURY AND
INTRACRANIAL HEMATOMAS
Traumatic brain injury (TBI) is a term used to describe
the damage to the brain that results from head trauma.
TBI can result from a closed head injury or a penetrating
head injury and is also considered a subset of acquired
143
brain injury (ABI). The gold standard imaging test for TBI
diagnosis in the emergency room is a CT scan, which
creates a series of cross-sectional X-ray images of the
head and brain and can show bone fractures as well
as the presence of subdural and intraventricular hem-
orrhages intraparenchymal hematomas, contusions, and
brain swelling. MRI may be used after the initial assess-
ment and treatment of the TBI patient to identify diffuse
axonal injury and more subtle changes in extracellular
water concentration (edema). Recently, several studies
have used optical methods to monitor the progression
of intracranial hemorrhages, subdural hematomas, brain
swelling, and increased intracranial pressure (ICP) in TBI
patients.
In 1995, Robertson et al.127 used NIRS to detect
the development of delayed hematomas in 167 patients.
The NIRS signals at 760 nm were measured in the
hemisphere with the hematoma as well as the con-
tralateral hemisphere for comparison during the first
3 days postinjury. Twenty-seven of the patients devel-
oped some type of late hematoma, of which 18 patients
required surgical evacuation. A significant increase in the
light absorption occurred in 24 of the 27 patients prior to
other detectable symptoms, such as a change in the neu-
rological examination or CT scan. Their work suggested
that NIRS may allow early identification of progressive
hematomas with earlier institution of therapy.
NIRS has also been utilized to monitor brain phys-
iology following TBI for prognostic purposes. Adelson
et al.128 performed a preliminary NIRS study in children
after severe TBI. Changes in HbO2 , Hbr, and Hbt were
compared to, ICP mean arterial pressure and arterial
PCO2 . They found that decreases in arterial PCO2 in-
duced desaturation of cerebral oxygen regardless of ICP
and high ICP correlated with increased Hbt and HbO2 .
Kampfl et al.129 also used NIRS to measure changes in
regional cerebral oxygen saturation in TBI patients. They
found that NIRS measurements were able to differentiate
high versus low ICP in spite of similar levels of arterial
partial pressure of oxygen (pO2 ), partial pressure of car-
bon dioxide (pCO2 ), and peripheral oxygen saturation.
Regional cerebral oxygen saturation in the higher ICP
group was significantly lower than those of the lower
ICP group. In addition, the low ICP group revealed a sig-
nificant increase in regional cerebral oxygen saturation
following induced hyperoxygenation, which was not de-
tectable in the high ICP group. Their results suggested
that NIRS can distinguish between patients with high
and low ICP. Dunham et al.130 also reported a correla-
tion between cerebral oximetry and cerebral perfusion.
In a small study of four patients, an increase in cere-
bral perfusion pressure was significantly correlated with
an increase in cerebral oxygen saturation ( p < 0.0001).
Their results suggested that the cerebral oxygen satura-
tion, measured with NIRS, could be a sensitive indica-
tor to monitor the development of increased ICP due to
144 SECTION I TECHNIQUES

A B C D

Figure 11–10. Cortical mapping of hemiparetic gait in patients with stroke. Cortical
activation maps are based on changes in HbO2 levels during gait before (pre) and
after (post) inpatient rehabilitation. Images in bottom row show site of lesions on
T2-weighted magnetic resonance imaging. “L” indicates left. (A) Cortical mapping of
gait in Case 2, with infarction in the left corona radiata (arrow ). On day 53 after stroke,
the patient needed moderate assistance to take a step. SMC activation was much
less in affected hemisphere than in unaffected hemisphere. After inpatient
rehabilitation (118 days after stroke), the patient needed minimal assistance to
perform the task. Sensorimotor cortex (SMC) activation was symmetrical, and new
activation was seen in supplementary motor area (SMA) and premotor cortex (PMC),
especially in affected hemisphere. (B) Cortical mapping of gait in Case 3, with
infarction in left corona radiata (arrow ). On day 107 after stroke, the patient needed
mild assistance with gait. There was less SMC activation in affected hemisphere than
in unaffected hemisphere, but PMC and SMA were bilaterally activated. On the
second imaging (176 days after stroke), the patient needed little assistance with gait.
SMC were symmetrically activated, and there was persistent activation in PMC and
SMA. (C) Cortical mapping of gait in Case 6, with diffuse infarction in right
frontoparietal lobe. On day 102 after stroke, the patient needed maximal assistance
with gait; this was the patient’s first opportunity to walk after the ictus. Mild activation
was observed in PMC and prefrontal regions in affected hemisphere, parietal regions
in unaffected hemisphere, and bilateral pre-SMA. There was little activation in the
medial SMC. On the second evaluation (173 days after stroke), the patient needed
mild assistance. Near infrared spectroscopy (NIRS) imaging revealed enhanced
activation in bilateral PMC, pre-SMA, and prefrontal areas and mild SMC activation in
unaffected hemisphere. (D) Cortical mapping of gait in Case 8, with a large
hemorrhagic lesion centered in right parietal lobe (arrow ). On day 32 after stroke, the
patient needed moderate assistance with gait. NIRS imaging showed prominent
activation in unaffected hemisphere. After inpatient rehabilitation (98 days after
stroke), the patient needed minimal assistance with gait, and enhanced activation
was observed in the bilateral SMC, PMC, SMA, and prefrontal cortices.

increases in cerebral perfusion. Other investigators, ments in ten patients with severe closed head injury
however, have not found NIRS to be useful for TBI. (Glasgow Coma Scale score ≤8). Poor correlation (r 2 =
In 1996, Lewis and his colleague131 compared contin- 0.04) between paired measurements and wide limits
uous jugular venous bulb oximetry and NIRS measure- of agreement (−13% to +21%) were demonstrated. In
CHAPTER 11 OPTICAL SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN—CLINICAL APPLICATIONS
fact, 14 clinically significant episodes of jugular venous
bulb desaturation were not detected by NIRS. Likewise,
Büchner et al.132 further investigated the possibility of us-
ing NIRS to measure cerebral oxygenation after severe
TBI in a larger population (n = 31). The NIRS measure-
ments were compared to several different standard inva-
sive monitoring methods, such as ICP, CPP, and regional
brain tissue–pO2 monitoring. Significant changes were
observed in all the patients with these invasive monitor-
ing methods, however, NIRS measurements were only
possible in 80% (using the INVOS oximeter) and 46%
(using the CRITIKON monitor). Only induced hyperoxia
(fraction of inspired oxygen (FiO2 ) = 1.0) revealed a
significant correlation between all modalities (r = 0.67,
p < 0.01), while lower or no correlation was found after
changing arterial carbon dioxide tension (paCO2 ) and
administering mannitol.
䉴 CONCLUSION
While more commonly used in animal studies to study
the functioning of the normal brain, the application
of optical spectroscopic to imaging pathological brain
states in humans may be more useful and have more im-
mediate clinical application than imaging normal func-
tional architecture. For example, optical spectroscopy
offers a unique and effective way to measure the spa-
tiotemporal dynamics of neurovascular coupling during
epileptic discharges,105 and the signals associated with
epilepsy are much larger than those associated with sen-
sory processing and are easier to record.While the ini-
tial dip is difficult to image in humans in the operating
room, the epileptic dip has been identified more read-
ily. Hence, optical spectroscopy holds promise for
identifying and predicting seizure onsets in humans.
Likewise, while the spatial resolution of transcranial
techniques such as NIRS and DOT may be too low
to map functional architecture, these techniques offer
a noninvasive method for identifying large areas of is-
chemia, or hematomas in evolution and may become a
standard of care in intensive care monitoring unit. Sim-
ilarly, optical epilepsy monitoring with NIRS may offer
complementary data to EEG monitoring and have suffi-
cient spatial resolution to identify a regional onset zone
in preparation for further invasive monitoring.
As the technology and our understanding of neu-
rovascular coupling evolve, optical spectroscopic imag-
ing (ORIS, NIRS, and DOT) will likely play an increasing
role in the clinic. Noise reduction will be a critical com-
ponent of this future work. Large signals arise from
vascular artifact84 such as the periodic dilation and con-
striction of blood vessels (vasomotor noise)133 and the
oscillation of cerebral oxygenation.134 The amplitude of
these periodic fluctuations is often similar to, or higher
than the activity-related changes. Although averaging
145
over multiple trails is an effective way to reduce this
noise, it is only applicable to events which are repetitive
and reproducible.
Other limitations and obstacles must be overcome.
NIRS and DOT are influenced by the absorption of light
of hair and reliable contact between the patient’s head
and the optodes. The subdural implantation of an op-
tical grid might be a resolution of these limitations, but
it is invasive. When optical components are subdurally
implanted, imaging can be performed chronically for ex-
tended periods of time. Continuous imaging might then
be possible while patients are hospitalized. Since light
scattering and absorption from the skull and hair will be
eliminated, the spatial resolution and imaging depth will
be increased.
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 Chapter 12
Electrocorticographic Spectral Analysis
Mackenzie C. Cervenka and Nathan E. Crone
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
䉴 INTRODUCTION AND
HISTORICAL PERSPECTIVE
Electrocorticographic (ECoG) spectral analysis is an
emerging method for mapping human brain function
that originally developed from the clinical circumstances
and needs of patients undergoing surgery for intractable
epilepsy. From almost the inception of epilepsy surgery,
identification of “eloquent” cortex relied primarily on
electrocortical stimulation mapping (ESM), in which di-
rect electrical stimulation of cortex interferes with mo-
tor, perceptual, or linguistic function. With the advent
of long-term intracranial electroencephalography (EEG)
monitoring for localization of the ictal seizure focus, ESM
was no longer limited to the stressful circumstances of
awake craniotomies,1 but its clinical utility was still lim-
ited by its propensity for inducing seizures and some-
times pain during stimulation. Furthermore, because
ESM had to be done sequentially at pairs of electrodes,
preferably finding the optimal stimulus intensity at each
pair, it was sometimes too time consuming to test more
than a few tasks at every stimulation site. For these
reasons, clinicians explored the possibility of mapping
cortical function by utilizing the ECoG signals already
being recorded for clinical purposes in these patients. Al-
though previous researchers had successfully exploited
the phase-locked components of ECoG responses to
stimuli or events (i.e., evoked and event-related poten-
tials [ERPs]) for this purpose, recent efforts toward
ECoG functional mapping have focused on task-induced
changes in ongoing cerebral activity that are not neces-
sarily phase-locked to a stimulus or event.
Broadly speaking, the general rationale and strat-
egy for analyzing ECoG spectra can be traced back to
the early days of EEG, when neuroscientists first de-
scribed specific background rhythms with distinct fre-
quency ranges, reactivities, and spatial distributions over
the cortex.2−5 Suppression of occipital alpha activity (in
the 8–12 Hz range) and central mu activity was ob-
served during functional activation of visual and senso-
rimotor cortices, respectively. These phenomena were
151
later quantified by event-related analysis of changes in
band-specific alpha power, as discussed later.6,7 Sev-
eral studies have revealed event-related changes in scalp
EEG spectra that correlate temporally and anatomically
with the planning and execution of movement,6−14 au-
ditory activation,15−18 visual stimulation,19−22 and lan-
guage processing.23−27
Recent clinical practice has evolved to allow for
placement of subdural electrodes directly on the sur-
face of the brain to measure electrocortical activity
with improved spatial resolution and signal quality.28
These ECoG recordings have yielded results similar to
the previous noninvasive EEG findings. In addition,
ECoG spectral analysis has revealed energy changes
in higher frequency bands such as gamma (30–60
Hz) and high-gamma (>60 Hz) frequency bands that
were undetectable or uninterpretable with surface EEG
recordings.29,30
ECoG spectral analysis is currently being used ex-
perimentally in humans to localize sensorimotor, audi-
tory, and language cortices during extraoperative inva-
sive monitoring for epilepsy surgery. The clinical utility
of this technique, including its sensitivity and specificity
with respect to ESM and other mapping techniques, is
still under investigation and is expected to evolve with
additional clinical research as well as continuing ad-
vances in instrumentation, data acquisition, and data
analysis. ESM is still widely considered to be the gold
standard for localizing eloquent cortex preoperatively.
In the future, however, the information obtained from
ECoG spectral analysis may complement the results ob-
tained from ESM and other mapping techniques and
could, in some circumstances, supplant ESM. In addi-
tion, ECoG continues to offer a rare opportunity to study
the working brain with unprecedented spatial and tem-
poral resolution. The application of ECoG spectral anal-
ysis to research in systems and cognitive neuroscience
has grown exponentially in recent years. In addition to
studies of the brain mechanisms of selective attention,
language, and memory, ECoG spectral analyses are being
used increasingly to drive brain–computer interfaces (BCI).
152 SECTION I TECHNIQUES
䉴 UNDERLYING PRINCIPLES
Event-related changes in EEG spectral energy can be an-
alyzed by averaging signals from multiple trials in the
time domain or in the frequency domain.7 Averaging in
the time domain consists of averaging each sample of
the raw EEG time series across multiple realizations or
trials of a task or behaviorally relevant event under study.
This procedure discards response components that are
not phase-locked to the event under study and neces-
sarily yields phase-locked responses commonly known
as evoked or event-related potentials. Averaging in the
frequency domain, in contrast, reveals changes in EEG
spectral energy that are time-locked, but not necessar-
ily phase-locked, to events. The procedure consists of
first converting the raw EEG time series into time- and
frequency-dependent estimates of signal energy. The re-
sulting time–frequency spectra are then averaged with
respect to the task or event under study. Note that the en-
ergy changes observed with this approach include both
nonphase-locked and phase-locked components unless
special procedures are used to mitigate the contribution
of phase-locked components.31−33
After averaging EEG signals in the frequency do-
main, event-related spectral changes can be quanti-
fied and statistically tested by comparing time- and
frequency-specific energy estimates during events with
those in a reference or “baseline” interval when the brain
is assumed to be “at rest,” that is, relatively inactive or
at least not engaged in the event or task under study.7
This reference interval is most commonly chosen imme-
diately prior to the onset of each trial. Changes detected
by this approach may consist of increases or decreases
of signal energy that depend on the frequency of the
signal as well as its temporal relationship to the task or
event under study and the location at which the signal
is recorded with respect to functionally activated cortex.
The terminology used to describe different event-
related spectral changes is still evolving in the literature
due to a lack of consensus about the functional signifi-
cance of different spectral phenomena, about the opti-
mal balance between lumping and splitting these phe-
nomena, and about how to best reflect our evolving
understanding of their neural generators and generat-
ing mechanisms. For example, the term event-related
desynchronization (ERD), originally coined by Gert
Pfurtscheller,34 is commonly used to refer to event-
related suppression of power. This power suppression is
usually observed most prominently in frequency bands
that are defined by peaks in the power spectrum dur-
ing baseline intervals. These band-limited peaks typi-
cally correspond to “resting rhythms” such as the occipi-
tal alpha rhythm of resting visual cortex,2 the central mu
rhythm of sensorimotor cortex,5 or the tau rhythm of
auditory cortex.35 These spectral peaks are assumed to
require the synchronization of a sizeable population of
cortical neurons into organized band-specific rhythms.
Band-limited power suppression during cortical activa-
tion is thus assumed to represent a loss of this syn-
chronization, thus the term desynchronization. However,
power suppression is not always restricted to frequen-
cies where there are well-defined peaks in the baseline
power spectrum, and in these circumstances it may be
more appropriate to adopt a more conservative, descrip-
tive terminology. Nevertheless, ERD may still be used by
some investigators as a convenient shorthand to refer to
power suppression associated with cortical activation.
Likewise, event-related power increases, that is, power
augmentation, are often referred to as event-related syn-
chronization (ERS).
ERS originally referred to band-limited power in-
creases in scalp EEG. For example, ERS was observed
in beta frequencies immediately after ERD in motor cor-
tex following movement,36,37 and it was observed in al-
pha frequencies over cortex not engaged by a task, that
is, at rest or idling.38 Subsequent observations of band-
limited power increases in gamma frequencies some-
times adopted the same ERS term for convenience. How-
ever, event-related spectral analyses may also reveal
power increases that are not band-limited. Because these
responses do not have a clear peak in the power spec-
trum, they do not necessarily reflect synchronization of
neuronal networks into rhythmic or oscillatory behavior
(see later), and thus the usual connotations of the ERS
terminology do not apply. For these reasons, it may be
most appropriate to limit the usage of ERD and ERS to
event-related power decreases or increases that are ob-
served in relatively narrow frequency bands. The distinc-
tion between narrow- and wide-band spectral responses,
however, is not well defined in the literature, and it is
not clear what spectral profile a response should have
in order to be called “oscillatory.”
The physiologic frequency bands in which event-
related spectral changes have been commonly inves-
tigated with noninvasive scalp EEG include the theta
(4–7 Hz), alpha (8–13 Hz), and beta (13–25 Hz) fre-
quency bands. Although scalp EEG has also been used
to study event-related spectra at gamma frequencies
(>30 Hz),11,39 ECoG recordings have offered much bet-
ter signal quality at high frequencies28,40,41 and have thus
been instrumental in studying the response properties
of event-related gamma responses, particularly those in
“high gamma” frequencies above the traditional band-
limited responses at 40 Hz,30,39 to be discussed in greater
detail later.
Interpretations of event-related power changes
must always take into account the timing of these
changes with respect to the timing of functional brain
activation. This time dependence of event-related spec-
tra was first demonstrated with scalp EEG recordings. For
example, ERD was observed in the alpha and beta fre-
quency ranges over the sensorimotor cortex before and
 CHAPTER 12 ELECTROCORTICOGRAPHIC SPECTRAL ANALYSIS
during movement.9 In contrast, alpha and beta ERS were
observed over surrounding areas responsible for move-
ment of other body parts, that is, leg, suggesting that
alpha and beta ERS may reflect cortical inhibition. Fol-
lowing movement, there was an increase in beta power
over the same region where ERD was observed during
movement, indicating a reset of the functional circuitry
within motor cortex.42 In general, power suppression or
ERD in alpha and beta bands likely reflects functional
activation of cortex while ERS in the same frequencies
may in some cases index cortical inhibition. An impor-
tant exception to this is the increase in low frequency
power that is often observed simultaneously with phase-
locked responses to stimulus onset.33 A broad, but often
useful, generalization is that power changes in higher
(gamma) frequencies have an inverse relationship to
those of power changes in alpha/beta frequencies. That
is, gamma power augmentation likely indexes corti-
cal activation,29,30,39,43 while gamma power suppression
may in some cases index cortical inhibition.44 However,
it is important to recognize that with any given cortical
activation the transition in the power spectrum between
power augmentation at higher frequencies and power
suppression in lower frequencies is quite variable, and
it is potentially dangerous to assume any fixed boundary
between the two.
䉴 METHODOLOGY
SUBJECT INCLUSION AND
PREPARATION
Intracranial EEG is indicated under a limited set of clin-
ical circumstances. The most common indication is for
patients with intractable epilepsy, in whom seizures have
not been adequately controlled with medications and are
occurring with sufficient severity and frequency to dis-
rupt the patient’s quality of life. In these patients, EEG
electrodes may be surgically implanted in order to better
localize the seizure focus and/or to map cortical function
when the seizure focus is suspected to be near or within
functionally critical cortex. Long-term monitoring with
intracranial electrodes is particularly useful for localizing
the ictal onset zone, which is more predictive of postsur-
gical outcomes than interictal epileptiform discharges.45
Other potential indications arise in patients with brain
tumors or vascular malformations in or near eloquent
cortex, though many of these patients may be candi-
dates for intraoperative stimulation mapping.
The placement of subdural grids, strips, and/or
depth electrodes is dictated solely by clinical con-
siderations derived from the patient’s seizure semiol-
ogy, ictal and interictal scalp EEG, structural and/or
functional magnetic resonance imaging (MRI), positron
emission tomography (PET), intracarotid amobarbital
153
test (Wada test), magnetoencephalography (MEG), and
or ictal/interictal single positron emission tomography
(SPECT). These findings help define the target of resec-
tion and/or predict whether it is near functionally impor-
tant motor, sensory, auditory, and/or language cortices.
Once patients have been selected for intracranial
EEG monitoring, functional mapping with ECoG spec-
tral analysis, like traditional ESM, requires patients to be
willing and able to cooperate with testing. Patients must
be able to respond quickly and consistently so that ei-
ther signal averaging, or stimulation in the case of ESM,
can be temporally aligned to functional brain activation.
Generally speaking, children younger than 5 years or
patients with severe cognitive or behavioral limitations
may have difficulty with this, though one recent study
suggested that ECoG might overcome some of the limita-
tions of ESM in children.46 Excessive sedation from pain
medications, or neurotoxic side effects from antiepileptic
medications, can also interfere with testing.
INSTRUMENTATION
Electrodes used for recording intracranial EEG vary be-
tween medical centers. Subdural electrode arrays are
most commonly used and consist of platinum–iridium
discs (4 mm diameter, 2.3-diameter exposed surface, 1.5
mm thickness) embedded in a soft silastic sheet with an
interelectrode distance of 1-cm (Ad-tech Medical Instru-
ment Corporation, Racine, WI). The electrode configura-
tion, including the position and number of electrodes, is
determined by the epilepsy and/or neurosurgical team
based on a variety of clinical considerations. Electrode
configurations can include one-dimensional strips of 4 to
8 electrodes or two-dimensional arrays (grids) of up to
8 × 8 electrodes (see Fig. 12–1). Several electrode ar-
rays can be combined to provide adequate coverage
of the cortical surface of interest and grids can be cut
to accommodate anatomic variability. Grids and strips
with smaller interelectrode distances are available, but
require a larger number of electrodes and EEG ampli-
fiers to cover a comparable cortical region.
Stereotactically implanted depth electrodes placed
according to a Talairach atlas and/or a patient’s MRI
findings provide another modality for obtaining invasive
EEG recordings. Depth electrodes are especially useful
when recording from deep brain structures such as the
amygdala, hippocampus, or a region of suspected cor-
tical dysplasia. Depth electrodes are typically smaller
than those used for subdural grid and strip implanta-
tion and may provide improved spatial resolution. Al-
though fewer studies of event-related spectral changes
have used these electrodes than subdural electrodes, the
results obtained with the depth electrodes do not appear
to be fundamentally different.47,48
154 SECTION I TECHNIQUES

Figure 12–1. An example of a patient with electrocortical stimulation mapping (ESM)

and ECoG spectral analysis during a reading task. Subdural intracranial grid
electrodes are depicted over the dominant hemisphere with blue circles. The colored
bars indicate electrode pairs that were stimulated with bipolar ESM. Green indicates
that reading was not inhibited. Purple indicates that reading was inhibited. The yellow
lightning bolts indicate that ESM produced a seizure and that those electrodes could
not be analyzed further with ESM. ECoG spectral analysis revealed significant gamma
and high-gamma activation at the electrode that could not be tested with ESM,
indicating that the region is active during reading task performance. On the spectral
plot to the right, time in seconds is on the X-axis and frequency in Hertz is on the
Y-axis. An increase in power is shown on the red to yellow scale and a decrease in
power is shown on a light to dark blue scale (to the right of the diagram).

RECORDING TECHNIQUES AND DATA
ACQUISITION
While scalp EEG has usually been able to accurately
detect frequency changes in the beta frequency range
and recently even the lower gamma frequency bands,39
electrocorticography accurately detects signal changes
in much higher frequency ranges.30,43 Sampling rates of
1000 Hz and higher are preferable to adequately study
these higher frequencies. The Nyquist–Shannon sam-
pling theorem49,50 states that the sampling rate frequency
must be greater than twice the maximum frequency be-
ing sampled in order to reconstruct the signal, and higher
sampling rate frequencies are required to accurately de-
scribe the waveform characteristics. In practice, it is often
better to oversample as much as is practical.
High gamma activity (>60 Hz) has a very low am-
plitude and, therefore, requires significant signal am-
plification for adequate detection and evaluation. The
bit-depth of analog-to-digital (A/D) converters is ideally
at least 16-bits. Because intracranial mapping can require
extensive use of multiple grids and strips, over 100 ECoG
channels may be required to capture all of the relevant
data. Clinical video–EEG monitoring systems with up to
128 ECoG channels are widely available, and a few sys-
tems now offer 256 ECoG channels. In our experience,
the more the better, particularly if one contemplates us-
ing high-density grid recordings.
Detection of event-related spectral changes (or
event-related potentials) requires placement of precise
record markers indicating the onset of a task elicit-
ing functional brain activation. This requires the use of
 CHAPTER 12 ELECTROCORTICOGRAPHIC SPECTRAL ANALYSIS
dedicated channels that mark events within the ECoG
recording for subsequent analyses in the time and fre-
quency domains. Detecting robust ECoG power changes
requires averaging over multiple trials; therefore, appro-
priate stimuli and numbers of trials must be chosen to
identify cortical areas of interest (i.e., somatosensory,
motor, language, auditory cortices). A minimum of 25
trials are recommended but greater than 50 trials may be
necessary, dictated by the quantity of interictal epilep-
tiform activity and patient performance, thus allowing
for rejection of artifact, bad trials, and inconsistent re-
sponses. In practice, we often use stimulus lists with no
fewer than 100 trials.
SIGNAL ANALYSIS
Event-related spectral analysis of ECoG signals is sim-
ilar to analysis performed on scalp EEG recordings.
However, ECoG signal analysis does not require the
same degree of spatial reformatting as scalp EEG51 be-
cause recordings from the cortical surface are already
strongly biased in favor of local potentials. A reference-
independent montage such as a common average refer-
ence is typically used to reformat ECoG data and remove
biases introduced by different distances between the ref-
erence electrode and active electrodes in the array.30
Placement of the reference electrode far from the active
electrodes can reduce this bias, but extracranial elec-
trode placement is more permissive of noise from scalp
myogenic potentials. Often, the most effective method is
to assign a reference electrode within the subdural array
that is as distant as possible from sites of epileptiform
activity and functional brain activity of interest.
ECoG signals are converted into the frequency do-
main in order to detect event-related changes in the
power spectrum. Band-pass filtering was one of the
earliest approaches developed for quantitative analysis
of scalp ERD and ERS.7,52 Algorithms employing short-
term Fourier and wavelet transforms have also been
used.49,53 A matching pursuit (MP) algorithm is routinely
being used by our group for ECoG spectral analysis.54−58
The algorithm is designed to decompose the EEG sig-
nal by selecting wavelet packet vectors that sequentially
optimize the signal approximation.59 It produces high-
resolution maps of event-related power changes within
the time–frequency plane by assigning dictionaries con-
structed from Gabor functions.
Once ECoG activity has been identified in various
cortical regions, this information can be coregistered
with surface renderings of three-dimensional MRI/CT
(computed tomography) reconstructions of the brain
and electrode locations. This allows for direct compar-
isons to be made with other cortical mapping modalities
such as PET, SPECT, MEG, functional MRI (fMRI), or ESM
(see Fig. 12–1).60−70
155
䉴 APPLICATIONS
ECoG spectral analysis has been used to map a va-
riety of functional–anatomical domains of human cor-
tex, including the frontal eye fields,44 visual cortex,71−74
auditory cortex,32,33,75,76 premotor and primary motor
cortices,29,77−85 somatosensory cortex,86 and language
cortex.46,58,69,70,87−91 ECoG spectral analysis has also
been used to study cortical mechanisms of attention and
memory.8,65,79,92−97
MAPPING SENSORIMOTOR FUNCTION
Mapping sensorimotor cortex may be motivated not only
by difficulties identifying the central sulcus by visual in-
spection through a craniotomy or with neuronavigation,
but also by the variability among individuals in the exact
location of different motor and sensory representations,
particularly in the setting of lesions that might distort
the anatomy or alter these representations. Localization
of hand area usually can be accomplished efficiently by
recording somatosensory-evoked potentials (SEPs) from
median nerve stimulation. This can be done intraoper-
atively with a strip of electrodes placed on the cortical
surface, or extraoperatively with subdural ECoG.86,98,99
This procedure, which can also be done noninvasively
with MEG,100 is usually successful in localizing the cen-
tral sulcus in the hand area though care must be taken
in the interpretation of the resulting potentials.101 In ad-
dition to median nerve stimulation, the tibial nerve and
ulnar nerve can be stimulated to obtain SEPs at other
sites along the central sulcus.102 Although this can be
a very efficient and effective means of identifying peri-
Rolandic cortex, ESM is often used in addition to SEPs or
in place of them to define the functional anatomy of sen-
sorimotor cortex. Under these circumstances, it may be
possible to complement ESM with maps of sensorimotor
cortex obtained through ECoG spectral analysis.
A growing number of studies have suggested the
clinical utility of ECoG spectral mapping for map-
ping sensorimotor function in patients undergoing
surgery.13,29,47,68,78,81,85,103,104 As with scalp EEG record-
ings, alpha and beta ERD has been observed during
ECoG recordings of various tasks designed to stimulate
and identify regions of the sensorimotor cortex.13,29,81,105
In one such study of visually cued isometric muscle
contractions, alpha ERD occurred in a relatively diffuse
distribution at onset of the motor response and coa-
lesced into a more discrete, somatotopically localized
pattern only later, as the isometric muscle contraction
was sustained.13 Beta ERD occurred in a more discrete
and somatotopically specific pattern but with a less ro-
bust, or absent, response at times. In addition, unilateral
limb movements were sometimes associated with alpha
and beta ERD over bilateral sensorimotor cortices with
156 SECTION I TECHNIQUES
overlapping patterns for different body parts. In contrast
to these patterns of power suppression, the same mo-
tor task was also associated with event-related gamma
power increases in spatial distributions that were more
discrete, more lateralized to contralateral sensorimotor
cortex, and more somatotopically specific than those of
alpha and beta ERD. In addition, power increases in “low
gamma” frequencies (35–50 Hz), like alpha ERD, were
sustained during the muscle contraction, while power in-
creases in “high gamma” frequencies (750–100 Hz) were
transient and covaried with the onset latency of motor
responses. The functional localization of gamma power
increases correlated well with ESM of motor function.
Several other studies have evaluated ECoG gamma
responses in sensorimotor cortex using a variety of
different tasks and methods for data acquisition and
analysis.47,81,103,106 For example, Ohara et al.78 observed
nonphase-locked gamma activity in SI and MI extending
up to 90 Hz during self-paced finger and wrist move-
ments. Both low and high-gamma ERS were observed
only during contralateral movements, and high-gamma
activity (60–90 Hz) in particular was highly tempo-
rally correlated with movement onset. During self-paced
tongue and finger movements, Pfurtscheller et al.104 also
observed broadband high-gamma responses (60–90 Hz)
over sensorimotor cortex in a topographic pattern that
was more discrete and somatotopically specific than the
more widespread mu (alpha) and beta ERD, and in a
temporal pattern that also corresponded more closely to
movement onset. ECoG high-gamma responses (60–200
Hz) have also been demonstrated during activation of
premotor cortex during a task designed to dissociate at-
tention from motor planning.79 A recent study correlated
alpha and beta ERD/ERS during voluntary movement in
a cognitive visuospatial task to functional MRI results
during performance of a similar task77 and determined
that there was an “evident overlap in most results” but
that the ECoG mapping was more sensitive at detect-
ing activity in the premotor and prefrontal cortices than
functional MRI.
In the largest series to date of ECoG spectral map-
ping of sensorimotor cortex, Miller et al.85 recorded sub-
dural ECoG in 22 subjects during a variety of motor tasks,
and the topographic patterns of ECoG power changes
were compared for low frequencies (8–32 Hz) ver-
sus high-gamma frequencies (76–100 Hz). High-gamma
power augmentation occurred in a more focused spatial
distribution than did ERD and corresponded well to the
results of ESM, as well as the somatotopic organization
for movement of different body parts. Reddy et al.106 re-
cently demonstrated in six patients that changes in high-
gamma activity (50–160 Hz) can be accurately differenti-
ated during hand movement of a joystick in four cardinal
directions (up, down, left, and right).
Despite the varying techniques used in the afore-
mentioned studies, all revealed high-gamma power
augmentation that correlated temporally and spatially
with the cortical populations responsible for movement.
Taken as a whole, these reports support the clinical util-
ity of ECoG spectral mapping in patients undergoing sur-
gical resections near or within motor cortex.
ECoG high-gamma responses have also been ob-
served during activation of somatosensory cortex. When
vibrotactile stimuli were attended to, they were associ-
ated with greater high-gamma responses than when they
were ignored.97 This was consistent with an MEG study
by Gross et al.107 in which perceived nociceptive stimuli
were associated with stronger 60–95-Hz gamma oscilla-
tions in primary somatosensory cortex than unperceived
stimuli of equal stimulus intensity. In another MEG study
by Ihara et al.,108 source power in a high-gamma band
(70–90 Hz) increased simultaneously in contralateral SI
and contra/ipsilateral SII at 80–180 milliseconds, sug-
gesting a role in functional connectivity between SI and
SII. In a subsequent MEG study by Hauck et al.,109
high-gamma responses to nociceptive stimuli were in-
creased by directed attention to the stimuli, and coupling
analysis of the high-gamma responses revealed stronger
functional interactions between ipsilateral and contralat-
eral sites during attention. Similarly, another MEG study
of normal subjects by Bauer et al.110 found that spa-
tial tactile attention enhanced high-frequency gamma
responses (60–95 Hz) over contralateral SI cortex. Al-
though the upper boundary of the gamma responses
observed in this and several other MEG studies have
been lower than those commonly observed with ECoG,
the sensitivity of MEG to higher frequency activity is
less than that of ECoG, and in some instances it may
be difficult to distinguish between band-limited gamma
oscillations and the broadband gamma responses more
commonly observed with ECoG.
LOCALIZATION OF VISUAL FUNCTION
ECoG gamma activity has been demonstrated in vi-
sual cortex during presentation of a variety of visual
stimuli.71−74 Epilepsy patients with implanted poste-
rior depth electrodes were primarily studied. During
one experiment, patients performed a face detection
task that revealed changes within a broad gamma fre-
quency range (40–200 Hz) over the occipital, parietal,
and temporal cortices, most notably the fusiform gyrus,
the lateral occipital gyrus, and intraparietal sulcus.71
The temporo-occipital changes were detected first, fol-
lowed by parietal activation. Alpha and beta activity
was notably suppressed during the increase in gamma
activity. Tallon-Baudry et al.72 demonstrated variable
gamma activity in the lateral occipital regions and the
fusiform gyrus during presentation of simple visual stim-
uli. Gamma oscillations were enhanced by increased at-
tention during visual stimulation in the fusiform gyrus,
 CHAPTER 12 ELECTROCORTICOGRAPHIC SPECTRAL ANALYSIS
whereas attention increased baseline gamma activity in
the lateral occipital cortex prior to stimulus presentation.
The authors concluded that the functional significance
of changes in gamma activity depends on the region of
activation.
Vidal et al.111 used MEG to demonstrate differen-
tial gamma frequency activation in response to various
visual task demands. During a visual task, high-gamma
band (70–120 Hz) activation was found over the central
occipital regions and low gamma activity (44–66 Hz) oc-
curred over the parietal regions during attentional tasks.
Asano et al.74 recently demonstrated high-gamma (50–
150 Hz) augmentation in the anterior–medial occipital
cortex, followed by the lateral–polar occipital cortex in
response to stroboscopic flash-stimuli in nine children
undergoing intracranial monitoring in preparation for
epilepsy surgery. Their results not only confirmed previ-
ous findings demonstrating high-gamma activation that
temporally and spatially correlated with visual cortical
activity, but demonstrated the safety and tolerability of
this technique in the pediatric population.
LOCALIZATION OF AUDITORY
FUNCTION
ECoG spectral mapping has been applied in several stud-
ies to auditory function.32,33,75,76 In one such study,32
four left hemisphere-dominant patients with subdural
electrodes over left superior temporal gyrus performed
auditory tone and phoneme discrimination tasks, and
event-related ECoG band power changes were investi-
gated. Phoneme discrimination produced a higher mag-
nitude of gamma augmentation over a more widespread
region of the superior temporal gyrus than did tone dis-
crimination. Gamma augmentation was detected at not
only 40 Hz but also high-gamma frequencies, extending
from ∼80 Hz to 200 Hz.
Edwards et al.75 performed ECoG recordings intra-
operatively on 11 patients undergoing tumor resection
with five to nine epipial electrodes placed over the left
lateral surface of the frontal, temporal, or inferior pari-
etal lobe. High-gamma activity was detected over the
superior temporal gyrus during repetitive tone stimuli
(500 Hz) and more anteriorly in response to deviant
stimuli (550 Hz), suggesting that goal-directed activity is
not required to produce a detectable high-gamma power
change during auditory stimulation.
MAPPING LANGUAGE CORTEX
ECoG spectral analysis has also been used to evaluate
the temporal and spatial characteristics of cortical activa-
tion during language tasks.8,46,58,69,88−90,112 Performance
of these complex tasks requires perception of auditory
and visual stimuli, utilizing some of the same cortical
157
regions assessed in the previous studies described (see
Sections “Localization of Visual Function” and “Localiza-
tion of Auditory Function”). Subsequent processing is re-
quired, however, in dominant frontal, parietal, and tem-
poral cortices. Several studies have directly compared
cortical mapping results with ECoG gamma activity map-
ping to ESM (for example, see Fig. 12–1).69,88,90 In one
such study,88 ECoG high-gamma changes were studied
during visual object naming, word reading, and word
repetition in a patient fluent in English and American
Sign Language by eliciting spoken and signed responses.
High-gamma power changes during auditory word rep-
etition had the greatest magnitude in the posterior su-
perior temporal gyrus, while activation during naming
and reading was most prominent in the basal temporal–
occipital cortex, including fusiform gyrus. Spoken re-
sponses activated tongue regions of motor cortex and
manual sign language responses activated more hand re-
gions. These ECoG results were found to correlate with
language ESM at many, but not all, sites.
Tanji et al.89 observed ECoG high-gamma (80–120
Hz) activity during picture-naming of line drawings of
animals and tools and during lexical–decision tasks in a
patient with bilateral lateral and basal temporal subdu-
ral grid implantation. They demonstrated bilateral high-
gamma activity during the naming tasks with significant
differences during naming of tool and animal stimuli.
The lexical–decision task comprise two distinct written
forms of Japanese, Kanji and Kana. Task stimuli included
words and pseudowords using each of these forms.
There was greater high-gamma activity over the dom-
inant left basal temporal region than the right during
the lexical–decision tasks with significant differences be-
tween Kanji and Kana words and also between words
and pseudowords. The authors concluded that changes
in high-gamma activity could accurately map language
function within the dominant basal temporal region.
Sinai et al.69 directly compared ESM and ECoG high-
gamma activity (80–100 Hz) during visual object naming
and found that the specificity of ECoG mapping relative
to ESM was 78%, with a relatively modest sensitivity of
38%. The authors concluded that ECoG mapping could
be used to create a preliminary map of language cortex
that could later be assessed with electrocortical stimula-
tion. This would enable a more focused evaluation when
performing ESM of language function, limiting potential
complications such as inflicting pain, stimulating after-
discharges, or inducing seizures. ECoG mapping could
also be used to evaluate sites at which ESM results are
equivocal or could not be obtained.
Towle et al. investigated the localization of ECoG
gamma power augmentation during auditory stimulation
(warning tones), followed by word repetition and recall
tasks in left hemisphere-dominant epilepsy patients.90
They demonstrated ECoG high-gamma (70–100 Hz)
power increases in primary auditory cortex in response
158 SECTION I TECHNIQUES
to auditory tones, in posterior temporal and parietal cor-
tices during the presentation of word stimuli, and in lat-
eral frontal and anterior parietal cortex during verbal re-
sponses. Comparing these results to language ESM, they
reported a sensitivity of 63%, with a specificity of 57%.
In another recent study, Sinai et al.70 compared au-
ditory high-gamma power changes with ESM over the
left lateral cortex of six patients with left hemisphere lan-
guage dominance based on Wada testing during speech
comprehension and tones detection. Electrocortical stim-
ulation interfered with speech comprehension but not
with tone detection in the posterior temporal region.
Statistical analysis revealed high spatial concordance be-
tween ESM and high-gamma (>60 Hz) power changes
with a specificity of 98%, a sensitivity of 67%, and a pos-
itive predictive value of 67%.
The excellent specificity with relatively modest sen-
sitivity compared to ESM as identified here as well as in
other studies previously discussed illustrates one of the
important potential limitations of mapping with electro-
corticography. Ideally, fMRI, ESM, and ECoG mapping
results based on performance of identical tasks should
be compared directly to postsurgical outcome results to
determine which modality provides the most accurate
functional language map.
Brown et al.46 evaluated three children with in-
tractable left-hemispheric focal epilepsy and demon-
strated gamma-power increases in the posterior superior
temporal gyrus when they were presented questions,
posterior lateral temporal and posterior frontal activation
between questions and responses, and pre- and post-
central gyri activation immediately preceding and dur-
ing responses. Their findings correlated with previous
results found in the adult population and indicated that
not only is ECoG analysis safe and reliable in children,
but that the language localization results described in
adults can be generalizable to the pediatric population.
Previous pediatric studies indicated that ESM often fails
to localize language in children, and even Wada testing
is less sensitive than in the adult population.113,114 There-
fore, ECoG analysis could potentially play a particularly
important role in functional language mapping prior to
surgical resection in the pediatric population.
MAPPING MEMORY FUNCTION
Preservation of memory function is a key concern for
planning epilepsy surgery, particularly in the temporal
lobe, and much of the preoperative assessment of pa-
tients is focused on determining the structural and func-
tional integrity of the neural substrates of memory, espe-
cially the hippocampus.115−117 In general, the likelihood
of postoperative memory impairment depends on the
amount of disease in mesial temporal structures to be
resected, as well as the degree to which contralateral
homologous structures have assumed critical memory
functions. Preoperative clinical assessment routinely in-
cludes structural MRI, neuropsychological testing, and
the intracarotid amobarbital test (Wada test). fMRI has
also been used for this purpose.118−122 There have also
been several recent studies of ECoG spectral changes
during memory tasks.65,92−96 However, as when inter-
preting language maps, care must be taken when in-
terpreting the results of activation-based maps of mem-
ory function, especially for ECoG assessment of memory
function since electrode implantations are usually uni-
lateral or asymmetric, making it difficult to compare the
relative contribution of left versus right mesial temporal
structures.
Sederberg et al.93 studied ten patients with im-
planted subdural grids and measured ECoG activity
while they memorized a list of common nouns. There
was an increase in theta (4–8 Hz) activity distributed
over the right temporal and frontal cortices, and more
widespread power increases in higher frequencies (28–
64 Hz) during successful encoding. In a follow-up study
of 39 epilepsy patients with surgically implanted sub-
dural and depth electrodes, Sederberg et al.96 demon-
strated increased gamma power (44–64 Hz) over the hip-
pocampus, left temporal, and left frontal cortices during
a similar recall task. Finally, Sederberg et al.95 recorded
intracranial EEG activity in 52 patients during memory
retrieval tasks and using a broader frequency range for
signal analysis. This study demonstrated a broadband in-
crease in gamma activity (28–100 Hz) in the hippocam-
pus and left temporal lobe as well as the prefrontal
cortex that distinguished retrieval of true versus false
memories.
Although short-term memory, that is, working mem-
ory, likely depends more on prefrontal cortex and is
not usually a major concern for epilepsy surgery, it is
of great interest to cognitive neuroscientists and, there-
fore, has also been studied with ECoG spectral analysis.
Howard et al.92 demonstrated an increase in gamma (30–
60 Hz) oscillatory activity during a working memory task
and showed a linear correlation between an increase in
gamma activity and memory load over multiple trials.
Mainy et al.112 evaluated nine patients with implanted
electrodes in mesial temporal structures and perisylvian
and prefrontal regions during a task of short-term con-
solidation in order to map encoding in working mem-
ory. They found an increase in high-gamma (50–150 Hz)
activity within an area referred to as the “phonological
loop,” including within the frontal lobe, the prefrontal
cortex, the precentral gyrus, and Broca’s area; in the
temporal lobe, the auditory cortex, the fusiform gyrus,
and the hippocampus; and in the postcentral gyrus of
the parietal lobe. They also concluded that these find-
ings correlated with previous fMRI localization of work-
ing memory. In another study, Axmacher et al.65 com-
bined ECoG spectral analysis and fMRI results to provide
 CHAPTER 12 ELECTROCORTICOGRAPHIC SPECTRAL ANALYSIS
evidence that the medial temporal lobe controlled ac-
tivity within the inferior temporal cortex during visual
working memory.
䉴 MAPPING FUNCTIONAL
CONNECTIVITY
Although clinical brain mapping has usually emphasized
the localization of function at individual cortical sites
or collections of these sites, there is a growing interest
in and appreciation for the role of cortical networks in
brain function. To this end, fMRI studies have used co-
variations in BOLD signal to identify networks of brain
sites that tend to be coactivated under different task con-
ditions, including at rest (i.e., default networks).123−126
In contrast to fMRI, however, the temporal resolution
of electrophysiological measures, such as EEG, MEG,
and ECoG, make them ideal for studying not only the
structure of these networks, that is, their anatomic com-
ponents, but also their event-related dynamics, that is,
how their components interact on the time scale of func-
tional tasks. A variety of methods have been devised
to study these interactions, including event-related co-
herence and partial directed coherence.127−129 One such
approach is based on the concept of Granger causality,
whereby a causal influence of one site on another can
be inferred if the ECoG signal of one can be used to pre-
dict that of the other. An adaptation of this method called
short-time directed transfer function (SDTF) can be used
to estimate the magnitude, frequency, timing, and direc-
tionality of task-related changes in causal interactions be-
tween ECoG recording sites.130,131 Variations of this ap-
proach have been used to analyze scalp EEG recordings
during movement imagery,82 to analyze ECoG record-
ings during visually cued movement,132 and to analyze
ECoG recordings during language processing.133 The
clinical relevance of these findings, obtained in a rel-
atively small number of subjects to date, is yet to be
determined. However, these and other studies like them
illustrate the potential of ECoG (and other electrophysi-
ological measures) not only to identify the regions of the
brain responsible for processing different types of infor-
mation, but also better define the functional role of these
regions by estimating the temporal sequence by which
they are activated and the direction of information flow
among them.
䉴 STRENGTHS AND WEAKNESSES
RELATIVE TO OTHER MAPPING
TECHNIQUES
With the exception of ESM, which also relies on surgi-
cally implanted intracranial electrodes, ECoG is more in-
159
vasive than competing techniques for human functional
mapping. An important consequence of this is that it
can only be done under limited clinical circumstances in
patients with lesions and/or seizure foci that could po-
tentially result in functional reorganization and/or alter
normal neurophysiological responses. A practical conse-
quence of this is that epileptiform discharges may con-
taminate ECoG signals and produce inaccurate or unus-
able data at specific electrodes that may be of interest.
This can be addressed by excluding segments or whole
channels of ECoG data contaminated by this activity, but
concerns about the effects of epilepsy on normal neu-
rophysiological responses can only be addressed by the
reproducibility of ECoG responses across a variety of
subjects with different seizure foci and/or lesions, or by
similar findings in normal populations using noninvasive
techniques. Compared to high-density scalp EEG and
MEG, ECoG mapping offers significant improvements in
signal-to-noise ratio and far greater sensitivity for high-
frequency cortical activity.28
As the previous sections have indicated, high-
frequency spectral responses represent an important
electrophysiological signature of cortical activation with
excellent temporal and spatial resolution. Several recent
MEG studies have reported spectral responses that sig-
nificantly overlap the broadband gamma responses ob-
served in ECoG studies107–111 , but direct comparisons
with ECoG are still forthcoming. A recent recording
of both high-density EEG and ECoG in the same sub-
jects found that with some enhancements of record-
ing techniques, scalp EEG is also capable of measuring
high-gamma responses, albeit with lower sensitivity.39 In
addition to its greater sensitivity to high-frequency ac-
tivity, artifacts from eye blinks and eye movements are
greatly attenuated, albeit not eliminated, in ECoG sig-
nals. A recent study comparing artifacts in invasive and
noninvasive EEG estimated that the signal quality of in-
vasive EEG is 20 to above 100 times superior to that of
simultaneously recorded noninvasive EEG. fMRI is also
clearly less invasive than ECoG, and its clinical utility in
patients undergoing epilepsy surgery has been studied
extensively, both for the purpose of lateralizing lan-
guage function134,135 and for localizing language func-
tion within the language dominant hemisphere.136−138
Although the fMRI scanning environment can limit the
functional tasks that can be performed during evalua-
tion, including motor tasks, and can be prohibitive for
claustrophobic patients, its noninvasive nature and its
growing availability are leading to more widespread ac-
ceptance. However, like ECoG and other electrophysio-
logical measures, fMRI relies on measures of functional
activation, and care must be taken when using it to pre-
dict the effect of surgical resection, that is, lesioning. The
main advantage of ECoG (and other electrophysiological
techniques) over fMRI is their superior temporal resolu-
tion. The fMRI BOLD response is an indirect and delayed
160 SECTION I TECHNIQUES
measure of synaptic activity that necessarily integrates
activity over time scales of seconds.30 At first blush, this
may not seem like an important consideration for clini-
cal functional mapping, but the latencies and sequences
by which different cortical regions are activated during
a functional task can give important clues as to their re-
spective functional roles and could, in theory, allow finer
functional–anatomical segregation. Whether this added
information could be used to make better predictions of
the functional impact of surgical resection remains to be
seen.
Because ESM can induce a brief, reversible, and
reproducible disruption of cortical function, in essence
mimicking the effects of a surgical resection, it remains
the gold standard for localizing language function prior
to resective surgery. However, this procedure can in-
flict pain through the stimulation of trigeminal afferents
in cortical blood vessels and can induce afterdischarges
and seizures. Time constraints during intraoperative ESM
can prohibit comprehensive mapping of language cor-
tex with multiple language tasks. Although more time is
available for ESM when it is done extraoperatively with
implanted electrodes, comprehensive language mapping
can still be quite time consuming, particularly with a bat-
tery of language tasks, since each task must be repeated
at each pair of electrodes, ideally after determining the
optimal stimulation intensity at each site. At times, re-
peated comparisons may produce equivocal results, re-
quiring even further testing.
There is no possibility of provoking pain or seizure
activity with ECoG mapping since it relies on passive
recordings and does not require cortical stimulation. In
addition, the entire electrode array can be recorded si-
multaneously during each functional task. Although av-
eraging in the time and/or frequency domains requires
more trials of each task than ESM, a battery of language
tasks can be recorded in 1–2 hours, yielding compre-
hensive functional maps of the entire recording array in
much less time than ESM. Recent advances in software
for ECoG signal analysis have made it possible to obtain
results from ECoG almost instantaneously.68,139−141
䉴 EXAMPLES IN CLINICAL
PRACTICE
Functional cortical mapping with ECoG spectral analysis
is being used with increasing frequency during surgical
planning prior to resection of epileptic foci and/or struc-
tural lesions such as tumors or vascular malformations.
ECoG mapping is safer than ESM and is potentially faster
since it can be done at all electrode sites at the same
time. However, its positive predictive value for surgi-
cal outcomes has not been fully evaluated, and at least
for now it should not be used as the sole determinant
of the safety of resecting any single site. Nevertheless,
there is mounting evidence that ECoG mapping can be
used to complement ESM and other mapping modali-
ties. Furthermore, recent studies have shown that ECoG
functional mapping can potentially be done in real- or
near real-time.
An important illustrative example of the clinical ap-
plication for ECoG functional mapping was provided
recently by Lachaux et al.141 The authors displayed real-
time spectral power changes during intracranial lan-
guage mapping of two epilepsy patients with implanted
depth electrodes for visualization by the patients and ex-
perimenters on a computer monitor. During evaluation
of one of the patients, investigators were able to iden-
tify high-gamma power changes in the middle portion
of the upper left superior temporal sulcus that occurred
during spontaneous conversation and performed addi-
tional language testing to further isolate the functional
characteristics of this region based on their initial ob-
servations. There were no measurable changes in high-
gamma activity when the patient was speaking, reading
aloud, or listening to a loud noise. The high-gamma
power changes were seen only when the experimenter
spoke, and increased more in response to sentences spo-
ken in the patient’s primary language than in languages
in which the patient was not fluent. These findings sug-
gested not only that the region being evaluated was
functionally responsible for phonological processing of
spoken language, but also that the spectral changes
could be detected in real-time and the testing paradigm
adapted during a single session to obtain a more precise
functional evaluation.
In the same patient, the ECoG mapping results were
compared to traditional ESM findings. Initially, no lan-
guage impairment had been demonstrated in the region
of interest during ESM. On review of the ESM language
tasks performed, the investigators discovered that the
patient had been asked to count aloud or to listen to
an examiner count, but had not been evaluated dur-
ing any sentence comprehension tasks. Because of the
positive ECoG language mapping results, a sentence
comprehension task was performed with ESM and also
demonstrated interference with language comprehen-
sion during cortical stimulation. Had the ECoG language
mapping not been performed, the treating neurosurgeon
might have resected this portion of the left superior
temporal sulcus on the basis of negative ESM, possibly
resulting in a profound language deficit in sentence com-
prehension.
Miller et al.140 also demonstrated that ECoG high-
gamma power augmentation is robust enough to be de-
tected during single trials, in this case, of a motor task
such as a handshake. More recently, Brunner et al.68 de-
scribed a new ECoG mapping procedure that creates a
functional cortical map in only a few minutes with a false
positive rate of 0.46% and 1.10% for hand and tongue
 CHAPTER 12 ELECTROCORTICOGRAPHIC SPECTRAL ANALYSIS
maps, respectively, compared to ESM, and no false nega-
tives. These findings indicate that ECoG functional map-
ping can be used in near real-time to investigate func-
tional cortical activation with much higher precision than
previously found.
ECoG spectral changes have also been investigated
for their utility in controlling BCI. Many neuromuscular
diseases such as amyotrophic lateral sclerosis, muscular
dystrophy, neuromuscular junction diseases, as well as
spinal cord trauma and brainstem lesions, leave patients
with a loss of voluntary motor control but with rela-
tively preserved cortical motor and premotor functions.
Tai et al. reviewed a series of articles addressing the po-
tential use of BCI for patients with locked-in syndrome,
including BCI using electrocorticography.142 Leuthardt
et al.143 demonstrated the use of ECoG signal detection
in controlling a one-dimensional cursor through real and
imagined motor and speech tasks in four patients under-
going intracranial electrode implantation in preparation
for epilepsy surgery. Additional studies have shown that
patients can utilize ECoG signal changes during auditory
as well as motor imagery to accurately control the move-
ment of a cursor.139,144 Ramsey et al.67 observed gamma
power increases within the dorsolateral prefrontal cortex
during mental calculation and proposed that this mea-
surable change could also be used as an input for BCI
applications.
Finally, studies investigating the treatment of in-
tractable pain with motor cortex stimulation have
demonstrated the potential safety of long-term intracra-
nial electrode implantation.145,146 Combining these re-
sults, it may be feasible to implant subdural electrodes
over the cortex for the sole purpose of detecting ECoG
spectral indices of cortical activation associated with in-
tent to move that can in turn be translated into the use
of a prosthetic device.
䉴 PEARLS AND PITFALLS
ECoG spectral analysis is still an emerging technique
for functional mapping, and its clinical applications are
still evolving, albeit rapidly. There remains much to be
learned about the neural mechanisms underlying the dif-
ferent event-related spectral changes that have been ob-
served during functional brain activation, and about how
they relate to behavioral and experimental variables, as
well as to other measures of neural function. It is, there-
fore, important to take care with experimental design
and data acquisition, and yet keep an open mind with
respect to data analysis and interpretation.
The design of experiments for both research and
clinical testing must always take into account that ECoG,
like EEG, MEG, fMRI, and PET, is a measure of functional
brain activation. When not engaged in an experimental
task, the human brain is still actively sensing the envi-
161
ronment, thinking, planning, etc. Experimental control
of the patient’s attention is, therefore, paramount. The
task itself should be relatively brief and simple so that
the timing of task-related cortical processing can be eas-
ily inferred from the timing of stimuli and/or responses.
Event-related designs are useful for this purpose and for
approximating on a trial-by-trial basis a “resting base-
line”, with which task-related ECoG temporal segments
can be compared. Proper task design should be used to
avoid contamination of the intertrial baseline with extra-
neous speech or noise, particularly when employing au-
ditory stimuli. Efforts should be made to keep the testing
room, usually the patient’s hospital room, as free from
unnecessary distractions as possible. These efforts may
include sound treatments to reduce noise from hallway
traffic and next-door neighbors, signs on the door noti-
fying visitors to wait until testing is finished, and simple
measures like unplugging the phone and turning off the
television.
During testing, the patient should be continuously
monitored for their level of arousal and attentiveness to
the task. Delayed or missing responses can be a sign of
fatigue and should be excluded from subsequent signal
analyses. Video recordings synchronized with ECoG and
test markers are useful for post-hoc review to exclude
trials with experimental artifacts or abnormal ECoG activ-
ity. During testing, the patient should be encouraged to
notify the testing staff if they have difficulty with testing
and/or need to take a break. Because ECoG mapping,
like ESM, is sensitive to the patient’s level of coopera-
tion, every effort should be made to ensure that the pa-
tient is comfortable. Patients vary considerably in how
quickly they recover from the surgery to implant intracra-
nial electrodes. Some patients are ready for testing the
next day, while others have persistent headache, nausea,
fatigue, and/or somnolence that prevent effective testing
for several days. Notwithstanding concerns about bleed-
ing in the immediate perioperative period, nonsteroidal
anti-inflammatory analgesics such as Toradol are usually
more effective than opiates for postcraniotomy pain and
are less likely to cause excessive sedation, nausea, and
constipation, or to suppress the patient’s appetite. These
medications should be withdrawn prior to surgical resec-
tion to avoid increased bleeding risk.
The technical specifications for data acquisition dur-
ing ECoG spectral mapping are somewhat more rig-
orous than are customary for the clinical purposes of
capturing interictal and ictal ECoG activity. Although
there is growing interest in high-frequency epilepto-
genic activity,147,148 most commercially available long-
term video–EEG monitoring systems have not been
optimized for the high-gamma activity that appears to be
so useful for ECoG spectral mapping. In addition to ad-
equate sampling rates (preferably greater than 1000 Hz)
and appropriate anti-aliasing filter settings (preferably
greater than 300 Hz), it is critical, as with ERPs, to
162 SECTION I TECHNIQUES
accurately record experimental markers indicating the
timing of experimental stimuli and/or responses rela-
tive to the recorded ECoG. For this purpose, it is prefer-
able to record the markers directly into the ECoG data
stream and to avoid relying on complicated synchro-
nization schemes or the promises of software vendors.
The markers themselves should be as direct a measure
of events as possible. For example, instead of relying
solely on markers for the onset of visual stimuli based
on Transistor-Transistor Logic (TTL) pulses, the timing of
which may depend on the computer operating system
and the experimental software, one can use a photodi-
ode to measure the luminance of a patch that is obscured
from view in a corner of the monitor and that changes
from black to white at stimulus onset.
When approaching analysis and interpretation of
ECoG data, there are a plethora of choices to be made.
Whenever possible, however, it is best to avoid precon-
ceptions about what aspect of the ECoG signal is relevant
to brain function. Although there is growing evidence
supporting broadband high gamma as an important in-
dex of cortical processing, research continues on its re-
sponse properties and generating mechanisms, as well
as those of other spectral phenomena such as band-
limited gamma responses and ERD/ERS in lower fre-
quencies. This research is driven in part by the exciting
prospect that different spectral changes in the ECoG sig-
nal may reflect different populations of neurons and/or
different levels of neural integration across cortical net-
works, possibly even reflecting different modes of in-
formation processing. It is, therefore, prudent to keep
an open mind when analyzing and interpreting experi-
mental ECoG data, particularly for research purposes. A
common pitfall in spectral analysis of EEG or ECoG is
to choose, a priori, particular frequency bands for anal-
ysis of power changes. Because of the variability across
individuals, experiments, and studies in the frequency
bands that are optimally reactive to functional activation,
this approach may lead to suboptimal or even uninter-
pretable event-related spectral analyses. Instead, prelim-
inary exploratory analyses should be considered using
time–frequency analyses of event-related power changes
in all frequencies at all task-relevant times. Subsequent
analyses can then focus on bands empirically derived
from these exploratory analyses. On the other hand,
because algorithms for the aforementioned exploratory
analyses can be computationally intensive and statis-
tically challenging, analyses for clinical mapping may
require pragmatic choices to be made. One of the ad-
vantages of using broadband high-gamma responses for
functional mapping, as illustrated in the previous sec-
tion, is that there is a greater tolerance for choosing
the frequency range for analysis as long as one avoids
power suppression (ERD) in lower frequencies, which
can, however, range as high as 40–50 Hz.
Finally, because ECoG spectral mapping remains in
the early stage of scientific and clinical investigation, in-
terpretation of its results should continue to take into
account the potential limitations of this new technology.
There is still much to be done to demonstrate the positive
predictive value of ECoG with respect to surgical out-
comes, and until then it is important to continue to com-
pare ECoG functional maps with those derived from ESM
and other established and emerging techniques. When-
ever possible, clinical decisions regarding the extent of
resection should be based on consistent findings across
multiple independent lines of evidence, always taking
into consideration the relative strengths and weaknesses
of the techniques that produced them.
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 Chapter 13
Pediatric Brain Mapping: Special
Considerations
Robert J. Bollo1 , Chad Carlson2 , Orrin Devinsky 2 , and Howard L. Weiner 2,3
1
Department of Neurosurgery, Baylor College of Medicine and Neurosurgical Service, Texas Children’s Hospital,
Houston, Texas
2
Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine,
New York, New York
3
Department of Neurosurgery, Division of Pediatric Neurosurgery, New York University School of Medicine,
New York, New York

䉴 INTRODUCTION subcortical white matter tracts critical to motor, sen-

BRAIN MAPPING IN THE
PEDIATRIC PATIENT
Advancements in noninvasive imaging of the substruc-
tures and function of the developing brain, including
new applications of magnetic resonance imaging (MRI)
and the development of other imaging modalities includ-
ing magnetoencephalography (MEG), positron emission
tomography (PET), and single photon emission com-
puted tomography (SPECT), have profoundly impacted
clinical neuroscience. Advanced MRI techniques are
rapidly becoming a standard part of pediatric neurol-
ogy and neurosurgery, including functional MRI (fMRI),
diffusion-weighted imaging (DWI), perfusion-weighted
imaging (PWI), and diffusion tensor imaging (DTI). The
ability to noninvasively map eloquent brain function
(fMRI, MEG, PET), ictal foci (SPECT, MEG, PET), and
white matter tracts (DTI), as well as the coregistration
of multiple imaging modalities, has changed how we
diagnose, evaluate, and manage epilepsy and brain tu-
mors in children.1−3 These techniques help guide and
in some cases replace direct mapping via electrocortical
stimulation (ECS), which remains the gold standard.
Advances in functional neuroimaging hold signif-
icant promise in the diagnosis and management of
other disorders, such as traumatic brain injury (TBI) and
psychiatric diseases.4−5 These techniques can provide
important insights into plasticity during brain develop-
ment.2,6 However, noninvasive brain mapping tech-
niques have limitations, especially in children, and few
have been rigorously tested in the pediatric population.1
The most common clinical indication for brain map-
ping in children is preoperative planning for the re-
section of a brain tumor or seizure focus. For exam-
ple, a detailed knowledge of the cortical regions and
sory and language function is essential to safe resec-
tion of tumors and ictal foci near eloquent cortical
areas.2,7−10 Functional reorganization in the context of
long-standing pathology (e.g., low-grade tumors or long-
standing epilepsy) may be more frequent in the devel-
oping brain.2,11,12
SPECIAL CONSIDERATIONS
Pediatric patients present unique challenges to brain
mapping. Immaturity and anxiety can lead to head
movement, lack of cooperation, or an inability to follow
directions during prolonged testing.13−15 Very young,
autistic, and developmentally delayed children may not
be candidates for current methods of fMRI or awake in-
traoperative mapping if they cannot comprehend or par-
ticipate in these tasks.15
Functional loci are poorly consolidated in the de-
veloping brain, with diffuse anatomical representation
compared to adults. Direct cortical stimulation mapping
of sensorimotor and language function is less sensitive in
children younger than 10–12 years, independent of pa-
tient cooperation.16−19 The Wada (intracarotid amobar-
bital) test for hemispheric dominance is also less sensi-
tive in children younger than 10 years.16 Wada testing is
also complicated in children by limited cooperation.20,21
PET and SPECT involve the administration of a radioiso-
tope, limiting research in children.1 Short seizure dura-
tion (less than 1 minute), common in children, can make
ictal SPECT injections difficult and less informative.1
SPECIFIC TECHNIQUES
Clinical brain mapping techniques in children can be
categorized by substrate (eloquent function, seizure

167
168 SECTION I TECHNIQUES

modality invasive test measured variable mapping substrate special considerations in children clinical applications in pediatrics references
MRI no
requires cooperative, still patient;
sensorimotor & language function, 2, 11, 22–41
sensitivity diminished by sedation
fMRI BOLD signal language lateralization & in children <7 year-old, language mapping surgical planning
(hemispheric dominance) requires active task paradigms

neonatal hypoxic-ischemic reperfusion injury,

DWI extrocellular water diffusion acute ischemia/infection none 42, 43, 44–49
ADEM, ictal focus localization (peri-ictal DWI)

DTI axonal water diffusion (large) white matter tracts none surgical planning TBI 48–52
tumor grading, differentiating tumor
PWI rCBV brain tumors, ischemic penumbra improved sensitivity in children recurrence from treatment response, 53, 54
stroke, TBI

MEG no
requires a cooperative, still patient;
sensotimotor & language function, sensitivity diminished by sedation
MSI magnetic source dipole ictal focus localization, surgical planning 23–88
ictal foci & in children under 6 years-old

PET no requires radioisotope

sensitivity diminished by sedation; tumor grading, targeting sterentactic biopsy,

FDG glucose metobolism brain tumors, ictal foci cannot differentiate ictal onset zones from differentiating tumor recurrence from 23, 33, 89–109
regions of rapid seizure propagation treatment response; identifying ictal foci

MET protein metobolism brain tumors, ictal foci none tumor grading, deliniating tumor boundaries 91, 97, 100–103
identifying ictal foci
FMZ GABA receptor density ictal foci none (more specific than FDG-PET), 90
especially crypotgenic cortical dysplasia
identifying ictal foci, especially among
AMT serotonin receptor density ictal foci none
children with multifocal pathelogy (e.g., TSC) 90, 105, 110

SPECT no requires radioisotope

no tracer uptake in many common pediatric differentiating treatment response from
MIBI cerebral perfusion brain tumors, relative perfusion deficits 91, 111–120
tumors recurrent neoplasm; Moya-Moya disease
ictal injection technically demanding
HMPAO cerebral perfusion ictal foci, relative perfusion deficits identifying ictal foci, Moya-Moya disease 106, 114, 121–125
sensitivty improved with SISCOM
Wada yes requires cerebral angiography
requires a cooperative patient;
10, 12, 16, 20–21, 24, 41, 89,
amobarbital language and memory function language and memory lateralization diminished sensitivity in children surgical planning
92, 126–129
<10 years-old

ECS yes requires open craniotomy

functional inhibition,
intraoperative
interictal EEG recording
functional inhibition,
extraoperative
ictal & interictal EEG recording
sensorimotor & language function,
ictal foci
sensorimotor & language function,
ictal foci
diminished sensitivity in children <5 years-
old; risk of seizures, diminished sensitivity of 2, 7-9, 13–14, 16, 19, 130,
EEG under anesthesia, awake craniosomy for
(intraoperative) surgical planning
131–139
language mapping poorly tolerated
diminished sensitivity in children <7 years-
2, 16–19, 22, 73, 75, 134, 135,
old; multiple surgeries with prolonged surgical planning
invasive monitoring 141–145, 146–152

Figure 13–1. Common techniques for pediatric brain mapping.

activity, white matter pathways) or technique (noninva- Figure 13–1 describes the most common techniques
sive and invasive). Noninvasive techniques assay relative for pediatric brain mapping, their clinical indications
changes in local perfusion (fMRI and SPECT), metabolism in children, and their present limitations in this patient
(PET), or magnetic flux (MEG) as surrogate markers of population.
increased neuronal activity during either spontaneous
activity or a specific task. DTI together with axonal trac-
tography allows the specific delineation of white matter 䉴 NONINVASIVE TECHNIQUES
tracts.
Invasive testing, including the Wada procedure for OVERVIEW
determination of hemispheric dominance and direct cor-
tical stimulation for mapping eloquent function, remain PET, fMRI, and MEG are powerful, noninvasive means
the “gold standards.”2,10,22 These studies use pharmaco- of mapping sensorimotor and language function.
logical (Wada) or electrical (ECS) methods to produce Frequently used in adults to guide surgical resec-
spatially and temporally restricted neuronal inhibition, tion of supratentorial lesions near eloquent cortical
while assessing the patient for a corresponding tem- regions,1,2,10,23−26,55,56,153−158 these techniques may be
porary clinical deficit. In addition, invasive electroen- difficult to perform in young children. In addition, the
cephalography (EEG) using subdural grid and strip elec- reliability of detailed functional maps obtained from
trodes and intraparenchymal depth electrodes remains these techniques remains controversial in children, es-
the “gold standard” for identifying the epileptogenic pecially for functional mapping of cortex near tumors,
zone. in patients with refractory epilepsy, and for language
There is strong interest in noninvasive techniques mapping.2,10,23,25,27,158,130
to identify the epileptogenic zone as well as eloquent Noninvasive functional imaging techniques differ
cortex. Experimental studies in children have focused fundamentally from their invasive counterparts. Nonin-
on developing clinical protocols that improve their suc- vasive mapping paradigms measure activation of a re-
cess and accuracy, with validation through comparison gion(s) in response to a particular task or series of tasks.
to invasive means of brain mapping. In contrast, invasive techniques rely on the inhibition
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS
of function using drugs (Wada) or inhibition or electric
current (ECS). As a result, direct comparisons of func-
tional regions identified using invasive and noninva-
sive testing should be carefully considered. Noninva-
sive methods may overestimate the area of functional
cortex for a given function which, in turn, may limit
resection.2 Noninvasive tests are limited by spatial res-
olution, changes in brain hemodynamics secondary to
tumors or arteriovenous malformations (SPECT, fMRI),
signal-to-noise limitations for paradigms relying on pa-
tient cooperation, and source localization secondary to
the underlying assumptions of the model (MEG).
A common clinical application of noninvasive func-
tional brain imaging is localizing a cryptogenic seizure
focus in children with refractory epilepsy. Seizures be-
gin during childhood or adolescence in 60% of epilepsy
patients.106 Approximately 30% of children become re-
fractory to medical treatment with multiple agents. Surgi-
cal resection of the ictal onset zone leads to either com-
plete elimination of seizures or a significant reduction
in seizure frequency in 80% of children with temporal
lobe epilepsy. Surgery is less successful for extratempo-
ral seizures, due to difficulty in localizing the focus with-
out a structural lesion on MRI, multifocal pathology, or
discordant localizing data from noninvasive studies.121
Functional neuroimaging techniques assessing focal ab-
normalities of brain perfusion or metabolism (SPECT,
PET), or ictal and interictal foci of abnormal electro-
physiology (invasive video EEG (VEEG), MEG) have
improved detection of the epileptogenic zone and in-
creased the number of children who may benefit from
surgical treatment. Microscopic areas of focal cortical
dysplasia are a common source of partial seizures in
children with a normal MRI.121
FUNCTIONAL MRI
fMRI measures microvascular changes in deoxyhe-
moglobin concentration, known as the blood oxygen
level dependent (BOLD) signal. Changes in oxyhe-
moglobin and deoxyhemoglobin ratios are a surro-
gate for neuronal activity, because increased neuronal
metabolism is coupled to local increases in perfusion un-
der physiological conditions.22,28 One limitation of fMRI,
especially when used for language mapping, is that it
reveals cortex specifically recruited during a particular
task. This may vary significantly according to the task
performed. Areas of activation may not be required for
task performance; conversely, direct cortical stimulation
only identifies essential cortex.23
General Considerations in Pediatrics
fMRI is noninvasive, does not involve ionizing radiation,
and has no known adverse effects,23,29 making it safe for
169
children. Factors that decrease the signal-to-noise ratio
include poor cooperation, anxiety and head movement,
sedation, small patient size, structural immaturity, and
physiological differences in cerebrovascular response.23
Behavioral effects may present the most significant ob-
stacle to fMRI in children, especially those with focal
neurological signs, developmental delay, or psychiatric
disorders such as autism. Children often experience rest-
lessness and anxiety and have difficulty following com-
mands, sustaining attention to functional tasks, and re-
maining still for extended periods in the MRI scanner.
Discomfort or anxiety leads to poor attention to func-
tional tasks, head movement, and the recruitment of
neural networks that are not function-specific. Behav-
ioral conditioning including the use of mock scanners
may diminish anxiety and decrease mapping failures.15
Having a child view a cartoon videotape in the scan-
ner reduces motion and improves successful functional
scanning, especially in children younger than 5 years
without sedation.30
Inferior frontal speech areas (Broca’s area) usually
require activation by a verb generation task, because in-
consistent activation is seen with passive stimuli (which
commonly activate posterior temporal primary auditory
cortex and receptive language centers). This may be
very difficult for young children. Passive tasks in chil-
dren with cerebral pathology may not be reliable, as
bilateral activation and failure to determine dominance
are frequently observed.23 However, creative passive
tasks, such a listening to a story with key words omit-
ted, have activated unilateral inferior frontal speech cen-
ters in small studies. Continued development of testing
paradigms may improve fMRI-based language mapping
in young children.31 Despite efforts to improve coop-
eration and decrease anxiety, the failure rate of fMRI is
approximately 30% children less than 8 years, and almost
60% in children less than 6 years.29
The developing brain has higher synaptic density
and relative gray matter volume compared to the mature
adult. In addition, there are differences in cerebral vascu-
lar responsiveness, especially in neonates.15 These fac-
tors affect the BOLD signal response, confounding fMRI
data in children.15,28,32,33 Patients younger than 12 years
have significantly more variation in the BOLD signal,
leading to increased noise, diminished signal-to-noise
ratio, and smaller activation volumes.28
The majority of brain growth is finished by 5 years,
but myelination continues into adulthood. Major white
matter tracts are visible by 3 years, and the ratio of gray to
white matter is comparable to adults at 7 years. Synap-
tic density peaks at 1 year and subsequently declines
until age 16; this is mirrored by changes in cerebral glu-
cose metabolism.15 A faster heart rate, thinner skull, and
smaller body prevent dampening of cardiac and respira-
tory motion, which contribute to increased physiological
noise in children.33 In addition, fetal hemoglobin
170 SECTION I TECHNIQUES
accounts for 20% all hemoglobin at 4 months, decreas-
ing the sensitivity of fMRI in neonates.33 Comparing fMRI
data between children and adults may be confounded
by differences in brain size. This introduces error in the
localization of functional activity when images are trans-
formed into a common stereotactic space. Spatial nor-
malization of MRI structural data is similar to the adult
by approximately 6 years of age.15 These factors are neg-
ligible in children more than the age of 7 years.
Half of all pediatric MRI scans, and the majority in
children less than the age of 7 years, require sedation.
Commonly used agents impact cerebral perfusion and
diminish the sensitivity of fMRI. Propofol causes a dose-
dependent inhibition of functional activation. Primary
motor and auditory cortex are easily activated, even at
high doses and in very young children.32,33 However,
association centers such as language cortex are highly
sensitive to propofol; in addition, less function-specific
passive tasks are required in the sedated patient.34,35 The
effects of other medications have not been studied.
Given these limitations, fMRI techniques must
be verified against direct cortical mapping in chil-
dren. Several studies in children undergoing craniotomy
have compared fMRI sensorimotor maps with intra-
operative cortical stimulation, with generally excellent
agreement.36,37 Future clinical applications of fMRI are
likely to evolve if normative patterns of brain devel-
opment can be established. This may enable the early
diagnosis of functional deficits, psychiatric disease, and
cognitive deficits in children, facilitating early interven-
tion and possibly improving outcomes.38
Brain Tumors
Changes in cerebral perfusion and metabolism in or
near a focal lesion (e.g., tumor, arteriovenous malfor-
mation) or chronic seizures may alter the BOLD sig-
nal and diminish the sensitivity of fMRI-based functional
mapping.2,11,32,35,39 This translates into 20% discordance
between fMRI and intraoperative ECS maps of sensori-
motor cortex, and as much as 66% discordance for lang-
uage maps.2,26 Malignant gliomas of the ipsilateral hemi-
sphere are associated with decreased fMRI activation
volumes and increased anatomic variability.24 However,
fMRI may be complementary to ECS among children
with tumors near eloquent cortex. fMRI may localize
function to areas inaccessible by ECS, such as dis-
tant from the craniotomy site or deep within cortical
sulci.11
Epilepsy
Functional reorganization is common in children with re-
fractory epilepsy.12,25,40,41 fMRI may improve the safety
of ictal focus resection by sparing functional cortex,
as well as inform treatment decisions when function is
identified within a structural abnormality or the epilep-
togenic zone.40 Determining hemispheric dominance
in children is challenging. Clinical data and structural
MRI may not accurately predict language lateralization,
possibly due to functional reorganization.32,40 Preoper-
ative fMRI may help direct the placement of subdural
electrode arrays, or surgery may be deferred if func-
tional activation is identified within the epileptogenic
zone.40
Cortical Plasticity and Reorganization
A better understanding of age-dependent plasticity may
inform surgical decision-making and help predict neu-
rological recovery after traumatic brain injury. For ex-
ample, the age at which complete disconnection of the
dominant hemisphere will result in permanent language
dysfunction is not precisely defined. Historically, a cutoff
of 6 years of age has been used to define the estimated
end of the critical period of language acquisition.41 How-
ever, fMRI studies in children as old as nine have corre-
lated recovery of language with recruitment of contralat-
eral perisylvian cortex.12
DIFFUSION AND PERFUSION MRI
DWI and DTI are increasingly being used in children.
DWI images the degree of random motion of extracel-
lular water molecules; pathology that restricts extracel-
lular water motion (e.g., cytotoxic edema) creates con-
trast on DWI. This technique is most commonly used
for the early detection of stroke in adults,42,43 but is be-
coming part of routine MRI in young children, especially
neonates.159
DTI measures diffusion of water molecules along
axons, and it can display large white matter tracts as dis-
tinct structures.50−52,160 DWI and DTI do not require pa-
tient cooperation. PWI utilizes intravenous gadolinium
to create maps of relative cerebral blood volume (rCBV)
and relative cerebral blood flow (rCBF). It is used in
assessing cerebral ischemia, brain tumors, and TBI.53
Diffusion-Weighted Imaging
DWI is superior to conventional MRI sequences in the
early differentiation of hypoxic-ischemic reperfusion in-
jury patterns in the neonate.43,44 For example, a modest
decrease in cerebral perfusion produces a “border zone”
pattern of restricted diffusion before changes are seen on
T1- or T2-weighted imaging. Prolonged hypoperfusion
leads to a more diffuse pattern, affecting the brainstem,
thalamus, paracentral white matter, and optic radiations.
DWI is more sensitive than conventional MRI techniques
for detection of diffuse ischemic injury, and differentiat-
ing this pattern from focal infarction in the newborn.42−44
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS 171

Among young children with traumatic brain injury, le- Perfusion-Weighted Imaging
sions on DWI correlate with an increased likelihood of
The most common technique for PWI used in children
seizures, neurosurgical intervention, mechanical ventila-
is dynamic susceptibility contrast imaging. During the
tion, and inpatient rehabilitation.44
first pass of gadolinium through the cerebral vascular
DWI may better distinguish cellular from cystic
bed, changes in T2 signal occur in the surrounding brain
brain tumors, such as medulloblastoma and pilocytic as-
parenchyma due to the high concentration of paramag-
trocytoma. DWI also aids in the differentiation of tumor
netic contrast. The intensity of change in T2 signal is
recurrence and radiation necrosis. Tumor recurrence is
strongly correlated with perfusion. This technique has
associated with restricted diffusion, whereas radiation
several advantages in children over other noninvasive
necrosis typically displays higher diffusion. In addition,
methods (e.g., PET and SPECT). This includes the su-
diffusion changes precede T2 signal change in children
perior spatial resolution of MRI, rapid image acquisi-
with leukoencephalopathy. DWI may also differentiate
tion, and the absence of ionizing radiation. In addition,
posterior reversible encephalopathy syndrome from ir-
PWI is highly sensitive to the microvasculature, which is
reversible neurological injury in children undergoing
the anatomic location of many types of cerebrovascular
chemotherapy. Preserved diffusion predicts reversible
pathology observed in children.53
injury, and restricted diffusion suggests irreversible dam-
Dynamic susceptibility imaging is wellsuited for
age due to cytotoxic edema, and correlates with a poor
children. The smaller cross-sectional area of cerebral
prognosis.43,45
vasculature and higher pulse combine to concentrate
As in adults, DWI is helpful in the diagnosis of
gadolinium as a rapid bolus in a relatively small vol-
cerebritis, encephalitis, or brain abscess, as well as mon-
ume, improving the signal-to-noise ratio. In children
itoring treatment response to antimicrobial therapy. DWI
younger than 5 years, these advantages may be offset
may reveal focal diffusion abnormalities with herpes
by the need for manual injection due to small venous
encephalitis prior to signal changes on routine MRI.
caliber.53 Clinical applications of PWI include the evalua-
Restricted diffusion among patients with acute dis-
tion and management of brain tumors, cerebral ischemia,
seminated encephalomyelitis (ADEM) predicts a poor
and traumatic brain injury. Higher maximum rCBV corre-
long-term outcome.43,46 Peri-ictal DWI shows decreased
lates with higher grade in gliomas. In children diagnosed
diffusion in the epileptogenic zone, and may help in lo-
with medulloblastoma, PWI is sensitive at differentiating
calizing this region in patients with refractory seizures
tumor recurrence from radiation necrosis, which may
and multifocal pathology or discordant MRI, EEG, and
be indistinguishable by conventional MRI.53 In the con-
seizure semiology.43 In addition, early studies using DWI
text of acute cerebral ischemia, such as Moyamoya syn-
to lateralize nonlesional temporal lobe epilepsy have
drome, PWI in combination with DWI may delineate the
demonstrated encouraging results.47
ischemic penumbra, or viable but dysfunctional tissue at
risk for infarction.53 Finally, the number and depth of
Diffusion Tensor Imaging microhemorrhages due to diffuse axonal injury correlate
with neurological outcome in children.54
DTI often demonstrates significantly diminished sig-
nal along frontal and supracallosal white matter tracts
among children following TBI. These changes correlate
with clinical deficits of executive function and motor MAGNETOENCEPHALOGRAPHY
speed.48 Among children with congenital malformations
such as holoprosencephaly, the size of the white mat- MEG records magnetic flux produced by electrical cur-
ter tracts correlates with disease type and severity.49−51 rents that result from ion flow across excited neu-
Among children undergoing surgery for brain tumor re- ronal membranes.57 The magnetic field generated by
section, DTI may assist in preoperative planning and these currents is not distorted or degraded by the
intraoperative navigation by delineating the relation- skull or scalp, so MEG has better spatial resolution
ship between neoplasm and functionally eloquent white with similar temporal resolution compared to scalp EEG
matter.51,52 DTI can also distinguish tumor infiltration recordings.56 MEG and EEG are complementary, be-
from compression of white matter tracts, which may im- cause they are each most sensitive to currents from dif-
pact surgical decision-making.52 Unlike DWI, DTI is not ferent sources. MEG is sensitive to tangential flux, gen-
sensitive to acute changes in extracellular diffusion. In erated from dipole sources within sulci, whereas EEG is
addition, present DTI techniques have relatively poor more sensitive to radial dipoles.58
spatial resolution compared to conventional MRI tech-
niques. This limits the clinical utility of DTI as a diagnos-
General Considerations in Pediatrics
tic tool.51 However, as more DTI studies are performed
in children with white matter pathology, additional clin- MEG is noninvasive and safe in children, with no known
ical applications are likely to emerge.50 side effects. Compared to fMRI, MEG has the advantage
172 SECTION I TECHNIQUES

of millisecond temporal resolution. Like fMRI, MEG Functional Mapping

can accurately localize interictal and ictal foci in rela-
Early studies in children with refractory epilepsy re-
tion to eloquent cortex. MEG is frequently an impor-
ported successful sensorimotor mapping with MEG in
tant part of the presurgical evaluation for intractable
54%.63 More recent studies comparing MEG-based sen-
epilepsy.59,60 Functional mapping with MEG also em-
sorimotor mapping with ECS in children with epilepsy
ploys task-oriented patient cooperation, and head move-
have demonstrated near-perfect concordance.56 In chil-
ment is a common source of error in children.23 MEG
dren younger than 6 years, MEG-based sensorimotor
directly monitors electrophysiology, rather than using a
mapping is less sensitive, because small patient size am-
surrogate marker such as perfusion or metabolism like
plifies physiological noise. Promising technical solutions
fMRI, SPECT, and PET. Sources of interictal spikes and
include spatial filtering, which has successfully mapped
functional activity can be accurately projected onto MRI
sensorimotor cortex in healthy children as young as
images using fiducial markers to coregister the mod-
3 years.64 Simultaneous EEG and MEG data may im-
eled activity to a structural MRI. This technique is mag-
prove the spatial accuracy of functional mapping of so-
netic source imaging (MSI). MEG may noninvasively
matosensory cortex in children with ipsilateral structural
map both functional cortex and ictal foci, and guide inva-
lesions.65 MEG has very high sensitivity (98%) and speci-
sive cortical mapping (Fig. 13–2).59 The use of sedation is
ficity (93%) for determining hemispheric dominance in
often required to ensure patient compliance during MEG
children older than 8 years.66 MEG may be a noninvasive
studies in young children and those with developmental
alternative to the Wada procedure. However, Wada test-
delay and behavioral problems.61,62 Midazolam signifi-
ing is still necessary if memory assessment is needed.66
cantly decreases the sensitivity of MEG for spike activity
Functional mapping of receptive language centers
and sensorimotor mapping, with reported failure rates
has demonstrated excellent test–retest reliability in small
of almost 30%. The combination of chloral hydrate and
studies including children older than 10 years.57 MEG-
propofol is associated with much lower failure rates in
based receptive language maps of healthy volunteers
children.61,62

B1 B2

B3 C

Figure 13–2. (A) Averaged response for 512 pneumatic tactile stimulation of the left
index finger from all 248 magnetometer sensors (4-D Neuroimaging, San Diego, CA)
with peaks at 24 milliseconds, 51 milliseconds, and 93 milliseconds. (B) The magnetic
source images (MSI) demonstrating localizations for the 24 (anterior ) and 51
(posterior) millisecond responses in the sagittal (B1 ), coronal (B 2 ) and axial planes
(B 3 ). (C) Composite three-dimensional rendering of digital imaging and
communications in medicine images with multiple left and right upper extremity digit
trials. Responses are shown in red.
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS
reveals adult patterns of cortical activation in children
more than the age of 7 years.67 In addition, sensorimo-
tor mapping via MEG correlates well with intraoperative
ECS in older children undergoing surgery for brain tu-
mor resection.34,68 MEG-based functional maps inform
surgical decision-making and intraoperative navigation
in children with tumor infiltrating or adjacent to MEG-
defined functional cortex.26,69
MEG studies have shown a high incidence of sen-
sorimotor reorganization in children as young as 2 years
with abnormalities of cortical proliferation (e.g., corti-
cal dysplasia), including relocation in the contralateral
hemisphere. Similar changes were not observed in chil-
dren with abnormalities of cortical organization, such
as polymicrogyria. This stresses the importance of func-
tional mapping in the preoperative evaluation of patients
with cortical dysplasia for epilepsy surgery.70 Cortical
reorganization may also inform negative mappings via
ECS, which is subject to sampling error due to its focal
employment and limited cortical coverage.
MEG/MSI studies are limited by the most common
method of localizing sources of evoked waveforms, the
equivalent current source dipole algorithm. This assumes
the source to be a zero-volume point in a homogeneous
sphere.71 Good correlation between ECS and motor, sen-
sory, and language point dipole localization on MEG
has been demonstrated in adults.26,55,68 However, this
method cannot precisely define the boundary between
a lesion and functionally critical brain.72
Epilepsy
MEG measures only interictal activity over short time
intervals (less than 1 hour), compared to video EEG
(VEEG) monitoring which records both ictal and inter-
ictal activity over a period of days. Despite this, MEG is
a sensitive noninvasive method of predicting the epilep-
togenic zone.73 The location of interictal spikes detected
by MEG accurately predicts the epileptogenic zone in
children,73−76 but cannot delineate the extent of abnor-
mal tissue.72 Like MRI, MEG acquisition is generally lim-
ited to the interictal period. However, in select children
with frequent, motionless partial seizures, ictal MEG may
be possible, good results compared to ictal SPECT and
EEG.77
Approximately one-third of children with refractory
partial epilepsy have a normal MRI.72 Outcome studies
demonstrate that MEG has a sensitivity of 50–60% and
a positive predictive value of 80–90% for identifying the
epileptogenic zone.73,75,76 The concordance of EEG and
MEG localizing a single seizure focus predicts postop-
erative seizure freedom.74,78 Bilateral MEG clusters or
the absence of an MEG cluster within an area of cor-
tex targeted for surgical resection correlates with poor
outcome.72,74
173
In children, refractory epilepsy is more often neo-
cortical than mesial temporal in origin.74 MEG is less
sensitive than invasive monitoring with intracranial elec-
trodes in identifying extratemporal seizure foci.75 How-
ever, MEG has a significantly better yield at identifying
neocortical foci compared to medial temporal disease
among patients with cryptogenic seizures.56,79 In addi-
tion, asymmetric MEG dipole clusters demonstrated high
concordance with intraoperative electrocorticography
(ECoG) in children with lesional, neocortical epilepsy.
The resection of remote ictal zones identified by MEG
and ECoG does not contribute to epilepsy outcome in
patients with tumors.74 However, in patients with corti-
cal dysplasia, the resection of remote ictal regions may
be critical to seizure outcome, as small populations of
intrinsically epileptogenic, dysplastic neurons are likely
to exist at these locations.74
Most authors recommended the use of iVEEG to
define the epileptogenic zone in patients with multi-
ple clusters on MEG.79 An emerging technique to map
the temporal and spatial spread of interictal spike ac-
tivity is gradient magnetic field topography, which may
complement the interpretation of interictal MEG in pa-
tients with multiple clusters by defining epileptogenic
networks.80 Invasive or scalp VEEG monitoring and MEG
provide complementary data. Simultaneous EEG record-
ing during MEG sessions have been shown to improve
sensitivity for the detection of interictal epileptogenic
activity.58,81 Like all noninvasive techniques of ictal focus
mapping, MEG provides the most information in the con-
text of a multimodality evaluation for refractory seizures.
MEG may be especially useful in identifying the
epileptogenic tuber in patients with tuberous sclerosis
complex (TSC) and focal seizures. 90% of patients suf-
fering from TSC experience seizures, and these are re-
fractory to medical treatment in 50% of cases.58 Focal
seizures are usually mapped to tubers and adjacent cor-
tex. However, the majority of these patients have multi-
ple tubers, and identifying the epileptogenic lesion may
be challenging.58 MEG has demonstrated high accuracy
in predicting the epileptogenic zone based on prelimi-
nary studies, and is superior to other noninvasive tech-
niques such as scalp VEEG or ictal SPECT.82,83 The pres-
ence of a single cluster compared to multiple clusters
or bilateral discharges was able to accurately differenti-
ate patients with a single, primary ictal onset zone from
those with multiple or bilateral ictal onset zones that are
part of a larger epileptogenic network.84 Taken together,
this data suggests that MEG may identify a subset of pa-
tients with focal epilepsy and TSC with a single epilep-
togenic tuber, who may not require invasive monitoring
with intracranial electrodes prior to tuber and ictal focus
resection.
In addition to TSC, MEG is part of the clinical
evaluation of Landau-Kleffner syndrome (LKS), acquired
epileptiform aphasia. MEG shows perisylvian interictal
174 SECTION I TECHNIQUES
discharges in many children.85 The temporal resolution
and sensitivity to interictal sources deep within the syl-
vian fissure of MEG has been combined with pharma-
cological sleep and methohexital suppression to iden-
tify a single sylvian pacemaker in some children with
LKS, and multiple subpial transections in this region have
stopped all interictal spike activity in a small number of
patients.86 Similar techniques have been used to iden-
tify unilateral interictal sources in patients with benign
rolandic epilepsy of childhood,87 as well as to study dif-
ferences between focal seizures and hypsarrhythmia in
children with West syndrome.88
POSITRON EMISSION
TOMOGRAPHY
PET uses radiolabeled tracers to image cerebral perfu-
sion ([15 O]-H2 O), glucose metabolism (2-[18 F]fluoro-2-
deoxy-D-glucose, or FDG), amino acid transport and pro-
tein metabolism ([11 C]-L-methionine, or MET), and GABA
receptor density ([11 C]-flumazenil, or FMZ).89−91 PET im-
ages coregistered to standard MRI allow anatomic lo-
calization of perfusion changes (functional mapping),
glucose or amino acid metabolism (ictal focus or tumor
mapping), or GABA receptor concentration (ictal focus
mapping).89
General Considerations in Pediatrics
PET has the advantage of an open environment reducing
the potential for claustrophobia and anxiety.92 Because
PET requires administration of radioisotopes, normative
pediatric data is scarce. This is especially problematic for
functional mapping of language during normal devel-
opment. In addition, a poor signal-to-noise ratio means
studies are often repeated.23 PET imaging is not widely
available, limiting its clinical use, especially in children.91
FDG, which delineates specific cortical regions of
high or low metabolism, is the most common PET tracer
used for brain mapping. Compared to technetium-99m
SPECT and FDG-PET studies in adults, relatively low-
radiation doses to the brain and bladder are adminis-
tered with FDG-PET studies in neonates. This may be
attributed to the short half-life of FDG compared to
technetium-99m DTPA, and the high ratio of brain to
total body mass in infants.93 However, clinical studies of
long-term outcome that quantify the risk to children are
lacking. Like fMRI and MEG, streamlined FDG-PET pro-
tocols (e.g., venipuncture instead of arterial sampling)
are used for infants and small children.94
Sedation with propofol in children undergoing
FDG-PET produces dose-dependent hypometabolism in
both parietal and occipital lobes. This may diminish the
sensitivity of FDG-PET in sedated children.95,96 PET has
been studied extensively in children undergoing cran-
iotomy. Indications include functional mapping ([15 O]-
H2 O), seizure focus mapping (FDG, MET, FMZ), and the
delineation of the boundaries of intra-axial neoplasms
(FDG, MET). In some centers, overlap between a seizure
focus and eloquent brain regions defined by PET is used
as a criteria for nonsurgical management of children with
medically refractory epilepsy.89
Functional Mapping
Functional mapping with PET has a lower spatial reso-
lution compared to fMRI. Small studies in children have
demonstrated excellent concordance between ([15 O]-
H2 O)-PET and hemispheric dominance on Wada test.92
Language mapping using PET was reported in children
as young as 3 years, using unverified speech activation
tasks.92
Brain Tumors
In adults and children, FDG and MET uptake in tu-
mors are predictors of outcome and tumor grade in-
dependent of histopathology.91,92,97,98 FDG uptake is a
more sensitive predictor of tumor grade than gadolinium
enhancement.98,99 However, low-grade tumors common
in children such as pilocytic astrocytoma and choroid
plexus papilloma, demonstrate brisk FDG uptake.98 Clin-
ically, MET and FDG-PET can assess response to treat-
ment and identify tumor recurrence.100 MET uptake is
more sensitive than MRI with gadolinium for identi-
fying the tumor boundaries.97 Late changes on MET-
PET in children with a remote history of low-grade
glioma may represent treatment-related pathology, such
as meningioangiomatosis.101
PET imaging with FDG and MET tracers coregis-
tered to MRI is used in some centers to select stereo-
tactic biopsy targets in children with infiltrative tumors
that display heterogeneous signal changes on traditional
MRI. This approach may decrease the incidence of non-
diagnostic biopsies (estimated to be approximately 5% of
MRI-guided stereotactic brain biopsies) and increase the
safety by decreasing the sampling rate.91,99 The safety
may be further improved with functional mapping us-
ing ([15 O]-H2 O)-PET. PET may also demonstrate resid-
ual tumor following resection, informing decisions about
early second-look operations and assisting in radiother-
apy planning.99,102 Functional and metabolic PET maps
may guide intraoperative tumor resection.103
Epilepsy
A strong correlation exists between foci of interictal hy-
pometabolism revealed by FDG-PET and epileptic foci
on iVEEG.90,104 Interictal FDG-PET has a sensitivity of
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS
60–80% for identifying foci of hypometabolism among
patients with chronic, refractory extratemporal epilepsy
and a normal MRI.90,105 This sensitivity is similar to ictal
SPECT.90,105 The sensitivity of interictal FDG-PET for pa-
tients with neocortical temporal lobe seizures is approx-
imately 90%.104,106 FDG-PET is more sensitive but less
specific in detecting cortical dysplasia.107 Areas of FDG-
PET hypometabolism include regions of rapid seizure
propagation in addition to the ictal onset zone. This poor
specificity is exaggerated in extratemporal epilepsy.90,105
FDG-PET also has a low sensitivity in children with new-
onset partial epilepsy; abnormalities on FDG-PET corre-
late with chronic seizure activity.33,105
Among neonates with infantile spasms, includ-
ing those with an EEG characterized by hypsarrhyth-
mia, FDG-PET may demonstrate one or more abnormal
foci (65% patients have multiple foci). The significance
of these changes in infants with generalized spasms
remains controversial.105,108 Longitudinal studies failed
to demonstrate a prognostic significance.108 However,
children with a single FDG-PET abnormality that corre-
lates with focal changes on EEG typically have an ex-
cellent outcome following seizure focus resection in-
clusive of the PET hypometabolic focus.105 FDG-PET
may have prognostic value in patients with infantile
spasms diagnosed with West syndrome. Persistent fo-
cal hypometabolism on FDG-PET after medical treat-
ment is correlated with developmental delay. Persistent
regions of hypometabolism after therapy that correlate
with focal EEG abnormalities represent structural ab-
normalities such as cortical dysplasia.109 This is con-
sistent with other data showing a higher incidence of
FDG-PET abnormalities in children with longer seizure
duration.33
The introduction of [11 C]-flumazenil, or FMZ, which
images GABAA receptor density, has refined the use
of PET in the identification of the ictal onset zone.90
Changes on FMZ-PET are more specific to the ictal on-
set zone when compared to FDG-PET. FMZ may demon-
strate mesial temporal dysfunction when MRI does not
clearly demonstrate hippocampal sclerosis. In addition,
FMZ-PET has a high sensitivity for demonstrating small
foci of cryptogenic cortical dysplasia (decreased FMZ up-
take due to decreased density of GABAA receptors).90
The novel PET tracer ␣-[11 C]-methyl-serotonin, or
AMT, which images tryptophan metabolism, has shown
promising results in preliminary clinical studies aimed
at distinguishing epileptogenic and electrically silent le-
sions in children with multifocal pathology.90,105 Stud-
ies in children with tuberous sclerosis and refractory
epilepsy have shown FDG-PET may complement MRI
with DTI in differentiating epileptogenic from clini-
cally silent tubers.110 Higher apparent diffusion coeffi-
cient (ADC) volumes on DTI and larger volumes of hy-
pometabolism on interictal FDG-PET compared to tuber
size distinguished epileptogenic tubers.110
175
SINGLE PHOTON EMISSION
TOMOGRAPHY
SPECT has become a commonly used tool in the
management of pediatric brain tumors and refractory
epilepsy.91 Unlike PET, a cyclotron is not required to
generate tracers and therefore SPECT is more widely
available. Although PET is reported to be more sensi-
tive for the detection of perfusion abnormalities, SPECT
is much more widely available in the clinical setting,111
and is more sensitive than FDG-PET in the clinical de-
tection of brain metabolism.91,112,113
General Considerations in Pediatrics
Brain perfusion SPECT imaging is most commonly per-
formed with 99m technetium-hexamethylene propylene
amine (99m Tc-HMPAO), 99m technetium-ethyl cysteinate
dimer (99m Tc-ECD),114 or N-isopropyl-(123 I) p-iodoamp-
hetamine (NPI).111 Less common tracers include 99m Tc-
methoxyisobutylisonitrile (MIBI), 99m Tc-tetrofosmin, and
99m
Tc-glucoheptonate.113 HMPAO is more sensitive than
ECD in identifying the epileptic zone, and is the most
common tracer used in pediatric epilepsy.115 SPECT
is commonly used to assess cerebral perfusion in
the pre- and postoperative management of Moyamoya
disease,116 and is increasingly being used to study the
response to psychiatric treatment117 and injury118 in chil-
dren.
Brain Tumors
Studies with multiple different tracers have failed to
establish SPECT as a valuable tool for predicting tu-
mor histology or recurrence in many pediatric brain
tumors.119,120 MIBI-SPECT studies show tracer accumu-
lation in both low- and high-grade infiltrative gliomas,
as well as brainstem gliomas. Other common pediatric
brain tumors including medulloblastoma, optic pathway
glioma, and ependymoma do not accumulate MIBI.119
Clinical studies using 99m Tc-tetrofosmin among children
with suspected tumor recurrence in the posterior fossa
failed to show tracer accumulation in most cases of tu-
mor recurrence.120 However, preliminary results suggest
99m
Tc-glucoheptonate SPECT may differentiate tumor re-
currence from radiation necrosis among children treated
for medulloblastoma with an equivocal MRI.113
Epilepsy
Ictal and interictal perfusion mapping with HMPAO-
SPECT may improve detection of the epileptogenic zone
in children.106 Like PET, ictal SPECT is clinically useful
among patients with refractory seizures and conflicting
clinical and MRI data or multifocal disease.114,121,122 Ictal
SPECT, where tracer injection is performed during a
176 SECTION I TECHNIQUES
seizure may demonstrate focal hyperperfusion corre-
sponding to the ictal onset zone. This sensitivity of this
technique is comparable to FDG-PET (50–80%) for lo-
calization of the ictal onset zone.121 Interictal SPECT,
which may demonstrate focal hypoperfusion, is much
less sensitive.122
The yield of ictal SPECT is optimal when the tracer
injection occurs within 45 seconds of seizure onset. Late
injections often lead to false positive or negative results
in children due to rapid seizure spread. Therefore, ic-
tal SPECT requires a monitored, inpatient setting with
trained staff and available tracer. Ictal injection failure is
minimized when patients are monitored in a dedicated
video EEG monitoring unit.114,121 Ictal injection is more
technically challenging in children because of the high
incidence of extratemporal seizures, short seizure dura-
tion, and frequent absence of an aura or warning signs
of an impending seizure.106 In addition, interictal injec-
tions may correspond to early or subclinical ictal activity
in 5% of patients.123
Combining interictal and ictal SPECT, such as by
subtraction ictal SPECT coregistered to MRI (SISCOM),
improves the sensitivity of ictal SPECT for localization
of the ictal onset zone.106,114,122 Among children with
cryptogenic focal epilepsy, SISCOM improved the sen-
sitivity of ictal SPECT from 80% to greater than 90% in
multiple studies.106,121 Like other noninvasive mapping
techniques, SISCOM may help plan intracranial elec-
trode placement, and in select patients may eliminate the
need for invasive monitoring.38,123 Frontal lobe epilepsy
(FLE) is often characterized by extremely rapid spread of
epileptic activity. Ictal SPECT may be especially useful
in providing preoperative guidance for intracranial elec-
trode placement in children with FLE, as rapid seizure
spread often renders false-localizing clinical and elec-
trophysiological data. Ictal SPECT has a sensitivity of
approximately 60% in detecting frontal ictal foci, which
may be higher with SISCOM.124,125
Similar to PET, NPI-SPECT has been used in in-
fants with West syndrome to monitor the effectiveness
of medical therapy, and normalization of multifocal hy-
perperfusion abnormalities correlates with neurological
outcome.111 This is concordant with PET data suggesting
perfusion abnormalities before treatment primarily rep-
resent transient phenomena rather than foci structural
lesions.109 A minority of patients with West syndrome
may have a single focus of hyperperfusion demonstrated
by ECD-SPECT or PET studies.105 Surgical resection of
this focus abolishes seizure activity in many patients.161
Additional Clinical Applications
Moyamoya disease is an inflammatory vasculopathy in
children characterized by progressive occlusion of the
carotid systems, and the development of a fine network
of small collateral vessels along the base of the brain.
Patients often develop focal neurological deficits and
developmental delay secondary to cerebral hypoper-
fusion and infarction. This is most commonly treated
by revascularization via indirect surgical bypass (e.g.,
pial synangiosis, encephaloduroarteriosynangiosis). Dy-
namic studies quantifying cerebrovascular reserve with
HMPAO-SPECT before and after acetazolamide stress
may predict ischemia, and patients with decreased
reserve by SPECT benefit from surgical revascu-
larization.116,162 In addition, dynamic SPECT after
revascularization predicts clinical outcome, and postop-
erative surveillance permits early intervention before the
development of neurological symptoms among patients
with persistently diminished cerebrovascular reserve.116
SPECT has been used to characterize cortical plas-
ticity and functional recovery among children after TBI.
Higher perfusion after injury correlates with improved
language and cognitive outcome 3 years later.118 Corti-
cal regions that subserve language normally demonstrate
late decreases in regional perfusion, corresponding to
late maturation of complex associative function.118,163
Significant increases in overall cerebral perfusion among
children with good language outcome following TBI
may reflect delayed but preserved functional maturation.
Finally, SPECT may help monitor treatment re-
sponse among children with attention deficit hyperac-
tivity disorder (ADHD).117 Children with ADHD have
regional hyperperfusion in the prefrontal and temporal
cortex on SPECT. Methylphenidate treatment is associ-
ated with lasting improvement in perfusion in the frontal
and temporal cortex among responders.117
䉴 INVASIVE TECHNIQUES
OVERVIEW
Direct ECS remains the gold standard for mapping elo-
quent cortex.2,10,22,164 It is performed intraoperatively
with a hand-held stimulator (requiring an awake patient
in the case of language mapping), or extraoperatively
across implanted subdural electrodes (Fig. 13–3). ECS
identifies discrete regions essential for a specific task,
which if resected, are likely to produce permanent neu-
rological deficits. Noninvasive tests discussed in the pre-
vious section highlight regions actively recruited during
a particular task, but not necessarily essential.2,140 Wada
testing, also known as the intracarotid Amytal test, is a
means of establishing hemispheric dominance for lan-
guage and memory function by asking the patient to
perform specific tests while one hemisphere is anes-
thetized by sodium amobarbital infusion directly into the
ipsilateral internal carotid artery.16,20,21 Both techniques
are used clinically in children undergoing evaluation for
craniotomy, especially for the resection of a seizure fo-
cus or brain tumor.
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS 177

A B

Figure 13–3. Photographs depicting intraoperative stimulation mapping. (A)

Hand-held bipolar stimulator applied to exposed frontal cortex to identify
sensorimotor function during craniotomy for epilepsy in a child under general
anesthesia. (B) A four-contact strip electrode (Adtech, Inc., Racine, WI) laid on
exposed posterior frontal cortex for identification of sensorimotor cortex by
stimulation across the strip electrodes prior to cortical resection.

WADA TESTING epilepsy or brain tumors, where functional reorganiza-

The Wada test can determine hemispheric dominance
for language and memory, with a sensitivity greater than
90% in children more than the age of 10 years.16 It
requires invasive cerebral angiography, with a compli-
cation rate of approximately 3% (major complications
include groin hematoma, vascular injury, and stroke).
Wada testing is safe in children.16,20,21,126,127 However,
an alert and cooperative patient is required. In chil-
dren younger than 10 years, the sensitivity is signifi-
cantly diminished (46–86%), although successful Wada
testing for language dominance has been reported in
children as young as 3-years-old.16,20,21,126 Patient coach-
ing before the procedure and propofol anesthesia dur-
ing groin puncture and initial angiography can improve
cooperation with functional testing.126 There is a very
low false-positive rate, and successful determination of
hemispheric dominance in children correlates well with
ECS.20
The Wada procedure cannot localize eloquent func-
tions within the hemisphere or define their anatomic
relationship to pathology.89,92 This is important in chil-
dren who often have functional reorganization due to
chronic seizures, low-grade neoplasms, or congenital
lesions.12,41,89,128 Most pediatric Wada studies report a
high rate of right hemisphere dominance, or signif-
icant bilateral speech representation.16,20,21 This sup-
ports fMRI and MEG studies in children with chronic
tion is common.12,24 However, the external validity of
published data is limited by small sample size and vari-
able criteria for establishing hemispheric dominance or
“successful” Wada testing.12,16,20,21,24,41 Wada testing of-
ten assists in predicting prognosis and counseling pa-
tients and families regarding the risks to memory and
cognitive function of proposed epilepsy surgery.129
INTRAOPERATIVE CORTICAL
STIMULATION
Intraoperative cortical and subcortical stimulation to map
motor cortex is performed routinely in the anesthetized
pediatric patient to guide the resection of lesions near
sensorimotor cortex.2,7−9,131 In addition, bipolar stimu-
lation can map motor nuclei on the floor of the fourth
ventricle,132 which may enhance the safety of tumor re-
section in the dorsal brainstem.
The most common method of direct electrocorti-
cal and subcortical stimulation (ECS) employs a bipo-
lar electrode with 5 mm between contacts, delivering a
train of biphasic square pulses at 50–60 Hz with a single
pulse duration of 1 millisecond. When strip electrodes
are used, contacts are typically 1 cm apart (Fig. 13–3).
Current is increased in a stepwise fashion from 2 to 16
mA until motor function is detected via electromyogra-
phy or direct visual observation of muscular movements.
178 SECTION I TECHNIQUES
Lower stimulation currents are used to map descending
subcortical motor pathways.8,19,132 Using this method,
current spread is less than 3 mm, allowing precise def-
inition of functional regions.132 While motor mapping
under general anesthesia is reliable, stimulation map-
ping of sensorimotor cortex requires higher stimulation
currents (4–16 mA); this technique is more sensitive in
the awake patient,133 where much lower stimulation cur-
rents are usually sufficient.132
A limiting factor of ECS is seizures, which occur in
as many as 20% of patients undergoing this procedure.132
Anticonvulsants are not fully protective. Seizures are
usually stopped by irrigation of the cortical surface with
cold lactated ringer’s solution.132 Short-acting GABA ag-
onists may also be effective, but additional mapping may
often need to be deferred.8,19,132 An alternative to bipo-
lar stimulation is multipulse stimulation, which may have
several advantages. A lower stimulation frequency of
2 Hz is used to deliver a short, discrete train of stim-
uli (5–7 pulses of 1 millisecond each), rather than con-
tinuous stimulation. This procedure has a lower risk of
seizures and can continuously monitor descending mo-
tor pathways during resection.132
Similar to Wada testing and fMRI, ECS of both senso-
rimotor and language function is less reliable in children
less than the age of 10 years.16,134 In children younger
than 5 years, the cortex is less excitable. Because of this,
motor mapping via direct cortical stimulation is less sen-
sitive in young children compared to adults, and suc-
cessful mapping may not be possible.8,16,19,132 Children
younger than 1 year typically require very high current
thresholds for functional activation, significantly increas-
ing the risk of seizures.132,134 If ECS is unsuccessful, the
central sulcus may be identified via phase reversal of so-
matosensory evoked potentials, which has a sensitivity
of greater than 90%.8,132
EXTRAOPERATIVE CORTICAL
STIMULATION
Extraoperative functional mapping is performed at the
bedside by stimulation across implanted subdural elec-
trode arrays (2.5 mm platinum electrodes 5–10 mm apart
mounted on silastic and implanted via craniotomy), and
is a well-established alternative to intraoperative corti-
cal stimulation. This technique is used in children who
are candidates for seizure focus or tumor resection, and
allows prolonged extraoperative iVEEG monitoring.2,140
Functional mapping can demonstrate the relationship
between the ictal onset zone and eloquent cortex. In
young children or patients with developmental delay,
awake craniotomy for language mapping may not be
feasible. The implantation of subdural electrodes allows
sensorimotor and language mapping in the awake pa-
tient under more comfortable conditions outside of the
operating room. This technique is safe and well toler-
ated in the pediatric population, and successful extra-
operative language and motor mapping have been re-
ported in children as young as 4 years and 18 months,
respectively.2,17,18,22,134,141,142 Stimulation is most often
performed with a continuous train of stimulation at
50 Hz, single pulse duration 0.3 milliseconds, for 3–5
seconds (Fig. 13–4).17
Studies in children indicate iVEEG has a sensitivity
of approximately 90%, which may be lower in extratem-
poral or cryptogenic epilepsy.73,75,143,144 Specific indica-
tions for invasive monitoring in children vary consid-
erably between epilepsy centers. Generally, candidates
have discordant noninvasive data, multifocal pathology,
a defined ictal onset zone in near eloquent regions, or
a structural lesion with chronic seizures, where the ic-
tal onset zone is often localized to cortex around the
lesion.145 Quantitative spectral analysis of peri-ictal EEG
changes may improve the sensitivity of this technique in
children.135
Extraoperative ECS of sensorimotor and language
function is less sensitive in children younger than 10
years, compared to older children and adults.8,16,17,19,134
Studies show an inverse relationship between age and
current thresholds required for motor stimulation, a find-
ing magnified in children with disorders of neuronal
migration.132 One possible explanation is a higher per-
centage of small, unmyelinated fibers, requiring an in-
creased charge density to elicit a response to stimu-
lation. The charge density is inversely proportional to
the area being stimulated, determined by the distance
between electrodes with bipolar stimulation.16,17 Thus,
placing the contacts closer together in implanted subdu-
ral electrode arrays increases the charge density without
increasing the applied current.16 We use 64-contact grids
with 5 mm between electrodes (Adtech, Inc., Racine, WI)
in children. In addition, stimulation protocols that vary
both current intensity and pulse duration may improve
the sensitivity of extraoperative functional mapping in
young children.17 Cortical plasticity and reorganization
in children with chronic seizures, a congenital malfor-
mation, or a brain tumor may lead to negative map-
pings, because functional centers may not be covered by
electrodes.16,19 Preoperative noninvasive mapping with
MEG, fMRI, or PET may overcome this limitation.
Extraoperative functional mapping carries the risks
inherent to a second operation for electrode implanta-
tion and prolonged invasive monitoring.126 In addition
to the general risks of additional surgery and anesthesia,
studies of grid implantations in children report a com-
plication rate of 10–15%.142,146−150 The most common
complications include CSF leak and positive CSF culture
in the absence of clinically evident meningitis.22,142,149
Other complications include transient neurological
deficit, cerebral edema, epidural or subdural hematoma,
and stroke. However, most complications do not cause
morbidity or require treatment.142,147 Complications are
less frequent in children compared to adults, and
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS 179

Figure 13–4. Ictal focus map and functional map generated from extraoperative
monitoring and stimulation across an implanted subdural grid and intraparenchymal
depth electrodes. The maps clearly delineate the anatomical relationship of a left
temporal tumor to the ictal onset zone, regions of rapid seizure spread, and interictal
spikes (A) as well as functional language cortex (B). (AT: anterior temporal; MT: mesial
temporal).

complication rates decrease with increasing surgical
experience.146,148−150 Factors correlated with complica-
tions include a large number of electrodes, a long du-
ration of extraoperative monitoring, and left-sided or
bilateral electrode placement.146 Low-grade fevers or
aseptic meningitis may occur more frequently.150 Three-
stage procedures with two extraoperative monitoring pe-
riods does not appear to significantly increase the com-
plication rate in children.22
Dexamethasone is effective at reducing cerebral
edema in children with implanted subdural grid elec-
trode arrays. However, it also may increase the risk of
infection and potentially decrease the seizure frequency,
leading to longer extraoperative monitoring periods to
capture sufficient data to localize the ictal focus.151
Pathological studies of cortex underlying subdural ar-
rays have revealed focal, transient inflammation in the
vast majority of patients, but the severity of this reac-
tion does not correlate with the incidence of infection
or long-term surgical outcome.152
To minimize the risks from subdural electrode
placement and chronic invasive monitoring, we employ
meticulous hemostasis at each operative stage, subdu-
ral and epidural surveillance cultures at each operative
stage, autograft duraplasty using pericranium or tempo-
ralis fascia, watertight dural closure around the electrode
cables, tunneling of the electrode cables through a sepa-
rate stab incision in the scalp, purse-string sutures placed
around each cable at the skin, continuous subgaleal
drainage for the duration of each monitoring period, and
broad-spectrum antibiotics for 72 hours perioperatively
for all procedures after the initial implantation. The bone
180 SECTION I TECHNIQUES
flap is replaced in-situ during monitoring, and reaffixed
with titanium miniplates after the final operative stage.144
AWAKE CRANIOTOMY IN CHILDREN
Intraoperative awake language mapping in children
presents many challenges.13,14,130,136 Although possible
with an experienced surgical team in a select group
of cooperative children,130 it lacks safety and reliabil-
ity in children less than the age of 12 years.8,13,14 Prob-
lems include pain, anxiety, nausea, and seizures.137 In
adults, the complication rate is approximately 16.5%,
similar to that for staged resection with extraoperative
mapping.138 The youngest patient reported to undergo
awake craniotomy with successful language mapping
was 9 years old.130 Recent advancements include the
use of dexmedetomidine (␣2 -adrenergic receptor ago-
nist) during the awake portion of the procedure to re-
duce anxiety without excessive sedation, as well as use
of the laryngeal mask airway.8,13,14,136 Successful awake
intraoperative language mapping has been performed in
children as young as 12 years with dexmedetomidine.13
ELECTROCORTICOGRAPHY
While iVEEG via implanted intracranial electrode arrays
can capture multiple ictal events, intraoperative ictal fo-
cus mapping by ECoG is limited to interictal data un-
der general anesthesia, which significantly diminishes
spike frequency.135 Technically, this procedure is sim-
ilar in adults and children. Electrodes are placed over
the area of interest and electrical activity is recorded. It is
generally reliable if an interictal spike frequency reaches
at least 1 spike per minute.135 This technique is widely
applied in children with brain tumors and refractory
epilepsy, where the ictal onset zone is frequently local-
ized to cortex adjacent to the tumor,19,139 and the resec-
tion of perilesional cortex with abnormal interictal spike
activity correlates with long-term seizure freedom.139
䉴 CONCLUSION
Mapping of cortical function and dysfunction in children
with cerebral pathology remains a challenge. The advent
and evolution of a variety of noninvasive techniques
including fMRI, MEG, PET, SPECT, and DWI or DTI
provide attractive alternatives to the traditional invasive
methods of direct cortical stimulation (invasive monitor-
ing with intracranial electrodes and the Wada test). How-
ever, despite promising data, children provide unique
challenges that often limit the sensitivity of noninva-
sive tests, including patient cooperation and the require-
ment for sedation, and differences in CBF regulation and
cortical maturation, especially in very young children.
Conversely, invasive mapping techniques are also chal-
lenging to apply in children, due to higher thresholds
for cortical activation with stimulation and sustained co-
operation required for the Wada test. Despite these chal-
lenges, the thoughtful combination of noninvasive and
invasive techniques in an experienced center is often
highly effective and useful in clinical mapping of brain
function in children.
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localization of temporal lobe language sites in patients
with gliomas. Neurosurg 1994;34:567.
156. Krings T, Reinges MH, Erberich S, et al. Functional MRI
for presurgical planning: problems, artefacts, and solution
strategies. J Neurol Neurosurg Psychiatry 2001;70:749.
157. Lee CC, Ward HA, Sharbrough FW, et al. Assessment of
functional MR imaging in neurosurgical planning. AJNR
Am J Neuroradiol 1999;20:1511.
158. Ruge MI, Victor J, Hosain S, et al. Concordance be-
tween functional magnetic resonance imaging and intra-
operative language mapping. Stereotact Funct Neurosurg
1999;72:95.
 CHAPTER 13 PEDIATRIC BRAIN MAPPING: SPECIAL CONSIDERATIONS
159. Ment LR, Bada HS, Barnes P, et al. Practice parame-
ter: neuroimaging of the neonate: report of the Quality
Standards Subcommittee of the American Academy of
Neurology and the Practice Committee of the Child Neu-
rology Society. Neurology 2002;58:1726.
160. Bonekamp D, Nagae LM, Degaonkar M, et al. Diffusion
tensor imaging in children and adolescents: reproducibil-
ity, hemispheric, and age-related differences. NeuroImage
2007;34:733.
161. Mori K, Toda Y, Hashimoto T, et al. Patients with West
syndrome whose ictal SPECT showed focal cortical hy-
perperfusion. Brain Dev 2007;29:202.
185
162. Touho H, Karasawa J, Ohnishi H. Preoperative and
postoperative evaluation of cerebral perfusion and va-
sodilatory capacity with 99mTc-HMPAO SPECT and ac-
etazolamide in childhood Moya-moya disease. Stroke
1996;27:282.
163. Devous MD, Altuna D, Furl N, et al. Maturation of speech
and language functional neuroanatomy in pediatric nor-
mal controls. J Speech Lang Hear Res 2006;49:856.
164. Najm IM, Bingaman WE, Luders HO. The use of subdu-
ral grids in the management of focal malformations due
to abnormal cortical development. Neurosurg Clin N Am
2002;13:87.
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SECTION II

SYSTEMS

187
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 Chapter 14
Mapping of the Sensorimotor Cortex
Roukoz Chamoun1 , Krishna Satyan1 , and Youssef G. Comair 2
1
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
2
Department of Neurosurgery, American University of Beirut, Beirut, Lebanon
䉴 INTRODUCTION
Techniques for mapping motor and sensory areas in
the human brain have progressively and dramatically
evolved in recent years, benefitting from technological
advances in structural and functional brain imaging and
improved understanding of the anatomical and neuro-
physiological properties of the brain. Each technique has
its own advantages and limitations, and an understand-
ing of the basic principles of these techniques is essential
for proper implementation and correct interpretation.
While in the past accurate identification of mo-
tor and sensory areas required invasive methods, ac-
curate noninvasive localization of sensorimotor cortex
is now routinely available. The location of these areas
in individuals can be defined accurately and noninva-
sive both by observing specific imaging landmarks with
structural imaging and by observing regional cortical ac-
tivation with functional imaging. This ability has changed
the way clinicians approach the treatment of pathology
within or near functionally critical motor areas; localiza-
tion of Rolandic cortex can be defined well in advance of
a neurosurgical intervention, which permits better treat-
ment planning and better patient counseling regarding
the risks of a proposed intervention. Furthermore, im-
ages from preoperatively obtained maps can be inte-
grated into image–guidance systems used for navigation
during surgery to help guide the procedure as it is per-
formed.
In spite of dramatic advances in noninvasive map-
ping of motor and sensory areas, invasive methods for
mapping remain important in optimizing clinical care.
Intraoperative mapping of sensiromotor cortex with the
brain exposed is routinely used as an adjunct in the re-
section of brain tumors and other structural brain lesions
that lie within or near the primary sensiromotor cortex.
This allows surgeons to perform a maximal safe resec-
tion without damaging nearby critical motor and sensory
areas defined by mapping. Invasive mapping of sensiro-
motor cortex is also commonly used in epilepsy surgery,
where the epileptic zone to be resected is often defined
by a physiological signature rather than an anatomically
identifiable structural lesion. In epilepsy surgery cases,
189
mapping is typically used to maximize the extent of re-
section of the epileptogenic zone, while at the same
time minimizing damage to critical areas for somatomo-
tor and somatosensory function. In epilepsy cases where
patients undergo invasive monitoring with semichroni-
cally implanted subdural electrodes in an epilepsy mon-
itoring unit, invasive mapping may also be carried out
extraoperatively using the implanted electrodes to de-
fine the location of sensiromotor cortex via recordings
or with direct electrical stimulation, with the same basic
methods employed for intraoperative mapping. A rela-
tively newer clinical application for mapping of sensiro-
motor cortex is in guiding the insertion of an epidural
implant of electrodes for chronic motor cortex stimula-
tion for the management of intractable pain. In these
cases, the sensiromotor cortex is localized to facilitate
accurate placement of an electrode array.
䉴 HISTORICAL PERSPECTIVES
Despite early observations that unilateral brain injury
can lead to paralysis on the opposite side of the body,
for many years the prevailing theory was that the brain
functioned as a single unit without discrete localization
of specific functions. Yet, as early as the first part of
the nineteenth century, clinical observations of brain
injury and stroke patients intrigued neurologists and
advanced the theory that specific functions, most no-
tably somatomotor and somatosensory are localized to
specific brain areas.1 The early period of the nine-
teenth century also witnessed the appearance of medical
applications of electricity to activating and identifying
somatomotor cortex. In 1802, Aldini reported strong
muscle contractions when applying electrical stimulation
to the dura and deep substance of the brain of an ox.2
In 1829, Luigi Rolando described the central vertical fis-
sure and central area, composed of the precentral and
postcentral gyri, that still carries his name: the Rolandic
cortex. 3 The acceptance of the modern notion of local-
ized motor function in the brain was further buttressed
by John Hughlings Jackson, who observed the progres-
sive spread of motor seizures across the hemibody and
190 SECTION II SYSTEMS
theorized that the convolutions of the brain contain or-
derly neural representations of movements.4 In 1870,
Fritsch and Hitzig conducted the first experimentally
controlled direct stimulation of mammalian cerebral cor-
tex, and for the first time, there was an experimen-
tal proof of a causal connection between activation of
Rolandic cortex and muscular contractions.5 The first re-
ported case of electric stimulation of the cortex of a hu-
man patient was in 1874.6 Robert Bartholow was treat-
ing a patient with an “epithelioma of the scalp” that had
eroded the skull, and when he applied electric stimula-
tion to the patient’s exposed cortex, a motor response
occurred on the opposite side of the body.
The elegant experimental cortical stimulation stud-
ies of Ferrier in a number of animal species demon-
strated more clearly than ever before that motor
responses were elicited by stimulation of the Rolandic
cortex. He also found that electric stimulation at specific
anatomic locations gives rise to predictable movements
of specific different parts of the body.7 At this time, a
general consensus evolved that the primary motor cor-
tex is located along the central sulcus in the both anterior
and posterior banks. In 1901, Grunbaum and Sherring-
ton used finer stimulation techniques and found that the
primary motor area is largely restricted to the gyrus im-
mediately anterior to the central sulcus.8
William Keen was the first American neurosurgeon
to perform cortical stimulation in a human patient during
craniotomy.9 Later, Charles Frazier of Philadelphia pub-
lished a map of human brain function that was partly
based on experience with cortical stimulation during
craniotomies.10 Fedor Krause, working in Berlin, per-
formed stimulation of the central area to map function
and treat epilepsy. He described one of the first detailed
maps of the motor cortex in humans.11 Otfrid Foerster,
who began his medical career as a neurologist in Ger-
many, started to treat patients surgically during World
War I, and then became a leading European neurosur-
geon. He performed surgeries under local anesthesia and
used cortical stimulation to localize function. He pro-
duced a detailed map of the brain from the results of
his stimulation work that included sensory responses as
well as functions outside the central area.12 Wilder Pen-
field spent 6 months with Foerster, and then moved to
Montreal and established the Montreal Neurological In-
stitute. Thereafter, the extensive work on human cor-
tical stimulation by Penfield and Theodore Rasmussen
led to further refinement of our understanding of the
sensorimotor cortex, including the classic description of
the somatotopic representation of the motor and sensory
representations along the Rolandic cortex as an “upside-
down man.”13 The more recent emergence of nonin-
vasive methods such as positron emission tomography
(PET), functional magnetic resonance imaging (fMRI),
and magnetoencephalography (MEG) has led to an ex-
plosion in mapping of human motor and sensory areas,
particularly in the clinical setting, with validation by clas-
sical invasive methods.
Further experience in cortical stimulation and
surgery in the central area in patients, as well as analysis
of motor and sensory responses in noninvasive exper-
iments in normal human subjects and invasive studies
in nonhuman primates, has revealed that sensorimotor
cortex is more complex in its organization and cannot
be simply reduced to the Penfield homunculus. Many
questions about this organization remained unanswered,
and our understanding of this region of the brain con-
tinues to evolve as a number of authors raise questions
regarding interindividual variability, mosaicism, redun-
dant representations.14
䉴 ANATOMY
The central sulcus is a deep sulcus extending through-
out the convexity and is the key to anatomically iden-
tifying the primary sensorimotor cortex. It begins to
develop embryologically at about 26-week gestation,
about the same time as the cingulate and superior tem-
poral sulcus. Unlike the development of the central sul-
cus in other primates, the human Rolandic fissure does
not appear to arise from two separate anlages that unite
to form a single sulcus. This may explain why it is in-
terrupted in only 1% of human brains.15,16 By the 28th
week of gestation, the central sulcus covers the entire
convexity as a relatively straight line.
As per Symington and Crymble (1913)17 , the central
sulcus has three genu. The superior and inferior genu
are convex anteriorly, while the middle genu is an inter-
vening concave bend. Broca described three annectant
gyri connecting the pre- and postcentral gyri: the “pli de
passage frontoparietal superieur” at the interhemispheric
fissure at the level of the paracentral lobule, the “pli
de passage frontoparietal inferieur” separating the cen-
tral sulcus from the sylvian fissure at the level of the
subcentral gyrus, and the “pli de passage moyen (PPM)”
that is mostly hidden within the central sulcus and found
at the level of the superior frontal sulcus.18
The precentral gyrus, or the primary motor cortex,
consists of four segments:
(1) The inferior segment is anteriorly convex, and
commonly communicates with the postcentral
gyrus via the pli de passage frontoparietal, giv-
ing rise to the central operculum.
(2) The middle segment of the precentral gyrus is
anteriorly concave, but usually does not have a
well-defined anterior border because it blends
with the middle frontal gyrus. The middle seg-
ment is characterized by the PPM, an annectant
gyral structure deep within the central sulcus.
 CHAPTER 14
The PPM elevates the floor of the central sul-
cus and forms a characteristic omega sign on MRI
bulging posteriorly from the precentral gyrus.19,20
Recently, Boling et al.21 demonstrated that the
whole-hand motor and sensory cortical regions
are consistently localized to the PPM.
(3) Following the somewhat sigmoid pattern of the
central region, the superior segment of the pre-
central gyrus is convex anteriorly. Near its junc-
tion with the middle segment, the superior seg-
ment is sharply distinct from the premotor area,
but as it reaches the interhemispheric fissure,
these boundaries blur. Consequently, the supe-
rior segment of the motor cortex commonly com-
municates with the supplementary motor area
(SMA).
(4) The paracentral segment of the precentral gyrus
is the fourth and final segment. This segment de-
fines the anterior aspect of the paracentral lobule,
and has no sharp border anteriorly. The paracen-
tral segment blends with the postcentral gyrus
at its inferomedial aspect, providing a significant
communication with the primary sensory area.
The central sulcus provides a posterior bound-
ary for a short distance of the paracentral seg-
ment, until the aforementioned communication
is encountered.
As with the precentral gyrus, the postcentral gyrus
can also be divided into four segments, which closely
parallel the course of the precentral gyrus’ segments. Of
note, the inferior, or opercular, region of the postcentral
gyrus is wider and thicker than in the precentral gyrus,
while the middle and superior segments are thinner in
the primary sensory cortex compared with the Rolandic
motor cortex.
The premotor cortex is a transitional area located
between the polar aspect of the frontal lobe and the
primary motor cortex. The boundaries of the premotor
cortex in humans are nebulous and highly variable. An
imaginary line joining the anterior border of the SMA
with the cortical eye fields is the supposed anterior bor-
der of the premotor cortex, while posteriorly it extends
to the depths of the precentral sulcus.
Anterior to the Rolandic cortex and on the medial
aspect of the brain, there are additional somatomotor ar-
eas that have been extensively studied and are of clinical
importance. These include the SMA, immediately ante-
rior to medial Rolandic cortex, and the pre-SMA, which
lies immediately anterior to the SMA. Penfield and Welch
(1951) described the SMA as located in the mesial aspect
of the superior frontal gyrus, superior to the cingulate
sulcus and anterior to the primary motor cortex.22 The
anterior boundary of the SMA has been described as a
line perpendicular to the AC-PC line passing by the an-
MAPPING OF THE SENSORIMOTOR CORTEX 191
terior most extent of the genu of the corpus callosum
(Talairach and Bancaud, 1966).23 However, no studies
have accounted for the variation in the gyral convo-
lutions of the superior frontal gyrus, and the anterior
boundary of the SMA remains ill defined.
Unlike the primary motor and sensory cortices, the
SMA has significant communication with its contralat-
eral counterpart via the corpus callosum. A large portion
of the corpus callosum is occupied by these crossing
SMA fibers, explaining the rapid spread of a stimulus
from these regions and difficulties in determining lat-
erality. The SMA provides direct contributions to the
corticospinal tract, which end in the gray matter of the
anterior horn of the spinal cord at different levels. These
direct projections are mostly involved in proximal limb
control.
䉴 STRUCTURAL LANDMARKS FOR
LOCALIZATION OF
SENSORIMOTOR CORTEX
Given the functional importance of the central region to
motor and sensory function, localization of the central
sulcus is a key component to many surgeries. An indirect
approach to its identification relies on skull landmarks,
and, subsequently, on brain reference coordinates. Two
widely used indirect methods are the Talairach method,
which is based on the AC-PC reference plane24,25 , and
the Olivier method, which is based on the callosal refer-
ence plane.26,27 Both provide a crude regional location
for the central sulcus, but are insufficiently precise for
its true identification.
With the advent of modern imaging techniques,
more sophisticated and direct methods are now avail-
able for the localization of the central sulcus with nonin-
vasive imaging. Using well-validated anatomofunctional
correlations, the clinician can often quickly determine
whether a certain lesion is in close proximity to eloquent
areas or not and decide about the need for additional
functional imaging and/or intraoperative mapping. Fur-
thermore, this localization with imaging can be used in
the operating room by correlating the anatomy of the
exposed brain to anatomy on preoperative images us-
ing standard surgical navigation systems.
The direct methods for identifying Rolandic cortex
on imaging studies rely on landmarks that are visible
on axial and sagittal CT and MR scans.28 These land-
marks proved to be reliable and usually easily identified
on structural brain imaging. Yousri et al. showed that
the motor hand area is represented on the cortex in a
specific segment of the precentral gyrus that has a char-
acteristic shape on brain imaging. It is knob-like in the
form of an inverted omega in the axial plane (Fig. 14–1)
192 SECTION II SYSTEMS

Figure 14–1. Axial T1-weighted MRI of brain with contrast. On the left side, the
inverted omega shape can be clearly recognized that allows the identification of the
central sulcus and the motor hand area. On the right hemisphere, there is an
enhancing lesion occupying the motor hand area on that side.

and appears as a posteriorly directed hook in the
sagittal plane.20 Berger at al. retrospectively correlated
brain maps, derived from intraoperative mapping in pa-
tients with brain tumors, with preoperative MR images
in the axial, sagittal, and coronal planes. They found
the Rolandic cortex was accurately identified on T2-
weighted axial images at the most rostral vertex by look-
ing for the central sulcus with its distinctive transverse
orientation. The central sulcus was more difficult to iden-
tify on sagittal imaging, but the postcentral sulcus, imme-
diately posterior to the postcentral gyrus, can readily be
identified as the posterior–superior terminal extension
of cingulate sulcus, also known as the marginal ramus
of the cingulate sulcus.29
While MRI landmarks for identifying the central
sulcus are readily correlated with the exposed brain
at surgery through standard neurosurgical navigation
systems, it can also be useful to attempt to identify
the Rolandic cortex by direct visual inspection of the
anatomy of the exposed brain. However, identification
of eloquent cortical areas based on anatomic landmarks
has been found to be unreliable in 16% of healthy
patients, and even more unreliable in patients with
pathology—35% due to distortions in anatomy and func-
tional organization.30 Still, simple inspection of the cere-
bral convolutions during surgery offers valuable clues
to the location of the sensiromotor area. Boling and
Olivier19 found that the sensory hand area corresponds
to the postcentral component of the “PPM.” The “PPM”
is a prominent gyral fold elevating the floor of the cen-
tral sulcus. It connects the pre- and postcentral gyri at
the level of the middle bend of the central sulcus. The
precentral component of this structure corresponds to
the motor hand, while the postcentral part corresponds
to the sensory hand area.19 Similarly, the tongue sensory
area was described as a triangular-shaped cortical region
of the postcentral gyrus sitting directly above the sylvian
fissure31 , and the sensory area of the face and lips is in
the narrow region of the postcentral gyrus located at the
apex of the triangular tongue area.32
Overall, identification of central sulcus by using
these anatomic landmarks on imaging studies is quite
reliable in normal human subjects, but is much less accu-
rate or consistent in the clinical setting, where anatomy
may be deformed by regional pathology or where devel-
opment anomalies may have led an atypical functional
organization. Identification of Rolandic cortex based
on surface anatomy of the exposed brain is even less
reliable.
䉴 DIRECT CORTICAL STIMULATION
Despite advances in functional neuroimaging, direct cor-
tical electrical stimulation, very similar to that carried
out by Penfield, may still be considered as the “gold
standard” technique for mapping somatomotor and so-
matosensory area. It entails the direct application of a
low-level electrical current to the cortex in order to
activate local cortical circuits. This results in the focal
 CHAPTER 14
muscular contraction when current is applied to pri-
mary motor cortex and the perception of a localized
somatosensory percept when it is applied to primary
sensory cortex. This cortical stimulation can be applied
intraoperatively during craniotomy, or extraoperatively
with a previously implanted subdural electrode array.
The technique can also be applied intraoperatively to the
subcortical white matter tracts that project from Rolandic
cortex into the internal capsule to identify critical motor
and sensory pathways.
The application of the electric stimulus can be done
through a monopolar or a bipolar method. In bipolar
stimulation, there is depolarization of the membrane at
the cathode (the negative electrode) and hyperpolariza-
tion at the level of the anode (the positive electrode). If
the membrane potential reaches a certain threshold, then
an action potential is generated.33 In the case of bipo-
lar stimulation, only the structures located between the
two electrodes are stimulated; many surgeons and neu-
rophysiologists prefer bipolar stimulation because it may
offer slightly lesser risk of diffusion of current, allow-
ing greater precision.34 In the case of monopolar stim-
ulation, there is one active electrode and one reference
electrode that is located at a distance, the current in this
case is distributed circumferentially around the active
electrode.
The intensity of the depolarization resulting from
cortical stimulation depends on the parameters of stim-
ulation and the characteristics of the membrane.33
Consequently, the result of stimulation depends on the
electrode design (monopolar vs. bipolar), stimulation
parameters (intensity, duration, etc.), and tissue charac-
teristics (such as impedance). The impedance and ex-
citability of the brain can be significantly affected by
medications (such as general anesthesia) and by the
presence of a pathological process (such as a tumor or
gliosis). The impedance was also found to be higher
in white matter compared with gray matter.35 Moreover,
the electric stimulation of the brain can induce seizures;
this is why many authors recommend using intraop-
erative electrocorticographic recording for detection of
“after-discharge potentials.”36 In these cases, the use of
ice cold solutions was found to be effective in aborting
seizures.37
The value of intraoperative electrocorticography ex-
tends beyond simply minimizing the risk of an intraop-
erative seizure. It also allows for confirmation that an ad-
equate level of electrical stimulation was delivered. This
is particularly important in cases where a functional re-
sponse to electrical stimulation is not observed, which
may often occur when a small exposure is employed and
an obviously functional response is not exposed (min-
imal exposure, or minimap craniotomy).38 If intraoper-
ative electrocorticography demonstrates that the current
used meets or exceeds the threshold for generating after-
discharge potentials, one can be more confident that
MAPPING OF THE SENSORIMOTOR CORTEX 193
the absence of a functional response is not simply a re-
flection of inadequate electrical stimulation, but instead
more likely reflects the absence of an elicitable function
in the region of cortex that was stimulated.
The interpretation of the cortical stimulation criti-
cally relies on the observation and documentation of the
patient’s response. Mapping of the motor cortex can be
done in awake as well as in anesthetized patients. In ei-
ther case, an examiner observes and documents patient’s
movements as a result of stimulation. Clonic movements
typically result from stimulation of the primary motor
area, while tonic or more complex movements can re-
sult from stimulation of the premotor cortex. Movements
can also sometimes be subtle or at a distant site and go
unnoticed, particularly when low current levels are em-
ployed. For this reason, continuous electromyographic
monitoring was proposed as an adjunct to detect motor
responses.39 Mapping of the sensory cortex with direct
electrical stimulation can only be done in awake pa-
tients, as it is necessary to have patient cooperation in
reporting subject percepts of somatosensory activation.
It is important to explain the intraoperative procedure to
the patient before surgery and make sure that the patient
understands the concept and purpose of the mapping
and is comfortable with the unfamiliar environment and
sensations (Fig. 14–2).
It has long been recognized that stimulations of the
SMA evoke more complex responses than those result-
ing from primary sensorimotor cortex stimulation. Re-
sults are classically reported as complex motor synergies,
sensory responses, autonomic changes, vocalization,
and speech arrest.22,23,40,41 Using subdural electrodes
Figure 14–2. Exposed brain surface (right
hemisphere) during awake craniotomy. After direct
cortical stimulation, the areas of the primary
sensorimotor cortex were identified. 1, sensory face;
2, motor face; 3, sensory hand; 4, motor hand; 5,
motor leg.
194 SECTION II SYSTEMS
in patients evaluated for intractable epilepsy, Fried
et al.42 performed a detailed electric stimulation mapping
of the SMA with currents below the threshold of after-
discharges. They classified the motor responses in three
categories: simple (discrete movement of one joint), re-
gional (several joints confined to one extremity or re-
gion), and complex (responses involving several body
regions). Overall, 34.2% of the responses were simple,
41.9% were regional, and 23.9% were complex. While
most responses were contralateral, some of them were
ipsilateral or bilateral. Sensory responses were less fre-
quent than motor and they were of three types: (1) sensa-
tion of tingling and numbness, (2) subjective experience
of movement in the absence of actual movement activity,
and (3) subjective urge to perform a movement. In ad-
dition, stimulation of the dominant hemisphere elicited
speech-related responses (vocalization, speech arrest,
and slowing or hesitancy). The authors were able to de-
tect a somatotopic organization (from posterior to ante-
rior: lower extremity, trunk, upper extremity, face, and
most anteriorly in the dominant hemisphere: speech).
Although a clear somatotopic organization of the SMA is
a matter of controversy, the stimulation results by Fried
at al.42 appear to be consistent with a number of animal
experiments43 and clinical studies correlating the clinical
deficit with the extent of resection of the SMA.44
䉴 SOMATOSENSORY-EVOKED
POTENTIAL PHASE REVERSAL
The use of the morphology of somatosensory-evoked
potentials (SSEPs) recorded from the cortical surface to
localize the central sulcus was developed by Goldring
in the late 1970s.45,46 This was based on the principle
that when a somatosensory potential is simultaneously
recorded from both the precentral and postcentral gyri,
responses of reversed polarity are observed across the
central sulcus. Therefore, the detection of this “phase
reversal” allows the determination of the location of the
central sulcus. Practically, a somatosensory stimulus is
delivered by transcutaneously, most often by stimulat-
ing the median nerve contralateral to the tested hemi-
sphere with an electrical current. Attempts at using the
tibial and trigeminal nerve to find the phase reversal at
the leg and face representation respectively appear to be
less successful and are still not well validated.47 A strip
or grid of electrodes is placed on the cortical surface for
recording. The electrodes array is generally positioned
with its long axis in the anteroposterior direction in order
to have the long axis of the array perpendicular to the
long axis of the central sulcus. When median nerve stim-
ulation is used, the electrodes have to be placed over the
suspected hand representation of the sensorimotor cor-
tex. The localization of the central sulcus is then made
Figure 14–3. A strip of electrodes is placed on the
cortical surface for recording. The electrodes array is
positioned with its long-axis perpendicular to that of
the central sulcus.
based on the recording of a large amplitude, biphasic,
negative–positive response from the postcentral gyrus,
and a corresponding lower amplitude, mirror (positive–
negative) waveform from the precentral gyrus. The la-
tency of this initial deflection of the waveform usually
occurs between 18 and 24 ms, and reflects the N20-P20
phase reversal (at 20 ms after each cutaneous stimulus
is delivered). To obtain a clean waveform and average
out the noise, multiple trials are collected and averaged
over a few minutes.47 (Figs. 14–3 and 14–4)
The success rate of this method in defining the loca-
tion of the central sulcus is usually better than 90% (91%
in the series reported by King et al.48 and Cedzich et al.49 ,
94% for Wood et al.50 and 97% for Kombos et al.51 ). Rom-
stock et al.47 found in a large series of patients that the
somatosensory evoked potential phase reversal method
can be significantly affected by the presence of a tumor
located in or around the central area. The pathophys-
iology of this phenomenon is possibly related to local
mass effect or to desynchronization of the propagated
afferent signals along the thalamocortical pathways by
the tumor. Although the phase reversal technique is usu-
ally considered as simple, fast, safe, and reliable, it has
a number of important drawbacks. In around 10% of
the cases, the phase reversal may be questionable or
even absent. When successful, this method can allow
determination of the central sulcus at the level of the
hand area, but extrapolation has to be made to trace the
sulcus proximally and distally. It does not allow for dis-
tinct localization of the somatotopic representation of the
hemibody, as can be done with direct electrical stimula-
tion; this may be important in cases where the surgeon
is willing to sacrifice the cortical face motor representa-
tion (which is generally recovers well over time and is
 CHAPTER 14
Figure 14–4. Detection of phase reversal allowing the localization of the central
sulcus.
well tolerated by patients), but wishes to spare the hand
representation. It also does not allow for repeated online
testing of the integrity of the motor pathways, which can
also be done with repeated direct electrical stimulation.
䉴 FUNCTIONAL MRI
The last decade has witnessed remarkable advances in
functional neuroimaging allowing the noninvasive ex-
amination and localization of brain functions. Blood
Oxygenation Level Dependant (BOLD) fMRI allows
mapping based on local physiological and metabolic
consequences that accompany neuronal activities. In-
creased neuronal activity is associated with an increased
use of energy due to neuronal depolarization and ac-
tion potential generation. Consequently, an increase in
the local blood flow occurs, affecting the ratio of oxyhe-
moglobin (oxyHb) to deoxyhemoglobin (deoxyHb) in
the region of neuronal activity. BOLD fMRI imaging is
generated based on the different magnetic properties of
oxyHb and deoxyHb.52 BOLD fMRI images are based
on relative signal intensity changes related to different
cognitive states during a single session: usually a block
design is used in order to compare the brain responses
in different states. In this design, there will be alternat-
ing periods between two states: a task or a stimulus is
applied in one state, the other state serving as baseline
or control.53
MAPPING OF THE SENSORIMOTOR CORTEX 195
fMRI has a number of advantages over other map-
ping techniques. It is a safe and noninvasive technique.
It can be repeated to study more functions, or to follow
a specific function in a certain patient over time to study
the impact of the progression of disease for example.
Compared with the gold standard (direct cortical stimu-
lation), fMRI has the advantages of examining a much
wider area. While cortical stimulation is limited by the
surgical exposure, fMRI can sample the whole brain. It
can also localize function in the depth of cortical sulci
that lie below the cortical surface. Compared with other
functional imaging, such as PET, fMRI has a higher spa-
tial resolution. The typical spatial resolution for fMRI in
the clinical arena is estimated to be in the order of 2–5
mm.54 Advanced MRI techniques, including higher field
strength, can potentially provide an even better spatial
resolution. The main disadvantages of fMRI include (1)
motion-related artifact, this can result in image distor-
tion in the case of some motor tasks for example, and
(2) the technique can be affected by large blood vessels,
making the interpretation of results mostly problematic
in the case of an arteriovenous malformation or highly
vascular tumor.
Several clinical studies have been conducted in or-
der to validate the fMRI findings in mapping the sen-
sorimotor cortex against the “gold standard” technique
of direct cortical stimulation. Such a validation process
has been conducted in patients harboring a brain le-
sion in the vicinity of the central area. Typically, an fMRI
196 SECTION II SYSTEMS
is done preoperatively, and then direct cortical stimula-
tion is performed during surgery. The comparison be-
tween the results of the two mapping techniques was
thus used to validate the use of fMRI as a reliable and
accurate mapping method. Although fMRI is also widely
used in healthy volunteers, validation against mapping
is not possible in these cases for obvious reasons. Ma-
jos et al.55 in a study involving 33 patients with brain
tumors in the vicinity of the central sulcus found that
the agreement in the location of motor centers between
fMRI and cortical stimulation was 84%. The agreement
for sensory centers was 83%. In similar studies, Fandino
et al.56 , Roux et al.57 , and Lehericy et al.58 found an
agreement of 82%, 87%, and 92%, respectively. Using
3-T fMRI, Roessler et al.59 found 100% correlation with
cortical stimulation data within 1 cm. In most of these
studies, the area activated on fMRI is usually larger than
that identified by direct stimulation. And, depending on
the task used, there may be many sites of BOLD signal
well beyond the primary motor cortex. This is a reflec-
tion of the fundamental nature of BOLD fMRI for motor
mapping: it is a technique that measures activity dur-
ing a motor task, and, therefore, will reveal activity in
brain areas that are activated during a motor task, such
as prefrontal cortex, but are not directly essential or a
proximate cause of motor function.
In general, BOLD fMRI is very dependent on the
task performed during data acquisition. Mapping each
muscle group along the entire primary motor cortex, for
example, would be very difficult because it would re-
quire a large number of tasks and a very long scan time.
For this reason, only a few selected motor tasks typ-
ically are performed in order to delineate key areas of
the primary motor cortex. Various motor tasks have been
used, including finger tapping, hand clenching, and el-
bow and shoulder movements. Berntsen et al.60 con-
ducted a study to determine a robust set of motor tasks
that could be used to delineate the motor cortex in a pre-
cise and accurate fashion. They found that tasks related
to finger, toe, and tongue movements were the most ef-
fective and associated with the highest success rates.
䉴 POSITRON EMISSION
TOMOGRAPHY
Brain mapping with PET relies administration of a ra-
dioactive tracer compound labeled with a positron-
emitting isotope to localize areas that are metabolically
active during a task. Scintillation detectors are used dur-
ing scanning in order to determine the position of the
isotope, and therefore, the portion of the brain acti-
vated by the task. For functional brain mapping, PET
is usually performed using 15 O or fluorodeoxyglucose
(FDG).15 O PET is used to measure cerebral blood flow
during the performance of a task. Blood flow under a
control condition is then subtracted from that measured
during task performance in order to detect regions with
increased flow. These changes can be used as an indi-
rect method for detection of neuronal activity. On the
other hand, FDG PET measures cerebral metabolism.
FDG PET can also be used for mapping; the areas with
increased metabolism compared with the control con-
dition are used for identification of increased neuronal
activity during a certain task.61
PET can be used to study a wide range of behav-
ioral tasks; however, the technique has a number of
significant disadvantages. Compared with fMRI, it has a
poor signal-to-noise ratio and spatial resolution. PET is
also considered invasive because of the administration
of a radioactive tracer that limits the number of studies
that can be done for one patient. With the widespread
availability and lower degree of invasiveness of BOLD
fMRI, PET is now rarely used for clinical mapping of
sensiromotor cortex. But it did play an important role
in the development of noninvasive functional mapping
of patients.
Bittar et al.62 studied 11 patients with tumors around
the central sulcus. All of them underwent H2 15 O PET
and fMRI before surgery for mapping of the somatomo-
tor and somatosensory areas. The average distance be-
tween activation peaks obtained using fMRI and those
obtained using PET imaging was 7.9 ± 4.8 mm, with 96%
of the peaks being located on either the same (52%) or
adjacent sulci and gyri (44%). Overlapping of voxels ac-
tivated by each modality occurred in 92% of the studies.
In another study, the same group validated PET mapping
of the sensory cortex against intraoperative cortical stim-
ulation. They found that in 22 (95.6%) of 23 statistically
significant PET activation foci, spatially concordant sites
on cortical stimulation were also observed. Intraopera-
tive cortical stimulation was positive in 40% of the PET
activation studies that did not result in statistically signif-
icant activation. All PET activation foci with a t-statistic
greater than 4.75 were associated with spatially concor-
dant sites of positive intraoperative cortical stimulation
(ICS). All PET activation foci with a t-statistic smaller
than 3.2 were associated with negative ICS.63 Schreck-
enberger et al. conducted a study involving 20 patients
with tumors of the central region to validate FDG-PET
mapping of the motor cortex. Using direct cortical stim-
ulation as the “gold standard,” they found that PET has
a 94% sensitivity and 95% specificity for identification of
primary motor areas.64
䉴 MAGNETOENCEPHALOGRAPHY
MEG is another noninvasive technique that measures
brain activity through measurement of magnetic fields.
 CHAPTER 14
In a sense, it is similar to electroencephalography (EEG),
but measures magnetic field changes instead of volt-
age changes to detect neuronal activity. Ion currents ac-
companying neuronal activity generate magnetic field
changes that can be detected using a biomagnetometer,
and used to reconstruct an image of the neural activi-
ties. When MEG is used for mapping purposes, a task
is performed multiple times, and then neuromagnetic
signals are averaged over multiple trials in order to de-
lineate the signals produced by focal active areas from
the background activity. MEG is mainly used for map-
ping of the somatosensory cortex. Motor mapping can
also be done but motor data are generally not as re-
producible or precisely located as sensory mapping.65
Magnetic source imaging (MSI) is the coregistration of
MEG data to a structural image to facilitate the anatomo-
functional correlations.
Like any other technique, MEG has both advantages
and disadvantages. Compared with EEG, MEG has a sim-
ilar excellent temporal resolution, but better spatial res-
olution (of approximately 2 mm), and better signal-to-
noise ratio. Moreover, MEG signals are not attenuated
by the cranium and scalp.66 However, MEG scanners re-
quire dedicated personnel and specially equipped and
shielded rooms. They are also very sensitive to environ-
mental magnetic noise. MEG scanners are currently very
expensive with limited availability.
Gallen et al.67 conducted a multicenter study to val-
idate MEG data for mapping of the primary sensory
cortex against intraoperative cortical stimulation. They
found that MSI results correctly identified the postcen-
tral gyrus in all of their six patients. The calculated dis-
crepancy between MSI-determined central sulcus and
the one determined by phase reversal ranged between
0.37 and 1.28 cm (with an average of 0.7 cm). In a similar
study, Rezai et al.68 performed a preoperative mapping
of the sensory and motor cortex using MEG in 50 pa-
tients with lesions located in close proximity to the cen-
tral sulcus. In ten of these patients, an integration of the
MEG data with an image-guided stereotactic system was
performed and used during surgery. This allowed an ac-
curate comparison between the functional data provided
by MEG and the intraoperative direct stimulation. They
found that preoperative MEG localization of the sensori-
motor cortex was successful in all patients. This allowed
aggressive but safe removal of the lesions. All patients
had gross total resections, eight of them with no change
in their neurological exam, and two with transient wors-
ening of a preoperative weakness. Schiffbauer et al.65
treated a total of 224 patients who underwent preoper-
ative MSI. The noninvasive mapping of the sensorimo-
tor cortex using MEG was done 2 days before surgery
to allow time for discussion of results with the patient.
The MEG data were registered to a high-resolution MRI
to form the MSI, the images were then transferred to a
MAPPING OF THE SENSORIMOTOR CORTEX 197
neuronavigation workstation. Awake craniotomies were
done in 54.3% of the cases. Somatosensory mapping us-
ing MEG was technically successful in 97% for digits
and hand, 90% for lips and 82% for toes. The three-
dimensional distance between somatosensory sites on
MSI and somatosensory sites on intraoperative cortical
stimulation ranged between 1.5 and 42.2 mm (mean:
20.5 mm). The mean two-dimensional distance was
12.5 mm.
䉴 TRANSCRANIAL MAGNETIC
STIMULATION
Transcranial magnetic stimulation (TMS) consists on the
noninvasive application of a magnetic field on the scalp
in order to stimulate neuronal electric activity. An elec-
tromagnetic coil is held over the cranium, creating a
magnetic field that induces a perpendicular electric field.
In 1985, the technique was introduced as a novel, non-
invasive, and painless application for mapping of the
human motor cortex.69 Subsequent studies used TMS
in conjunction with frameless neuronavigation systems
and tried to validate the findings against direct cortical
stimulation. Krings et al.70 applied this technique in two
patients. TMS was well tolerated with no reported side
effects. They also found good correlation between TMS
and direct stimulation. In locations of more than 2.5 cm
distant from the site of direct cortical stimulation, com-
pound muscle action potentials were not elicited in ei-
ther patient. TMS responses that were 75% of maximum
motor evoked potential amplitude or larger were elicited
over cortical regions that were within 1 cm of the corti-
cal region where direct stimulation elicited movements
of the same muscles. No responses smaller than 50% of
the maximum motor evoked potential (MEP) amplitude
were elicited within 0.5 cm of the cortical areas of direct
cortical stimulation. The same group conducted another
study to correlate the findings of TMS with fMRI. 71 They
found strong correlation between the two techniques
in three volunteers and two patients. Peak MEP ampli-
tudes consistently coincided with peak fMRI activation,
although the area of TMS responses was larger than the
area of fMRI activation. TMS sites further than 2 cm from
the cortical surface projection of the fMRI produced no
MEPs. Neggers et al.72 applied a frameless stereotactic
device using structural and fMRI data to guide TMS coil
placement. The distance between the MEP responses
and the maximum fMRI activation areas was on average
less than 5 mm. Kantelhardt et al.73 conducted a pilot
clinical study on the use of robot-assisted, image-guided
TMS for mapping the motor cortex. The areas of maxi-
mal MEP response localized within the “finger tapping”
activated areas by fMRI in all of their six patients, and re-
peated TMS measurement showed high reproducibility.
198 SECTION II SYSTEMS
䉴 CLINICAL APPLICATIONS
RESECTIONS WITHIN THE
ROLANDIC CORTEX
Sir Victor Horsley was perhaps the first person to suc-
cessfully perform surgical resections within the primary
sensorimotor cortex in order to control abnormal in-
voluntary movements (epilepsy).74 His pioneering work
was instrumental in the understanding of the central cor-
tex. Thereafter, multiple reports on procedures involv-
ing extirpation of parts of the primary motor cortex ap-
peared between 1886 and 1950, but rarely since then.75
The work of Penfield and Rasmussen showed that large
resections in the precentral gyrus produce complete, im-
mediate paralysis followed by spasticity. Long-term re-
covery led to significant improvement in proximal limb
function but poor recovery of the distal parts. In the
modern era of neurosurgery, resections of parts of the
primary sensorimotor cortex have been largely avoided,
because of concerns regarding a permanent neurolog-
ical deficit. As a consequence, residual tumors as well
as epileptogenic foci are commonly left in this area,
at the expense of suboptimal seizure control and tu-
mor extent of resection. However, in carefully selected
cases, particularly in surgery for intractable epilepsy, se-
lective resections within the sensorimotor cortex can
be made with an acceptable deficit. Patients’ counsel-
ing is of paramount importance in these cases; the ex-
pected postoperative deficit as well as realistic expec-
tations regarding recovery should be clearly explained
to them based on the best available data to date. Duf-
fau et al.76 reported their experience in resections of
low-grade glioma in eloquent brain, eight of their cases
involved the primary sensory cortex and three of them
the primary motor face area. In sensory resections, all
patients had a severe postoperative sensory loss, but re-
covered within 3 months, with mild residual dysesthesias
in two cases. In the case of motor face area resection, all
three patients had a central facial palsy that recovered
completely within a month. The transient deficit after re-
sections of the sensorimotor face area is also consistent
with the results reported by Lehman et al., thus advo-
cating resections of epileptogenic foci in this region.77
These findings are also consistent with the experience of
the senior author (YC). Between 1997 and 2005, Youssef
Comair treated 33 patients with seizure onset in the pri-
mary sensorimotor cortex (unpublished data). The un-
derlying pathology was glioma in 19 patients, cortical
dysplasia in 10, and vascular lesions in 5. All patients
underwent respective surgeries with an overall seizure-
free outcome rate of 65%. The functional outcome was as
follows for hand and/or leg motor resections progressive
recovery of function occurred 6-week postoperatively
and continued to improve over 2–3 years, with return
of individual finger movements but not toe movements.
Sensory hand resections led to a proprioceptive deficit
that significantly improved with time. Sensory leg resec-
tions lead to persistent numbness in the foot. A transient
weakness following face resections was noted, recovery
occurred in 2–3 weeks.
PRESERVATION OF ROLANDIC
CORTEX IN SURGERY FOR INTRINSIC
BRAIN TUMORS
Because surgery within Rolandic cortex often results in a
permanent and disabling deficit, mapping is often used
to curtail a resection to avoid this deficit. In general, the
aim of surgery in the treatment of intrinsic brain tumors
is to maximize the extent of resection while minimizing
the risk of postoperative neurological deficit. When tu-
mors are located in close vicinity to the central sulcus, it
is of utmost importance to determine the exact location
of the sensorimotor cortex and its relation to the tumor.
Preoperative studies including high-resolution MRI and
functional imaging help in the identification of the elo-
quent cortex and its relation to the lesion, thus allowing
a clear discussion with the patient about the feasibility of
gross total resection and the risks of surgery. The data
gathered from the preoperative work-up is then used
during surgery typically in conjunction with intraopera-
tive mapping techniques that are still considered as “gold
standard”.
Although surgical resection constitutes a crucial el-
ement in the management of intrinsic brain tumors, the
efficacy of extent of resection in improving patients’ out-
come remains a matter of debate.38 With the exception
of World Health Organization grade I tumors, where
cure is the goal of surgery, the vast majority of patients
with glioma are expected to have tumor recurrence at
some point. The median survival rates are in the order
of 12–18 months for glioblastoma78 , and 41 months for
anaplastic astrocytoma.79 The 5-year survival for low-
grade glioma varies between 40% and 90%.80−82 In the
case of low-grade gliomas, there is mounting evidence
suggesting that a more extensive resection is associated
with increased survival. Although class I evidence is
lacking, multiple studies that included volumetric anal-
ysis showed that the extent of resection is a significant
predictor of 5-year survival and 5-year progression-free
survival.83−86 In the case of high-grade gliomas, the im-
pact of the extent of resection is more controversial.
While a number of studies showed that aggressive re-
sections were associated with a survival benefit and a
delay in tumor progression, an almost equal number of
studies failed to show such a correlation.79,87−89
Intrinsic brain tumors frequently involve eloquent
brain areas. The benefits of performing a gross total
resection in these cases have to be balanced against
the risks of inflicting significant neurological deficit with
 CHAPTER 14
potentially devastating consequences on the quality of
life and survival. Intraoperative brain mapping allows
the surgeon to identify the eloquent brain regions during
surgery and to preserve them; this will result in maximiz-
ing the extent of resection while minimizing the risk of
deficit. Chang et al.90 recently reported the experience
of the University of California in San Francisco regard-
ing resection of low-grade gliomas in eloquent areas of
the brain. Between 1989 and 2005, they treated 281 pa-
tients; most of them (174 patients) had tumors involv-
ing “presumed” eloquent areas based on preoperative
anatomical MRI, these patients had significantly lower 5-
year overall survival and progression-free survival. How-
ever, when analyzing the role of mapping, they found
that 127 patients with tumors “presumed” to involve elo-
quent structures underwent intraoperative mapping. In
81 patients, the tumor was indeed found to directly in-
filtrate eloquent structures (“true-eloquent” cases), while
it spared functional areas in 46 patients, thus allowing a
more aggressive resection (“false-eloquent” cases). The
analysis also showed that the overall survival in the case
of “false-eloquent” location was not statistically different
from that of tumors involving noneloquent areas. These
findings underline the importance of mapping whenever
the tumor is suspected to involve eloquent structures,
and show that it can improve the extent of resection
and long-term outcome, because it allows delineating
tumors that truly invade functional structures from those
that do not. These findings are consistent with the ex-
perience of other authors who consider that mapping
allowed resection of tumors previously considered un-
resectable and that it can improve outcome by virtue of
maximizing the extent of resection.91 (Fig. 14–5).
MOTOR CORTICAL STIMULATION
FOR NEUROPATHIC PAIN
Central pain is by definition, damage to or dysfunction,
of the central nervous system resulting in long-lasting
pain. A large number of etiologies have been implicated,
including stroke, trauma, and tumors. Peripheral nerve
injury can also be the cause of central pain by secon-
darily affecting the central nervous system.92 In view of
limited success of medical treatment in general, corti-
cal stimulation has emerged as a promising option. The
presumed mechanism for pain relief is based on the ex-
citability modification of neuronal activity, thus cortical
stimulation is thought to interfere with pain signals re-
sulting in modulation of abnormal activity. In a recent
systematic review of the literature, the mean responders
rate to epidural motor cortex stimulation was 64%.93 The
technique consists of introducing epidural electrodes to
stimulate the motor cortex, the localization of the motor
cortex appears as such to be an integral part of the pro-
cedure. Numerous mapping techniques have been used
MAPPING OF THE SENSORIMOTOR CORTEX 199
Figure 14–5. Intraoperative picture of the exposed
surface of the right hemisphere during awake
craniotomy for tumor resection. Anatomically the
tumor occupies the precentral gyrus; however, the
functional areas were identified by direct cortical
stimulation: 1, proximal arm motor; 2, face motor;
3, 4, and 5, face sensory; 6, hand sensory; 7, wrist
sensory; 8 and 9, hand motor. As a result, the tumor
(the swollen part of the gyrus) was mostly involving
noneloquent area. However, it invaded the motor
face inferiorly. Gross total resection of the tumor was
achieved, including removal of the motor face area.
Patient developed facial weakness initially but this
recovered well, as expected.
to this end. The intraoperative epidural cortical mapping
using epidural stimulation and/or SSEPs is widely used.51
Pirotte et al. used fMRI data registered in a navigation
system to treat 18 patients with intractable pain. They
found correspondence between fMRI and intraoperative
cortical mapping in 17 of them.94
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344-359.
 Chapter 15
Mapping of Human Language
Nitin Tandon
Department of Neurosurgery, University of Texas Medical School, Houston, Texas
䉴 INTRODUCTION AND
HISTORICAL BACKGROUND
Language is a uniquely developed human skill, essential
for the normal functioning of an individual in society.
It is the inveterate symbolic or spoken representation
of abstract concepts, consistent across a group within
a species. While certain bees,1 birds,2 simians,3 and
cetaceans4 are able to communicate information vocally
or symbolically, the human ability to produce and com-
prehend symbolic and spoken language is unique. The
limitations of interclass homology (confounding the rel-
evance of insect and avian data), coupled with practi-
cal and ethical considerations in the invasive research
of marine mammals or free ranging simians have pre-
cluded the development of animal models of language
acquisition and production that could then be applied
to humans.
The first spatially specific representations of lan-
guage came from careful studies of cerebral lesions
produced in humans by “experiments of nature.” Paul
Broca5 and Carl Wernicke6,7 used these to develop a
model that represented specific language processes. The
next advance after lesion localization came from the use
of focal currents for language localization. This tech-
nique of intraoperative language mapping with elec-
tricity was first reliably accomplished in Germany by
Otfrid Foerster, a neurologist turned surgeon, who
treated soldiers with epilepsy following penetrating cere-
bral trauma in World War I. Foerster pioneered the
use of intraoperative electrocorticography (ECoG)8 to
localize seizure foci and developed the earliest maps
of language using this technique.9 These techniques
were later adapted by Wilder Penfield10 at the Mon-
treal Neurological Institute, to make more precise and
detailed maps of cortical localization.11−13 His work12,14
established that language could be localized to discrete
cortical areas, quite a bit smaller than the larger re-
gions described by Broca and Wernicke. These areas
were subsequently designated as “eloquent” and cortical
stimulation mapping (CSM) with electrical currents has
since been the mainstay for the preresection localiza-
tion of language function. Penfield’s work established
that stimulation of the inferior frontal gyrus leads to
203
interference with language output—including speech ar-
rest, alexia, agraphia, paraphasia, and anomia.13,12 Even
more detailed and comprehensive language maps were
generated by Ojemann15 who systematically compiled
data relating to language localization in large numbers
of patients. Intraoperative mapping techniques devel-
oped for the management of patients with epilepsy,
were then also broadly applied to the resection of glial
neoplasms.16 Population data compiled in this way15,17,18
were represented as two-dimensional representations of
language loci overlaid on schematic outlines of the brain
and major sulci.19 Such maps are well suited for individ-
ual patient management, but are untenable for accurate,
unbiased comparisons between patients, or with func-
tional imaging data. Despite these and other limitations
(see later), these maps have been vital to the develop-
ment of modern concepts regarding the organization of
human language, and are broadly accepted as the cur-
rent clinical standard for language localization.
䉴 LATERALIZATION VERSUS
LOCALIZATION
The goal of language localization cannot be reason-
ably accomplished without definitive a priori knowl-
edge of which hemisphere is dominant for language.
Even though the exact proportion of normal humans in
the general population who have left, right, or bilateral
language dominance is not known, about 9% of right-
handed patients scheduled for epilepsy surgery have
atypical language dominance, while as many as 46% of
ambidextrous and 69% of strongly left-handed epilepsy
patients have atypical cerebral dominance.20 However,
atypical language lateralization is likely less common in
normal humans and those with lesions acquired after
the first decade of life, by which time the ability of the
previously nondominant hemisphere to take over major
language function is limited. A study of healthy adults,
using repetitive transcranial magnetic stimulation (rTMS)
to temporarily disrupt language revealed atypical domi-
nance in only 4.2% of right handers and in 10.5% of left
handers.21 In addition, the vast majority of adult brain
204 SECTION II SYSTEMS
tumor patients with proven right hemispheric language
organization are left-handed.22
A pragmatic approach to decide when language lat-
eralization should precede localization is as follows. The
threshold to formally assess language lateralization in
patients undergoing resections for epilepsy should be
lower than in patients with tumors, especially in cases
where epilepsy involves the dominant hemisphere and
the age of onset of seizures is in the first decade of life.
In adult patients with gliomas, handedness, the clini-
cal history, and the bedside exam are critical metrics of
the need for formal measures of language lateralization.
Subtle disfluency, dysnomia, or altered comprehension
consequent to peritumoral edema, or to seizures at pre-
sentation are powerful indicators of laterality. In cases
where these are not noted, left-handedness should gen-
erally be a trigger for testing to lateralizing language prior
to proceeding further.
The stated “gold standard” for determining language
laterality is the Wada procedure.23 An intracarotid injec-
tion of sodium amobarbital (or methohexital or propofol
or etomidate)24 is carried out into each carotid artery.
After injection, the patient’s responses to a battery of
expressive and receptive language tests and memory
function are measured.25 A temporary aphasia is usu-
ally induced when the dominant hemisphere is injected.
However, Wada testing is invasive, costly, and carries
some risk.26,27 This prompted the utilization of nonin-
vasive functional assessments of laterality—functional
magnetic resonance imaging (fMRI),28−31 magnetoen-
cephalography (MEG)32,33 —and other less commonly
used measures (positron emission tomography (PET),
functional transcranial Doppler’s and TMS) to assess
hemispheric dominance for language. Of these, fMRI
is the most widely used. The strongest correlation be-
tween Wada and fMRI determined laterality is obtained
by comparing activity in Broca’s area with its contralat-
eral homolog.29
It is important to recognize that the classical meth-
ods of functional localization, the Wada procedure and
electrical CSM, produce transient “lesions” of the brain.
On the other hand, functional imaging techniques reveal
regions involved in, but not necessarily essential for the
task being performed. In addition, enormous variability
exists across centers in how functional imaging studies
are performed, the paradigms used, the scanner type,
and the thresholds used for the purpose of laterality es-
timation. Lastly, this testing needs a nonsedated, coop-
erative patient able to reliably perform the tasks in the
confines of a scanner. Patients with even minor degrees
of claustrophobia or cognitive/language limitations can-
not be easily evaluated. While many centers have moved
away from routinely performing the Wada procedure
for language lateralization in patients with epilepsy,34
it remains relevant in patients with unusual handedness
and in those where the lesion in the presumed domi-
Figure 15–1. The major language pathways in the
dominant hemisphere—the arcuate fasciculus (blue),
the inferior fronto-occipital fasciculus (orange), the
uncinate fasciculus (yellow ), and the inferior
longitudinal fasciculus (purple)
nant hemisphere developed early in life (arteriovenous
malformations (AVMs) or epilepsy). In these situations,
functional imaging modalities can be viewed as screen-
ing tests. Patients in whom activation is not definitively
lateralized can then be studied with the Wada test. In
addition, combined use of Wada testing and functional
imaging may be useful in cases where both hemispheres
support language function.35,36
A newer, task independent measure of language
laterality relies on the evaluation of the white matter
pathways subserving language function. The arcuate fas-
ciculus (AF) connects cortical areas in the frontal lobe
important for articulation to areas in parietal and tempo-
ral lobes important for comprehension7,37−39 and can be
identified using diffusion tensor imaging (DTI).40 Given
the rapid rates at which language is perceived and pro-
duced, it is reasonable to expect the presence of highly
anisotropic fiber pathways in the AF of the dominant
hemisphere to mediate the rapid flow of information.41,42
Comparative estimates of the numbers of the compo-
nent fibers of the AF and their anisotropy may allow for
the lateralization of the language dominant hemisphere43
(Figs. 15–1 and 15–2). The broad clinical applicability of
this new strategy awaits further evaluation.
䉴 CORTICAL AND SUBCORTICAL
SUBSTRATES OF LANGUAGE
Language can be considered as a disseminated cogni-
tive process reliant upon interdependent nodes essen-
tial for subfunctions such as phonology, semantics, and
syntax.44 From a clinical standpoint, a broad understand-
ing of the language system is essential, as it allows the
surgeon to integrate data from invasive and noninva-
sive mapping strategies into devising a plan for a safe
 CHAPTER 15
A
B neuropsychological data proposes that auditory word
Figure 15–2. Representation of three major language
pathways—the arcuate fasciculus (AF—green), the
inferior longitudinal fasciculus (ILF—yellow ), and the
uncinate fasciculus (UF—blue) in a given patient (Fig.
15–2B) and the laterality index computed using a - b/a
+ b method for each fiber pathway (Fig. 15–2A) at
increasing thresholds for the mean fractional
anisotropy along each fiber pathway. The AF is the
best pathway among these three for lateralizing
language function (From Ellmore T M, Beauchamp
M S, Breier J I, et al. Temporal lobe white matter
asymmetry and language laterality in epilepsy
patients. Neuroimage 2010;49:2033–2044.)
resection. Traditionally, the focus of mapping has been
to localize cortical substrates. However, it is now quite
apparent that critical language pathways that mediate in-
formation flow also need to be localized and preserved
to prevent language impairment.45,46 Newer models of
the language system should therefore also incorporate
interregional connectivity of cortical substrates.47
MAPPING OF HUMAN LANGUAGE 205
The classic anatomical model of language pro-
cessing proposed by Lichtheim48 was derived from le-
sional studies of Broca5 and Wernicke.6 In this model,
language expression is localized to the left posterior
inferior frontal lobe (Broca’s area) and language com-
prehension to the posterior superior temporal lobe
(an area with vaguely defined boundaries—Wernicke’s
area). The classical model also describes the AF,49,50
connecting these two areas. This classical model is
an underdeveloped predecessor that does not include
other anatomical substrates of language.51−53 In addi-
tion, terms such as comprehensive and expressive, used
to describe posterior and anterior language sites are per-
haps simplistic, as semantic and phonological processes
occur in both Broca’s and Wernicke’s areas. A more con-
temporary view of the functional roles of distinct brain
regions is listed in Table 15–1. These regions have been
incorporated into a plethora of models of language that
seek to depict information flow between them.
We now briefly review four contemporary mod-
els of language, which deal with three major language
processes. These models integrate data about cortical
and subcortical language sites. Levelt’s model of lexi-
cal access54,55 breaks down the process of naming into
an overtly serial process in which a core conceptual-
syntactic entity called the “lemma” is selected in the
anterior middle temporal gyrus (MTG), followed by mor-
phophonological code selection in posterior MTG and
Wernicke’s area, and syllabification in Broca’s area, fol-
lowed by eventual articulation using primary sensorimo-
tor cortex (Fig. 15–3).
A model integrating written and spoken language
comprehension,53 derived using functional imaging and
analysis occurs in the superior temporal cortex and vi-
sual analysis occurs in the posterior inferior temporal
gyrus (visual word form area) and in temporo-occipital
cortex. This model holds that semantic processes involve
a network including the angular gyrus and the anterior
inferior temporal cortex and that lexical retrieval occurs
via two routes: a semantic route through posterior infe-
rior temporal cortex, and a nonsemantic route through
the posterior superior temporal cortex (Wernicke’s area).
Friderici’s model56 of sentence processing invokes
a temporofrontal network that identifies and integrates
syntactic and semantic information. According to this
model, syntactic processing occurs before semantic pro-
cessing with integration of the two only in the later stages
of language processing.
Hickok and Poeppel57 modeled speech perception
by proposing that that two asymmetric bidirectional au-
ditory streams originate from each superior temporal
gyrus. The ventral semantic stream projects to the pos-
terior middle temporal gyrus, and interfaces between
phonological representations of speech in the supe-
rior temporal gyrus and widely distributed conceptual
206 SECTION II SYSTEMS

䉴 TABLE 15–1. CORTICAL SUBREGIONS THAT ARE COMPONENTS OF THE LANGUAGE SYSTEM

Eponym Location Function

Broca’s area Pars opercularis and pars triangularis Phonological assembly and encoding
of inferior frontal gyrus Semantic decoding
Wernicke’s area Posterior superior temporal gyrus Phonological decoding and repetition
Posterior middle temporal gyrus (MTG) Posterior MTG Lexical and semantic processing
Geschwind’s territory Angular and supramarginal gyri Semantic and lexical processing
Visual word form area Posterior inferior temporal gyrus Lexical decoding
Parahippocampal place area Posterior parahippocampal gyrus Place recognition
Fusiform face area Posterior occipitotemporal gyrus Face recognition
Anterior insula Anterior insula Articulatory planning
Premotor cortex Caudal middle frontal gyrus Articulatory planning
Supplementary motor area Posterior superior frontal gyrus Articulatory planning
Dorsolateral prefrontal cortex Rostral middle frontal gyrus Verbal working memory
Primary sensorimotor cortex Inferior precentral gyrus Articulation

Note: The commonly used descriptor is in column 1, the anatomic locus in column 2, and the functional role most commonly ascribed
to the region is in the last column.

representations. The dorsal phonological stream projects
to the inferior parietal lobe and ultimately to frontal re-
gions, and maps sound to its articulatory representations.
This network provides a mechanism for the develop-
ment and maintenance of “parity” between auditory and
motor representations of speech.
In addition to these four “corticocentric” models of
language, others have details of the roles of subcortical
pathways mediating information flow in the language
system.51,47 There is increasing recognition that the ar-
cuate AF40,58,59 and the inferior fronto-occipital fasciculi
(IFOF)60 play crucial roles in fluent language production.

Figure 15–3. Schematic representation of a meta-analysis of functional imaging tasks

during word production. Colors in the two panels indicate relations between regions
and functional processing components. The numbers indicate the time windows
(in milliseconds) during which the regions are activated in picture naming. The right
panel is the time course of the picture naming process. (From Indefrey P, Levelt W J.
The spatial and temporal signatures of word production components. Cognition
2004;92:101–144.)
 CHAPTER 15 MAPPING OF HUMAN LANGUAGE 207

Figure 15–4. Corepresentation of schematic representation of the AF and cortical

language regions. Distinct subregions of the AF connect anterior versus posterior
components of Broca’s area with the middle and superior temporal gyri respectively.
These cortical–subcortical units are postulated to mediate specific language
processes. (From Glasser M F, Rilling J K. DTI tractography of the human brain’s
language pathways. Cereb Cortex 2008;18:2471–2482.)

At the current time, the existing data propose a partici-
patory, noncritical role for the uncinate fasciculus (UF)61
and the inferior longitudinal fasciculus (ILF)62 in nam-
ing and fluent speech production. Glasser and Rilling51
have related the Hickok and Poeppel57 model and the
Price model to the connectivity of anterior and posterior
language systems by the components of the AF (Fig.
15–4). Such models integrate information about corti-
cal and subcortical substrates, and are likely to provide
more ecologically valid and clinically relevant predic-
tions about the impact of planned cerebral lesions dur-
ing neurosurgical procedures.
䉴 MAPPING METHODS
This sections outlines methods used to localize language.
Details about methodological aspects not in this portion
of the text can be found in the references listed and
in chapters on the relevant method elsewhere in this
book.
DIRECT CORTICAL STIMULATION
This is the classical, time-tested method for localizing
language function using the application of artificial cur-
rents directly to the cortex. Language mapping using fo-
cal electrical currents—or CSM is carried out in one of
two clinical settings. The first, historically older method,
involves the use of a bipolar probe to stimulate a small
volume of cortex and is carried out in an operating room
with the cortex exposed by a craniotomy. It is char-
acterized as intraoperative CSM (iCSM). The other, ex-
traoperative CSM (eCSM),63 involves passing controlled
currents into semichronically implanted subdural elec-
trodes (SDEs) and is typically carried out in the epilepsy
monitoring unit, with ongoing video-electroencepha-
lographic monitoring. The choice between iCSM and
eCSM is largely dictated by the patients’ diagnosis, and
their ability to participate in an awake craniotomy. In
patients undergoing SDE placement to localize seizure
onset sites, eCSM is generally performed. Rarely SDEs
are implanted purely for purposes of eCSM, such as in
patients too young, too claustrophobic, or with very vas-
cular lesions (AVMs) that cannot be safely mapped using
iCSM. While maps created using eCSM and iCSM are gen-
erally similar, there are some relative pros and cons of
each method. The amount of cortical surface covered by
iCSM is generally smaller than that for eCSM, as regions
beyond the craniotomy are not stimulated. Also, there is
a limited amount of time available for sophisticated cog-
nitive or sensorimotor testing in the operating room, im-
posing limits on data acquisition using iCSM. However,
the sites of stimulation in eCSM are fixed, while they
can be dynamically varied for iCSM to accommodate
208 SECTION II SYSTEMS
1–15 mA
200–500 μS
50 Hz
Figure 15–5. Characteristics of the electrical current
typically used for both intraoperative and
extraoperative cortical stimulation mapping. The
balanced square wave current minimizes charge
deposition.
for sulcal anatomy and to tailor resection margins pre-
cisely. Also, the iCSM stimulating probe has electrodes
5 mm apart, which provides a higher resolution spatial
map than accomplished with traditional SDEs that have
10 mm interelectrode spacing.
Methods
In either case, mapping is carried out with the patient
on anticonvulsants after he or she is familiarized with
the testing process, using a balanced faradic current,
delivered at 50 Hz. The duration of each set of waves
varies from 200 to 500 microseconds, with longer du-
ration waves used for mapping in children. A train of
these waves is delivered for 3–5 seconds during task
performance, via two contacts located on the corti-
cal surface (Fig. 15–5). Stimulation currents range from
1 to 15 mA, and mapping is performed at 15 mA or at
1 mA below the potential that results in persistent after-
discharges (AD),64 overt phenomenology or discomfort,
whichever is lowest. It is preferable to maximize currents
at each cortical site regardless of adjacent AD threshold
rather than to map the entire cortex at a single current
level.65,66 Concurrent ECoG is essential to monitor for
ADs and seizures. It also provides visible evidence of
completeness of the electrical circuit, by the presence of
artifacts in the recording. The passage of currents meet-
ing these parameters has been shown to be generally
safe and does not appear to cause neuronal injury.67 The
pulse generators commonly used for mapping are the
Ojemann stimulator OCS-1 (Integra LifeSciences Corp,
Plainsboro, New Jersey), a portable, constant current,
battery-powered unit that generates biphasic rectangular
waveforms with 5–100 Hz, 0.1–2 milliseconds duration,
0–20 mA and is powered by four 9-volt alkaline batteries,
and the S88 Grass stimulator and variants thereof (Grass
technologies, West Warwick, Rhode Island), which can
generate one or two trains of biphasic rectangular waves
with greater variations of range (0.01–1000 Hz, 0.01–
10,000 milliseconds duration, 0–1000 mA).
The tasks used for CSM vary across institutions, but
the ones commonly used are68−70 :
t Object naming in an overt manner, using pictorial
stimuli from the Boston naming test71 or other
similar sources.72−74
t Repetition of spoken words or phrases.
t Auditory comprehension using the token test or
one/two step commands.75
t Spontaneous speech—counting, reciting the al-
phabet, nursery rhymes, etc.—useful in mapping
anterior language sites and in mapping patients
with prominent verbal deficits.
t
Verb generation from pictures of objects, actions,
or from written nouns.
t Reading sentences out aloud.
t Auditory naming—naming driven by a phrase or
a sentence (e.g., question—what a king wears on
his head—answer—crown).
Caveats
The neural substrates involved in language tasks may
vary based on the degree to which the same task is
overlearned.76 If CSM is performed using a small group
of stimuli, a region may be nonessential only for an over-
learned task.77 To minimize such confounds, it is useful
to have a large battery of stimuli per task and to minimize
repetition of individual stimuli. Electrodes or stimula-
tion sites where the task results in a delay, paraphrasias,
anomia, or speech arrest are noted, as are those locations
where stimulation produces overt phenomenology. CSM
carries a small risk of producing seizures. A seizure dur-
ing stimulation may severely curtail the mapping process
or lead to a postponement of the planned resection. To
minimize this possibility, patients should be on thera-
peutic doses of anticonvulsants prior to mapping. It is
also useful to administer an intravenous loading dose
of phenytoin or fosphenytoin before commencing map-
ping. Despite these measures, stimulation of perilesional
cortex can result in seizure induction. In the setting of
iCSM, this can be controlled by irrigation of the brain
surface with ice-cold saline.78 In the context of eCSM,
the seizure can sometimes be aborted with a second
pulse of stimulation79,80 applied at the same electrodes at
the peak of the negativity of the AD. These CSM tech-
niques have been successfully used to map language in
patients as young as 4 years and as old as 80 years of
age.81
Overview of Published Series
Several compilations of CSM data resulting from maps
of large numbers of patients have been reported. The
best known of these is George Ojemann’s seminal
publication82 that is based on intraoperative awake map-
ping of 117 left hemispheric dominant patients. This
revealed that language sites are diffusely organized
all around the left perisylvian region, with additional
language sites in the middle frontal gyrus and less
 CHAPTER 15
commonly in the superior frontal gyrus. The middle and
inferior gyri of the anterior temporal lobe were relatively
bereft of language function, and no sites associated with
anomia were found in the inferior temporal gyrus. Sim-
ilar findings have been noted in a larger series of 250
patients undergoing awake language mapping for the
resection of gliomas,83 suggesting that it is safe to carry
out an aggressive resection of a neoplasm in the absence
of any positive stimulation sites. Both these large series
suggest that significant variability exists in the organiza-
tion of language sites between individual humans. This
variability is much greater in the location of posterior
temporal and temporoparietal language sites15 than in
the location of frontal lobar language sites. Language
does not always reside in the typical confines of classi-
cal language sites. In Ojemann’s work, no language sites
were found in the vicinity of Wernicke’s area in 36% of
subjects and none were found in Broca’s area in 21%.82
Other work revealed that no posterior language areas
were identifiable in 10% and no anterior language site
could be identified in 9% of patients.81 CSM reveals in-
teresting characteristics about “essential” language sites.
Their cortical surface area is rather small: less than or
equal to 6 cm2 in 85% of individuals, especially so in
individuals with a high verbal fluency. There is a strik-
ing subspecialization of cortical regions with regards to
different language functions, with distinct loci in many
instances for naming, reading, phoneme identification,
and so forth. More than half of all sites localized by
stimulation mapping are involved in only one aspect of
language.15
There is some diversity in opinion in regards to
the extent of interpatient variability of language sites.
A study of 45 patients with implanted SDEs,17 with ex-
haustive extraoperative language testing, and a specific
evaluation of “negative” motor areas, revealed language
sites in and around classical Broca’s and Wernicke’s
locations and in the basal temporal lobe only. How-
ever, most awake mapping (iCSM) studies suggest that
otherwise. This disparity may be attributable either to
the statistical threshold used in the awake mapping
techniques.82,83 These iCSM techniques make an incom-
plete distinction between sites where a dysnomia is
always produced, versus those where it is produced
above a certain statistical threshold. This raises ques-
tions about whether these sites are truly essential for lan-
guage. These data may also be affected by the inherent
limitations of making population language maps based
solely on cortical surface anatomy. However, the multi-
tude of functional imaging studies and lesional analysis
studies of language all suggest a significant amount of
intersubject variability in language sites. Taken together,
these findings suggest that language sites need to be lo-
calized for each individual and for each function that
is considered important. Their locations cannot be de-
rived reliably using heuristic strategies based on popu-
MAPPING OF HUMAN LANGUAGE 209
lation maps or surface anatomic landmarks. A compari-
son of a large series of standard right versus left tempo-
ral lobectomies, in whom typical language lateralization
had been shown by Wada testing revealed that in the
absence of language mapping, about 7% of patients did
have a significant deterioration in naming ability at 6
months postoperatively.84
Limitations
CSM is a technology that has been used in an almost
unchanged form for over a century. Its limitations are
therefore well known and understood. Testing in a given
individual may be difficult or inconsistent.66 The method
is less than ideally sensitive—perhaps due to the fact that
only one-third of cortex is on the surface, and therefore
testable—no language sites are found in Wernicke’s area
in 36% and none in Broca’s area in 21%.82,85 Depend-
ing on the tasks used for mapping, it may not consis-
tently prevent postoperative language deficits.70 Lastly,
three pragmatic considerations impact upon the utility
of CSM—the induction of seizures, the need for an ad-
ditional procedure (SDE placement for eCSM) or oper-
ative time (for iCSM), and constraints on the extent of
language assessment imposed by the time available.
Older studies have suggested that the local spread
of cortical currents and hence the range of the dis-
ruptive effect of stimulation on cognitive processing is
localized.86,87 However, remote changes in local field po-
tentials (LFPs) occur following even a single suprathresh-
old electrical pulse lasting less than 0.3 milliseconds, as
evidenced by the recordings of cortico-cortical evoked
potentials (CCEPs)88,89 (Fig. 15–6). It may well be use-
ful to view CSM as a process that disrupts information
flow in a broad network, rather than just at a specific site
(Fig. 15–6).
Summary
CSM strategies have provided unique insights into
the biology of human language and have served as
the standard used to evaluate some models of language
organization.90 Ojemann’s work, revealed the parallel
activation of multiple function specific modules during
language processing,85 a model that has stood in distinc-
tion to traditional models of hierarchical serial processes
starting with decoding in the posterior temporal lobe and
eventual phonation by the inferior frontal lobe.91 This
parallel processing model is widely accepted today.92
Surgical techniques that specifically target the resec-
tion of mesial temporal lobe structures while minimizing
neocortical resections might appear to be a useful strat-
egy to avoid the need for mapping in cases of epilepsy
originating due to mesial temporal lobe sclerosis in the
dominant hemisphere. However, no improvement in
outcome has been noted with a selective transsylvian
approach.93 The reason for this may be the disregard for
210 SECTION II SYSTEMS

Figure 15–6. Corepresentation of diffusion tensor imaging pathways and cortico-

cortical evoked potentials (CCEPs) from stimulation of Broca’s area in a single
subject. Stimulation was carried out over Broca’s area (black electrodes) at 1 Hz,
10 mA, using pulses of 500-microsecond width. Subsequent N1 peak from the CCEP
response measured at all other electrodes represented in terms of amplitude (radius
of electrode) and latency (color scale). Electrodes without CCEP response within
40 milliseconds are depicted as white spheres. All pathways passing 1 cm of the
stimulating pair are shown as green streamlines. A clear relationship between the
tracts and the elicited CCEPs is noted.

subcortical damage, especially to important white matter
fibers in the temporal stem, including the UF, the IFOF,
and the cholinergic outflow from the nucleus basalis of
Meynert91 A subtemporal approach that spares most of
the temporal neocortex may minimize the decline in
verbal memory94 ; but this approach needs to be sub-
stantiated in languages that use syllabograms rather than
morphograms, and its long-term impact on temporal
lobe epilepsy needs to be qualified.
What matters ultimately is the specificity and sensi-
tivity of mapping results as related to the language out-
come following focal resections. In this regard, Ojemann
and others have pointed out that carrying the resection
to within 1 cm of a site that leads to consistent anomia or
speech arrest is likely to result in a permanent long-term
verbal deficit.15,95 No such outcomes data are available
for other mapping strategies (which are discussed later).
Though there is some plasticity96,97 in the language sys-
tem in adults, it remains preferable to not have to rely
upon it for a good long-term outcome following resec-
tions.
FUNCTIONAL IMAGING
Modalities
The concerns regarding the spatial specificity and sensi-
tivity of CSM listed previously, along with the need for
additional procedures (SDE placement for eCSM) or op-
erative time (for iCSM), have led to efforts to supplant
CSM for localizing language function with functional
imaging techniques. Positron emission tomography,98
fMRI,55 event-related potentials (ERPs), and MEG99 —
have all been used to localize regions involved in the
component processes of speech production and lan-
guage perception. Of these, fMRI-mapping techniques
possess the best spatial resolution, and several prior
comparative estimates of maps generated with BOLD-
fMRI and CSM have been made.
Comparisons with CSM
While efforts to supplant CSM for localizing regions in-
volved in motor function with NIMS have been gen-
erally successful,100 functional imaging methods have
had limited applicability for presurgical localization of
language sites.101 This is especially true for temporal
and temporoparietal language regions,102−104 and less
so for frontal language sites.105 This limitation of func-
tional imaging is likely due to several reasons. The first
is that these techniques provide a map of the network
involved in, but not of the nodes of that network essen-
tial to, language generation. This problem worsens with
increasing sensitivity of the mapping technique used—
as more functional areas are detected by lowering the
statistical threshold used to create the language map—
the specificity of the map becomes lower. The second
reason is that the cognitive “load” of “simple” language
tasks such as object naming that are typically used for
CSM are relatively low—such that the neuronal activa-
tion or its hemodynamic correlate are not easily dis-
cernible from background activity. This has led imagers
to use different tasks for generating the functional acti-
vation map, as compared to the tasks used during CSM,
leading to inherent mismatches between such compar-
isons. A third, and relatively tractable limitation relates to
 CHAPTER 15
technical issues: spatial resolution of the imaging tech-
nique; mismatches in co-registration of functional data
sets with high-resolution MRI scan data used for intra-
operative stereotactic guidance; and problems with pa-
tients’ abilities to comprehend the task or cooperate with
scanning.106 Lastly, speech production in both MEG107
and clinical fMRI environments is generally covert (ex-
cept in event-related fMRI—which has worse signal to
noise characteristics), as movement associated with ar-
ticulation produces artifacts and signal dropout. Covert
speech does not activate some of the frontal opercular
regions that are essential for articulation, limiting the ap-
plicability of these techniques for mapping these frontal
language sites.105 Importantly though, functional imag-
ing maps of language have been compared with CSM
maps, but not to the patient’s functional state following
a resection.
Summary
Taken together, the published literature on functional
imaging suggests that while useful in lateralizing the
language dominant hemisphere, functional imaging
techniques are largely unsuccessful in demonstrating
absolute and reliable concordance between CSM
and functional imaging derived maps.106,108 Hence,
stimulation-based mapping remains the prevailing stan-
dard for functional localization of language regions at
the current time.109 Maps derived using fMRI are of some
value in guiding CSM and in providing a better under-
standing of language organization in patients with atyp-
ical results following an intracarotid amytal procedure.
STRUCTURAL IMAGING
Broca’s Morphology
As opposed to other functional regions that bear a
strict relationship with cortical surface landmarks, (e.g.,
the central sulcus, the pli de passage moyen, or the
calcarine fissure), most language regions do not bear
a constant relationship with the surface landmarks. In
the case of Broca’s area, the relationship between func-
tion and anatomy is relatively better defined, but not
invariant. CSM of the pars opercularis is often associated
with speech arrest, and CSM of pars triangularis can lead
to paraphrasic errors, errors in auditory cued naming and
disfluency. The component regions of the posterior in-
ferior frontal gyrus can be well visualized using sagittal
MRI images.110 Pars opercularis and triangularis in the
language dominant hemisphere are generally accepted
to constitute Broca’s area. Localizing these subregions
in relation to the planned resection, allows for guidance
regarding CSM. In addition, the relative volumes of pars
triangularis and111 pars opercularis may help predict lan-
guage lateralization.112,113
MAPPING OF HUMAN LANGUAGE 211
DTI Tractography
DTI uses the relative anisotropy induced by the pres-
ence of axonal cell membranes and myelin on the diffu-
sion of water in the brain, to deduce the orientation of
white matter tracts in each imaging voxel. As discussed
previously and shown in Figs. 15–1 and 15–2, cortical
language sites are extensively interconnected. The AF
connects Broca’s area with Wernicke’s area and is well
known from fiber dissection techniques.114 DTI tractog-
raphy has led to the identification of other components
of the AF of which both connect Geschwind’s area (in-
ferior parietal lobe) with Broca’s area and Wernicke’s
area.40 The AF mediates comprehension, repetition, and
semantic processes.7,115,116,117 The IFOF connects pos-
terior occipitotemporal regions to anterior temporal re-
gions, linking disseminated components involved in
object, face, and written words recognition62,116,118,119
and mediates semantic processes and naming. The UF
connects the anterior temporal lobe with the medial and
lateral orbitofrontal cortex and is related to semantic
processes and to confrontation naming.120−122 Electrical
stimulation of these pathways—the AF,123,124 the ILF,62
and the IFOF—60 has been shown to interfere with lan-
guage production.
A clue that the anatomical asymmetry in hemi-
spheric connectivity may support different functional
roles was first evident, when it was noted that the direct
segment of the AF linking Broca’s to Wernicke’s area,40
did not exist in the right hemisphere. Instead, in the
presumed nondominant hemisphere, only the two indi-
rect segments that connect Broca’s and Wernicke’s areas
separately to Geschwind’s area exist. Evaluations of the
fractional anisotropy of the AF in each hemisphere reveal
that differences in these measures may be sufficient in
some cases to categorize language dominance.43 The AF
can also be used to predict the location of language sites.
Upto 80% of all essential language sites (ELS) are situated
in intimate proximity to the terminations of the AF.58
Intuitively, it stands to reason that ELS should exhibit
robust long-range connectivity, therefore a greater
understanding of the relationship between cortical and
subcortical language sites may allow for newer ways
of functional localization that are independent of both
the need to produce transient lesions and functional
activation.
LOCAL FIELD POTENTIAL
RECORDINGS FROM INTRACRANIAL
ELECTRODES
Functional imaging, CSM, and DTI methods taken to-
gether map a disseminated language network that in-
cludes regions outside traditional Broca’s, Wernicke’s,
and Geschwind’s areas—for example the ventral
212 SECTION II SYSTEMS
temporo-occipital region, anterior lateral temporal lobe,
premotor cortex, and insula.125,55 However, those meth-
ods do not readily explain the dynamics of informa-
tion processing within the disseminated network. ECoG
recordings from SDEs, while the patient is engaged in
task processing reflect the activity of small cortical neu-
ronal assemblies coherently activated during language
processes, and are characterized as LFPs.126 SDEs make it
possible to observe interactions in large cell assemblies,
spanning distributed cortical regions, by sampling both
low- and high-frequency signal components such as
those in the gamma-frequency range, which are damped
by the media around the brain.127 The local nature of LFP
sampling greatly minimizes the “inverse problem” (com-
puting the dynamic spatial locus as well as the com-
ponent frequencies of an averaged electric or magnetic
signal) that confounds such measures made with MEG
and ERP.
Such recordings provide an unparalleled opportu-
nity to study the dynamics of information flow during
language processes. A localized desynchronization in
the alpha-beta 10–20 Hz range,82 greatest between 700
and 1200 milliseconds after stimulus presentation, with
persisting gamma 30–200 Hz activity, occurs at most
temporoparietal naming sites.126 Such response is not
typically associated with frontal naming sites. Other early
work revealed that slow potential shifts at the onset of
naming in frontal naming sites as well in motor cortex126
and that changes in electrical activity in the frontal and
temporoparietal language sites occur in parallel and not
sequentially.81
More recent work has focused on studying corre-
lated activity between language regions, at higher fre-
quency ranges.128 Activity in the high-gamma range
70–150 Hz, has been shown to be spatially correlated
with CSM-derived language maps.129−132 At this time, the
degree of such correlation is poor, 40% specific and 84%
sensitive.133 Optimization of the criteria used to define
sites of “significant” change, particularly in regards to the
frequencies chosen to designate significance, may lead
to this technique becoming clinically meaningful for lan-
guage localization.134
䉴 CLINICAL APPLICATIONS AND
CAVEATS OF MAPPING
STRATEGIES
As outlined previously the dominant and most proven
method for language localization in the current era re-
mains CSM. Newer technologies such as DTI and ECoG
may provide alternatives in the future. Functional imag-
ing techniques are often adequate to confirm the lateral-
ization of language suspected on clinical grounds, but it
must be remembered that all of these measures may be
imprecise in certain cases. The Wada test remains essen-
tial to confirm language laterality in selected cases. In ad-
dition to the methodological and pragmatic concerns dis-
cussed previously, there are special situations in regards
to language mapping, which should be considered.
LANGUAGE MAPPING IN
YOUNG CHILDREN
SDEs may sometimes need to be implanted purely for
functional mapping in children, as some of them are
unable to participate in iCSM.90 Mapping language in
children with CSM can be difficult, both due to poorly
developed language skills at an early age as well as due
to the fact that it is generally difficult to disrupt cortical
processing in children using electrical stimuli. Stimula-
tion parameters that work well in adults often do not
work well in children, possibly because partly myeli-
nated or unmyelinated nerve fibers need longer pulse
durations to be activated.135 This difficulty may be over-
come by lengthening the pulse durations beyond the
usual 300 microseconds (upto 3500 microseconds in an
incremental fashion), coupled with stepwise progression
in the intensity, to arrive at the appropriate chronaxy136
for each individual child. If these measures are not taken,
it is possible to obtain one or more false-negative sites
of stimulation in children.
LANGUAGE ORGANIZATION IN
MULTILINGUAL PATIENTS
Lesion studies in aphasic polyglots tell us little about
the organization of multiple languages in the cortex.
Plasticity and the difficulty in estimating premorbid lin-
guistic competence in each language, prevent definitive
conclusions. In addition, the limited spatial resolution
of functional neuroimaging techniques prevents precise
delineation of adjoining cortical regions that perform
similar functions in different languages.137 Hence, elec-
trical mapping techniques possess unique characteristics
suited for the study of multilingualism.157 CSM maps re-
veal that naming areas in languages acquired later in life
(L2) cover larger cortical regions than the language that
is acquired earlier in life (L1). As proficiency in a lan-
guage develops, the ELS related to it tend to become
more compactly organized.81 CSM of bilingual patients,
often, though not always, reveals that sites responsible
for naming and reading in two different languages are
distinct from each other,138,139 and that L2 specific sites
tend to be located exclusively in the posterior tempo-
ral and parietal regions.145 This corresponds well to data
obtained by functional imaging of individuals who learnt
L2 late in life.137 On the basis of the spatial disparity of
language sites in polyglots, mapping in each language
 CHAPTER 15
that the individual is proficient in should be carried out,
whenever practicable, to minimize the possibility of a
monolingual decline in verbal fluency.139 This is espe-
cially true if the proposed resection is proximate to the
posterior language sites.
BASAL TEMPORAL LANGUAGE
On the basis of clinicopathological data, Mills and Mar-
tin postulated141 the existence of a “naming center” in
the basal temporal lobe. The region has since been
well described by CSM142 and functional neuroimaging
techniques.140 CSM studies have called the region the
basal temporal language area (BTLA) and stimulation
here during naming, produces a specific deficit in con-
frontation naming. In some instances, auditory and vi-
sual comprehension may also be impaired.143,144,146,147
Both fMRI and CSM have shown the region to con-
tain subdivisions, which preferentially process particular
visual stimuli, such as written words (visual word form
area),140 faces (fusiform face area),148 and places such as
buildings (parahippocampal place area). The represen-
tation of particular categories of objects or faces appears
to not be sharply delimited, but do display a spatial to-
pography across the ventral temporal region.149,150
The term BTLA is sometimes loosely used to de-
scribe language regions in the entire ventral surface of
the temporal lobe, from the temporal tip to the temporo-
occipital junction, and including the inferior tempo-
ral gyrus. Comprehensive characterization of the region
by Lüders and colleagues,146 and others143,147,151 have
found that this language region involves the parahip-
pocampal and fusiform gyri, extending from 11 to 75
mm caudal to the temporal tip. In most cases, however,
the BTLA is restricted to a zone that has a 2–4 cm extent
in the rostrocaudal axis.144 By varying the onset of elec-
trical interference relative to a behavioral task (so-called
time slicing) it appears that processing of verbal object
meaning in the occipitotemporal gyrus occurs 450–750
milliseconds after stimulus presentation.152
Deficits seen after dominant temporal lobectomy,
comparing patients who undergo a resection of the
BTLA is resected with those where it is not, involve only
confrontation naming. Deficits in nonvisual language
processing are generally not noted.153,154 Recent studies
in Japanese subjects who speak using Kanji and Kana
characters have shown that the BTLA may play an
important role in connecting visual semantic decoders
(Kanji characters, like Cantonese, uses morphograms;
Kana characters, like English, are syllabograms) with
phonological processors.154 To this end, there is a spe-
cial interest in designing surgical strategies that would
spare as much of the fusiform gyrus as possible by using
a subtemporal-transventricular-transchoroidal approach
for hippocampectomy,155 for speakers of languages
MAPPING OF HUMAN LANGUAGE 213
that use morphograms. Whether this actually results
in improved verbal fluency without compromising
seizure-free outcomes is unproven so far.
FUNCTIONAL LOCALIZATION BASED
ON POPULATION MAPS AND THE
NOTION OF DEGENERACY
The ability to co-register imaging datasets to each
other, with adjustments made for individual anatomic
differences, allows for the generation of population
maps of cerebral anatomy and functional activation. The
generation of high-resolution three-dimensional (3D)
cytoarchitectonic maps113 or spatial probability maps
from meta-analyses of functional imaging data156 that
are can be co-registered onto a patient’s 3D structural
MRI provide novel ways for functional localization.
The four functions of interest in the neurosurgical
setting are language, motor control, vision, and mem-
ory. The cortical regions without which these functions
would no longer be considered to be normal are des-
ignated as “eloquent.” This designation does not imply
that other neural functions are not essential or that there
are necessarily noneloquent brain regions that can be
resected with impunity.158 Instead, it is a categorization
of cortical regions based on the lasting effects of le-
sions and the impacts of these lesions upon the activ-
ities of daily living. The term “eloquent” has been used
here, to allude to cortical regions without which lan-
guage function could not be discerned as normal.5,6 It
is clear from multiple lesional studies that a reorganiza-
tion of language function can occur even in the adult
brain.159 Recently, it has been shown that sites localized
by CSM demonstrate spatial plasticity both acutely160 and
as slow-growing lesions encroach upon them.161 While
resection of language sites generally does result in an
acute language impediment, significant and sometimes
complete recovery of function can occur, over a pe-
riod of 3–6 months.96,97 Lasting deficits are more likely
when the subcortical substrates of function are dam-
aged in some way.7 The best level of recovery is gen-
erally observed, when compensatory recruitments take
place in the perilesional area, along the rim of the in-
jured tissue, rather than in the homologous region of the
nondominant, contra-lateral hemisphere.162−164 These
findings, along with the fact that large amounts of domi-
nant temporal neocortex can be resected with relatively
few deficits support the concept of an implicit degener-
acy in language systems. The term “degenerate” is used
to describe structurally discrete neural elements that per-
form the same function.165 This approach has recently
been used to create a map of “truly essential” brain re-
gions, and such approaches may have a bearing on the
need for as well as the interpretation of cortical mapping
studies.166 Holistic approaches that integrate the results
214 SECTION II SYSTEMS
of functional imaging, lesional analysis, CSM, and the
potential for plasticity (based on age, site of planned re-
section) would probably provide a more precise way of
determining which cortical regions are truly eloquent.
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 Chapter 16
Mapping of the Human
Visual System
Muhammad M. Abd-El-Barr 1 , Mario F. Dulay 2 , Paul Richard 3 , William H. Bosking4 ,
and Daniel Yoshor 5
1
Department of Neurosurgery, University of Florida, Gainesville, Florida
2
Department of Neurosurgery, The Methodist Hospital Neurological Institute, Houston, Texas
3
Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
4
Max Planck Florida Institute, Jupiter, Florida
5
Department of Neurosurgery, Baylor College of Medicine, and Neuroscience Center, St. Luke’s Episcopal Hospital,
Houston, Texas

䉴 INTRODUCTION localization of visual cortex may help in choosing a sur-

Vision is a complex process in which characteristics of
our environment such as color, contrast, location, mo-
tion, and orientation are encoded by functionally spe-
cialized clusters of neurons. A large percentage (∼20%)
of the human cortex is dedicated to the processing of
visual information, highlighting its importance to hu-
man behavior, and survival. Perhaps the most impor-
tant property of the visual image is its spatial arrange-
ment, so it not surprising that spatial representations of
visual images are found throughout the visual cortex.1 In
human visual cortex, there are multiple distinct “retino-
topic” maps that preserve (with varying levels of fidelity)
the spatial content of visual stimuli projected onto the
retina. This is analogous to the multiple somatotopic
maps of the human body that exist for sensory or mo-
tor processing.2,3 Each of these areas differ in terms of
receptive field properties, connectivity, and physiology,
and are thought to contribute to visual processing in dis-
tinct ways. Collectively, these areas contribute to human
behaviors such as perception of object shape, color, and
motion, object discrimination, visual-motor control, vi-
sual memory, and visual planning. Mapping of the visual
cortex is a difficult process because of its complexity,
but technological advances in invasive and noninvasive
structural and functional mapping techniques have led
to a better understanding of the human brain and visual
processing.
This chapter will review the role of structural and
functional mapping techniques in providing useful in-
formation in a clinical setting, particularly for addressing
clinical problems that involve the visual system. These
techniques are important for providing optimal care in
clinical neurological settings. For example, preoperative
gical route to minimize functional deficits, and may also
define the optimal limits for resection of some brain
lesions. Mapping techniques are particularly useful in
planning and guiding the resections of lesions that are
not anatomically well defined. This includes cases of
nonlesional epilepsy or infiltrative brain tumors. Map-
ping helps to conceptualize risks associated with surgery
that can be used in the preoperative counseling of a pa-
tient. Mapping visual cortex can also be useful for un-
derstanding visual abnormalities in patients who present
with visual complaints. Finally, mapping in patients of-
fers a unique opportunity for study of visual processing
in the human brain.
䉴 HISTORICAL PERSPECTIVE
Although earlier work had established the basic anatomy
of the visual pathways, it was only in the 18th and 19th
centuries that we first gained an understanding of how
visual information from the retina is physically mapped
in the cerebral cortex. In 1776, Francisco Gennari pro-
vided the first indication that the cortex was not homo-
geneous by describing a white stripe, later known as
the stria of Gennari, that was especially prominent in
the area we now know as primary visual cortex, “striate
cortex,” or V1.4 Subsequently, evidence from multiple
disciplines converged on the conclusion that this area of
occipital cortex was associated with the sense of vision.5
This included anatomical work by Gratiolet (1854) and
later by Flechsig (1886) that identified that the optic ra-
diations targeted the same area that had been identi-
fied by Gennari, and experiments in animals by Munk
(1881) and Shafer (1888), which showed a loss of vision
associated with lesions of this area.5,6 Furthermore, by

219
220 SECTION II SYSTEMS
extensive study of clinical cases, Henschen identi-
fied damage to this area as causing homonymous
hemianopia.7 Henschen, also introduced the idea of the
“cortical retina” and was able to correctly map the lower
retina (upper visual field) to the lower bank of the cal-
carine fissure, and the upper retina (lower visual field)
to the upper bank.7,8 However, he incorrectly located
the foveal representation to the anterior portion of the
cuneus.7
A more accurate depiction of how the visual field
is mapped onto the cortex resulted from the work of
Inouye, who studied the visual field deficits produced
by focal lesions to the cerebral cortex sustained by sol-
diers in the Russo-Japanese war, and then Holmes, who
studied similar patients from World War I.8−11 Inouye
and Holmes corrected Henschen’s mistake by placing
the cortical representation of the fovea near the poste-
rior pole of occipital cortex, and the peripheral represen-
tation further anterior in the cuneus. The Holmes map
was the standard for many years until it was updated
by use of magnetic resonance imaging (MRI) to exam-
ine the location of lesions associated with specific visual
field deficits.12
Further refinements of our understanding of the
retinotopic organization of primary visual cortex came
from animal experiments that used evoked poten-
tials recorded from contacts placed on the cortical
surface.13,14 These investigations revealed the large over-
representation of the fovea in primary visual cortex, and
were the first to formally introduce the idea of the corti-
cal magnification factor, which is a quantitative descrip-
tion of the physical amount of visual cortex that rep-
resents one degree of the visual field. Later work by
Hubel and Wiesel revealed that a columnar organiza-
tion of cells with similar response properties existed in
primary visual cortex,15 as had been demonstrated in
the somatosensory cortex,16 and that not only the loca-
tion of an object in visual space, but other features such
as the orientation of a stimulus are precisely mapped
across the cortical surface.17 The ability of activity in lo-
calized portions of human primary visual cortex to actu-
ally support the perception of a simple visual sensation,
or phosphene, in a corresponding part of visual space
was uncovered with electrical stimulation studies con-
ducted by Penfield,18 Brindley and Lewin,19 and Dobelle
and Mladejovsky.20
Later, the demonstration that visual space is mapped
not once but many times in the cerebral cortex initially
came from electrophysiological investigations in nonhu-
man primates. The response properties of cells in these
areas, and the connections between areas, have been
used to sort these visually responsive areas into path-
ways and hierarchies.21−23
The ability to demonstrate the complete map of
visual space using noninvasive techniques in humans
emerged with the development of positron emission
tomography (PET) technology.24−26 However, this tech-
nique requires the injection of radioactive tracers, and
has limited spatial resolution. The development of func-
tional MRI (fMRI) allowed for the truly noninvasive and
accurate mapping of visual cortex in humans.27−30 Imag-
ing studies in humans and monkeys have revealed many
similarities in the organization of visual cortex between
the two species, especially for early visual areas such as
V1 and V2, but have also highlighted important differ-
ences in functional organization of the two species that
appear as early as V3 and V3a.27,31−33
Intracranial recordings from subdural electrodes
placed during clinical monitoring of epilepsy patients
offer a unique opportunity to directly measure electrical
activity from human visual cortex and have been used
to confirm and extend observations made by monkey
electrophysiology and human fMRI.34,35
䉴 NEUROANATOMY,
NEUROPHYSIOLOGY, AND
ORGANIZATIONAL PRINCIPLES
OF VISUAL CORTEX
ANATOMY AND PHYSIOLOGY
There are a number of pathways in the brain that
incorporate information transmitted by light. Some of
these pathways involve the control of circadian rhythm
or pupillary reactivity, and function relatively indepen-
dently of conscious awareness. In this chapter, we will
only consider pathways directly relevant to perceptual
processing of visual objects, although the other path-
ways may be important in clinical settings.36,37 Much
of our understanding of the perceptual processing of
visual objects originates from studying nonhuman pri-
mates; while, many findings in visual cortex of nonhu-
man primates may be generalized to humans, important
differences do exist and should be considered.38
Visual processing begins when information from
the environment reaches the receptive field of photore-
ceptors in the retina (see Fig. 16–1).39 These receptors
(which consist mostly of rods and cones) transmit their
responses to retinal ganglion cells (RGCs) through spe-
cialized interneurons (bipolar cells). Axons of the RGCs
form the optic nerve and travel to the optic chiasm where
inputs from the nasal retina cross over to the contralat-
eral hemisphere, while inputs from the temporal retina
continue ipsilaterally. After this partial decussation at
the optic chiasm, the visual fibers then travel via the
optic tract to synapse in (1) the lateral geniculate nu-
cleus (LGN) of the thalamus, and (2) the superior col-
liculi of the midbrain. The latter projections to the col-
liculi are important in controlling saccades, or fast eye
movements, and are not thought to be directly involved
in visual perception.40 From the LGN, magnocellular
 CHAPTER 16 MAPPING OF THE HUMAN VISUAL SYSTEM 221

Right visual field

Left visual field

Temporal

Nasal
Temporal

Optic
chiasm

Amygdala

Pulvinar nucleus

Lateral geniculate
nucleus
Superior colliculus

Optic radiation

Primary visual
cortex

Figure 16–1. Visual pathways from retina to primary visual cortex. Light from the right
visual field (shown in blue) is projected onto the nasal hemiretina of the right eye and
the temporal hemiretina of the left eye. Axons of the retinal ganglion cells (RGCs) form
the optic nerve. Those from the nasal retinal ganglion cells, cross the midline at the
level of the optic chiasm, while those from the ganglion cells of the temporal retina
remain ipsilateral. After the optic chiasm, the axons of the contralateral nasal RGCs
and the ipsilateral temporal RGCs form the optic tract. The majority of these axons will
synapse in the lateral geniculate nucleus (LGN), while some will synapse in the
superior colliculus (shown as dotted lines). The superior colliculus is thought to play
roles in saccades and papillary control. After forming synapses in the LGN, the
postsynaptic cells will send axons (which form the optic radiations) to the ipsilateral
primary visual cortex. The optic radiations are split into a superior and inferior divisions
(not shown), which are important in considering clinical resections. (Reproduced with
permission of WM Norton & Company, from Gazzaniga MS, Ivry RB, Mangun GR.
Cognitive Neuroscience: The Biology of the Mind. Vol 1. New York: Norton, 2002,
(various pagings).

(M-cells, specialized for high-contrast and noncolored
stimuli) and parvocellular (P-cells, specialized for low-
contrast and color stimuli) cells send projections through
the retrolenticular fibers of internal capsule and then,
via the optic radiations, to layer four of the primary
visual cortex, located along the banks of the calcarine
fissure in the occipital lobe.41 A third pathway originat-
ing from koniocellular cells of the LGN also projects
via the optic radiations and appears to carry specific
color information to the superficial layers of V1, and
to portions of extrastriate cortex.42,43 Before terminat-
ing in the occipital lobe, the optic radiations split into
a superior division that forms the retrolenticular limb of
the internal capsule and ends in the upper bank of the
calcarine sulcus (cuneus), and an inferior division that
travels through the temporal lobe (Meyer’s loop) and
ends in the lower bank of the calcarine sulcus (lingual
gyrus). Following V1, processing continues in a large ar-
ray of other visual cortical areas.44,45 Figure 16–2 gives an
indication of the complexity of the primate visual system,
222 SECTION II SYSTEMS

Figure 16–2. Hierarchy of visual areas in the macaque monkey. In addition to the
retina and the lateral geniculate nucleus, over 30 areas of the cerebral cortex are
thought to play a role in visual information processing. Most of the connections shown
have been shown to be bidirectional. The order of each area within the visual
hierarchy was established by an analysis of the laminar specificity of feed-forward,
feedback, and lateral connections. (Reproduced with the permission of Oxford
University Press, from Felleman DJ, Van Essen DC. Distributed hierarchical processing
in the primate cerebral cortex. Cereb Cortex 1991;1(1):1–47.)

as demonstrated by the number of reciprocal subcorti-
cal and cortical anatomical connections among the more
than 30 visual areas that have been identified in the
macaque monkey.46
Beginning early on in the hierarchy of visual cortex,
there is an organized segregation of information into two
functionally specialized streams, or pathways, that deal
with different aspects of visual processing.23 Following
primary visual cortex, these two pathways diverge and
follow routes that proceed toward either more dorsal
or ventral aspects of the cerebral cortex. This physical
and functional segregation appears to be well conserved
between nonhuman primates and humans.38 Fig. 16–3
provides a schematic illustration of this model of cortical
organization.47
In humans, the ventral stream lies in the occipi-
totemporal areas of the cerebral cortex. This pathway
is commonly referred to as the “what” pathway because
it is involved in processing of object color and form, and
in object recognition. From V1 at the occipital pole, the
 CHAPTER 16
Figure 16–3. Parallel processing in the visual system.
This highly simplified schematic indicates the main
flow of information through two processing streams
that are thought to contribute to the perception of
object location (the “where” pathway also known as
“dorsal,” or “parietal”), and object shape and color
(the “what” pathway, also known as “ventral,” or
“temporal”). LNG, lateral geniculate nucleus.
(Reproduced with the permission of Lippincott
Williams & Wilkins, from Ozdemir A, Black PM.
Mapping of Human Visual Cortex. Neurosurgery
Quarterly 2005;15(2):65–71.
ventral stream projects to V2, V3, hV4, and on to the
inferior temporal lobe (IT), in a generally posterior to
anterior projection. The “h” in hV4 is used to differen-
tiate this human visual area from macaque V4, as there
is considerable debate about the homology of this area
between species.1
The dorsal stream, often called the “where” path-
way, is involved in processing object location, object
motion, and control of the eyes and arms, especially
when visual information is used to guide motor behav-
iors (saccades or reaching). Beginning at V1, the dorsal
stream projects to V2 and V3, V5/hMT+ (analogous, but
not entirely the same as area MT/V5 in the macaque)
in the medial temporal area, and to the inferior parietal
lobule.48
The schematic shown in Fig. 16–3 is highly simpli-
fied, and there is considerable evidence to suggest that
the ventral and dorsal streams are not completely seg-
regated, or functionally independent, as there are sig-
nificant interactions among the two pathways at multi-
ple stages.22,49−51 Specifically, it would be inappropriate
to think of the dorsal and ventral streams in the cor-
tex as simple continuations of the pathways begun in
the retina. Instead, a recombination of input from the
MAPPING OF THE HUMAN VISUAL SYSTEM 223
magno-, parvo-, and koniocellular is created in the V1
that is then fed into these two streams in specific ways.52
ORGANIZATIONAL PRINCIPLES
In addition to the division of visual processing into dorsal
and ventral streams (where and what pathways), there
are other important principles that underlie the organi-
zation of visual cortex, and which are useful for map-
ping visual areas. Retinotopic organization is a recurrent
motif, and is perhaps the most important principle in
identifying and delineating discrete visual areas. Visual
areas are said to be retinotopically organized, if there
is a structured correspondence between points on the
retina (and hence the visual field) and points in the cor-
tex. For example, in V1, as already noted, the upper
bank of the calcarine sulcus responds strongly to stimu-
lation in the lower half of the visual field, and the lower
bank of the calcarine sulcus responds to stimulation of
the upper half of visual field. In general, within each
visual area, we expect to find only one map of visual
space, and we expect most parts of visual space to be
represented, although not necessarily equally. The most
obvious departure from equal representation is the large
overrepresentation of the central visual field in V1 where
the central 10◦ of the visual field occupies about half of
the surface area of V1.12
Retinotopic mapping techniques use visual stimu-
lation of a set of different points in the visual field to
reconstruct the representation of the visual field on the
cortex. Since many visual areas contain retinotopic
maps, this organization can then be used to define and
label the borders of individual visual areas. The vertical
and horizontal meridians of the visual field often define
the border between two visual areas. A subset of the to-
pographically organized visual areas are presented on a
three-dimensional model of the occipital–temporal cor-
tex and on a flat map in Fig. 16–4.53
For individual locations within a visual area, the re-
ceptive field of that site can be defined as the region of
visual space that will drive significant activity from the
site in question when stimulated with a suitable stim-
ulus. For example, Fig. 16–5 depicts the determination
of the receptive field for a site located on the lateral
surface of occipital cortex of a human subject recorded
with a standard clinical subdural (cortical surface) elec-
trode (2.2 mm diameter recording surface) using a small
checkerboard stimuli.35
Another important organizational principle is that
the visual system processes information in a hierarchi-
cal manner. The strongest evidence that the cortex is
organized in this manner comes from the study of feed-
forward, feedback, and lateral connections between vi-
sual areas. These connections terminate in a stereotyped
fashion in each cortical area, and can be used to trace
224 SECTION II SYSTEMS

B F

A C D E G

Figure 16–4. Functional specialization in human visual cortex. (A) Topographically

organized visual areas shown on a flat map of occipito-temporal cortex in the Visible
Man. (B) The same areas on a medial view of the occipital lobe. (C) The same regions
on a lateral view of the hemisphere. (D) Cortical regions implicated in processing of
color. Green dots denote centers of activation foci, and lighter green denotes cortex
with the 10-mm uncertainty limit. (E) Cortical regions implicated in the processing of
motion (M); form (F); form and color (FC); form and motion (FM); and motion, color,
and spatial relations (MCS). Question marks denote additional regions potentially
involved in processing of color (green), motion (red), and spatial relations (yellow ).
(F) The same functional specializations shown on lateral and ventral 3D views. (G) The
same pattern on extensively smoothed surfaces. (Reproduced with the permission of
the National Academy of Sciences, from Van Essen DC, Drury HA, Joshi S, et al.
Functional and structural mapping of human cerebral cortex: solutions are in the
surfaces. Proc Natl Acad Sci USA 1998;95:788–795.

the main routes of information flow through the cortex.46
Corresponding with this anatomically defined hierarchy,
there are a set of functional changes that are observed
with movement further along the cortical hierarchy.
These changes include larger receptive fields, longer
response latencies, more complex response proper-
ties, and less orderly visual field maps. For example,
within the ventral pathway, visual processing begins in
V1, which has short response latencies, small receptive
fields, and which can be activated by relatively simple
visual stimuli such as lines or gratings. Visual process-
ing in later areas of the ventral pathway tends to have
longer latencies, larger receptive fields, and requires
more complex stimuli for activation, such as objects or
faces.
Parallel processing is another guiding organizational
principle for understanding the visual system. Parallel
processing, or organization, exists at many levels within
the visual cortex. As we have already discussed, at a
coarse level, the visual system processes information si-
multaneously through multiple pathways.23,48 Further-
more, within each pathway, a single visual stimulus typ-
ically activates at least several different cortical areas. At
a still finer level, parallel processing occurs within each
retinotopically organized visual area, since columns of
cells within each part of the area process information
for different parts of the visual field in a largely parallel
fashion.
One final principle of functional organization that
is important to mention is that there are likely to be
multiple features that are mapped within each area. For
example, in primary visual cortex, it is not just visual
space that is mapped across the surface, but also ori-
entation preference, and ocular dominance. Orientation
preference refers to the fact that each column of cells in
V1 tends to respond best to lines or contours placed at
a particular angle or orientation in the visual field. Oc-
ular dominance refers to the fact that inputs from the
contralateral and ipsilateral eye are routed through spe-
cific layers of the LGN and then to partially segregated
columns of cells in V1. To fully predict the responses of
a given site in V1, it is therefore necessary to know not
just the receptive field of that site, but also the preferred
orientation and ocular preference. Other visual areas are
likely to contain maps of other stimulus features, and it
appears that mapping of these features dominates over
 CHAPTER 16 MAPPING OF THE HUMAN VISUAL SYSTEM 225

C
A

Figure 16–5. Quantitative characterization of receptive fields in human visual cortex

measured with subdural electrodes. (A) Average voltage response (black curves) and
99% confidence intervals (gray shaded regions) for each of the 36 visual field
locations tested for one electrode located on the lateral surface of the occipital cortex
near the occipital pole (red circle on schematic). Each panel shows the time period
from 0 to 200 milliseconds after stimulus onset. Stimulus duration was 200
milliseconds. (B) Root Mean Squared (RMS) voltage calculated for each position using
the time interval between 40 and 200 milliseconds after stimulus onset. One level of
interpolation has been used for presentation of the RMS data resulting in an 11 × 11
grid rather than a 6 × 6 grid. (C) The best fit two-dimensional Gaussian envelope to
the data shown in panel B. The black ellipse indicates the half maximum response
contour. (Reproduced with the permission of Oxford University Press, from Yoshor D,
Bosking WH, Ghose GM, Maunsell JH. Receptive fields in human visual cortex
mapped with surface electrodes. Cereb Cortex 2007;17(10):2293–2302.

accurate mapping of the visual field at later stages in
visual processing. The importance of understanding the
underlying fundamental maps in each area of cortex for
understanding data from fMRI experiments is reviewed
by Op de Beeck et al.54
䉴 MAPPING METHODS
Technological advances have revolutionized the map-
ping of visual cortex by providing invaluable invasive
and noninvasive tools to infer localized brain function in
vivo. For example, with the advent of modern mapping
methods, as many as 16 visual areas have been identified
with retinotopic mapping in human cortex (see Wandell
et al. for a review).1 Each mapping method has relative
strengths and weaknesses relating to properties such as
the invasiveness of the procedure, the ability to use mul-
tiple sets of stimuli, the spatial and temporal resolution
of the technique, and the type of signal that is being
measured.
In this section, we begin with a discussion of
anatomical and structural imaging techniques that are
useful for localization of visual areas, briefly describe
functional neuroimaging methods useful for mapping
human visual cortex, provide interesting examples from
human research with healthy controls in the study of
the visual system, and then discuss important issues to
226 SECTION II SYSTEMS

A B

Figure 16–6. Relating structural magnetic resonance imaging (MRI) to functional

visual cortex. (A) Coronal MRI of occipital lobe cortex. (B) Arrangement of V1, V2, and
V3 visual cortices, as well as connections between them. (Reproduced with the
permission of Elsevier, from Wichmann W, Müller-Forell W. Anatomy of the visual
system. Eur J Radiol 2004;49(1):8-30.)

consider when using the these methods to map the vi-
sual system in health and disease.
STRUCTURAL IMAGING
Before the era of functional neuroimaging, brain map-
ping researchers correlated behavioral impairments with
structurally defined lesions to characterize the relation-
ship between visual function and neuroanatomy. As de-
scribed earlier, this method was used initially to help
identify the location and organization of primary visual
cortex, and more recently it has been used to study
localization of function within extrastriate areas. For ex-
ample, cerebral achromatopsia, a loss of ability to dis-
criminate color, was associated with MRI defined le-
sions to occipital–temporal cortex,55,56 which suggested
the existence of a color center in the human brain.57
Problematically, this method is often imprecise for map-
ping human visual cortex because even relatively focal
lesions routinely affect more than one functional area
of the visual system. Also, studies that rely on lesions
or inhibition of activity in a particular area can only
be used to show the necessity of that area for a par-
ticular function, and not sufficiency.58 Nonetheless, le-
sion studies have made seminal historical contributions
to our understanding of the visual brain, and continue
to make contributions to our understanding of cortical
function.56
Today, structural imaging methods play an impor-
tant role by providing precisely detailed neuroanatomy
that can be co-localized with data from functional
studies. Systems such as Analysis of Functional Neu-
roimaging (AFNI) and other software suites allow for
functional data to be easily fused with anatomical data in
three-dimensional reconstructions of the brain surface.
Regardless of the functional imaging or recording tech-
nique used, structural MRI and computed tomography
(CT) identified structures provide a common reference
frame to estimate neural activity. Structural MRI can now
be used to provide detailed anatomical information with
a spatial resolution as small as 1 mm3 ,28 and at a min-
imum, can be used to identify typical sulci or gyri that
are located near particular visual areas. In some cases,
high-resolution structural MRI has even been used to re-
veal differences in cytoarchitectonics, which can help
identify particular visual areas. For example, Fig. 16–6
shows typical surface-based landmarks identifiable on
structural MRI for the locations of V1, V2, and V3 within
cortical folding along the calcarine fissure.59 Talairach
and Tournoux coordinates are used with neuroimaging
data to provide standard coordinate system based on
gross morphology.60 A limiting factor in combining data
across multiple subjects is that brain topography varies
 CHAPTER 16 MAPPING OF THE HUMAN VISUAL SYSTEM 227

among individuals. To overcome this problem, unique

methods such as surface warping have been utilized to
make population averages of cortical areas based on
landmarks such as cortical folds.53,61,62
A relatively novel use of MRI, diffusion tensor imag-
ing (DTI), can be used to model the restricted movement
of water molecules diffusing within a given volume of
neural tissue.63 By subjecting tissue to multiple magnetic
field gradients, a tensor (or matrix) can be formed that
can estimate the amount of diffusion of water in any
arbitrary direction. Since the diffusion of water in neu-
ral tissue is direction-dependent, or anisotropic, being
greatest in the direction of white matter tracts, this tech-
nique can be used to predict the local trajectory of a
given white matter path found within a particular voxel.
By starting at one voxel in the imaged area and then
following the predicted trajectory from voxel to voxel, it
is possible to trace an entire white matter pathway from
one structure to another within the brain using this tech-
nique. One advantage of this methodology is that it can
be easily combined with both structural MRI and fMRI,
and allows for careful visualization of the white matter
tracts, which are not as well delineated using structural
MRI technology63−66 (see Fig. 16–7). This method has
been particularly useful in tracing the optic radiations
(see later), and is readily integrated into surgical naviga-
tion systems for guiding intraoperative dissection.

FUNCTIONAL NEUROIMAGING

Functional neuroimaging techniques are now standard

tools used to study visual cortex, both for research pur-
poses and to guide clinical decision-making. Functional
imaging of visual cortex in healthy subjects continues to
advance our understanding of the organization and func-
tion of various parts of the visual system. These imaging
techniques have been used to identify the location of,
and boundaries between, specialized areas of visual cor-
tex, and to study the specificity of the responses in those
areas. Data from healthy controls also provide a basis
to better understand the impact of clinical problems on Figure 16–7. Tractography and magnetic resonance
brain function. In this section, we review how advanced imaging. (Top) Bihemispheric reconstructions of the
imaging techniques, in particular fMRI, have been used optic nerve and tract (red) as well as of the optic
to map human visual areas in healthy subjects. Many of radiation (yellow ). (Bottom) Dissection of the optic
radiation into Meyer’s loop (yellow ), central bundle
these methods are readily applied to patients as well.
(green), and dorsal bundle (blue). R, right; L, left.
(From Hofer S, Karaus A, Frahm J. Reconstruction
Functional MRI and dissection of the entire human visual pathway
using diffusion tensor MRI. Front Neuroanat
fMRI allows localization of task-related neural activity by
2010;4:15.)
measurement of changes in blood flow and blood oxy-
genation levels (the blood oxygenation level dependent
(BOLD) signal or response).67 Because fMRI is noninva- One of the first uses of fMRI was to identify and
sive, has high spatial resolution, and can be used with differentiate the borders of multiple retinotopically orga-
many different tasks and visual stimuli in the same sub- nized areas with high-spatial precision (e.g., Fig. 16–4).
jects, it has become one of the dominant tools for study The stimuli used in these experiments are typically
of the visual system. small checkerboard or grating stimuli that elicit robust
228 SECTION II SYSTEMS
responses from sites in early visual cortex. By slowly
moving these stimuli to different locations in the visual
field, and analyzing the time course of the fMRI response
from each voxel, it is possible to reconstruct the region of
the visual field that best stimulates each location within a
particular visual area. This procedure, known as “phase-
encoding,” is an extremely powerful technique since it
enables generation of high-resolution visual field maps
simultaneously for multiple visual cortical areas in a rel-
atively short period of time.27−30 Before the advent of
fMRI and the development of phase-encoding stimu-
lation and recording techniques, to create these maps
would have required tens or hundreds of electrode pen-
etrations painstakingly acquired in animals, and simply
would not have been possible in humans.
Visual cortical areas contain maps of the visual field
that are either mirror images of the world, or nonmirror
images. Reversals in the direction of mapping of visual
space across the cortical surface, and the location of
changes from mirror image to nonmirror image repre-
sentations can be used to establish the borders between
visual areas.29,30 By using fMRI, and varying both the
nature of the task for the subject, and the type of visual
stimuli used, retinotopic organization has been found
not only in early areas in the occipital cortex such as V1,
V2, and V3, but also areas in the lateral occipital cortex
(LOC) (LO-1, LO-2, hMT+), the ventral occipital cortex
(hV4, VO-1, VO-2), dorsal occipital cortex (V3a, V3b),
and the posterior parietal cortex (IPS 0–4) (list and ter-
minology from Wandell et al.).1 Interestingly, visual areas
appear to occur in clusters, with shared borders that rep-
resent one of the visual meridians, and confluent repre-
sentations of the fovea.68−70 The high-spatial resolution
of fMRI also allows researchers to study spatial organiza-
tion and functional specificity of processing within visual
areas. For example, while the measurement of orienta-
tion columns in humans is still slightly beyond the capa-
bility of fMRI, ocular dominance columns in V1, which
are approximately 500 microns in width, have been im-
aged using 4T or 7T magnets.71,72
fMRI has been used extensively to examine how
stimulus properties such as color, motion, and object
category are represented in the visual cortex. In the
case of color, fMRI studies have suggested the existence
of several different specialized areas in an organized
stream beginning with primary visual cortex and extend-
ing through V4,73 V8,74 and LOC.75 For motion, fMRI
has demonstrated the existence of an area (or complex
of related areas) known as hMT+ that is an analogue to
monkey area V5/MT.76,77 Because of the excellent spatial
resolution of fMRI, it has been possible to identify subre-
gions within hMT+ that are selective for different types
of motion, such as radial and circular motion.78 These
subdivisions may correspond to area MT and the other
motion sensitive areas that surround MT in the monkey
such as MST and FST.79 Grossman and colleagues have
described an additional motion sensitive area anterior to
hMT+ on the ventral bank of the occipital extent of the
superior temporal sulcus that responds specifically to bi-
ological motion (i.e., the motion of people and animals)
compared to nonbiological motion.80
Perhaps the largest amount of fMRI research has
focused on studying the object selectivity of the hu-
man visual system.81,82 fMRI has been used to docu-
ment a region within the LOC that responds selectively
to objects.83,84 Ventral to the LOC exist two regions de-
scribed by Kanwisher and colleagues, the fusiform face
area (FFA)81 and parahippocampal place area (PPA).85
These areas, as their names imply, respond specifically
to identifying faces and places, respectively. The FFA is
consistently located at the fusiform gyrus and demon-
strates a strong foveal bias, while the PPA is closer to
the parahippocampal gyrus and has a more peripheral
visual field bias. More dorsally, there are also areas that
respond to objects located around areas V3a and V7, but
these areas are poorly understood. Grill-Spector et al.
have shown with high-resolution imaging that a patchy
organization exists in FFA such that both objects and
faces are processed in this area, but that the informa-
tion may be averaged out only showing the most robust
“face” signals.57 Haxby et al.82 proposed a distributed
neural network associated with the processing of faces
(see Fig. 16–8) that initially incorporates primary visual
cortex, superior temporal sulcus, and fusiform gyrus, but
then incorporates areas such as amygdala, anterior tem-
poral lobe, and insula based on the requirements of the
visual facial stimuli (e.g., processing an angry face incor-
porates the amygdala).
Methodologically, although fMRI has good spatial
resolution, on the order of 1 mm, the temporal resolu-
tion is limited by changes in cerebral blood flow (CBF)
and is on the order of seconds. That is, although fMRI
data can be collected at 50–100 millisecond intervals, the
slow changes in blood flow limit the conclusions that can
be made about the temporal characteristics of functional
visual areas. Event-related fMRI has helped to resolve the
temporal resolution issue, but as with any method based
on blood flow or other measures of metabolic demand,
fMRI will always be an indirect measurement of neuronal
function. Other advantages of fMRI include that it is non-
invasive, does not require isotope injection (e.g., PET),
and affords better spatial resolution and localization than
visual evoked potentials (VEPs) or PET. Furthermore, re-
peating testing with different tasks or stimuli is easily
possible in each subject.
Positron Emission Tomography
A PET scanner quantifies regional CBF (rCBF) or
metabolism during voluntary behavior. Clinically, PET
imaging is used to identify brain regions with re-
duced metabolism or decreased blood flow, which in
turn suggests functional impairment. Fluorine-18 fluo-
rodeoxyglucose (FDG) is the most widely used PET
 CHAPTER 16 MAPPING OF THE HUMAN VISUAL SYSTEM 229

Figure 16–8. A model of the distributed human neural system for face perception.
This model consists of a core system, which consists of three regions of the visual
extrastriate cortex, and an extended system, which consists of components
important for other cognitive functions. Note bidirectional relationships of many of the
constituents. (Reproduced with the permission of Elsevier, from Haxby JV, Hoffman
EA, Gobbini MI. The distributed human neural system for face perception. Trends
Cogn Sci 2000;4(6):223–233.

tracer in a clinical setting to evaluate cortical glucose
metabolism. Oxygen-15 (O-15) is a PET tracer used to
evaluate CBF that is more commonly used in experi-
mental settings because of its short half-life (2 minutes),
which makes it better suited for studies that require rapid
and repeated presentation of visual stimuli.86
PET methodology has several strengths and weak-
nesses when localizing functional areas of visual cortex.
PET spatial resolution, while not as good as fMRI, is on
the order of several millimeters, especially with the ad-
vent of technology that makes it easier to co-localize
PET scans with anatomic CT and structural MRI. As with
fMRI, PET has poor temporal resolution, which is a ma-
jor limitation because the visual system processes infor-
mation quickly. Another limitation is that PET requires
radioactive marker substances to be injected into the
subject’s bloodstream. Also like fMRI, PET provides an
indirect estimate of neuronal activity based on hemo-
dynamic parameters (CBF, blood volume, and oxygen
content). As discussed later, other methods, like magne-
toencephalography (MEG), VEP, and subdural grids ac-
tually measure neuronal electrical activity. Although PET
was the imaging technique first used to noninvasively in-
vestigate the functional organization of visual cortex, it
has now largely been replaced by fMRI for this purpose.
OTHER NONINVASIVE METHODS
Magnetoencephalography
MEG attempts to localize brain activity by recording mag-
netic fields generated by electrical activity, or local field
potentials (LFPs), that become synchronized in response
to a given activity.87 However, the spatial resolution of
MEG has traditionally been poor, due to the nonunique-
ness of the inverse problem of trying to ascribe current
dipoles to the magnetic fields measured. To overcome
this problem, MEG can be combined with structural MRI
in a method called magnetic source imaging.
The main advantage of MEG over other methods
is better temporal precision. Because of this property,
some have used it to attempt to unravel the temporal
sequence of neural activation in various brain areas dur-
ing visual perception. The waveform elicited by visual
stimuli (i.e., the visual evoked magnetic field or VEF)
is used to quantify the location and latencies required
in processing the information. There has been consid-
erable work trying to assign particular VEF waveforms
to certain areas of visual cortex.88−90 One problem with
MEG is that it can incorrectly assign neuronal activity
when multiple areas of visual cortex are responding
simultaneously.91
Visual Evoked (or Event-Related)
Potentials
VEPs are another noninvasive approach to mapping vi-
sual cortex. The method capitalizes on measuring whole
brain scalp waveform recordings of EEG data in re-
sponse to a time-locked visual event.92 By studying
normal controls, the location and latency of several spe-
cific waveforms from visual cortical areas have been de-
termined. The timing of different peaks and valleys of
230 SECTION II SYSTEMS
waveforms are thought to provide a signature of the
hierarchical timing (as with MEG technology) of the pro-
cessing of different visual stimuli. While this methodol-
ogy has good temporal resolution, its spatial resolution
is highly limited. Recently, there has been an interest in
trying to differentiate different visual pathways based on
spectral analysis of the VEP waveforms.93
Transcranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) involves place-
ment of an electromagnetic coil on the scalp and then
high-intensity electrical current is rapidly turned on and
off in the coil through the discharge of capacitors. The
goal is to provide focal magnetic stimulation to a specific
brain region. TMS involves either stimulating local exci-
tation of neurons, leading to an overt behavior, or local
suppression of neurons leading to cessation of an ongo-
ing behavior. Elicitation or suppression of behavior is de-
pendent on stimulation parameters (frequency, intensity,
pulse duration, stimulation site). Effective interference of
stimulation of visual cortex by TMS is often confirmed
when reaction time is slower when performing a visual
task compared to reaction time on the task without stim-
ulation. TMS of visual cortex has been used to induce
phosphene perception,94,95 which subjects typically de-
scribe as a flash of gray or white light. TMS has also
been used to interfere with the visual perception of form
by stimulation of striate96,97 and extrastriate cortex.98 It
has also been used to interfere with the perception of
motion99 and with visual memory100 in healthy subjects.
DIRECT CORTICAL STIMULATION
Mapping with direct cortical stimulation (DCS) typically
involves the manually controlled delivery of suprathresh-
old electrical current to a discrete area of the brain. These
procedures are performed either intraoperatively or from
chronically implanted subdural grid or strip electrodes
in patients undergoing extended exploration to better
characterize a seizure focus. As with TMS, DCS involves
either the generation of an overt behavior or percept that
the patient can report, or the disruption of performance
in some sort of task. DCS is considered a gold standard
for mapping cortical functions when used to stimulate
overt behavior. Unlike methods that assess subject per-
formance following a lesion or inhibition of a particular
brain area, which only proves necessity, DCS stimulation
of an overt behavior strongly suggests the sufficiency of
the stimulated region of cortex, or at least of a small net-
work including that region of cortex, for the production
of that behavior.
DCS with cortical surface electrodes has been ap-
plied to characterize visual function in the occipital and
temporal cortex of patients. These studies have em-
ployed standard clinical DCS techniques, both in the
operating room, or extraoperatively using the standard
clinical electrodes implanted for monitoring of epilepsy
patients (electrodes with a recording surface diameter
of about 2.2 mm). The level of current employed was
also in the standard milliampere range that is routinely
used for DCS mapping in the clinical arena. Several stud-
ies have reported that DCS of specific cortical areas can
inhibit specific visual perceptual abilities. For example,
Allison et al. (1994) and Mundel et al. (2003) reported
that DCS of the fusiform gyrus produces a temporary
inability to name famous or familiar faces.34,101 Further-
more, Blancke et al. reported that DCS of area hMT+/V5,
the visual area that responds selectively to visual mo-
tion, results in the bias of a patient’s perception of visual
motion.102
DCS of visual cortex has also been shown to elicit vi-
sual percepts. For example, Lee et al. reported inducing
(1) the percepts of geometric shapes, triangles, and dia-
monds with DCS to lateral occipital gyrus and fusiform
gyrus, (2) color perception with DCS to lingual gyrus,
fusiform gyrus, and interior occipital gyrus, and (3) the
perception of movement with DCS to the basal temporal-
occipital junction, lateral posterior temporal cortex and
occipital pole.103
While traditionally DCS studies have reported only
qualitative information about subject percepts follow-
ing stimulation, it is possible to design studies to pro-
vide more quantitative information about the efficacy
of stimulation at each site tested. Murphey et al. per-
formed a systematic study using DCS in subjects with
implanted subdural electrodes undergoing extraopera-
tive monitoring for epilepsy.104 In addition to noting
any visual percepts elicited by DCS, they also used
two alternative forced choice psychophysical methods
to quantify the level of current required for the sub-
jects to perform above chance in detecting the electrical
stimulation. DCS of early visual areas, such as V1 and
V2, was found to reliably elicit the perception of visual
phosphenes, while similar stimulation of later visual ar-
eas, even with higher currents, rarely elicited a verifiable
visual response. However, in the rare examples in which
a percept was elicited by DCS of a later visual area, per-
cepts were still generally reported to be phosphenes,
more complex than phosphenes generated in early vi-
sual areas, but not complex visual objects or scenes. In-
terestingly, for sites where DCS did elicit visual percepts,
the amount of current necessary to elicit the percept
did not vary significantly across the hierarchy of visual
cortex.
Overall, DCS is useful for identifying early visual
cortex, but does not appear to reliably distinguish be-
tween different visual areas. It does remain a useful tech-
nique for studying visual cortex because, unlike other
mapping methods, which only demonstrate correlations
between visual stimulation and cortical activity, DCS
 CHAPTER 16
stimulation can demonstrate a causal relationship be-
tween brain activity and visual perception. Perhaps in
the future DCS will prove even more useful in dissecting
extrastriate visual cortex if it is employed while subjects’
engaged in various controlled visually guided behaviors.
LOCAL FIELD POTENTIAL
RECORDINGS FROM INTRACRANIAL
ELECTRODES
LFPs evoked by visual stimulation are readily recorded
with the subdural electrodes that are used clinically
to characterize epileptic foci in patients. A handful of
papers have studied LFP responses to map recep-
tive fields using subdural electrodes of primary visual
cortex35 or to study later visual areas in response to faces
and objects.34,105 In a set of classic papers, McCarthy and
associates106−108 were able to show robust event-related
potentials at 200 milliseconds latency (N200) in human
ventral temporal cortex in response to face stimuli, and
were able show specificity and modulation of this signal.
In another study, Yoshor et al. were able to precisely
map spatial receptive fields in human visual cortex us-
ing small checkerboard stimuli presented while patients
performed a letter detection task at the fixation point.
They showed that receptive fields increased in size when
moving from V1 to later visual areas in ventral occipi-
tal cortex, and that there was a concomitant increase in
response latency, as would be expected for later visual
areas.35 Furthermore, small but orderly changes in recep-
tive field location could be measured for successive con-
tacts on the same subdural recording strips. These exper-
iments suggest that with improvements in the size and
spacing of electrical contacts on recording grids or strips
it should prove possible to perform detailed mapping in
visual cortex of these subjects.
Finally, recording of LFPs from subdural electrodes
has also been used to study the degree to which spatial
attention can cause modulation of visual responses in
early visual cortex.109 This is an example of how record-
ing of LFPs from these electrodes can be used as a bridge
between single-unit electrophysiological studies in mon-
keys and fMRI experiments in humans, which had pro-
duced conflicting results on this issue in the past.
Thus, although there are a limited number of oppor-
tunities to record from patients who have electrodes im-
planted over visual cortex, these electrodes can provide
extremely valuable information when they are available.
CONCORDANCE ACROSS METHODS
There is now a huge amount of information from many
sources about the general importance of the occipital
cortex for vision, and of the importance of primary visual
MAPPING OF THE HUMAN VISUAL SYSTEM 231
cortex in particular, for generation of visual percepts. Ex-
periments using fMRI, subdural LFP recordings, and DCS
in humans, as well as single-unit electrophysiology and
lesion work in monkeys, are all in concordance on this
general point. But, even for V1, there are discrepancies
when we move from asking about the basic response
properties, or the basic ability of this area of cortex to
support vision, to more complicated issues such as the
ability of spatial attention or task demands to modu-
late activity. For example, fMRI experiments have shown
large effects of changing spatial attention on the activity
measured in V1, while single-unit studies in monkeys,
and LFP recordings from subdural electrodes in humans
have shown only very small effects.109
These discrepancies are not surprising given the
different type of signals measured by each technique,
and the different spatial and temporal resolution of
each technique. It is the intersection of the spatial
temporal pattern of activity across the cortex in re-
sponse to a particular stimulus, the type of signal being
measured, and the spatial and temporal resolution of
the specific technique being used to measure that sig-
nal, which results in a given measured “activity” pattern.
First, consider just the spatial resolution of various
recording techniques. Imagine a stimulus that evokes
a strong increase in the firing rate of neurons in some
columns of a cortical area of interest, and strong de-
creases in firing from other columns of cells in the same
area. In a single fMRI voxel, many thousands of cells
would be activated in both directions, and the overall
change in activity might be quite small. This could lead
to the incorrect conclusion that the stimulus did not ef-
fectively drive cells in that area at all. Recording from
single cells or from small groups of cells with electrodes
would reveal a much different story.
One strategy that has been employed by experi-
menters to overcome limits in the spatial resolution of
fMRI relative to the scale of the local architecture in vi-
sual cortex is to use visual adaptation. Visual adaptation
refers to the phenomenon wherein repeated presenta-
tions of a preferred visual stimulus typically result in a
diminished neural response in visual cortex. Functional
imaging studies can take advantage of this property by
testing the relative effectiveness of several stimuli after
a period of adaptation. If following this adaptation pe-
riod it can be shown that a particular cortical area now
shows reduced responses to the adapting stimulus, but
does not show reduced responses to another stimulus,
this implies that the area contains cells that are selective
for the first stimulus (a preferred stimulus). This is a use-
ful method for demonstrating visual selectivity that does
not require spatial resolution at the scale at which the
preferred stimulus property is encoded. This technique
has recently been used to examine three-dimensional
motion selectivity in human MT110 and orientation se-
lectivity in human V1.111
232 SECTION II SYSTEMS
Next, consider some of what we know about the
signal that is measured by each recording technique.
As outlined by a recent review,112 many neuronal cir-
cuits consist of both excitatory and inhibitory inputs,
feed-forward and feedback systems, and finally output.
Though a great oversimplification, one can think of the
BOLD response as an overall measure of changing ex-
citatory and inhibitory neuronal inputs and perhaps as-
trocytic function,113 while electrophysiological recording
of spiking is a direct measurement of neuronal output.
LFPs are also a measurement of overall neuronal (and
perhaps astrocytic) response. Thus, it is not surprising
that there seems to be more of an agreement between
fMRI and LFPs compared to fMRI and single or multiunit
spike recordings.67
䉴 CLINICAL APPLICATIONS
Mapping methods predominantly used in neuroscience
to study the visual system may also play a role in the di-
agnosis and treatment of patients. The efficacy of func-
tional mapping methods in a clinical setting lies in the
ability of these techniques to provide useful information
to spare eloquent areas of visual cortex or optic radia-
tions, identify the effects of tumors or other structural ab-
normalities on vision, or to characterize areas that have
reorganized. In this section, we discuss the application
of clinical mapping methods in neurological and neuro-
surgical settings.
Before reviewing the use of different modalities for
mapping visual areas as an adjunct to clinical care and
in particular for guiding neurosurgical resections, it is
important to recognize the functional redundancy, and
more importantly the bilateral representations, of later
visual areas that may render patients relatively resistant
to adverse effects with unilateral resections. Early vi-
sual areas, such as V1, are highly retinotopic and are
composed of neurons with small spatial receptive fields.
When a portion of V1 is lesioned or resected, a corre-
sponding contralateral visual field deficit or scotoma will
invariably result. But later visual areas encode a far less
veridical representation of the visual world and typically
contain visually responsive neurons with large, even bi-
lateral, receptive fields. So, it is not surprising that an
isolated unilateral surgical resection or stroke involving
a later visual area such as hMT or LOC does not result
in a readily apparent visual deficit that alters a patient’s
quality of life. Bilateral lesions of a later visual area, in
contrast, are likely to result in a functional deficit. Fortu-
nately, bilateral homotopic surgical resections are almost
never a clinical consideration anyway. In a practical clin-
ical sense, this means that while mapping studies reveal
large swaths of cortex that are visually responsive, for
many of these areas, particularly those that fall late in
the hierarchy of visual processing, unilateral resections
can be carried out without significant functional conse-
quence. In contrast, for early visual cortex and V1 in
particular, resection of the cortex or its projections re-
sults in obvious visual deficits.
Similarly, the optic radiations running from the lat-
eral geniculate nuclei to primary visual cortex are also
a place where damage can have profound effects on
patient outcome. It is well known that lesions may com-
promise visual tracts en route to visual cortex and result
in characteristic visual field defects. However, an impor-
tant clinical application is the avoidance of these path-
ways in the attempt to resect lesions in the temporal
lobe or deep within cortex such as in the atrium of the
lateral ventricles.114,115 The relative anatomic position of
these tracts should be considered in planning surgical
trajectories, such as in temporal lobectomy surgery or
approaches to deep tumors.116 These tracts may be iden-
tified with DTI; the DTI images can be integrated into a
surgical navigation system used at surgery, to help the
surgeon avoid damaging these fibers.114
FUNCTIONAL MRI
Several studies have validated fMRI techniques in a
clinical setting by comparing the results of visual acti-
vation patterns based on fMRI with those of perimet-
ric evaluation (the gold standard for identifying sco-
tomas) in patients with visual field defects.117,118 The
results of these studies demonstrate high consistency be-
tween decreased fMRI activation with visual paradigms
and visual field defects measured using perimetric eval-
uation. For example, Kollias et al. (1998) used fMRI
(with a binocular repetitive photic stimulation task) in
the presurgical planning of 10 patients with space-
occupying lesions involving the posterior afferent visual
system.119 Results showed concordance for nine of the
ten patients between asymmetric response (e.g., an ab-
sence or minimal fMRI activation) in visual cortex corre-
sponding to the visual field deficits (e.g., homonymous
hemianopsias).
Functional imaging has also been used to guide
surgery in patients with space-occupying lesions to
help spare eloquent visual areas.120 For example, Fried
et al.120 used fMRI (with a binocular photic stimulation
of 8.3-Hz flashing red lights task) to map visual cortex in
a patient who had intractable seizures originating near a
temporo-occipital cyst. By using this fMRI to guide a sub-
sequent surgical resection, they were able to resect the
seizure focus and leave the patient with only a limited
visual hemifield defect. Similarly, Roux et al.117 reported
how fMRI was helpful in minimizing postoperative vi-
sual field defects in five patients who underwent occip-
ital cortex tumor removal. These authors noted, how-
ever, a very important limitation of fMRI data when de-
termining the extent of a resection, which is an absence
 CHAPTER 16
of functional activity does not always imply that neural
tissue is not capable of being functional. For example,
they presented data on a patient with a right homony-
mous hemianopsia who had no functional activation in
the left lingual gyrus (corresponding to the location of a
grade III astrocytoma). The functional importance of the
area around the tumor could not be discerned because
the visual defect could have resulted from mass effect
that led to the absence of functional activation, or may
have corresponded to tumor.117
DTI, or MR tractography, has also proved useful in
helping to preserve visual function during neurosurgi-
cal procedures. This is particularly true for resections
of tumors or epileptic foci that may neighbor or in-
vade the extensive visual pathways from retina to pri-
mary visual cortex. In fact, there has been a resurgence
of interest in studying these tracts using cadavers121,122
and subsequent suggestions for new methods to
resect lesions that may neighbor these radiations. Pow-
ell et al. (2005) showed that for two patients undergoing
anterior temporal lobe resections, one had the stereo-
typical contralateral homonymous hemianopsia and the
other patient did not. Comparing pre- and postoper-
ative DTIs, they showed that in the patient who had
a visual field defect, the optic radiations were in fact
traversed.123 Taking this approach further, Nimsky et al.
(2006) showed how DTI can be integrated into stan-
dard intraoperative MRI navigation to map out the optic
radiations.64
Interestingly, Govindan et al. (2008) using DTI,
measured water diffusion-related changes in the optic
radiations ipsilateral and contralateral to occipital lobe
resections in ten children who had undergone surgery to
treat intractable epilepsy.124 They validated the method
by showing a strong relationship between optic radia-
tion tract damage and visual field losses. Their data also
found that contralateral optic radiations underwent sig-
nificant changes in anisotropy after resection, suggesting
that plasticity changes occur elsewhere to compensate
for ipsilateral damage.
POSITRON EMISSION TOMOGRAPHY
PET is used for brain mapping in a clinical setting for
many different types of purposes. For example, it is used
as tool in the diagnosis of Alzheimer’s disease,125 and to
differentiate radiation necrosis from tumor recurrence in
patients who had already undergone radiation therapy
to treat the tumor.126 For clinical brain mapping of visual
areas, the largest area of research comes from the presur-
gical evaluation of individuals with epilepsy. FDG-PET
is an integral component of the presurgical evaluation
because it can aid in the confirmation of an epileptic
seizure focus in patients with medically intractable oc-
cipital lobe epilepsy (OLE).127,128
MAPPING OF THE HUMAN VISUAL SYSTEM 233
In an interesting study of patients without OLE,
Wong et al.127 used FDG-PET to study occipital lobe
hypometabolism in seven patients who had visual
field cuts and four patients without field defects post-
temporal lobectomy. Imaging results indicated occipi-
tal lobe hypometabolism corresponding to visual field
defects in the seven of the patients with defects, and
hypometabolism was found in one of the patients with-
out a field defect. The hypometabolism was proposed to
occur due to deafferentation after interruption of optic
pathways because of the temporal lobectomy.127
With its ability to measure receptor distributions,
PET may find future use in delineating subtle changes
in visual pathways or maps in normal and neuropsycho-
logical diseases. For example, Gerstl et al. (2008) were
able to differentiate between V1 and V2 in early human
cortex based on 5-HT1A receptor distribution and this
seems to be corroborated in postmortem studies.129,130
MAGNETOENCEPHALOGRAPHY
MEG is useful in localizing eloquent cortex for surgi-
cal planning in patients with brain tumors or intractable
epilepsy.131 A distinct advantage over fMRI and PET in
a presurgical epilepsy setting is that MEG may be able
to capture ictal spread to better identify seizure foci.132
Several studies have also demonstrated the efficacy of
MEG in presurgical planning for tailored resection of tu-
mors in visual cortex.133,134 For example, Grover et al.
(2006) reported on the efficacy of MEG in helping to
minimize visual field defects after resection of tumors in
temporo-parieto-occipital areas.133
In a unique clinical application, MEG has been
used to study the cortical reorganization of visual cortex.
Understanding unexpected change in visual cortex is
important to help characterize irregular localization of
function, reflecting reorganized or displaced cortex. For
example, Burneo et al. (2004) demonstrated that visual
functions are more likely to be reorganized with cortical
dysplasia but not polymicrogyria.135 Inoue et al. (2004)
combined three-dimensional anisotropy contrast (e.g.,
anisotropic DWI that shows isotropic water motion) and
MEG VEFs to identify optic radiations and primary vi-
sual cortex in a 26-year-old patient with a tumor along
the right calcarine fissure.134 They demonstrated that the
techniques could be combined to tailor a resection to
avoid postoperative visual impairments.
EVENT-RELATED SCALP VISUAL
EVOKED POTENTIALS
Analogous to motor-evoked potentials and somato-
sensory-evoked potentials used in cranial and spinal
cases, VEPs can be used intraoperatively to monitor the
robustness of the visual pathways.136 Unfortunately, as
234 SECTION II SYSTEMS
VEPs have poor localization, VEPs do not give a priori
information to guide resection or procedure, and often
times, it is only after damaging a visual tract that one
sees a difference in VEPs.
Often clinical practice provides evidence for ex-
perimental hypotheses. For example, Tobimatsu and
Celesia137 illustrate the usefulness of VEP in an interest-
ing case presentation of a 62-year-old patient who suf-
fered from carbon monoxide poisoning who then pre-
sented with visual agnosia. His structural MRI indicated
severe damage to parieto-occipital cortex bilaterally with
no damage to V1. His VEPs to simple checkerboards
also suggested intact V1. However, when presented with
face stimuli, the patient had no early responses (which
he should have had, as predicted by normal VEPs to
checkerboards). The authors interpreted this finding as
providing support for the presence of a feedback sys-
tem from extrastriate cortices to V1, which suppressed
the normally intact V1 response in the patient.
In another interesting study, Kamada et al. (2005)
combined real-time VEPs and optic radiation DTI trac-
tography to monitor visual pathways intraoperatively.
They were able to spare functional visual areas in one
of the patients reported and showed how loss of VEPs
occurred in a patient that had a subsequent visual field
defect138 (see Fig. 16–9).
TRANSCRANIAL MAGNETIC
STIMULATION
Repetitive TMS (rTMS) has been used clinically to treat
migraine, stroke, and Parkinson’s disease, as well as de-
pression (see Fitzgerald et al.139 for a review). There has
been little use of TMS in planning surgical resections in
the visual cortex, or to avoid optic radiations, but TMS
has shown promise in mapping motor areas140 and has
potential in unraveling visuospatial judgements and as-
sociated defects.141,142
LOCAL FIELD POTENTIAL
RECORDINGS FROM INTRACRANIAL
ELECTRODES
There are few reports of using LFPs evoked by visual
stimulation to tailor surgical resections to minimize visual
deficits.143,144 Curatolo et al.144 used a flashing strobe
light to elicit LFPs in two patients with OLE being eval-
uated for surgery. They found that the use of photopic
stimulation to map visual cortex helped to preserve cen-
tral vision after occipital lobe surgery.144 While our group
has primarily used retinotopic mapping of visual cortex
as a research tool,35 we have also found it useful for
defining the location of early visual cortex and in tai-
loring a resection with maximal preservation of visual
function.
DIRECT CORTICAL STIMULATION
MAPPING
DCS has a long history in clinical neurosurgery, begin-
ning with the works of Penfield who showed that he
could elicit phosphenes during electrical stimulation of
early visual areas.145 As our understanding of the intri-
cacies of the visual cortex has blossomed over the last
decade and technology has similarily progressed, intra-
operative and extraoperative DCS for both research and
clinical uses has seen a resurgence. By using extraopera-
tive DCS, Lee et al. showed that stimulation of early areas
of the visual cortex mostly resulted in patient’s describ-
ing simple forms and stimulation of more distal areas re-
sulted in more complex forms, laying credence to a hier-
archical organization of visual processing.103 Our group
has shown that the probability of eliciting precepts in the
visual cortex is indirectly related to the distance from the
occipital pole, with thresholds for these precepts being
directly related to this distance.104 Nguyen et al. recently
reported a single case in which they used DCS and fre-
quent monitoring of a patient’s visual fields during an
awake craniotomy to resect an occipital glioma, while
preserving the patient’s visual field.146 Subcortical stim-
ulation can similarly be implemented to help define the
maximum depth of resection.147
䉴 PEARLS AND PITFALLS
In this chapter, we have provided an overview of the
clinical utility of mapping methods. The body of liter-
ature that covers these topics is vast and complex and
must be considered and applied carefully in clinical (and
research) settings.
Despite advances in neuroimaging and neurophys-
iology techniques over the past three decades that have
helped in identifying structural lesions and functional
impairment, serious limitations exist with each method.
Some of these limitations are technological in nature,
such as the spatial resolution of fMRI, but many of them
are inherent to the different techniques, such as the fact
that one is only indirectly measuring neuronal activ-
ity with fMRI. While technologies such as fMRI contiue
to improve, it is necessary for the clinician to under-
stand inherent limitations in order to use and interpret
data effectively. Furthermore, it is in the combination
of these technologies and their overlapping strengths
that the most comprehensive picture and understand-
ing of visual information processing in the brain will be
unraveled.
Several clinical realities are particularly important
and are relevant even with the most judicious combina-
tion of various structural and functional mapping tech-
niques. The first reality is the fact that many patients have
underlying pathological disease that may affect normal
 CHAPTER 16 MAPPING OF THE HUMAN VISUAL SYSTEM 235

C B

Figure 16–9. Combining visual evoked potentials (VEPs), tractography, and

navigation. (A) Consecutive changes in the VEPs during tumor resection. VEPs
became undetectable when the optic radiation was damaged at 13:12 (black arrow ).
(B) Two-dimensional magnetic resonance imaging (MRI) scans on neuronavigation
demonstrating that resection had reached the ventricular wall, where the optic
radiation was embedded. (C) Three-dimensionally reconstructed whole-head MRI
data on neuronavigation showing the optic radiation (purple), the tumor (yellow ), and
the navigation probe (blue bar ). (Reproduced with the permission of Wolters Kluwer
Inc., Kamada K, Todo T, Morita A, et al. Functional monitoring for visual pathway using
real-time visual evoked potentials and optic-radiation tractography. Neurosurgery
2005;57(1 Suppl):121–127; discussion 121–127.

structure/function relationships. Lesions, whether they
are tumors, vascular or genetic in nature, may cause
reorganization of visual areas, or affect the neuronal
pathways leading to visual cortex.119,122 These poten-
tial changes must be taken into consideration by the
clinician. For example, there is evidence that low-grade
gliomas may have functional cortex and white matter
tracts within them,130 while other lesions (e.g., menin-
gioma) may displace cortex and white matter tracts. The
clinical management of these two situations is potentially
different and extent of resection, with known effects on
patient survival, must be weighed against neurological
deficit.
Another clinical reality that is not addressed by com-
binatorial use of preoperative structural and functional
mapping techniques is intraoperative shifts in brain
236 SECTION II SYSTEMS
tissue. This should be helped with the advent
of intraoperative structural and functional mapping
techniques.122,131
Finally, it is important to recognize that unilateral
resection of later visual areas may be well tolerated due
to the additional presence of these functional areas on
the contralateral hemisphere. For example, unilateral re-
section of area IT, which is critical for object processing,
does not result in overt deficits in object recognition,
presumably because the contralateral area IT in itself
provides sufficient function. But resection of an early
retinotopic visual area on one side, such as a portion of
V1, will typically result in a permanent visual field deficit
because this particular spatial representation is not also
present in the contralateral hemisphere.
As technology advances, different methods of vi-
sual mapping will provide a greater understanding of
this exciting and complicated field. Similarly, as basic re-
search progresses, the clinician will have a broad span
of literature on which to base clinical decisions and re-
search. But the road connecting technology and basic
research with clinical endeavors should by no means
be a one-way street. Rather, clinicians, with their ability
to probe different questions directly in human patients,
whether it be subdural electrodes for epileptic seizure
location or DCS, can play a major role in shaping our
understanding of visual information processing in the
brain.
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pathway using real-time visual evoked potentials and
optic-radiation tractography. Neurosurgery 2005;57(1
Suppl):121–127; discussion 121-127.
139. Fitzgerald PB, Fountain S, Daskalakis ZJ. A comprehen-
sive review of the effects of rTMS on motor cortical ex-
citability and inhibition. Clin Neurophysiol 2006;117(12):
2584-2596.
140. Neggers SF, et al. A stereotactic method for image-guided
transcranial magnetic stimulation validated with fMRI and
motor-evoked potentials. Neuroimage 2004;21(4):1805-
1817.
141. Sack AT, et al. Imaging the brain activity changes underly-
ing impaired visuospatial judgments: simultaneous FMRI,
TMS, and behavioral studies. Cereb Cortex 2007;17(12):
2841-2852.
142. Sack AT, et al. The temporal characteristics of motion pro-
cessing in hMT/V5+: combining fMRI and neuronavigated
TMS. Neuroimage 2006;29(4):1326-1335.
143. Blume WT, Whiting SE, Girvin JP. Epilepsy surgery in the
posterior cortex. Ann Neurol 1991;29(6):638-645.
144. Curatolo JM, et al. Intraoperative monitoring to pre-
serve central visual fields during occipital corticectomy
for epilepsy. J Clin Neurosci 2000;7(3):234-237.
145. Penfield W. Some Mechanisms of Consciousness Discov-
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Acad Sci U S A 1958;44(2):51-66.
146. Nguyen HS, et al. A method to map the visual cortex dur-
ing an awake craniotomy. J Neurosurg 2011;114(4):922-
926.
147. Duffau H, et al. Intra-operative mapping of the subcor-
tical visual pathways using direct electrical stimulations.
Acta Neurochir (Wien) 2004;146(3):265-269; discussion
269-2670.
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 Chapter 17
Mapping of Hearing
Albert J. Fenoy1 and Matthew A. Howard 2
1
Department of Neurosurgery, University of Texas Health Science Center, Houston, Texas
2
Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa
䉴 INTRODUCTION AND
HISTORICAL PERSPECTIVE
More than 125 years ago, the superior temporal gyrus
(STG) was identified as the site of cortical areas involved
in auditory processing in both monkeys,1 and then later
in the human.2 It was thought that functional specializa-
tion of cortex did exist, but it was not later until archi-
tectonic mapping techniques (e.g., Brodmann (1909)3 )
could definitively differentiate cortical areas in the
human brain.
Several investigators have mapped the subdivisions
and connections of the auditory cortex in nonhuman
primates using microelectrode recording techniques
and histological and tracing methods.4−8 In agreement
among these studies is the existence of “core” auditory
fields, located on the superior temporal plane, which are
surrounded in a belt-like arrangement by other cortical
fields within STG with a variety of distinct cytoarchitec-
tural and physiological features.
Tonotopic organization is a hallmark feature of the
auditory sensory system as it ascends from cochlea
to cortex. The degree of both the frequency tuning
resolution—neuronal predilection to respond best (or
fire) to a certain “best frequency”—and tonotopic organi-
zation changes as the encoded information moves from
subcortical regions to the cortex, where neurons with a
similar “best frequency” are arranged in rows that are
organized along a frequency gradient (e.g., Merzenich
and Brugge (1973)4 ). Electrophysiological testing in each
defined field, in both the monkey and human, has pro-
vided well-defined characteristics of neuronal behavior
that further help to distinguish and classify these regions.
Although homologies are not exact, it is useful to look
at these well-researched nonhuman primate studies as
an introduction to modeling human auditory cortical or-
ganization and function.
In the macaque monkey, three distinguishable fre-
quency gradients have been reported in the core re-
gion, each responding well with short latencies to pure
tones, with narrow frequency tuning at their character-
istic frequency8,9 ; they are labeled A1 (primary area),
R (rostral area) and RT (rostrotemporal area). A1 and
241
R share a common low-frequency border, and R and RT
may share a high-frequency border7,10 ; refer to Fig. 17–1.
As distance increases from the core region, frequency
tuning to pure tones becomes less sharp, although tono-
topic gradients are shown.4,9,11 These belt neurons have
more complex receptive field properties than the core
and prefer complex tones,12 showing optimal response
profiles as a function of stimulus bandwidth for broad-
band sounds as well as sensitivity to direction and extent
of frequency modulation.9,11,13−16 The parabelt region
has even more complex and less definable “preferred
stimuli,” projecting more diffusely, with cortico-cortico
connectivity patterns that are similarly complex.
Human auditory cortex similarly exhibits tonotopic
organization. Several studies have found evidence for
cortical tonotopy using noninvasive recordings to calcu-
late the equivalent dipole source location as a function
of frequency.17−20 Howard21 has demonstrated the ex-
istence of a tonotopic organization in human primary
auditory cortex (PAC) on medial Heschl’s gyrus (HG)
directly using single-unit recordings from a stereotacti-
cally implanted depth electrode on STG. Over the past
10 years, our lab has been able to directly record si-
multaneous activity within medial HG, lateral HG, and
STG and provide evidence for the existence of multiple
auditory fields in the human, each associated with dif-
ferent response latencies and preferred stimuli (Brugge
and Howard, unpublished data).
䉴 OVERVIEW OF NEUROANATOMY
AND NEUROPHYSIOLOGY
Nonhuman primate studies on architecture, connectivity,
and tone-frequency serve as comparative models for the
sparse data obtained in humans, and continue to guide
ongoing research in human auditory cortical organiza-
tion and function.
Kaas and Hackett10,22−24 present a model of au-
ditory cortical organization in nonhuman primates in
which a primary “core” field, located upon the lower
bank of the transverse (sylvian) sulcus, is encircled by
242 SECTION II SYSTEMS
A
B Anatomical studies have also consistently shown
Figure 17–1. Lateral view of the macaque cerebral
cortex. (Adapted from Kaas JH, Hackett TA.
Subdivisions of auditory cortex and processing
streams in primates. Proc Natl Acad Sci U S A
2000;97:11793–11799; copyright 2000, National
Academy of Sciences, USA). (A) The approximate
location of the parabelt region of the superior
temporal gyrus (STG) (dashed orange line). (B)
Dorsolateral view after removal of the overlying
parietal cortex, as demarcated by the dashed black
line. The approximate locations of the core region
(solid red line), caudal and lateral portions of the belt
region (dashed yellow line), and the parabelt region
(dashed orange line) are shown. The core region
contains three subdivisions: primary area (A1), rostral
area (R), rostrotemporal area (RT). The medial
portion of the belt region and rostral pole of the core
in the ventral circular sulcus are not visible. AS,
arcuate sulcus; CS, central sulcus; LS, lateral sulcus;
INS, insula, STS, superior temporal sulcus.
nonprimary belt fields and on the lateral aspect by para-
belt fields (see Fig. 17–1), which, in turn, make connec-
tions with more distant cortex of the temporal, parietal
and frontal lobes.
The core has a highly granular and densely myeli-
nated appearance, and receives ascending inputs from
the ventral medial geniculate nucleus (MGN). The core
projects to ipsilateral and contralateral core areas, as well
as to the adjacent belt region, which includes seven
or eight nonprimary fields. These belt areas have re-
duced cell density and columnar spacing, and less dense
myelination relative to the core; inputs are received both
from the adjacent core field and from dorsal and medal
divisions of the MGN. The parabelt receives afferents
largely from neurons in the belt,10,22,24 but also from the
MGN.
Human auditory cortex is likewise comprised of
an array of fields distributed both on the exposed sur-
face of the STG and on the supratemporal plane, deep
within the sylvian fissure (SF) beneath the overlying
parietal cortex. Although the number and boundaries
of the fields are not well known, and homologies with
the well-researched cortical auditory fields of nonhuman
primates not well verified, cytoarchitectonic studies have
been able to consistently identify an area of koniocortex
confined to the posteromedial two-thirds of the first
transverse temporal gyrus, or HG, located on the
supratemporal plane.25,26 This area, considered by most
to be the site of PAC or A1, has a high-cell density (espe-
cially in layers II–IV), is heavily myelinated, and exhibits
a distinct but inhomogeneous chemoarchitecture27−31
suggesting that perhaps it may be more representative
of a primary cortical complex, or auditory core, homol-
ogous to the monkey and composed of more than one
field.32
a belt of cortical fields on the supratemporal plane
surrounding the core koniocortex, extending into the
insula31 and the frontal and parietal operculum.27 By
using morphological criteria, much of this nonprimary
region has been segregated into planum polare (PP, ante-
rior to HG) and planum temporale (PT, posterior to HG),
but borders are not clearly defined (see Fig. 17–2).33
Architectonic3,25,27,32,34,35 and histochemical30,31 parcel-
lations of this nonprimary cortex, although not in full
agreement on number and location, have identified as
many as seven belt fields. One or two auditory fields
have been identified lateral to belt fields, on the postero-
lateral exposed surface of the STG,30,36 possibly analo-
gous to the parabelt fields seen in the monkey. Simi-
larly, our laboratory has identified a circumscribed area
that overlaps a region on the posterolateral aspect of
the STG and is activated by acoustic stimulation, a re-
gion we refer to as posterior lateral superior temporal
area (PLST); see later and Fig. 17–2.33
A hierarchical model derived from anatomical and
physiological studies suggests that information about
spectrotemporal features of a natural sound are pre-
served in core cortex and from there transmitted to belt
and parabelt fields in serial as well as parallel fash-
ion, where ultimately through further circuitous interac-
tions they are transformed into more complex cerebral
representations.10,37
The exact homology between human and nonhu-
man primate for belt and parabelt fields is less known
relative to that observed in core koniocortex.26,29,32,36
 CHAPTER 17 MAPPING OF HEARING 243

A B

Figure 17–2. Photographs of the lateral surface (A) and superior temporal plane
(B, C) of a postmortem human brain showing the relative size and location of
posterior lateral superior temporal area (PLST) (blue) estimated from the distributions
of averaged click-evoked evoked potentials (EPs) recorded in our experimental
subjects (see Howard MA, Volkov IO, Mirsky R, et al. Auditory cortex on the posterior
superior temporal gyrus of human cerebral cortex. J Comp Neurol 2000;416:76–92,
for more details). The mesial auditory field on Heschl’s gyrus (HG) from which auditory
EPs were recorded is designated A1 (green). The dashed arrow indicates a projection
from the mesial Heschl’s gyrus (HG) auditory field (A1) to PLST. (Reprinted with
permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Cortico-cortico connectivity studies10 as well as single In humans, a recent meta-analysis of functional

cell recordings15,38 have been used to define parabelt
borders in the monkey, with rostral (anterior) parabelt
receiving afferents from anterior belt areas and project-
ing anteriorly to multiple sites within the temporal lobe
and into the ventrolateral frontal cortex, and caudal (pos-
terior) parabelt receiving input from posterior belt, and
projecting posteriorly and dorsally into the temporopari-
etal junction and dorsolateral prefrontal cortex.10,24,38
For illustrative purposes, Fig. 17–314 depicts the so-called
“what” and “where” streams as hypothesized in their
studies on the macaque.
Nonetheless, evidence from functional magnetic
resonance imaging (fMRI) studies suggests that a func-
tional hierarchy may also exist for human auditory
cortex,39 where cortical processing of complex sound
occurs in two separate streams.14,40−42
imaging studies by Arnott et al.43 has supported the dual
stream hypothesis by demonstrating that posterior pari-
etal and superior frontal regions were more frequently
activated during auditory spatial processing.30,44−46 Fur-
thermore, fMRI studies have provided evidence for
the implication of posterior temporal cortex in spatial
processing.47,48 In contrast, anterior temporal and infe-
rior frontal areas were more often activated during non-
spatial auditory processing.45,49,50 Fig. 17–4 depicts the
results of the meta-analysis of the 11 sound localization
and 27 nonspatial sound studies in which activation was
seen by either positron emission tomography (PET) or
fMRI, plotted in Talairach space.43
Such noninvasive methods favor homology be-
tween human and nonhuman primate data, but it is still
essential that studies using complimentary experimental
244 SECTION II SYSTEMS

Figure 17–3. Schematic flow diagram of “what” and “where” streams in the auditory
cortical system of primates, as depicted by Rauschecker and Tian. (Rauschecker JP,
Tian B. Mechanisms and streams for processing of “what” and “where” in auditory
cortex. Proc Natl Acad Sci U S A 2000;97(22):11800–11806; copyright 2000, National
Academy of Sciences, USA). The ventral “what” stream is shown in green, the dorsal
“where” stream in red. PFC, prefrontal cortex; PP, posterior parietal cortex; PB,
parabelt cortex; AL, ML, CM and CL, anterolateral, middle lateral, caudomedial, and
caudolateral auditory belt; T2/T3, anterior temporal lobe; MGd and MGv, dorsal and
ventral parts of the medial geniculate nucleus.

approaches, including invasive mapping, be undertaken
if we are to fully understand the functional organization
of human auditory cortex and the substrates involved in
the processing and perception of complex sound, such
as speech.
䉴 MAPPING METHODS
STRUCTURAL IMAGING AND
OPERATIVE ANATOMY
Gross Anatomy
Understanding the neurophysiology and neuroanatomy
of the auditory cortex at the superstructural or gross
anatomical level provides insights into the spatial or-
ganization of distributed neural networks that mediate
different aspects of acoustic sound perception.
Although “auditory cortex” may not signify a specific,
easily definable brain structure, historic cross-modality
experimentation on both human and nonhuman pri-
mates has revealed that most neurons chiefly responsive
to acoustic stimuli reside in the superior portion of the
temporal lobe, both on the exposed STG and on the
hidden supratemporal plane, deep within the SF.51
In Fig. 17–233 are photographs of a postmortem hu-
man brain specimen depicting the lateral surface (A) and
superior temporal plane (B, C), showing the relative size
and location of HG and more lateral STG. More specific
anatomy of the upper surface of the temporal lobe is
shown in a dissection by Rhoton52 in Fig. 17–5. Here, the
three gross partitions of the superior temporal plane—
PP, HG, and PT, can be clearly visualized.
von Economo and Horn,53 as well as Pfeifer54,55 out-
lined in detail the normal anatomy of the supratemporal
plane, characterized by one strongly developed convo-
lution, or transverse gyrus, known as HG on the left side
and two on the right, as confirmed by others.56−58 This
pattern, so-called “Pfeifer’s norm,”53 is however quite
variable, with the frequent occurrence of several trans-
verse gyri on either side of the brain.
Broca59 and Wernicke60 first inferred a functional
asymmetry of the brain for language following from ob-
servations that language could be disrupted in patients
affected by lesions on the left side of the brain. Anatom-
ically, it has been shown that the SF is asymmetric at its
posterior end,61 where the right side curves upward pos-
teriorly and ends at a higher position that the left, and in
the majority of cases of shorter length than the left. The
PT, which lies on the superior surface of the temporal
lobe posterior to HS, (Heschl’s sulcus, the sulcus pos-
terior to the first transverse temporal gyrus (or HG)) is
influenced by SF asymmetry as it is mostly larger on the
left side.54−55 Such asymmetry might be contributive in
defining language dominance, although no defining evi-
dence has been provided. (see Shapleske et al. (1999)62 ).

Figure 17–4. Sagittal and axial views of all spatial
(blue triangles) and nonspatial (red spheres) data
points showing activation as compiled from the
meta-analysis by Arnott et al. (2004) (Arnott SR,
Binns MA, Grady CL, Alain C. Assessing the auditory
dual-pathway model in humans. Neuroimage
2004;22(1):401–408.), plotted in Talairach space.
Sagittal (x = +29 mm) and axial (z = −4 mm) Talairach
images are displayed for reference.
Structural Imaging: MRI and Diffusion
Tensor MRI
Current MRI protocols are able to provide relatively fine
definition of cortical and subcortical structures in indi-
vidual subjects, with quite exquisite detail that improves
with increased magnet strength. As elsewhere, our lab-
oratory creates three-dimensional (3D) MRIs to help lo-
calize cortical areas of interest with respect to electrode
placement, and the derived models simulate anatomy
well (e.g., see Fig. 17–14B; Brugge and Howard, unpub-
lished data).
Although conventional T2-weighted MRI of the
brain has been unable to provide information on sub-
cortical fiber direction, advances in diffusion weighted
CHAPTER 17 MAPPING OF HEARING 245
Planum polare
Superior temporal gyrus
Temporal stem
Temporal horm
Heschl’s gyrus
Transverse temp. gyri
Planum temporale
Atrium
Figure 17–5. Superior view of the upper surface of
the left temporal lobe that forms the floor of the
sylvian fissure (SF). It has been disconnected medially
from the thalamus through the choroidal fissure,
anteriorly and medially from the globus pallidus,
anteriorly and laterally from the insula, and superiorly
from the temporal stem. The superior surface is also
called the opercular surface, and it is the temporal
operculum of the SF. It presents three
morphologically distinct parts, from anterior to
posterior: the planum polare (PP) (free of gyri and
has a shallow trough to accommodate the course of
the middle cerebral artery), Heschl’s gyrus (or the
most anterior transverse temporal gyrus), and the
planum temporale (usually formed by the transverse
temporal gyri posterior to Heschl’s gyrus). The lateral
edge of the PP is formed by the superior temporal
gyrus. The stem of the temporal lobe, the relatively
thin layer of white and gray matter that connects the
temporal lobe to the lower insula, is positioned above
the lateral and anterior edge of the temporal horn.
The temporal horn and the atrium are inferior and
posterior segments of the lateral ventricle,
respectively. (Adapted from Rhoton AL Jr. The
Supratentorial cranial space: microsurgical anatomy
and surgical approaches. Neurosurgery
2003;53(Suppl, Part 2):39).
(DW) MRI have shown that, by applying diffusion
weighting in at least six different directions, one can ob-
tain the diffusion tensor (DT) and quantitative measure-
ments of the anisotropy of the white matter tracts. Studies
246 SECTION II SYSTEMS
of auditory cortex using DT imaging (DTI), though, are
few.
By using DTI, Hiwatashi et al.63 were able to show
on normal subjects that the fractional anisotropy of the
subcortical white matter of first HG to be higher than that
in the ipsilateral STG. This finding supports the presence
of a more prominent “core” projection of the acoustic
radiation to HG relative to STG, commensurate with the
evidence of “core” PAC on HG and “parabelt” on more
lateral STG.
Recently, Upadhyay et al.64 through stroboscopic
event-related fMRI, were able to demonstrate mirror-
symmetric tonotopic organization within the human
PAC, and, by using anatomical functional image analy-
sis in conjunction with DT fiber tractography and prob-
abilistic mapping, characterize the axonal projection
patterns present within tonotopically defined areas. DTI
reconstructed fiber projections revealed the presence of
both cross-field isofrequency and within-field nonisofre-
quency-specific axonal projections in human PAC, where
the number of short-length nonisofrequency-specific
fibers located within the same auditory fields sig-
nificantly outnumbered the long-range isofrequency-
specific fibers located in distinct auditory fields (see
Fig. 17–6)64 . This suggests that the majority of projec-
tions within the human PAC remain intrinsic to that au-
ditory region, similar to the observations in primate audi-
tory cortices,65 where structural connectivity within and
among distinct auditory fields exists and is necessary to
integrate and process various sound properties.
FUNCTIONAL IMAGING
PET and fMRI provide good spatial maps of brain acti-
vation, with resolution of a few centimeters or less, but
temporal resolution is poor because they reflect changes
in blood flow; they are both indirect measures of brain
activity, and are fundamentally limited by the character-
istics of the hemodynamic response on which the acti-
vation signal is based.66 In contrast, electroencephalog-
raphy (EEG) is sensitive to scalp surface measurements
of electrical activity produced by synchronous neural fir-
ings in the brain, and magnetoencephalography (MEG)
is sensitive to scalp magnetic fields directly generated by
this electrical activity. Thus both measures provide infor-
mation about the millisecond time course of brain activ-
ity, but they suffer from estimations in the source of the
electrical generators, leading to poor spatial resolution.
Let us fist look at the information obtained by func-
tional mapping. fMRI has become more prevalent in re-
cent years than PET due to the ease by which it can
be administered, it’s more widespread availability, and
the fact that multiple observations can be made on the
accuracy of the derived maps.
As there are many different parameters that con-
tribute to our understanding of auditory cortex physi-
ology, it is prudent to concentrate on the response of
auditory cortex to single parameter variance. Later in
the chapter we have explored and summarized the cur-
rent findings from functional imaging studies investigat-
ing cortical response properties to individual acoustic
parameter testing.
Frequency
Within the auditory system, by far the parameter of
frequency provides the most useful organizational infor-
mation. Several groups have utilized neuroimaging tech-
niques as a means to noninvasively detail tonotopy in
humans.17,21,67−81 These studies have depicted spatially
distinct activity based on responses to tones varying in
frequency, some depicting mirror-symmetric tonotopy,
arousing the hypothesis that the connectivity patterns
observed within the PAC in nonhuman primate tracer
studies also exist in the human.
Two PET studies have reported more laterally lo-
cated auditory activation by a 500-Hz tone than by a
4000-Hz tone,67,76 although the precise locations are
indeterminate due to the low resolution of the tech-
nique. fMRI, however, has corroborated these findings
of separate response areas to low- and high-frequency
tones.72,73 The fMRI investigation by Talvage et al.82 re-
vealed multiple tonotopic fields encompassing both the
HG and surrounding fields on the STG using a variety of
increasingly complex stimuli, from pure tones to music.
At least four tonotopic gradients were identified, with
locations ascertained by the overlay of individual func-
tional maps onto anatomical maps for each of six sub-
jects; one such high–low frequency gradient seems to ex-
ist from posteromedial to anterolateral HG, with adjacent
tonotopic fields sharing either a low- or high-frequency
border, possibly homologous to the macaque.
Recent fMRI work performed by Formisano et al.79
and Talvage et al.80 has shown activation maps in PAC
similar to the mirror-symmetric tonotopic organization
revealed by electrophysiological recordings in nonhu-
man primates24 and intracranially in humans, to be dis-
cussed next.21,33,83,84
Nonprimary auditory areas corresponding to the
belt regions in the macaque are believed to be more pref-
erentially activated by more complex, broadband sounds
than pure tones, as in the core. This is supported by the
fMRI study by Wessinger et al.39 in which responses to
single-frequency tones at 0.5 kHz, 2 kHz or 8 kHz were
far less widespread than those obtained using 1-octave
wide, band-passed noise at the same center frequencies
(see Fig. 17–7). Hall et al.85 also reported greater activa-
tion beyond HG when activation by a single-frequency
tone was subtracted from that by a harmonic complex
tone of the same pitch.
 CHAPTER 17 MAPPING OF HEARING 247

A B

C D

Figure 17–6. Mirror symmetric tonotopic organization for one subject. (Adapted from
Upadhyay J, Ducros M, Knaus TA, et al. Function and connectivity in human primary
auditory cortex: a combined fMRI and DTI study at 3 Tesla. Cereb Cortex
2007;17(10):2420–2432). (A) Two high-frequency regions, one caudomedial and one
rostrolateral, were mapped within primary auditory cortex (PAC); between these
areas was a low-frequency region. Activation maps are present within the PAC,
specifically along the transverse temporal gyrus of Heschl (TTG) and transverse
temporal sulcus (TTS) and spanned a distance of 25.2 mm, as depicted on an inflated
brain representation in the Talairach coordinate system. (B) Three-dimensional
high-frequency (blue) and low-frequency (light blue–green) activation clusters were
projected and created in coregistered T1-weighted structural magnetic resonance
imaging and DTI datasets in the non-Talairach coordinate system. These
three-dimensional clusters were used as seeding points for fiber tractography and
probabilistic mapping. LS, lateral sulcus; PSTG, posterior superior temporal gyrus;
STG, superior temporal gyrus; SIG, short insular gyrus. (C) Zoomed view of a sagittal
slice depicting the isofrequency-specific fibers connecting the caudomedial and
rostrolateral high-frequency region of interests (ROIs) (blue). (D) Zoomed view
depicting the nonisofrequency-specific fibers (low-high frequency fibers) projecting
from the low-frequency ROI (light blue–green) to both caudomedial and rostrolateral
high-frequency regions, which are located within the dashed red lines

extent,76,86 or only an increase in either extent87 or

Sound Level
PET and fMRI studies have reported systematic changes
in activation of the auditory cortex with changing sound
level, although evidence is not uniform. Activation has
been seen with an increase in both magnitude and
magnitude.88 A few fMRI studies have investigated the
differential sensitivity to sound level across subregions
of the auditory cortex,86,89 agreeing that the majority of
cortex most sensitive to increasing sound level corre-
sponded to PAC on HG.
248 SECTION II SYSTEMS

Figure 17–7. Axial slices for two subjects showing their individual auditory activation
as a function of frequency spectrum. (Adapted from Wessinger CM, VanMeter J, Tian
B, Van Lare J, Pekar J, Rauschecker JP. Hierarchical organization of the human
auditory cortex revealed by functional magnetic resonance imaging. J Cogn Neurosci
2001;13:1–7). Activation is plotted for all voxels exceeding Z = 14.2. Areas shown in
blue represent activation by pure tones, yellow represents activation by band-passed
noise and green represents the overlap between the two activation patterns.

Temporal Aspects of Sound

Animal vocalizations and human speech alike rely on a
processor that is able to continuously extract changing
frequency and amplitude information over time. Tem-
poral acoustic patterns are important determinants of
the sound stimulus and can be broadly classified into
three divisions: envelope (<50 Hz), periodicity (50–500
Hz), and fine structure (>500 Hz). 90,91 For human listen-
ers, temporal variations ≤50 Hz are important for accu-
rate speech recognition (e.g., Drullman et al. (1994,)92,93 ;
Shannon et al. (1995)94 ), whereas waveforms exceeding
50 Hz create the percept of pitch. Acoustic temporal
structure can be present separately in each channel,
but can also be created through binaural interaction
across channels. The fine temporal relationships be-
tween the signals at the two ears generally determine
spatial qualities such as the width and location of the
sound source.91,95
Pitch is the auditory percept associated with the fre-
quency ( f ), and hence the period (T = 1/ f ), of sound
wave vibrations in the audible frequency range (∼20 Hz–
20 kHz).51,66 By using manipulations in temporal regu-
larity (and thus altering pitch), recent PET and fMR imaging
studies have identified regions of the auditory cortex
that are preferentially activated by temporal acoustic pat-
terns at rate >50 Hz, defining that lateral HG and PT
were the most highly sensitive to periodicity95−101 and
fine structure102,103 above all areas studied. Such activa-
tion was also seen to increase with the strength of the
pitch, or increased temporal regularity, perhaps giving
evidence for the engagement of HG based on temporal
cues. To better differentiate responsiveness to different
parameters of temporal acoustic structure, Hall et al.91
used fMRI to find the greatest activation to both pitch and
increasing temporal regularity (and thus pitch strength)
in lateral HG, whereas reliable activations related to both
pitch and the spatial width of sound to be localized to
PT (see Fig. 17–8). These activation patterns were in-
terpreted by the authors to be consistent with a larger
role of lateral HG in perceptual analysis than temporal
acoustic structure, and an overall concept that more lat-
eral auditory cortex (including PT) integrates different
classes of sound information to form auditory objects.
Spectrotemporal patterns of sound have also been
studied using frequency- and amplitude-modulated (FM
and AM) tones. fMRI studies on AM (e.g., Giraud et al.
(2000)104 ) and FM tones85 reported significant responses
in bilateral primary and nonprimary areas, strongest
in the posterolateral regions of the STG. Zatorre and
Belin105 independently manipulated the frequency and
timing information in sequences of single frequency
tones, comparing responses to each modulated sound to
each other, rather to an unmodulated control as in other
studies;85,104 here, greater responses to spectral changes
(over temporal changes) were found instead in bilateral
anterior STG. Griffiths et al.96,106 found via PET imaging
that both anterior and posterior STG were preferentially
activated by a melodic pitch sequence.
 CHAPTER 17 MAPPING OF HEARING 249

Figure 17–8. Results from the group analyses showing the patterns of sensitivity to
pitch- and location-related acoustic attributes. The group activation maps were
derived from conventional t-test and the four stimulus effects are represented by solid
colors. All maps are overlaid onto the same five horizontal brain images (z = 16-16
mm). This base image is an average of the 64-slice whole brain set that was acquired
for all participants and is displayed in neurological convention (Left = Left). (Adapted
from Hall DA, Barrett DJ, Akeroyd MA, Summerfield AQ. Cortical representations of
temporal structure in sound. J Neurophysiol 2005;94(5):3181–3191, for individual
analyses).

Together, the results of these studies give evidence
that the processing and analysis of combined spec-
trotemporal information in sound relies mostly on non-
PAC, with activity moving anterolaterally away from HG
as the processing of melodic sounds proceeds.
Sound Localization
Rauschecker and Tian,14 and similarly Kaas and
Hackett,24 suggest, based on nonhuman primate stud-
ies, that the auditory space is processed in a posterior
(caudal) pathway leading dorsally from the PAC in HG
up to the inferior parietal cortex through the caudal belt
and parabelt in the STG, a so-called “where” pathway,
whereas nonspatial auditory information is processed in
an anterior (rostral) direction along the anterior portions
of the lateral belt, or “what” stream (see Fig. 17–3).14
Several studies in humans have corroborated this
concept. Investigations using a sound localization
task45,107 have found that the inferior parietal lob-
ule is more preferentially activated by spatial process-
ing than by frequency discrimination, or even sound
identification.46 This area’s ability to be activated in
the disambiguation of overlapping auditory sources108
is suggestive that the spatial properties of sound acti-
vate a posterior nonprimary auditory circuit. A recent
meta-analysis of PET and fMRI studies of auditory
processing,43 also, underlined the importance of the in-
ferior parietal lobe in sound localization (as discussed
previously, see Fig. 17–4). As seen in noninvasive
recordings, moving sounds often produce bilateral ac-
tivation in primary and nonprimary regions of the
auditory cortex101,109,110 but may incur greater activa-
tion in a lateral area of the right PT than stationary
sounds89,47 as well as selectively recruit activity in pari-
etal cortex.96,101,106,111
On the other hand, the role of hemispheric domi-
nance in sound localization is still debated. Some stud-
ies support lateralization in the processing of acous-
tic space,96,106,107,112,113 while others found no evidence
of such.114,115 However, right hemisphere dominance is
more often suggested than none. A behavioral study by
Zatorre and Penhune116 based on patients with unilateral
temporal lobe lesions concluded that damage to the right
anterior STG, not encroaching upon the PAC, produced
a sound localization deficit in both hemifields. Palomaki
et al.117 had similar observations in their MEG study find-
ing strong N1m responses bilaterally but increased acti-
vation in the right hemisphere for either right- or left-
lateralized noise bursts.
Brunetti et al.118 employed both fMRI and MEG to
localize activation as well as to disclose temporal dy-
namics during the processing of sounds coming from
different auditory locations (right, left, or both). The fMRI
results indicated activation of a complex circuit involv-
ing HG, posterior STG, supramarginal gyrus, and frontal
lobe; concomitant MEG data analysis observed sequen-
tial increased latencies in activation times, starting with
HG, suggesting a pathway analogous to the “where”
pathway in monkeys. Both hemispheres were activated,
but the right hemisphere was activated more strongly
(see Fig. 17–9).118 These results are in accordance with
other studies confirming the presence of such a “dorsal
stream” activation path in spatial processing involving
posterior STG, parietal and frontal regions.45,46,119
NONINVASIVE RECORDINGS
Surface Electrical Recordings
Unlike functional imaging, noninvasive electrophysio-
logical recordings provide information about the mil-
lisecond time course of brain activity, but have poor
spatial resolution. Thus, EEG and MEG data comple-
ment the spatial maps derived from PET and fMRI data
250 SECTION II SYSTEMS

x = 52 z = 11

A B

Figure 17–9. (A) Results from the group analysis of 11 patients ( p < 0.05, corr.):
activated areas observed by functional magnetic resonance imaging during auditory
stimulation in the three conditions: Mixed (upper ), right (middle), and Left (lower ).
(Adapted from Brunetti M, Belardinelli P, Caulo M, et al. Human brain activation during
passive listening to sounds from different locations: an fMRI and MEG study. Hum
Brain Mapp 2005;26(4):251–261). In the mixed condition the bilateral Heschl’s gyrus
(HG) and right posterior superior temporal gyrus (STG) were activated and activation
was greater than in the left and right conditions. The STG activation extends caudally
(y = −49). Activation in the supramarginal gyrus is present in this condition only. During
both the right and the left conditions, bilateral HG and the right posterior STG were
activated. (B) MEG analysis of one subject. The four equivalent current dipoles (ECDs)
of the source model are superimposed on the individual structural magnetic
resonance imaging (MRI): (a) bilateral sources in HG; (b) one source in the caudal
region of the STG; (c) one source in the supramarginal gyrus; and (d) the three ECDs
in the right hemisphere are shown in a sagittal view. The positions of the two ECDs in
(b) and (c) were constrained in a cube with 6 mm side centered on the “center of
mass” of the corresponding functional MRI (fMRI) activation. Across nine subjects
undergoing magnetoencephalography analysis for mixed presentations, the mean
peak latency from stimulus onset was 139 milliseconds in bilateral HG, 156 milliseconds
in caudal STG, and 162 milliseconds in the supramarginal gyrus. (Both (A) and (B) are
reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

reviewed previously and for the most part corroborate
such findings. The poor spatial resolution of EEG or MEG
techniques can be greatly offset when complemented by
the adjunctive use of functional imaging studies (e.g.,
Brunetti (2005)118 ), combing temporal resolution in the
first modality and spatial localization in the latter.
Electrophysiology, however, has provided the most
direct demonstration of a frequency gradient along HG.
Using MEG and EEG, a systematic relationship has been
shown between dipole sources and stimulus frequency
in the auditory cortex (e.g., Romani et al. (1982)17,18 ,
Huotilainen et al. (1995)19 , Pantev et al. (1995)68 , Pantev

et al. (1988)69 , Yamamoto et al. (1992)120 , Lütkenhöner
and Steinsträter (1998)121 , Lütkenhöner et al. (2001)122 ,
Rosburg et al. (2000)123 ). Lütkenhöner and Steinsträter121
demonstrated a lateral shift in the location of the re-
sponse within HG as tone frequency was presented at
steps of 2000 Hz, 1000 Hz, 500 Hz, and 250 Hz, although
the exact spatial localization of these dipole locations
could not be entirely validated due to the limitations of
the technique.
On amplitude, EEG recordings show that the ampli-
tude of the main response progressively increases with
sound level,124,125 which is consistent with findings from
neuroimaging studies. By using MEG and a model of two
dipole sources, Gutschalk et al.126 have shown that both
a source posterior to HG, as well as one on the border
between HG and PT, exhibited an increase in response
amplitude as the stimulus sound level was increased.
Most studies investigating a single acoustic parame-
ter have employed stationary sounds in their protocols,
and it has now become apparent, only stationary sound
can be modeled using dipoles located in auditory
cortex. In their MEG study, Xiang et al.127 found that
responses to both moving and stationary tones can
be fitted using dipole sources in bilateral auditory
cortex, but only moving sounds are best fitted with an
additional source located in the right parietal cortex.
Ducommum et al.128 used EEG to directly compare
auditory location and motion perception, finding that
moving sounds specifically involve the right parietal
cortex. These evoked responses are suggestive of partly
segregated networks for stationary and moving sound,
and corroborate the observations of functional imaging
studies of nonauditory cortex activations for motion
processing.66,96,106
Gamma Range Oscillations
In the past decade, there has been much interest in the
oscillatory activity in the so-called “gamma range,” op-
erationally defined as more than 30 Hz, as it seems to
be indicative of regional cortical processing.129 Synchro-
nization at gamma frequencies was hypothesized to form
a temporal code that may dynamically “bind” spatially
segregated neurons into networks representing higher
order stimulus properties,130,131 which after observation
in primate cortex,132,133 has since been studied exten-
sively in humans with scalp EEG and MEG.
In auditory cortex, such nonphase locked or “in-
ducible” activity at approximately 30 Hz has been
demonstrated by EEG, correlating with word stimuli.68
To further identify the networks involved with process-
ing of spatial auditory information, Kaiser et al.134 used
MEG to visualize if oscillatory responses differed using a
stationary lateralized artificial distorted noise compared
to a biological sound (barking dog). In this approach,
CHAPTER 17 MAPPING OF HEARING 251
contralateral posterior temporoparietal areas were seen
to have enhanced spectral amplitude increases between
approximately 60 Hz and 80 Hz to both sounds. On
the other hand, only biological sounds gave rise to 30
Hz desynchronization over contralateral sensorimotor ar-
eas, parietofrontal gamma coherence increases as well
as beta coherence reductions between sensorimotor and
prefrontal sensors, possibly reflecting activation of mo-
tor networks involved in the automatic preparation for
orientating.
Such localization of induced gamma activity at the
level of cortical gyri has often been difficult to ascertain,
though, as the skull acts as a low-pass filter,135 with ar-
tifacts present in the gamma band from cranial muscle
activity.136,137 Thus, the signal-to-noise ratio for gamma-
band activity in invasive electocorticography (ECoG) is
much better than it is in scalp EEG, and combined
with shorter interelectrode distances (∼1 cm), spatial
resolution is much improved. Even in studies not ana-
lyzing gamma-band oscillatory activity, intracranial sub-
dural electrode recordings provide detailed information
of cortical and/or deep white matter neuronal activity
otherwise not sufficiently resolved. The results of this
technique provide detailed mapping of functional au-
ditory cortex, and examples of such will be elaborated
upon in the following.
DIRECT CORTICAL STIMULATION
As discussed previously, the results of recent imaging
studies reveal that a hierarchical auditory processing
model for human cortex seems to exist as it does for non-
human primates,39,138 but the anatomical connections
between cortical auditory fields are largely unknown.
Anatomical track-tracing methods using dyes cannot be
conducted in living humans, unlike in the primate. Post-
mortem examinations on human auditory cortex have
been performed using DiI injections139 as well as car-
bocyanine dyes and have revealed the presence of both
intrinsic140 and extrinsic141 cortico-cortical connections
within the STG; only examination of short pathways,
however, can be performed due to technical limitations.
Diffusion tensor imaging is a promising new technique
to assist in in vivo track tracing, but this method has
only begun to elucidate functional connectivity in audi-
tory cortex.64
An alternative method of tracing neural pathways in
the cortical auditory system involves focal electrical stim-
ulation of one cortical site, while systematically mapping
the resultant evoked activity from distant sites.33,83,142−149
Although no direct information on the exact cellular ori-
gins, anatomical pathways, or terminal arborations can
be detailed, this approach does provide us with func-
tional connectivity between the site(s) of stimulation and
recording in the living human.148
252 SECTION II SYSTEMS

Liegeois-Chauvel et al.83 reported the first evidence
for a functional connection between auditory cortical
fields in the human. They found that electrical stimula-
tion of mesial HG in human evoked activity on laterally
adjacent HG cortex as well as on the PT. These are ar-
eas that subsequently have been identified both anatom-
ically and functionally as part of an auditory belt30,31,39,82
that surrounds an auditory core.10,24
In our series of over 150 epilepsy-surgery patients,
we have adopted this method of stimulation, via both
electrical and acoustic stimuli, and simultaneous record-
ing at multiple sites to characterize the response patterns
and functional connections of different auditory cortical
fields. As part of the treatment plan, in most patients
depth electrodes were inserted into HG on the supratem-
poral plane, while grid electrodes were implanted over
perisylvian cortex of either the left or right hemisphere.
The modified hybrid depth electrodes (HDEs) were tar-
geted stereotactically for the left or right HG.21
Our approach routinely employs a variety of con-
trolled sounds, ranging from brief click trains to human
vocalizations, to generate auditory evoked potentials
(AEPs) that, by simultaneous recordings through these
electrode arrays, have been used to characterize the
existence of at least three distinguishable auditory
cortical fields—two on HG and a third on the pos-
terolateral surface of the STG. Our ongoing work has
thoroughly detailed the functional connectivity of these
regions via the analysis of generated waveforms to elec-
trical stimulation33,148,150 (Brugge and Howard, unpub-
lished data).
Using bipolar electrical stimulation of HG, we have
shown that polyphasic evoked activity occurs within a
circumscribed area that overlaps a region on the pos-
terolateral aspect of the STG activated by acoustic stim-
ulation, a region we refer to as area PLST33 (see Fig.
17–10).148 The most robust and complex waveform,
characterized by having an initial positive component

B
A

C D
Figure 17–10. (A) Magnetic resonance imaging (MRI) showing location of recording
grid on lateral surface, overlaying posterior aspect of superior temporal gyrus (STG)
and extending above sylvian fissure (SF) and below superior temporal sulcus (STS), in
a representative subject. (See Brugge JF, Volkov IO, Garell PC, Reale RA, Howard MA
3rd. Functional connections between auditory cortex on Heschl’s gyrus and on the
lateral superior temporal gyrus in humans. J Neurophysiol 2003;90:3750–3763). (B)
Axial MRI section at level of Heschl’s gyrus (HG) showing trajectory of depth electrode
and location of bipolar stimulation sites within HG. (C) and (D) Response fields on
lateral STG resulting from click-train stimulation and electrical stimulation of mesial
HG. Averaged evoked potentials derived from 100 repetitions of respective stimuli.
Relative positions of recorded waveforms on maps of C and D represent relative
positions of electrodes on recording grid shown in A. Gray lines represent locations of
SF and STS. Asterisks mark sites of maximal response within two response fields.

HG
A belt situated more laterally on HG (see Fig. 17–12).148
B tional projection from auditory cortex on HG to an as-
[L4]
STMA
STMB
STMA
STMB
50 μv
50 ms
Figure 17–11. Effects of changing stimulus site on
Heschl’s gyrus (HG). (Adapted from Brugge JF,
Volkov IO, Garell PC, Reale RA, Howard MA 3rd.
Functional connections between auditory cortex on
Heschl’s gyrus and on the lateral superior temporal
gyrus in humans. J Neurophysiol 2003;90:3750–
3763). Averaged waveforms recorded at eight
recording sites at and around site of maximal
amplitude in response to stimulating mesial (A) and
lateral (B) sites on HG. Asterisks mark site of maximal
amplitude of response. Dashed lines mark latency of
negative peaks obtained when stimulus was applied
to mesial HG.
followed by twin negative peaks, occurred within 50
milliseconds of stimulus onset, and resulted from stim-
ulation of sites within about the mesial half of HG. Re-
ducing the interstimulus interval (ISI) from 1000 to 200
milliseconds diminished the amplitude and lengthened
the latency of the first peak only. When more lateral
HG was stimulated, the recorded waveforms on PLST
had, when present, an earlier appearing and more at-
tenuated first negative peak; the second peak was not
evident. Summarizing these results, it appears that both
negative peaks in the evoked waveform arise from ac-
tivating one or more corticocortical circuits originating
in mesial HG, as evidenced by the systematic decrease
in latency of the first peak with decreasing distance be-
tween stimulation and recording sites; the differential ef-
fect of changing stimulus rate on the response waveform
suggests a complex combination of circuitry and inputs
(see Fig. 17–11).148 Conversely, in the cases in which
PLST was stimulated, a positive–negative complex wave-
form was recorded on HG, corroborating the existence
of cortico-cortical circuitry. Moreover, the waveform pro-
duced increased in amplitude mediolaterally on HG until
a transition zone was reached, whereupon the wave-
CHAPTER 17 MAPPING OF HEARING 253
form altered its shape and diminished substantially in
amplitude, further supporting existence of a functional
boundary between PAC on mesial HG and an auditory
These results provide direct evidence for a func-
sociational auditory cortex (PLST) on the lateral surface
of the STG in human.148 This method, however, useful
intraoperatively for resection surgery (discussion to fol-
low), does not provide detailed information about neural
pathway transmission. Regardless, as we shall see, these
connections give further insight into interpreting the re-
sults of local field potential recordings and single-cell
recordings as our patients are presented with acoustic
stimuli.
Recently, the application of the algorithm of di-
rected coherence (DCOH) has shed new light on au-
ditory cortical connectivity patterns. Introduced by Saito
and Harashima151 and based on multivariate autoregres-
sive (AR) models and Granger causality, the algorithm
outputs the directional coherences between two EEG
signals recorded from two given leads in distinct cor-
tical regions. This can be viewed in terms of delay in
propagating a signal. In epilepsy patients undergoing
invasive seizure monitoring, Gueguin and colleagues152
recorded simultaneous responses to AM white noise in
depth electrodes implanted in the insula, HG, PT, and
Brodmann area (BA) 22. Among other findings, estima-
tions of causality using DCOH found a predominant au-
ditory stream from medial to lateral within PAC on HG,
unidirectional connections from PAC on HG to lateral
HG and PT, and an overall auditory propagation from
posterior to anterior areas at low modulation frequen-
cies. (see Fig. 17–13).152 These findings suggest both
serial and parallel cortical processing of auditory infor-
mation, as inferred in animal studies, which can be in-
terpreted as reflective of a constant interaction between
adaptive and plastic cortical areas.
LOCAL FIELD POTENTIAL
RECORDINGS FROM INTRACRANIAL
ELECTRODES
Evoked potentials (EPs) obtained in response to a wide
range of both simple and complex sound have been
recorded directly from the superior temporal plane
of neurosurgical patients both acutely in the operat-
ing room153−159 or chronically through implanted mul-
tichannel depth electrodes and surface cortical grid
electrodes.83,84,160−165
With concurrent adequate anatomical localization of
recording sites, these EPs can be distinguished into their
representation of distinct auditory fields. Posterome-
dial HG, with robustly responsive, frequency tuned and
tonotopically organized neuronal clusters, as recorded
254 SECTION II SYSTEMS

HG

P
L M 1 cm
A
100 μv
100 ms

HG

50 μv
100 ms

Figure 17–12. Waveforms evoked along Heschl’s gyrus (HG) by bipolar electrical
stimulation of most active site on PLST in two representative subjects. (Adapted from
Brugge JF, Volkov IO, Garell PC, Reale RA, Howard MA 3rd. Functional connections
between auditory cortex on Heschl’s gyrus and on the lateral superior temporal gyrus
in humans. J Neurophysiol 2003;90:3750–3763). Location and polarity of bipolar
stimulation shown. Arrows point to site along HG where evoked waveform changed
abruptly. Small circles, high-impedance contacts; Large circles, low-impedance sites.

via HDE by Howard et al.166 and presently in our lab,
provide evidence for this area being field A1. More an-
terolaterally recorded waveforms on HG are of relatively
longer latency and lower amplitude,83,84,154 perhaps in-
dicative of a second auditory “belt” field on HG adja-
cent to the auditory core. EPs recorded directly from the
exposed posterolateral STG exhibit waveforms and re-
sponse sensitivity grossly different from that recorded
on HG, defined as the posterolateral superior temporal
auditory field (area PLST).33,148,149
Over the past decades of recording auditory evoked
activity directly from the cortex deep within the SF,
such clear anatomic reconstruction of electrode sites has
varied, and ultimately improved with imaging technol-
ogy. By using summary data maps estimating locations
anatomically with reference to the temporal pole, de-
rived from pooled data, Celesia et al.154 unfortunately
did not take into account intersubject variability.
Liegeois-Chauvel and colleagues83,84 utilized cere-
bral angiography to obtain 3D coordinates of each HG
electrode lead in relationship to the temporal branch of
the middle cerebral artery, the insula, and the SF. Godey
et al.167 also carried out anatomical reconstruction of
recording sites by visualizing the electrode tracks with
stereotaxic MRI after the electrodes had been removed.
All of these studies inserted depth electrodes perpendic-
ular to the exposed lateral surface of the STG, which
resulted in traversing HG obliquely (see later).
The progress of our laboratory in defining these
three distinct auditory fields on the STG are partially
based, among many other stimuli, on the responses to
a brief click train (5 clicks at 100 Hz) recorded simul-
taneously from 14 microcontacts and 4 macrocontacts
on a HDE that traversed within gray matter, the long
axis of HG, and from 96 contacts of a grid overlaying
the posterolateral STG. See Fig. 17–14 for a representa-
tion of a usual scenario (Brugge and Howard, unpub-
lished data). At our institution, these recordings occur in
epilepsy surgery patients over 7–14 days, who as part of
their treatment plan, require such electrode placement
for diagnosis and ultimately surgical resection of their
epileptogenic focus. Details of the placement and MRI
localization of the HDE and grid electrode can be found
elsewhere,148,166 but can be summarized as follows.

Figure 17–13. Corticocortical connections within the
auditory areas of one subject. (Adapted from
Guéguin M, Le Bouquin-Jeannés R, Faucon G,
Chauvel P, Liégeois-Chauvel C. Evidence of functional
connectivity between auditory cortical areas revealed
by amplitude modulation sound processing. Cereb
Cortex 2007;17(2):304–313). Arrows indicate the
direction of auditory stream. Localization of
intracerebral electrodes in auditory cortex is
superimposed on the patient’s magnetic resonance
imaging slices. Each dashed line (labeled T, H, and P)
indicates the anatomical location of a single electrode
(each white segment corresponding to a given
electrode contact). Each blue, yellow, orange-red,
white, or green-circled line indicates which auditory
region is recorded. Note that a single electrode can
record cortical activity from different areas. Primary
auditory cortex, medial and intermediate Heschl’s
gyrus (HG); SAC, lateral HG and planum temporale
(PT, posterior part of superior temporal gyrus (STG));
BA22 (Brodmann area 22), anterior STG, in front of
HG; HS, Heschl’s sulcus
The HDE is stereotactically placed through the long
axis of either left or right HG, and consists of both macro-
contacts (impedance ∼5 k , 1.6 mm circumferential
platinum discs spaced 10 mm apart) and microcontacts
(impedance ∼0.08–0.2 M , consisting of 40-micrometer
exposed end wires cut flush with the electrode shaft
and distributed at 1–2 mm intervals) (Howard, unpub-
lished data). Usually, the cortical surface array consists of
12 × 8 platinum–iridium disc electrodes embedded in a
silicon membrane, with 5 mm center–center electrode
spacing (diameter 5 mm); references for all electrodes
are at the vertex of the skull near the midline in con-
tact with the galea. Detailed intraoperative photographs,
postimplantation X-rays, and pre- and postimplantation
3D MRIs are used together in localizing the grid and
depth electrode recording sites; coordinates of the depth
electrodes are determined by computer algorithm.
CHAPTER 17 MAPPING OF HEARING 255
By using this click train stimulus we, at our Hu-
man Brain Physiology Laboratory, have been able to
distinguish one field from another based not only on
the waveform of the AEP evoked by the abrupt onset of
the click train but also by the synchronized, frequency-
following response (FFR) to individual clicks in the train.
Figure 17–14 depicts filtered EPs, with details shown in
Fig. 17–15 (Brugge and Howard, unpublished data).
Supporting previous findings,148,149 the robust, polypha-
sic potentials of early latency (9.6 milliseconds) recorded
within posteromedial HG are in contrast to the smaller
amplitude, later negative deflections obtained further an-
terolaterally. Moreover, the ability of posteromedial HG
to have an FFR that was not present more anterolater-
ally signifies the simultaneous recording of two auditory
fields, with the characteristics of posteromedial HG con-
sistent with it being part of auditory core. Also simultane-
ous with the HG recordings were a cluster of polyphasic
AEPs recorded on the posterolateral aspect of STG that
were demonstrably different, characterizing field PLST,
as mentioned previously.33,148,149
Differences in temporal response patterns between
auditory cortical fields can also be assessed by their ca-
pacity to synchronize to AM noise, as has been a key
component in our routine laboratory studies as well as
elsewhere. Recently, Liegeois-Chauvel and colleagues168
used their intracortical stereoelectroencephalography
array to determine the temporal response properties of
different auditory cortical areas in humans by record-
ing the phase-locked neural activity to AM white noises.
Traversing PAC in medial HG, secondary auditory cor-
tex on lateral HG and PT, the insula, and BA 22, the pre-
dominant response of the electrodes in the cortical areas
was to the lowest AM frequencies (4–16 Hz) presented
matching the range of AM frequencies crucial for speech
intelligibility (e.g., Drullman et al. (1994)92,93 , Shannon
et al. (1995)94 , Smith et al. (2002)95 (see Fig. 17–16).168
Also, AEPs showing best synchronization to 16 Hz and
32 Hz appeared only in PAC, suggesting increased tem-
poral resolution relative to more lateral areas and pos-
terior STG. These results corroborate those of an fMRI
study on human subjects,104 which shows that regions
lateral and posterior to HG are more sensitive to the low
frequencies of 4 Hz and 8 Hz, and give support to the
probability of functional specialization of auditory areas.
CONCORDANCE ACROSS METHODS
As is evident from the preceding sections, the use of var-
ious methods to map the function of the auditory cor-
tex has largely been corroborative. As new techniques
emerge, they verify findings from older key studies and
hone details, investigating parameters on a detail hereto-
fore unseen. The use of intracranial electrical stimulation
and recording has been by far the most sensitive method
256 SECTION II SYSTEMS

Figure 17–14. (A) Auditory evoked potentials (AEPs) recorded from 14 microcontact
and 4 macrocontact sites along the length of Heschl’s gyrus (HG) of the left
hemisphere of one subject, in response to a click train (5 clicks at 100 Hz) (Brugge
and Howard, unpublished data). AEPs in left column were filtered from 1.6 to 1000 Hz,
those in right column from 70 to 1000 Hz. Asterisk marks two sites of maximal
amplitude of response, in posteromedial and anteromedial HG. Dashed line denotes
where a functional transition takes place in the sequence of AEPs. Drawings of
magnetic resonance imaging (MRI) cross-sections show the position of the recording
electrode (closed red circle) within the grey matter at the two representative
recording locations marked with the asterisk. Light red shading denotes the estimated
medio-lateral extent of HG. The electrode trajectory and location of each recording
site are shown on the surface rendering of the superior temporal plane. Open circles,
high-impedance contacts; closed circles, low-impedance contacts; ats, anterior
transverse sulcus. (B). All-pass AEPs recorded from the 96-contact grid on the
perisylvian cortex. The locations of the recording contacts are shown on the magnetic
resonance imaging rendering of the lateral surface of the cerebral hemisphere.
Asterisk marks the site of maximal amplitude of response. Expanded view shows the
AEPs recorded at each site. STG, superior temporal gyrus; SF, sylvian fissure.
 CHAPTER 17 MAPPING OF HEARING 257

A E I

B F J

C G K

D H L

Figure 17–15. AEP waveforms obtained at the sites of maximal amplitude on

posteromedial (A–D) and anterolateral (E–G) Heschl’s gyrus and from posterolateral
superior temporal gyrus (I–L) plotted at different time scales, in reference to Figure
17–14 (Brugge and Howard, unpublished data). Filters: 1.6 to 1000 Hz for all but D, H,
L, for which a high-pass filter (70–1000 Hz) was employed. Latency (milliseconds) of
major deflections shown on figures. Note: different time scale than in Figure 17–14.

for defining eloquent auditory cortex and for differenti-
ating various auditory fields. This invasive method has
in general confirmed and refined the findings on EEG,
PET, and fMRI, but its invasive nature causes it to see
limited usage aside from presurgical candidates.
As already mentioned, though, spectral analysis of
synchronized “gamma-range” oscillatory activity, more
than 30–40 Hz, is becoming more prominent as a means
of studying and understanding auditory cortical physi-
ology. Its presence in primate cortex,132,133 as well as
in human sensorimotor and visual cortex,169−174 seems
to be indicative of “binding” spatially segregated neu-
rons into networks representing higher order stimulus
properties.130,131 As we shall see in the next section, this
method is gaining acceptance in its comparable results
to intracranial stimulation and recording.
䉴 CLINICAL APPLICATIONS
Direct cortical stimulation (electrical interference) is
a well-established technique for mapping speech-
language and motor functions in patients who are
surgical candidates for treatment of intractable seizures,
tumors, or arteriovenous malformations.175−179 Origi-
nally developed for intraoperative use to test for local-
ization of eloquent cortex,175,176 this technique induces
a low-level (10–15 mA) bipolar electrical current for
258 SECTION II SYSTEMS

A B

Figure 17–16. Spatial distribution of responses to amplitude modulation investigated in

the right (A) and left (B) auditory cortices in two patients. (Adapted from
Liégeois-Chauvel C, Lorenzi C, Trébuchon A, Régis J, Chauvel P. Temporal envelope
processing in the human left and right auditory cortices. Cereb Cortex 2004;14(7):
731–740). Thirty contacts in Case A, electrodes labeled T, H, and P, and 11 contacts in
Case B, electrodes labeled T and H (each white segment corresponding to a given
electrode contact). Each blue, yellow, red, or green line indicates which auditory
region is recorded and its anatomical location on the electrode superimposed on the
magnetic resonance imaging. Spectral magnitude is represented by a color code.
Note that a single electrode can record cortical activity from different areas, with
contacts numbered from medial to lateral. (A) Note the spatial segregation of corner
or best modulation frequencies (CMFs or BMFs) within primary auditory cortex (PAC):
BMFs of 8 Hz are observed in H3, BMFs of 32 Hz are observed in H4 and CMFs or
BMFs of 4, 8, and 16 Hz are observed in H5 (these leads are located in the anterior
PAC). The green arrow indicates that H6 passes through a sulcus between Heschl’s
gyrus and planum temporale. (B) BMFs of 16 Hz are observed in H13 and H14, while
CMFs of 4 Hz are observed in T11, T12, and T13.

2–3 seconds, using a 100-milliseconds pulse width be-
tween pairs of electrodes located on the lateral surface of
the cortex.33,148,150 The so-called “functional” lesion that
is induced is temporary (<5 seconds), discretely local-
ized to less than 1 cm2 , and highly reproducible.33,178−182
To map language function in the awake patient intraop-
eratively, the stimulating current is carefully adjusted to
the proper strength, using motor and/or sensory cortical
stimulation induced movements or paresthesias as cues,
careful not to exceed afterdischarge threshold. This can
be evaluated concurrently with the use of a four contact
electrode strip placed on adjacent cortex to the site of
stimulation.
We also routinely employ electrical stimulation
functional mapping (ESFM) extraoperatively to test for
location of eloquent cortex in the language-dominant
hemisphere prior to planned resection in patients with
medically intractable epilepsy. Most of these patients
have depth electrodes stereotactically implanted into bi-
lateral amygdala as well as into HG on the supratemporal
plane, with grid electrodes implanted over perisylvian
cortex of either the left or right hemisphere.21,33

Other investigators may have variants on this tech-
nique, but we usually implant a surface array of 12 ×
8 platinum–iridium disc electrodes embedded in a sil-
icon membrane, with 5-mm center-to-center electrode
spacing; electrode contact diameter is 1.5 mm. Strip elec-
trodes with 1-cm intercontact spacing are placed on the
mesial surface of the inferior temporal gyrus; reference
electrodes are attached to the skull near the midline
in contact with the galea. Detailed intraoperative pho-
tographs, postimplantation X-rays, and pre- and postim-
plantation 3D MRIs are used together in localizing the
grid and depth electrode recording sites.
These patients usually remain on the epilepsy ward
for 10–14 days under video-EEG surveillance, where lan-
guage mapping is performed just prior to resection. This
is performed by presenting the patient with pictures of
common objects to name, while stimulating pairs of ad-
jacent electrodes on the lateral surface, searching for
sites within the field where deficits in speech occur. As
performed intraoperatively, afterdischarge threshold in
stimulation current is not exceeded by observing the
concurrently recorded EEG.
Aside from electrical cortical stimulation (ECS), the
gold standard technique, there have been applications
of noninvasive functional mapping modalities to identify
eloquent language cortex in presurgical planning.
The Wada test,183 or the intracarotid injection of
sodium amobarbital, has been used to establish the lat-
erality of language function in preoperative planning
for decades. Functional brain mapping using PET to
measure regional cerebral blood flow (rCBF) has also
been used as a preoperative assessment of language
function. Pardo and Fox184 used CBF PET in 11 pa-
tients with complex partial epilepsy to detect language
dominance and they found their results to be compa-
rable to those of Wada testing. Kaplan et al.185 used
2-deoxy-2-[18F]fluoro-D-glucose (FDG) and L-[methyl-
(11)C]methionine (CMET) PET scans coregistered with
MR images in five pediatric patients to accurately de-
fine structural and functional cortical areas as well as to
grade tumors, which was instrumental in achieving effec-
tive neurosurgical planning. In this patient population,
PET scanning was deemed advantageous over MRI as it
provided less claustrophobic anxiety for the patient, tu-
mor grading capability, and mapping in a single session.
Although fMRI regimens demonstrate compara-
ble results to Wada testing for language lateralization,
correlation between pre- and postoperative fMRI and
intraoperative ECS remains inconsistent. Roux et al.186
compared language areas showing fMR activations by
naming and verb generation tasks with intraoperative
speech mapping using ECS in 14 right-handed patients
with left hemisphere tumors.
Only 5 of 22 language sites identified by ECS were
associated with preoperative fMR activation, leading the
authors to conclude that although fMRI may be a helpful
CHAPTER 17 MAPPING OF HEARING 259
adjunct it is insufficient to be used alone as a tool to form
critical preresection decisions. In addition, as only three
of eight patients examined with postresection fMRI cor-
roborated the language foci identified by intraoperative
ECS, the authors contend that perhaps such low sensi-
tivity and specificity can be improved by modifying the
behavioral paradigms employed. In contrast, in a study
on patients with mesial temporal lobe epilepsy, Carpen-
tier et al.187 found good concordance in intrahemispheric
language maps generated by fMRI and intraoperative
ECS. Here, additional eloquent foci were identified by
fMRI, which the authors attribute to limited cortical cov-
erage by electrodes and the inherent differences in the
techniques between fMRI (imaging) and ECS (electrical
interference).
ACOUSTIC PROCESSING
Penfield and Rasmussen188 first reported that electrical
pulses applied to the STG of patients undergoing awake
craniotomies produced alterations in auditory percep-
tion, referred to as “auditory illusions.” Most of these
patients suffered from seizures and were undergoing
exploratory stimulation for eloquent cortex. “Experien-
tial” responses were elicited from less than 10% patients
tested, ranging from “crude” auditory percepts such as a
“tone, a buzzing or knocking sound” from HG stimula-
tion to “voices” or “someone calling” when lateral STG
was stimulated.189−192
These early records of objectively quantified per-
ceptions confirmed the presence of a hierarchical audi-
tory cortex on STG, with increased complexity of elicited
responses from laterally stimulated sites.
In the course of performing ESFM in patients with
medically intractable epilepsy, we were also able to
evoke sound perceptions within posterior medial HG,
such as a “tone” or “chopping sound,” localized to the
contralateral ear. In contrast, we also were able to in-
duce hearing suppression in both ears, which persisted
beyond the period of electrical stimulation, during stimu-
lation of sites within anterior lateral HG and posterior lat-
eral STG, as rarely reported before.191 This suppression
was perceived as a “muffling” sound, and in a patient
with long-standing tinnitus, caused it to “quiet down”
(see Fenoy et al.150 ). This finding of hearing suppres-
sion due to stimulation of sites within known auditory
cortical fields offers the suggestion of the presence of
corticofugal efferent pathways that project to auditory
thalamic, midbrain and brainstem structures, and pos-
sibly the cochlea, as seen in other animals.193−199 The
corticofugal pathways, which originate in different au-
ditory cortical fields, including PAC on HG, may exert
different functional influences on auditory processing;
subjective suppression of hearing induced by electrical
stimulation is one such effect.
260 SECTION II SYSTEMS
SPEECH AND LANGUAGE
PROCESSING
By far, the most pertinent application of clinical brain
mapping in the realm of hearing is to identify and pre-
serve human speech and language function. In recent
years, there has been a rise in the number of brain
mapping studies using functional lesion methods to
investigate the neural bases of speech perception. These
studies have been performed on neurosurgery patients
prior to planned resections of language-dominant tem-
poral lobe. Boatman et al.200 reviewed these stud-
ies and summarized the individual functional circuitry
activated for specific speech processing. Within left
STG, electrocortical mapping studies identified a cir-
cumscribed anterior region within the middle-posterior
left STG associated with acoustic–phonetic processing
(as measured by auditory discrimination of phonetic
features),179,182,200−204 anterior and posterior sites as-
sociated with phonological processing, as assessed by
phoneme identification (repetition, picture word match-
ing, orthographic matching),179 and a wide cortical distri-
bution of sites associated with access to lexical–semantic
information (as measured by sentence comprehension),
including the temporoparietal junction as well as anterior
regions in the frontal lobe.176,179,182,205−207 The location
of electrode sites where discrimination of both syllables
and spectrally complex FM tones was impaired during
cortical stimulation is depicted in Fig. 17–17.202
Boatman et al. suggest that, in accordance with
recent animal studies,9,23,38 the functional organiza-
Figure 17–17. Location of electrode sites where
discrimination of consonant-vowel syllables and
spectrally complex frequency-modulated (FM) tones
was impaired during cortical stimulation in 11 patients,
normalized to a standard brain representation. (See
Boatman DF. Cortical auditory systems: speech and
other complex sounds. Epilepsy Behav 2006;8(3):
494–503; Epub 2006. Review, 2006.). Discrimination
of pure tones, vowels, and simple FM sweeps
remained intact at these sites. Light gray lines
represent sites where no auditory discrimination
deficits were induced.
tion of the STG and other cortical regions that sup-
port speech perception is hierarchical, with more basic
speech processing (i.e., syllable discrimination) posteri-
orly based and larger network activation with increased
complexity of speech processing, using different tempo-
ral lobe pathways extending both anteriorly and poste-
riorly. Such a view is consistent with results of primate
and human neuroimaging studies that suggest different
transmission streams depending on stimulus and task
demands.8,14,23,38,208
If by chance afterdischarges are evoked, these can
evolve into clinical seizures if left unchecked.209,210 Af-
terdischarges and seizures elicited during stimulation
mapping do not accurately reflect the patient’s seizure
focus.209
Alternatively, Crone et al.129 contend that functional
maps based on passive recordings of event-related ECoG
gamma activity avoids the possibility of afterdischarges
that may prevent comprehensive language mapping and
shortens the time of acquisition, as a map can be ob-
tained for all implanted electrode sites at once. This vari-
ation on mapping using the same subdural electrode ar-
rays improves upon limitations of functional imaging.
Whereas fMRI has been used preoperatively recently for
some functional mapping, it may not accurately predict
eloquent areas186,211−213 ; the poor temporal resolution
caused by the time lag between synaptic activity and
changes in blood flow makes it unsuitable for monitor-
ing language function.214
Crone and colleagues have been in the process of
comparing the maps derived from event-related ECoG
gamma-band changes with maps obtained by electrical
stimulation mapping (ESM) through the same subdural
electrodes172,215 to evaluate their potential application to
functional brain mapping.
In previous studies, Crone et al.171 found event-
related synchronization (ERS) more than 30–40 Hz to
occur in a relatively focused spatial distribution over the
dominant superior gyrus, coinciding with the onset of
the N100 of the auditory EP but lasting longer, and occur-
ring with greater magnitude in association with speech
stimuli than with tone stimuli. This study analyzed over-
lapping frequency bands, finding, as in other studies, the
presence of activity well above 100 Hz. Edwards et al.216
in their study of deviant auditory stimuli detection, re-
ported high-gamma oscillations in the frequency range
of 60–250 Hz, centered at approximately 100 Hz.
Sinai et al.215 recently compared the spatial pat-
terns of high-gamma (80–100 Hz) spectral changes
obtained during picture naming with ESM maps of nam-
ing in the same clinical subjects undergoing epilepsy
surgery (see Fig. 17–18).215 By using the average number
of 12 electrode sites with statistically significant high-
gamma ERS, electrocorticographic high-gamma ERS
during confrontation naming appeared to predict ESM
interference with naming and mouth-related motor
 CHAPTER 17 MAPPING OF HEARING 261

200 200
Gamma Power Gamma Power

Percent Change

Percent Change
150 80–100 Hz 150 80–100 Hz

100 100

50 50

0 0
–50 –50
0.0 1.0 2.0 3.0 0.0 1.0 2.0 3.0
Time (seconds) Time (seconds)

200
Gamma Power
Percent Change

150 80–100 Hz

100

50

0
–50
0.0 1.0 2.0 3.0
Time (seconds) Electrical Cortical Stimulation
Mouth Naming
No Impairment Other Language

Figure 17–18. Comparison of event-related electocorticography (ECoG) high-gamma

activity with electrical stimulation mapping (ESM) in an individual subject. (See Sinai A,
Bowers CW, Crainiceanu CM, et al. Electrocorticographic high-gamma activity versus
electrical cortical stimulation mapping of naming. Brain 2005;128:1556–1570). White
circles denote electrode sites where ECoG was recorded. Yellow plots show the
magnitude of high-gamma activity as a percentage change (y-axis) with respect to
baseline. The onset of the pictured object to be named occurred 400 milliseconds
after disappearance of a fixation point at 0 seconds (x-axis). Colored bars join
electrode pairs where electrical cortical stimulation was performed, color-coded for
the occurrence and types of functional effects. Note that ESM was not performed at
some sites where ECoG was recorded (pain was encountered at some
temporal-occipital sites).

function with good specificity (84%) but relatively low
sensitivity (43%). Such favorable specificity of high-
gamma ERS suggests that it could predict at which sites
ESM would disrupt naming, and thus could possibly be
useful in the construction of a functional map. However,
due to the low sensitivity in the study, for sites within
the planned cortical resection at which high-gamma ERS
was not observed, the authors agree that ESM would still
be necessary to protect eloquent cortex. The authors
attribute the low sensitivity to perhaps too restricted
a frequency band of analysis, too wide electrode spac-
ing (1 cm), or perhaps difficulty in the interpretation of
magnitude that is indicative of cortical processing.215
To investigate whether causal interactions at high-
gamma frequencies belies functional cooperation of
distributed cortical networks, SdDTF (short-time direct
directed transfer function) has been used recently by
Korzeniewska et al.217 to estimate event-related causal
interactions between multiple electrocorticography sig-
nals during auditory word repetition and other speech
production tasks. Such interactions were seen to occur
between perisylvian cortical regions at multiple high-
gamma frequencies, especially bidirectional interactions
between STG and inferior frontal gyrus.
Such studies using multichannel electrocorticogra-
phy as well as evaluating the role of high-gamma oscil-
lations are likely in the future to provide much more
detailed information regarding dynamic interactions
across distributed cortical networks. Moreover, current
research is continually finding new applications for spec-
tral analysis to uniquely investigate of brain function.
In a recent study, Lachaux and colleagues218 used
real-time spectral analysis of brain signals in the post-
electrode implantation, preresection evaluation of two
patients with intractable epilepsy to find a highly specific
functional and spatial organization of high-gamma (60–
140 Hz) power in the anterior superior temporal lobe
associated with speech and music perception. These
results complemented concurrent standard ESM, again
making this a promising tool in presurgical mapping.
Furthermore, using direct visual feedback, it shows po-
tential as an online exploratory tool that can lead to
262 SECTION II SYSTEMS
novel experimental paradigms that can be tailor de-
signed to systematically probe the spatial, temporal, and
spectral aspects of cognition.
䉴 PEARLS AND PITFALLS
There has been considerable scientific progress over the
past decade in the development of new technological
applications to elucidate our current thinking and un-
derstanding of the human brain. These new applications,
such as improved fMRI and MEG, and the spectral analy-
sis of high-gamma activity, however, is most useful when
used together or in conjunction with preexisting “gold
standard” techniques, such as intracranial recording and
stimulation. It is of little doubt that less invasive imaging
will hopefully one day supplant invasive recordings or
stimulations, but as we have reiterated, the most valuable
information has been yielded by a combination of tech-
niques, so as to make up for the disadvantages of any
one particular modality applied individually. The com-
plexity of function of the human brain is not fully known,
and as each human has a specific, unique cortical map
designated for audition, speech, and language, we must
still proceed cautiously in presurgical mapping to ensure
that eloquent cortex is fully detailed. It shall be inter-
esting to see what developments in research occur in
the next decade to augment our artillery of investigative
tools.
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213. Pouratian N, Bookheimer SY, Rex DE, Martin NA, Toga
AW. Utility of preoperative functional magnetic resonance
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214. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG. En-
ergy on demand. Science 1999;283:496-497.
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ticographic high-gamma activity versus electrical corti-
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 Chapter 18
Mapping of Memory
Jeffrey G. Ojemann and Richard G. Ellenbogen
Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington
䉴 INTRODUCTION
Though extensive neurosurgical experience has shaped
our understanding of motor and language systems, other
functions have not been consistently explored. The un-
derstanding of mapping memory suffers not only from
this dearth of neurosurgical experience, but also from the
many different aspects of memory1 and the correspond-
ing taxonomy (e.g., encoding vs. retrieval, short-term vs.
long-term, semantic vs. episodic). Further difficulties re-
late to the fundamentally mercurial nature of memory,
meaning that only when memories are formed or re-
trieved we are able to directly assess memory processes,
even though memory itself covers the “storage” interval
between these two tangible events.
Memory has been studied first through neuropsy-
chological measures from subjects with normal memory
function and from patients with neurological disorders,
and more recently through neuroimaging studies, such
as functional magnetic resonance imaging (fMRI).2−4 Im-
pairment of several different cortical and subcortical
structures are associated with memory disorders.5 The
role of the medial temporal lobe for memory formation
and retention is well established, especially as the se-
vere consequences of bilateral damage to medial tem-
poral structures.6 Other areas such as the frontal lobe
have particular research and clinical relevance.7,8
WHAT IS MEMORY?
The memory process may be conceptualized as consist-
ing of the steps of encoding (initial exposure to the thing
being remembered), storage (the retention of the mem-
ory), and retrieval (the culmination of memory in the act
of remembering).
Encoding has significant overlap with perception
and attention. For example, a word that is studied or ma-
nipulated will be remembered better than a word that is
merely viewed or read. Thus, if you see the word “build-
ing” and are asked to think of a synonym for the word,
you will have a better chance of recognizing the word
on a list than if you merely read the word.
269
Storage refers generically to all processes that
extend beyond “working memory.” Working memory
refers to the “scratch pad” (see also Baddeley (1992)).9
of information that we use during a task. This type of
memory is limited. For example the number of digits
that you can easily remember at one time may be a
telephone number, while a longer string of numbers
may be more difficult. Working memory is also gener-
ally preserved in cases of amnesia. Once the working
memory phase is exceeded, some sort of storage oc-
curs. Over time, memories are consolidated. These con-
solidated memories are much more stable. For example,
in head injury patients a retrograde amnesia may occur
for some period of time (days) but longerterm mem-
ories are preserved. Longer term memories are dam-
aged in more diffuse pathologies, such as Alzheimer’s
disease.
Retrieval is the event most typically thought of
in memory studies, as it is unambiguously a memory
phenomenon. However, overlap with the brain regions
involved in encoding is seen consistently in imaging
studies.
Memory can also be broken down into different
types. So-called episodic memory, refers to memory for
specific events. For example, if you remember what you
had for breakfast yesterday, that requires memory for a
specific moment and context. However, if you remem-
ber that eggs are a common breakfast food you are
accessing semantic memory, or memory for facts and
knowledge of the world.1 Semantic memory strongly
overlaps with language systems from a clinical perspec-
tive.
Finally, procedural memory is another term used
to describe skills or changes associated with practice
and repetition.1 This type of memory appears to be de-
pendent on a certain system, such as the motor sys-
tem for the acquisition of motor learning, and largely
happens on a subconscious level. It can be seen in
simple motor tasks, repetitive cognitive tasks, or even
repetitive exposure to the same list of words. Again,
the deficits seen with this type of memory would be
expected to overlap with the primary system affected,
such as visual processing, somatosensory, or language
processing.
270 SECTION II SYSTEMS

Figure 18–1. Schematic diagram showing some of the areas involved in memory.
Though the medial temporal regions (black, left panel) are well known to show
memory deficits with lesions, cortical regions including lateral temporal, parietal, and
frontal lobe (black, right panel, indicating approximate regions involved) play a role in
various memory processes.

MEMORY ANATOMY
Memory deficits can result from lesions in various brain
regions (Fig. 18–1). Limbic system lesions are classically
associated with significant memory problems, especially
when bilateral. In addition to medial temporal struc-
tures, damage to the fornix, mamillary bodies, and an-
terior thalamic nuclei are all associated with memory
disturbances, each with specific designated syndromes.
Frontal lobe damage seems to affect memory as well,
though the nature of the deficit may not be obvious on
cursory clinical evaluation.8,10 However, on tests of in-
terference in the memory process, frontal lobe patients
perform quite poorly and their clinical complaints of
memory loss often reflect problems with semantic mem-
ory retrieval, such as being unable to remember names
or places. For some patients following epilepsy surgery,
material specific memory (verbal vs. nonverbal material)
may be the most affected process. Attempts to identify
these processes have been ongoing, if only partially suc-
cessful.
From an anatomic perspective of memory, the neu-
rosurgically relevant observations are limited to two ma-
jor findings. First, it is consistently seen that memory
deficits are lateralized and thus resections of the dom-
inant hemisphere temporal lobe will be more likely to
give verbal memory deficits compared to nondominant
resections. Second, the deficit may not be directly linked
to hippocampal resection. When a memory deficit is
found following temporal lobe resection, a traditional
view may suggest that this be due to medial temporal
resection. However, one of the few studies of the effect
of resection on deficit found that the extent of lateral,
rather than medial temporal lobe resection was the best
predictor of postoperative memory deficit.11 .
䉴 TECHNIQUES FOR ASSESSMENT
OF MEMORY
FUNCTIONAL IMAGING
Investigators using fMRI have attempted to activate the
medial temporal lobe reliably.12−15 However, it has been
noticed for some time that a simple memory task is
more likely to activate frontal lobe systems than the
hippocampus.1,7,8 More successful efforts to activate the
hippocampus and medial temporal lobe have focused on
tasks that require the patient to assess stimuli for nov-
elty or for specific relations between stimuli.12 In addi-
tion to an incomplete understanding of the physiology
of hippocampus and medial temporal lobes (e.g., What
activates them?) technical limitations of fMRI include
the relatively small size of the hippocampus and local
susceptibility artifacts from the nearby aerated petrous
bone.16 These limitations are not insurmountable and
the next few years are likely to bring progress in the
understanding, if not the mapping, of these functions.
NONINVASIVE ASSESSMENTS
For elective cases, such as surgical treatment of epilepsy,
a thorough neuropsychological assessment can be in-
valuable for understanding memory function. In partic-
ular, well-defined cases of dominant hemisphere mesial
 CHAPTER 18 MAPPING OF MEMORY 271

temporal sclerosis are typically associated with decreases

in measures of verbal learning. Preoperative verbal
memory performance is a very strong negative indica-
tor of memory loss with surgery.17 A variety of studies
have shown material specific deficits depending on the
side of surgery,18,19 which may have variable affects on
activities of daily living.

CEREBRAL AMOBARBITAL (WADA)

The intracarotid amobarbital (Wada) test (see chapter 6)

is frequently used to assess memory dominance for pre-
operative neurosurgical evaluation. It has been used to
identify which candidates for temporal lobectomy might
be at risk for global amnesia due to preexisting dysfunc-
tion of the side opposite to that considered for surgery. It
has also been reported to be a predictor of verbal mem-
ory decline from anterior temporal lobectomy20,21 ; how-
ever, the actual predictive value may be relatively low
and depend on the type of psychological test used.22
CORTICAL STIMULATION
There have been a very limited number of studies using
cortical stimulation to map memory. Stimulation through
intraoperative or extraoperative mapping11,23 can be ap-
plied during a short-term memory task with the electri-
cal current applied during encoding, storage, or retrieval
(see Fig. 18–2). Errors in any aspects of memory can be
found focally throughout frontal, temporal, or parietal
cortex (see Fig. 18–3). In one reported series of patients,
resection of neocortical sites showed a greater decline
in postoperative verbal memory than those with resec-
Figure 18–2. Type of stimuli used for memory
mapping. A typical trial would include a target
presentation (encoding), which is named, a distracter
task during storage, and a recall cue (retrieval).
Stimulation during any of these stages can result in
the eventual inability to recall the target. With this
technique, correct recall can occur even if stimulation
induces a naming error during target presentation. If
the error occurs with stimulation during recall or if
the error is due to disruption of language circuits, an
error at target presentation naming would be
expected, as oppose to an error only with stimulation
during recall implying that the site stimulated is
specific for memory retrieval.
Figure 18–3. A typical map of memory may find
errors (asterisks) in several temporoparietal sites
including fairly anteriorly in lateral temporal cortex.
tions sparing these sites.23 This would be in line with
findings that the extent of lateral temporal resection is a
predictor of postoperative verbal memory declines11 in
dominant temporal lobectomy. Further support for the
role of the lateral temporal lobe in memory comes from
the observation that experiential phenomenon can occur
from lateral temporal lobe structures alone.24
INTRACRANIAL RECORDINGS
The study of memory with electrical recordings has been
of long interest, but intracranial studies are rare. Repeat
exposure to an item can alter the response of a sen-
sory evoked potential and novelty responses, such as the
P300, can be modified by repeated exposure.25 Frontal
lobe changes in high-gamma (chi band) frequency have
been reported preliminarily with working memory tasks,
consistent with fMRI findings.26 Extensive research on
intracranial recordings from the lateral temporal lobe27
or hippocampus28 has provided some insight on basic
mechanisms of the neuronal basis for memory in these
regions.
䉴 CLINICAL APPLICATION
Memory mapping techniques used to determine a “risk
versus benefit ratio” in a neurosurgical setting have
largely focused on patients undergoing anterior temporal
lobe resection (ATR) of seizure foci. Neuropsychological
assessment, intracarotid injection of amobarbital (Wada
testing), and more recently fMRI, are the primary tools
used to determine the functional status of the temporal
lobe to be resected. The “functional adequacy” model
272 SECTION II SYSTEMS

would predict greater risk of decline if memory is ade-
quately supported by the temporal lobe to be resected.29
On the other hand, if memory is poor for the ipsilat-
eral temporal lobe before surgery, then the risk is re-
duced because there may be a limited amount of func-
tion or nothing to lose. Memory mapping techniques
are also used to determine the functional status of the
temporal lobe contralateral to the side of resection. The
“cognitive reserve” model would predict better memory
outcome for patients with a functional contralateral tem-
poral lobe.29
In this section, Wada testing and fMRI memory map-
ping validation studies are briefly reviewed. Both of
these techniques are discussed in further detail else-
where in this volume (Chapters 3 and 4 for fMRI and
Chapter 8 for Wada testing). There is also an extensive
discussion of the utility of presurgical neuropsychologi-
cal assessment in predicting postsurgical memory decre-
ments associated with ATR in Chapter 7.
is predictive of increased risk of postsurgical verbal
memory decline (e.g., Stroup et al. (2003)17 , Kneebone
et al. (1995)33 Furthermore, adequate Wada testing per-
formance after injection of the hemisphere contralateral
to the to be resected temporal lobe is predictive of good
verbal memory outcome (e.g., Bell et al. (2000)30 , Chiar-
avalloti et al. (2001)31 . However, not all studies are in
agreement. For example, Kubu et al.39 demonstrated
that patients who failed the Wada test bilaterally had
relatively few losses in memory abilities after surgery
(and no global amnesia), and as previously discussed,
the predictive value of Wada testing is more limited
when taking into account other factors such as presur-
gical neuropsychology-defined verbal memory ability
and side of surgery.17,20,40 Few studies have evaluated
Wada testing in predicting nonverbal memory decline
after a nonlanguage dominant ATR with results being
equivocal.

FUNCTIONAL MRI
WADA TESTING
Table 18–2 summarizes all of the studies that have eval-
Table 18–1 summarizes the extant literature studying uated the efficacy of fMRI activation as a predictor of
the utility of Wada testing in predicting material spe- postoperative memory impairment after ATR. In all of the
cific memory impairments after unilateral temporal lobe studies, greater ipsilateral activation (or greater asymme-
resection. A variation in Wada testing methods and pro- try vs. the contralateral hemisphere; commonly known
cedures make comparisons across studies difficult. How- as a laterality index) is related to greater memory de-
ever, generally speaking, most studies find that ade- cline after surgery to varying degrees using different
quate patient performance after amobarbital injection testing materials. Two of the studies compared the pre-
of the to be resected language-dominant temporal lobe dictive validity of both fMRI and Wada testing.42,46 Us-
ing an auditory semantic memory encoding task, Binder
et al.42 showed that greater left-sided fMRI activation be-
䉴 TABLE 18–1. WADA PREDICTION OF fore surgery predicted postsurgical verbal memory de-
POSTOPERATIVE NEUROPSYCHOLOGICAL cline, whereas Wada testing was noncontributory. By
MEMORY OUTCOME AFTER UNILATERAL using a visual encoding of scenes task, Rabin et al.46
ANTERIOR TEMPORAL LOBE RESECTION showed that greater ipsilateral fMRI activation of the hip-
Predicts Verbal Memory Does not Predict pocampus, parahippocampal gyrus, and fusiform gyrus
Decline Verbal Memory Decline predicted visual memory decline after surgery, whereas
Wada testing was noncontributory.
Baxendale et al. (2007)20 Kirsch et al. (2005)38
Bell et al. (2000)30 Kubu et al. (2000)39
Chiaravalloti and Glosser Lineweaver et al. (2006)40
(2001)31
FUNCTIONAL MRI VERSUS
Joiket et al. (1997)32 Loringet al. (1990) 41 WADA TESTING
Kneebone et al. (1995)33
Lacruz et al. (2004)34 Table 18–3 summarizes all of the studies that validated
Lee et al. (2005)35 fMRI memory paradigms compared to Wada testing.
Loringet al. (1995)21 fMRI would be an attractive alternative to Wada testing
Sabsevitz et al. (2001)36 in determining cognitive risks associated with surgery
Stroupet al. (2003)17 given that it is less invasive, can be repeated multi-
Wyllie et al. (1990)37 ple times, is widely available and poses minimal risks.
Predicts Nonverbal Does not Predict Nonverbal However, it is unclear if fMRI methodology is valid and
Decline Memory Memory Decline reliable enough to replace Wada testing given the vari-
ability in results shown in Table 18–3. The first studies to
Lacruz et al. (2004)34 Chiaravalloti and Glosser
publish data were very promising14,15 as there was 100%
Lineweaver et al. (2006)40 (2001)31
concordance between fMRI and Wada in identifying
 CHAPTER 18 MAPPING OF MEMORY 273

䉴 TABLE 18–2. FUNCTIONAL MAGNETIC RESONANCE IMAGING (fMRI) PREDICTION OF

POSTOPERATIVE NEUROPSYCHOLOGICAL MEMORY CHANGE AFTER UNILATERAL ANTERIOR
TEMPORAL LOBE RESECTION

Study N/Sample Task Results

Binder et al. (2008)42
Frings et al. (2008)43
Janszky et al. (2005)44
Powell et al. (2007)45
Rabin et al. (2004)46
Richardson et al. (2004)47
Richardson et al. (2006)48
60 left-ATR Auditory encoding animal Greater left-side fMRI activation before
surgery predicted
62 right-ATR Decision task 11% of variance in postsurgical verbal
memory decline beyond the 54% of
variance accounted for by preoperative
memory testing and age at onset
22 ATR Object location memory Greater ipsilateral hippocampal fMRI
activation correlated (r = 0.49) with
verbal learning decline after surgery
16 right-ATR Route learning task Greater ipsilateral fMRI activation before
surgery correlated (r = 0.71) with visual
memory decline after right-ATL
15 ATR Visual encoding of words, Greater ipsilateral mesial temporal lobe
pictures of common fMRI activation (compared to
objects, and faces contralateral activation) correlated with
postsurgical verbal memory decline after
left-ATR and nonverbal memory decline
after right-ATR
25 ATR Visual encoding of novel Greater ipsilateral fMRI activation of
scenes mesial temporal lobe before surgery was
correlated (r = − 0.56) with visual
memory decline after surgery
10 left-ATR with HS Visual encoding of words Greater left hippocampal activation (vs.
right) correlated (r = 0.82) with verbal
memory decline after surgery
12 left-ATR with HS Visual encoding of words Greater left hippocampal activation, but
not right hippocampus or amygdala
activation, predicted worsening in word
list learning ability after surgery

ATR, anterior temporal lobe resection; HS, hippocampal sclerosis.

䉴 TABLE 18–3. COMPARISON OF FMRI MEMORY LATERALIZATION PARADIGMS TO WADA TESTING

IN INTRACTABLE EPILEPSY SURGERY CANDIDATES

Study N/Sample Task Concordance Rates with Wada

Branco et al. (2006)49 5 epilepsy Visual encoding of novel 60% concordance

Deblaere et al. (2005)50
Detre et al. (1998)15
Golby et al. (2002)14
Rabin et al. (2004)46
Szaflarski et al. (2004)51
patterns, scenes, and words
18 TLE Visual encoding of novel vs. old
pictures of common objects
9 TLE Visual encoding of scenes
9 TLE Visual encoding of novel
patterns, faces, scenes, and
words
35 TLE Visual encoding of novel scenes
5 TLE Visual encoding of novel scenes
1 ET that varied in verbal
encodability and the presence
of people
Concordance rates not reported; fMRI
activation correlated with Wada results
in right-TLE but not left-TLE
100% concordance
100% concordance
Concordance rates not reported;
correlation (r = 0.60) between fMRI and
WADA asymmetry ratios for right-TLE
but not significant for left-TLE
50% concordance; fMRI nonlateralizing in
two cases and discordant in one case
vs. Wada

TLE, temporal lobe epilepsy; ET, extratemporal.

274 SECTION II SYSTEMS
the functional status of the mesial temporal lobes.
Problematically, later studies showed that concordance
was not perfect, and suggested that fMRI and Wada re-
sults are similar in identifying the functional status of
the nonlanguage dominant hemisphere, but not the lan-
guage dominant hemisphere.46,50
SUMMARY OF CLINICAL APPLICATION
Practically speaking, the best predictors of memory dis-
turbance following epilepsy surgery remain the preop-
erative MRI and preresection neuropsychological status.
Patients with normal MRI and good presurgical function
have the greatest risk of new deficit. The use of Wada
testing still has a role in patient assessment although
somewhat limited by the factors discussed previously.
The role of fMRI is still evolving. The role of intraop-
erative mapping remains largely unexplored as the very
nature of memory is much less well understood than
other, more commonly mapped functions.
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 INDEX
Note: Page numbers followed by f and t indicate figures and tables, respectively.

A localization, 8–9, 9f starting parameters, 95t

Acoustic processing applications, 259 optical imaging in animals and humans, subject preparation, 94
AEFs. See Auditory evoked magnetic fields 135 video-EEG, 96, 98t
AEPs. See Auditory evoked potentials Auditory evoked magnetic fields (AEFs), 123 intraoperative cortical mapping
AF. See Arcuate fasciculus Auditory evoked potentials (AEPs), 256f–257f anesthesia, 104
Afterdischarge (AD) threshold, 97 Auditory illusions, 259 in clinical practice, 106
Alexia, 105 Auditory stimulation, 43f, 137, 250 craniotomy, 104
Amygdala, 27 AVMs. See Arteriovenous malformations electrocorticography, 105
Anatomic landmarks, 3 vs. extraoperative cortical mapping,
Anatomic modularity, 56 B 98–99
Anatomical localization Barbiturates, 110–11 language mapping, 105–6
auditory function, 8–9, 9f Basal temporal language area (BTLA), 213 positioning, 104
cortical structural anatomy, 4 Baseline, or Frankfurt plane, 4 postoperative outcomes, 106
language function, 5, 7–8, 7f Benzodiazepines, 110 principles, 103
motor and sensory functions, 4–5 Bipolar stimulation, 95 sensorimotor stimulation, 105
visual function, 8, 9f Blood oxygen level dependent (BOLD) fMRI, somatosensory evoked potential
Anesthesia, brain mapping surgery 31, 33, 34f, 195–96 recording, 104
anesthetic management, 114–15 Brain architecture, optical imaging sensorimotor cortex
anesthetics effects, 109 auditory cortex, 135 cerebral hemisphere, 19–20
barbiturates, 110–11 language cortex, 137, 139 clinical applications, 198–99
benzodiazepines, 110 somatosensory cortex, 135–37, 136f direct cortical stimulation, 192–94
craniotomy, 113 visual cortex, 134–35 electrocorticographic spectral
dexmedetomidine, 112 Brain diseases, optical imaging pathology analysis, 156–57
etomidate, 111 epilepsy, 139–40 functional MRI, 195–96
general, 115–16 intracranial hematomas, 143–45 historical perspectives, 189–90
intraoperative cortical mapping, 104 stroke, 141–43 localization, 191–92
intraoperative monitoring, 114 traumatic brain injury, 143–45 magnetoencephalography, 196–97
ketamine, 111 Brain fissural patterns, 13 positron emission tomography, 196
local anesthetics, 110 Brain mapping, 94 primary motor cortex, 190–91
management, 114–15 electrocorticographic spectral analysis somatosensory-evoked potentials,
nitrous oxide, 112–13 advantages and pitfalls, 161–62 194–95
opiates, 111 auditory function localization, 157 transcranial magnetic stimulation, 197
preoperative care, 113–14 in clinical practice, 160–61 Brain mapping in children
propofol, 112 historical perspectives, 151 clinical indications, 167
sedatives, 109 instrumentation methodology, 153 diffusion tensor imaging, 171
volatile anesthetic neuropharmacology, language cortex mapping, 157–58 diffusion-weighted imaging, 170–71
113, 113t mapping functional connectivity, 159 functional MRI
Anesthetic agents mapping sensorimotor function, brain tumors, 170
barbiturates, 110–11 155–56 cortical plasticity and reorganization,
benzodiazepines, 110 memory function mapping, 158–59 170
dexmedetomidine, 112 principles, 152–53 epilepsy, 170
etomidate, 111 recording techniques and data general considerations in pediatrics,
ketamine, 111 acquisition, 154–55 169–70
nitrous oxide, 112–13 signal analysis, 155 magnetoencephalography
opiates, 111 strengths and weaknesses, 159–60 epilepsy, 173–74
propofol, 112 subject inclusion and preparation, 153 functional mapping, 172–73
Anterior basal orbitofrontal sulci, 24f, 25 visual function localization, 156–57 general considerations in pediatrics,
Anterior temporal lobectomy (ATL), 62–63, extraoperative functional mapping 172
63f, 79 cortical stimulation, 96, 96f perfusion-weighted imaging, 171
Arcuate fasciculus (AF), 204f–205f electronic principles, 95 positron emission tomography
Arteriovenous malformations (AVMs), 48 historical perspectives, 93–94 brain tumors, 174
Association of deficits, 57 instrumentation, 95 epilepsy, 174–75
ATL. See Anterior temporal lobectomy vs. intraoperative functional mapping, functional mapping, 174
Attention, 60, 66 98–99 general considerations in pediatrics,
Auditory cortex language task, 96 174
electrocorticographic spectral analysis, methodology, 94 single photon emission tomography
157 saftey and adverse effects, 97–98 additional clinical applications, 176

277
278 INDEX

Brain mapping in children (Cont.) Central sulcus superior temporal sulcus, 16–17
brain tumors, 175 cerebral hemisphere, 15, 15f sylvian opercula, 13–15, 14f
epilepsy, 175–76 localization, 4–5, 6f temporal lobe, 15f, 18–19
general considerations in pediatrics, imaging approaches, 20 Cerebral localization
175 Cerebral amobarbital testing activation map creation, 39, 40f
specific techniques, 167–68, 168f advantages and pitfalls, 87–88 clinical inferences, 41–44, 43f
Brain mapping surgery applications, 86 data analysis, 33–39, 36f, 38f
anesthetic agents in clinical practice, 87 MRI and MR scanners, 33, 34f
barbiturates, 110–11 data acquisition and data analysis MRI data collection, 33, 35f
benzodiazepines, 110 language, 84–85 thumbnail sketch, 31–33, 32f
dexmedetomidine, 112 memory, 85–86 visualization on cortical surface, 39–41,
etomidate, 111 historical perspectives, 79–80 40f, 42f
ketamine, 111 instrumentation methods, 81–83 Cerebral oxygen volume (COV), 142
nitrous oxide, 112–13 invasive pediatric brain mapping, Cerebral sulci, 13, 14t
opiates, 111 177 Cingulate sulcus, 22, 22f
propofol, 112 principles, 79–80 Clinical applications
anesthetic management, 114–15 recording techniques, 83–84 functional MRI
anesthetics effects, 109 strengths and weakness, 87 arteriovenous malformations, 48
craniotomy, 113 subject preparation methods, 80–81 brain tumors, 47–48, 47f, 49f
with general anesthesia, 115–16 validation techniques, 86–87 epilepsy, 48, 50
intraoperative monitoring, 114 Cerebral blood oxygenation (CBO), stereotactic radiosurgery, 50, 50f
local anesthetics, 110 141–42 surgical navigation, 46–47, 48f
preoperative care, 113–14 Cerebral blood volume (CBV), 132 surgical planning, 46, 47f
sedatives, 109 Cerebral hemisphere hearing, 257–59
volatile anesthetic neuropharmacology, anterior speech area, 17f, 20–21 acoustic processing, 259
113, 113t calcarine sulcus, 23 speech and language processing,
Brain morphology, 13, 14t central sulcus, 15, 15f 260–62
Brain sulcation, 13 cingulate sulcus, 22, 22f language
Brain sulci frontal lobe, 15f, 17–18, 17f basal temporal language area, 213
primary, 13, 14t frontomarginal sulcus, 17 multilingual patients, 212–13
secondary, 13, 14t gyri notion of degeneracy, 213–14
tertiary, 13, 14t and anterior basal orbitofrontal sulci, young children, 212
Brain tumors 24f, 25 magnetoencephalography
functional MRI, 47–48, 47f, 49f and posterior basal temporal sulci, vs. electroencephalography, 119
intrinsic, 198–99 24f, 25 evoked magnetic activity, 122
pediatric brain mapping gyri of mesial surface language-related brain magnetic
functional MRI, 170 cingulate gyrus, 22f, 24 fields, 124–26
positron emission tomography, 174 cuneus, 22f, 25 movement-related magnetic fields,
single photon emission tomography, gyrus rectus, 23, 24f 123
175 lingual gyrus, 22f, 25 somatosensory evoked magnetic
Brain-behavior relationship medial frontal gyrus, 24 fields, 123
data analysis, 61 paracentral lobule, 24 spontaneous magnetic activity,
data interpretation, 61–62 precuneus, 22f, 24 120–22
evaluation methods, 58–59 supplementary motor area, 24 visual evoked magnetic fields, 123
historical perspective, 55–56 inferior and mesial surface, 24f, 25 memory
investigation tools inferior frontal sulcus, 15–16 functional MRI, 272, 273t
attention, 60 inferior precentral sulcus, 15 functional MRI vs. Wada testing, 272,
cognitive speed, 60–61 insula of Reil, 19 273t, 274
executive functions, 61 intraparietal sulcus, 16, 16f Wada testing, 272, 272t
intelligence, 59 lateral sulcus, 13–15, 14f optical spectroscopic imaging
language, 60 lateral surface, 13 diffuse optical tomography, 133
memory, 59–60, 60f gyri, 15f, 17 near infrared spectroscopy, 133
visual perception, 60 limbic lobe region, 25–28, 26f neurovascular coupling, 131–32
working memory, 60 mesial surface, 22, 22f optical recording of intrinsic signal,
principles mesial temporal region, 25–28, 26f 132–33, 132f
clinical mapping, 56–57 occipital lobe, 18f, 19 physiological characteristics, 131
lesion method, 57–58 parietal lobe, 18, 18f optical spectroscopic imaging
Broca’s area, 7, 8f parieto-occipital sulcus, 22–23 architecture
BTLA. See Basal temporal language posterior speech area, 18f, 21–22 auditory cortex, 135
area precentral sulcus, 14f, 16 language cortex, 137, 139
premotor cortex, 20 somatosensory cortex, 135–37, 136f
C rostral sulci, 22, 22f visual cortex, 134–35
Calcarine sulcus, 8, 23 sensorimotor cortex optical spectroscopic imaging pathology
Callosomarginal sulcus, 22 postcentral gyrus, 20 epilepsy, 139–40
CBO. See Cerebral blood oxygenation precentral gyrus, 19–20 intracranial hematomas, 143–45
CBV. See Cerebral blood volume striate visual cortex, 23 stroke, 141–43
Central pain, 199 superior frontal sulcus, 16, 16f traumatic brain injury, 143–45

pediatric brain mapping
single photon emission tomography,
176
sensorimotor cortex
motor cortical stimulation, 199
Rolandic cortex, 198–99
visual cortex
direct cortical stimulation, 235
event-related scalp visual evoked
potential, 233–34
functional MRI, 232–33
local field potential recordings, 235
magnetoencephalography, 233
positron emission tomography, 233
transcranial magnetic stimulation,
234–35
Clinical indications
language-related brain magnetic fields,
124
pediatric brain mapping, 167
Cognitive speed, 60–61
Collateral sulcus, 25
Concordance across methods
hearing, 255, 257
visual cortex, 231
Cortical plasticity, 170
Cortical stimulation, 271
Cortical stimulation mapping (CSM), 209
Cortical substrate, 204–7
Craniotomy, 104, 113, 180
Cuneus, 25
Current intensity, 95
D 174–75
DCS. See Direct cortical stimulation
Design fluency, 66–67
Dexmedetomidine, 112
Diffuse optical tomography (DOT), 133, 137f
Diffusion tensor imaging (DTI), 171, 251
tractography, 211
Diffusion-weighted imaging (DWI), 170–71
Direct cortical stimulation (DCS), 257
hearing, 251–53
sensorimotor cortex, 192–94
visual cortex, 230, 235
Domain specificity hypothesis, 57
Dorsal stream, 223
DOT. See Diffuse optical tomography
Double dissociation, 58
DTI. See Diffusion tensor imaging
DWI. See Diffusion-weighted imaging
E Expressive language-specific cortex,
Echo-planar imaging (EPI), 33
eCSM. See Extraoperative CSM
EEG. See Electroencephalography
Electrical interference. See Direct cortical
stimulation (DCS)
Electrical stimulation, 69
Electrocortical stimulation mapping (ESM),
151, 154f, 158
Electrocorticographic (EcoG) spectral
analysis
advantages and pitfalls, 161–62
applications
auditory function localization, 157
language cortex mapping, 157–58
mapping sensorimotor function,
155–56
memory function mapping, 158–59
visual function localization, 156–57
in clinical practice, 160–61
historical perspectives, 151
mapping functional connectivity, 159
methodology
instrumentation, 153
recording techniques and data
acquisition, 154–55
signal analysis, 155
subject inclusion and preparation, 153
principles, 152–53
strengths and weaknesses, 159–60
Electrocorticography
brain mapping, 105
invasive pediatric brain mapping, 180
Electroencephalography (EEG)
dose responses, 110f
vs. magnetoencephalography, 119
Wada testing, 82f–83f
Encoding, 269
Epidural stimulation, 98
Epilepsy
executive functions, 68f
functional MRI, 48, 50
imaging pathology in animals and
humans, 139–40
pediatric brain mapping
functional MRI, 170
magnetoencephalography, 173–74
positron emission tomography,
single photon emission tomography,
175–76
Episodic memory
definition, 269
nonverbal, 63–64, 64t
verbal, 62–63, 63f
ERS. See Event-related synchronization
ESM. See Electrocortical stimulation mapping
Etomidate, 88, 111
Event-related potentials, 152
Event-related scalp visual evoked potential,
233–34
Event-related synchronization (ERS), 152
Evoked-related potentials, 152
Executive functioning
epilepsy, 68f
frontal lobe localization, 67
neuropsychological testing tool, 61
125–26
Extraoperative cortical stimulation, 178–80,
207
Extraoperative CSM (eCSM), 207
Extraoperative functional cortical mapping
cortical stimulation, 96, 96f
electronic principles, 95
historical perspectives, 93–94
instrumentation, 95
vs. intraoperative functional mapping,
98–99
language task, 96
methodology, 94
saftey and adverse effects, 97–98
INDEX 279
starting parameters, 95t
subject preparation, 94
video-EEG, 96, 98t
F
Face sensory function, 5, 7f
Fixed battery approach, 58
Flexible battery approach, 58
Fluorine-18 2-fluoro-2-deoxy-D-glucose
(FDG), 228
PET, 233
uptake, 174
fMRI. See Functional magnetic resonance
imaging
Frontal lobe
cerebral hemisphere, 15f, 17–18, 17f
neuropsychological testing
attention, 66
design and verbal fluency, 66–67
executive functioning, 67, 68f
working memory, 66
Frontomarginal sulcus, 17
Full scale IQ, 59
Functional brain regions
anterior speech area, 17f, 20–21
calcarine sulcus, 23
central sulcus, 15, 15f
cingulate sulcus, 22, 22f
frontal lobe, 15f, 17–18, 17f
gyri
and anterior basal orbitofrontal sulci,
24f, 25
and posterior basal temporal sulci,
24f, 25
gyri of mesial surface
cingulate gyrus, 22f, 24
cuneus, 22f, 25
gyrus rectus, 23, 24f
lingual gyrus, 22f, 25
medial frontal gyrus, 24
paracentral lobule, 24
precuneus, 22f, 24
supplementary motor area, 24
inferior and mesial surface, 24f, 25
inferior frontal sulcus, 15–16
inferior precentral sulcus, 15
insula of Reil, 19
intraparietal sulcus, 16, 16f
lateral sulcus, 13–15, 14f
lateral surface, 13
gyri, 15f, 17
limbic lobe region, 25–28, 26f
mesial surface, 22, 22f
mesial temporal region, 25–28, 26f
occipital lobe, 18f, 19
parietal lobe, 18, 18f
parieto-occipital sulcus, 22–23
posterior speech area, 18f, 21–22
precentral sulcus, 14f, 16
premotor cortex, 20
rostral sulci, 22, 22f
sensorimotor cortex
postcentral gyrus, 20
precentral gyrus, 19–20
striate visual cortex, 23
superior frontal sulcus, 16, 16f
superior temporal sulcus, 16–17
280 INDEX
Functional brain regions (Cont.)
sylvian opercula, 13–15, 14f
temporal lobe, 15f, 18–19
Functional imaging methods
hearing
frequency, 246
sound level, 247
sound localization, 249
temporal aspects of sound, 248–49
language
vs. cortical stimulation mapping,
210–11
modalities, 210
memory assessment technique, 270
functional magnetic resonance imaging
(fMRI)
cerebral localization
activation map creation, 39, 40f
clinical inferences, 41–44, 43f
data analysis, 33–39, 36f, 38f
MRI and MR scanners, 33, 34f
MRI data collection, 33, 35f
thumbnail sketch, 31–33, 32f
visualization on cortical surface,
39–41, 40f, 42f
future experiments, 50–52
memory, 272, 273t
neurosurgical applications
arteriovenous malformations, 48
brain tumors, 47–48, 47f, 49f
epilepsy, 48, 50
stereotactic radiosurgery, 50, 50f
surgical navigation, 46–47, 48f
surgical planning, 46, 47f
paradigms, 45–46, 46f
pediatric brain mapping
brain tumors, 170
cortical plasticity and reorganization,
170
epilepsy, 170
general considerations in pediatrics,
169–70
pitfalls, 50, 51f
sensorimotor cortex, 195–96
techniques, 45
visual cortex, 227–28, 232–33
vs. Wada testing, 272, 273t, 274
Functional mapping techniques
extraoperative
cortical stimulation, 96, 96f
electronic principles, 95
historical perspectives, 93–94
instrumentation, 95
vs. intraoperative, 98–99
language task, 96
methodology, 94
saftey and adverse effects, 97–98
starting parameters, 95t
subject preparation, 94
video-EEG, 96, 98t
intraoperative
anesthesia, 104
in clinical practice, 106
craniotomy, 104
electrocorticography, 105
vs. extraoperative, 98–99
language mapping, 105–6
positioning, 104
postoperative outcomes, 106
principles, 103
sensorimotor stimulation, 105
somatosensory evoked potential
recording, 104
visual cortex
advantages and pitfalls, 235–36
clinical applications, 232–35
concordance across methods, 231
direct cortical stimulation, 230
electrocorticographic spectral
analysis, 156–57
historical perspectives, 219–20
local field potential recordings,
230–31
neuroanatomy, 220–23
neurophysiology, 220–23
noninvasive neuroimaging, 227–30
operative anatomy, 225–27
optical imaging in animals and
humans, 134–35
organizational principles, 223–24
structural imaging, 225–27
G subcortical substrate, 204–7
Gamma range oscillations, 251
General linear model, 35
General anesthesia, 115–16. See also
Anesthesia
Granger causality, 159
Gyri
and anterior basal orbitofrontal sulci, 24f,
25
lateral surface, 15f, 17
of mesial surface
cingulate gyrus, 22f, 24
cuneus, 22f, 25
gyrus rectus, 23, 24f
lingual gyrus, 22f, 25
medial frontal gyrus, 24
paracentral lobule, 24
precuneus, 22f, 24
supplementary motor area, 24
and posterior basal temporal sulci,
24f, 25
H noninvasive neuroimaging techniques
Hearing
advantages and pitfalls, 262
clinical applications, 257–59
acoustic processing, 259
speech and language processing,
260–62
concordance across methods, 255, 257
direct cortical stimulation, 251–53
functional imaging methods
frequency, 246
sound level, 247
sound localization, 249
temporal aspects of sound, 248–49
gross anatomy, 244
local field potential recordings, 253–55
localization of, 8–9, 9f
neuroanatomy and neurophysiology,
241–44
noninvasive recordings
gamma range oscillations, 251
surface electrical recordings, 249–51
structural imaging methods, 245–46
Hemifield stimulation, 123
Hemorrhage, 98
Heschl’s gyrus, 9, 9f
Human language mapping
clinical applications
basal temporal language area, 213
multilingual patients, 212–13
notion of degeneracy, 213–14
young children, 212
cortical substrate, 204–7
direct cortical stimulation, 207–10
functional imaging mapping, 210–11
historical background, 203
intracranial electrodes, 211–12
intraoperative cortical mapping, 105–6
lateralization versus localization, 203–4
local field potential recordings, 211–12
localization, 5, 7–8, 7f
neuropsychological testing, 60
structural imaging mapping
Broca’s morphology, 211
DTI tractography, 211
temporal lobe localization, 65
Wada test, 84–85
Human visual system
advantages and pitfalls, 235–36
clinical applications
direct cortical stimulation, 235
event-related scalp visual evoked
potential, 233–34
functional MRI, 232–33
local field potential recordings, 235
magnetoencephalography, 233
positron emission tomography, 233
transcranial magnetic stimulation,
234–35
concordance across methods, 231
electrocorticographic spectral analysis,
156–57
historical perspectives, 219–20
local field potential recordings, 230–31
neuroanatomy, 220–23
neurophysiology, 220–23
functional MRI, 227–28
magnetoencephalography, 229
positron emission tomography,
228–29
transcranial magnetic stimulation,
229–30
visually evoked potentials, 229
operative anatomy, 225–27
optical imaging in animals and humans,
134–35
organizational principles, 223–24
structural imaging, 225–27
I
ICP. See Intracranial pressure
iCSM. See Intraoperative CSM
Imaging pathology, animals and humans
epilepsy, 139–40
intracranial hematomas, 143–45

stroke, 141–43
traumatic brain injury, 143–45
Implicit memory, 59, 64–65
Inferior frontal sulcus, 15–16
Inferior precentral sulcus, 15
Insula of Reil, 19
Intelligence, 59
Intelligence quotient (IQ)
full scale, 59
performace, 59
verbal, 59
verbal vs. performance, 62
Intracarotid amobarbital testing
advantages and pitfalls, 87–88
applications, 86
in clinical practice, 87
data acquisition and data analysis
language, 84–85
memory, 85–86
historical perspectives, 79–80
instrumentation methods, 81–83
invasive pediatric brain mapping, 177
principles, 79–80
recording techniques, 83–84
strengths and weakness, 87
subject preparation methods, 80–81
validation techniques, 86–87
Intracarotid Amytal test. See Wada testing
Intracranial hematomas, 143–45
Intracranial pressure (ICP), 143
Intracranial recordings, 271
Intraoperative cortical mapping, 103
in clinical practice, 106
vs. extraoperative cortical mapping, 98–99
operating room methods
anesthesia, 104
craniotomy, 104
electrocorticography, 105
language mapping, 105–6
positioning, 104
sensorimotor stimulation, 105
somatosensory evoked potential
recording, 104
postoperative outcomes, 106
principles, 103
Intraoperative cortical stimulation, 177–78
Intraoperative CSM (iCSM), 207
Intraoperative monitoring, 114
Intraoperative seizures, 104
Intraparietal sulcus, 16, 16f
Intrinsic brain tumors, 198–99
Invasive pediatric brain mapping techniques
awake craniotomy, 180
electrocorticography, 180
extraoperative cortical stimulation,
178–79
intraoperative cortical stimulation, 177–78
vs. noninvasive techniques, 176
Wada testing, 177
Investigation tools, neuropsychological
testing
attention, 60
cognitive speed, 60–61
executive functions, 61
intelligence, 59
language, 60
memory, 59–60, 60f
visual perception, 60
working memory, 60
IQ. See Intelligence quotient
K visual function, 8, 9f
Ketamine, 111
L
Language
clinical applications
basal temporal language area, 213
multilingual patients, 212–13
notion of degeneracy, 213–14
young children, 212
cortical substrate, 204–7
direct cortical stimulation, 207–10
functional imaging mapping
vs. cortical stimulation mapping,
210–11
modalities, 210
historical background, 203
intracranial electrodes, 211–12
intraoperative cortical mapping, 105–6
lateralization versus localization, 203–4
local field potential recordings, 211–12
localization, 5, 7–8, 7f
neuropsychological testing, 60
structural imaging mapping
Broca’s morphology, 211
DTI tractography, 211
subcortical substrate, 204–7
temporal lobe localization, 65
Wada test, 84–85
Language cortex
electrocorticographic spectral analysis,
157–58
optical imaging in animals and humans,
137, 139
Language-related brain magnetic fields
(LRFs)
clinical indications, 124
expressive language-specific cortex,
125–26
hemispheric dominance, 124–25
Lateral occipitotemporal sulcus, 25
Lateral sulcus, 13–15, 14f
Lateralization versus localization, 203–4
Lesion neurological testing method,
57–58
LFPs. See Local field potentials
Lingual gyrus, 22f, 25
Local anesthetics, 110
Local field potentials (LFPs)
hearing, 253–55
language, 211–12
visual cortex, 230–31, 235
Localization
auditory function, 8–9, 9f
cerebral, using fMRI
activation map creation, 39, 40f
clinical inferences, 41–44, 43f
data analysis, 33–39, 36f, 38f
MRI and MR scanners, 33, 34f
MRI data collection, 33, 35f
thumbnail sketch, 31–33, 32f
visualization on cortical surface,
39–41, 40f, 42f
INDEX 281
cortical structural anatomy, 4
language function, 5, 7–8, 7f
vs. lateralization in language, 203–4
motor and sensory functions, 4–5, 7f
LRFs. See Language-related brain magnetic
fields
M
Magnetic source imaging, 229
Magnetoencephalography (MEG), 119
auditory evoked magnetic fields, 123
vs. electroencephalography, 119
evoked magnetic activity, 122
language-related brain magnetic fields
clinical indications, 124
expressive language-specific cortex,
125–26
hemispheric dominance, 124–25
movement-related magnetic fields, 123
pediatric brain mapping
epilepsy, 173–74
functional mapping, 172–73
general considerations in pediatrics,
171–72
sensorimotor cortex, 196–97
somatosensory evoked magnetic fields,
123
spontaneous magnetic activity, 120–22
visual cortex, 223, 229
visual evoked magnetic fields, 123
Mapping functional connectivity, 159
Matching pursuit (MP) algorithm, 155
Material specificity hypothesis, 57
Medial frontal gyrus, 24
Medial occipitotemporal sulcus, 25
MEG. See Magnetoencephalography
Memory
anatomy, 270
assessment techniques
cerebral amobarbital, 271
cortical stimulation, 271
functional imaging, 270
intracranial recordings, 271
noninvasive assessments, 270–71
clinical applications
functional MRI, 272, 273t
functional MRI vs. Wada testing, 272,
273t, 274
Wada testing, 272, 272t
definition, 269
electrocorticographic spectral analysis,
156–57
episodic, 269
definition, 269
nonverbal, 63–64, 64t
verbal, 62–63, 63f
implicit, 64–65
neuropsychological testing, 59–60, 60f
procedural, 269
Wada test, 85–86
working, 60, 66, 269
Mesial temporal sclerosis (MTS), 62
Methohexital, 88
MNI. See Montreal Neurological Institute
Monopolar stimulation, 95
Montreal Neurological Institute (MNI), 79
282 INDEX
Motor and sensory functions
anatomical localization, 4–5, 7f
central cortex, 20
Motor cortical stimulation, 199
Motor hand function, 5, 7f
Movement-related magnetic fields (MRFs),
123
Moyamoya disease, 176
MRFs. See Movement-related magnetic fields
MRI scanners, 33
MTS. See Mesial temporal sclerosis
Multilingual patients, 212–13
Multivariate generalized linear hypothesis, 35
N spontaneous magnetic activity, 120–22
Near infrared spectroscopy (NIRS), 133,
144f
Neurologic specificity, 56
Neuropathic pain, 199
Neuropharmacology, volatile anesthetic, 113
Neuropsychological testing
data analysis, 61
data interpretation, 61–62
evaluation methods, 58–59
historical perspective, 55–56
investigation tools
attention, 60
cognitive speed, 60–61
executive functions, 61
intelligence, 59
language, 60
memory, 59–60, 60f
visual perception, 60
working memory, 60
principles
clinical mapping, 56–57
lesion method, 57–58
subject preparation methods, 59
Neuropsychological testing applications
case study, 70–71
frontal lobe localization
attention, 66
design and verbal fluency, 66–67
executive functioning, 67, 68f
working memory, 66
left versus right hemisphere
global versus local processing of
information, 62
verbal versus performance IQ, 62
parietal and occipital lobes localization,
67, 69
strengths and weaknesses, 69–70
temporal lobe localization
episodic nonverbal memory, 63–64,
64t
episodic verbal memory, 62–63, 63f
face processing, 65
implicit memory, 64–65
language, 65
olfaction, 65, 66t
Neuropsychology, 55
Neurosurgical applications
functional MRI
arteriovenous malformations, 48
brain tumors, 47–48, 47f, 49f
epilepsy, 48, 50
stereotactic radiosurgery, 50, 50f
surgical navigation, 46–47, 48f
surgical planning, 46, 47f
magnetoencephalography
auditory evoked magnetic fields, 123
vs. electroencephalography, 119
evoked magnetic activity, 122
language-related brain magnetic
fields, 124–26
movement-related magnetic fields,
123
pediatric brain mapping, 172–74
sensorimotor cortex, 196–97
somatosensory evoked magnetic
fields, 123
visual cortex, 223
visual evoked magnetic fields, 123
Neurovascular coupling, 131–32
NIRS. See Near infrared spectroscopy
Nitrous oxide, 112–13
Noninvasive imaging techniques
pediatric brain mapping
diffusion tensor imaging, 171
diffusion-weighted imaging, 170–71
functional MRI, 169–70
vs. invasive mapping, 168–69
magnetoencephalography, 172–74
perfusion-weighted imaging, 171
positron emission tomography,
174–75
single photon emission tomography,
175–76
visual cortex
functional MRI, 227–28
magnetoencephalography, 229
positron emission tomography,
228–29
transcranial magnetic stimulation,
229–30
visually evoked potentials, 229
Noninvasive recordings
gamma range oscillations, 251
surface electrical recordings, 249–51
Nonverbal memory, 63–64, 64t
Notion of degeneracy, 213–14
Nyquist–Shannon sampling theorem,
154
O 177–78
Occipital lobe
cerebral hemisphere, 18f, 19
neuropsychological testing, 67, 69
Ocular dominance, 224
Ohm’s law, 95
Olfaction, 65, 66t
Operating room methods, intraoperative
mapping
craniotomy, 104
electrocorticography, 105
language mapping, 105–6
positioning, 104
sensorimotor stimulation, 105
somatosensory evoked potential
recording, 104
Opiates, 111
Optical recording of intrinsic signal (ORIS),
132–33, 132f, 138f, 140f
Optical spectroscopic imaging method
diffuse optical tomography, 133
imaging architecture in animals and
humans, 133–34
auditory cortex, 135
language cortex, 137, 139
somatosensory cortex, 135–37, 136f
visual cortex, 134–35
near infrared spectroscopy, 133
neurovascular coupling, 131–32
optical recording of intrinsic signal,
132–33, 132f
pathology in animals and humans
epilepsy, 139–40
intracranial hematomas, 143–45
stroke, 141–43
traumatic brain injury, 143–45
physiological characteristics, 131
Orientation preference, 224
ORIS. See Optical recording of intrinsic
signal
Oxygen-15 (O-15), 228
P
Paracentral lobule, 24
Parallel processing technique, 223f, 224
Parallel sulcus, 16
Parietal lobe
cerebral hemisphere, 18, 18f
neuropsychological testing, 67, 69
Parieto-occipital sulcus, 22–23
Pediatric brain mapping
clinical indications, 167
diffusion tensor imaging, 171
diffusion-weighted imaging, 170–71
functional MRI
brain tumors, 170
cortical plasticity and reorganization,
170
epilepsy, 170
general considerations in pediatrics,
169–70
invasive techniques
awake craniotomy, 180
electrocorticography, 180
extraoperative cortical stimulation,
178–79
intraoperative cortical stimulation,
vs. noninvasive techniques, 176
Wada testing, 177
magnetoencephalography
epilepsy, 173–74
functional mapping, 172–73
general considerations in pediatrics,
172
perfusion-weighted imaging, 171
positron emission tomography
brain tumors, 174
epilepsy, 174–75
functional mapping, 174
general considerations in pediatrics,
174
single photon emission tomography
additional clinical applications,
176
brain tumors, 175

epilepsy, 175–76
general considerations in pediatrics,
175
specific techniques, 167–68, 168f
Performance IQ (PIQ), 62
Perfusion-weighted imaging (PWI), 171
Peripheral vision, 8
PET. See Positron emission tomography
Pfeifer’s norm, 244
Phase encoding procedure, 227
Phonological loop, 158
PIQ. See Performance IQ
Positron emission tomography (PET)
noninvasive pediatric brain mapping
brain tumors, 174
epilepsy, 174–75
functional mapping, 174
general considerations in pediatrics,
174
sensorimotor cortex, 196
visual cortex, 228–29, 233
Posterior basal temporal sulci, 24f, 25
Precentral sulcus, 14f, 16
Precuneus, 24
Premotor cortex, 20
Primary brain sulci, 13, 14t
Primary visual cortex, 8, 9f, 221f, 224
Procedural memory, 269
Propofol, 112
PWI. See Perfusion-weighted imaging
R SSEPs. See Somatosensory-evoked potentials
Radiosurgery, stereotactic, 50, 50f
Retinotopic mapping techniques, 223
Retrieval, 269
RFFT. See Ruff figural fluency test
Rolandic cortex, 198–99
Rostral sulci, 22, 22f
Ruff figural fluency test (RFFT), 61
S epidural, 98
SDEs. See Subdural electrodes
SDTF. See Short-time directed transfer
function
Secondary brain sulci, 13, 14t
Sedatives, 109
SEFs. See Somatosensory evoked magnetic
fields
Semantic memory, 269
Sensorimotor cortex
cerebral hemisphere
postcentral gyrus, 20
precentral gyrus, 19–20
clinical applications
motor cortical stimulation, 199
Rolandic cortex, 198–99
direct cortical stimulation, 192–94
electrocorticographic spectral analysis,
156–57
functional MRI, 195–96
historical perspectives, 189–90
localization, 191–92
magnetoencephalography, 196–97
positron emission tomography, 196
primary motor cortex, 190–91
somatosensory-evoked potentials, 194–95
transcranial magnetic stimulation, 197
INDEX 283
Sensorimotor functional unit, 19 paracentral lobule, 24
Sensorimotor stimulation, 105 precuneus, 22f, 24
Short-time directed transfer function (SDTF), supplementary motor area, 24
159 inferior and mesial surface, 24f, 25
Single dissociation, 57–58 inferior frontal sulcus, 15–16
Single photon emission tomography (SPECT) inferior precentral sulcus, 15
noninvasive pediatric brain mapping insula of Reil, 19
additional clinical applications, 176 intraparietal sulcus, 16, 16f
brain tumors, 175 lateral sulcus, 13–15, 14f
epilepsy, 175–76 lateral surface, 13
general considerations in pediatrics, gyri, 15f, 17
175 limbic lobe region, 25–28, 26f
Single quadrant stimulation, 123 mesial surface, 22, 22f
Somatosensory cortex mesial temporal region, 25–28, 26f
optical imaging in animals and humans, occipital lobe, 18f, 19
134–35 parietal lobe, 18, 18f
Somatosensory evoked magnetic fields parieto-occipital sulcus, 22–23
(SEFs), 123 posterior speech area, 18f, 21–22
Somatosensory evoked potential recording, precentral sulcus, 14f, 16
104 premotor cortex, 20
Somatosensory-evoked potentials (SSEPs), rostral sulci, 22, 22f
194–95 sensorimotor cortex
Sound postcentral gyrus, 20
level, 247 precentral gyrus, 19–20
localization, 249 striate visual cortex, 23
temporal aspects of, 248–49 superior frontal sulcus, 16, 16f
SPECT. See Single photon emission superior temporal sulcus, 16–17
tomography sylvian opercula, 13–15, 14f
Speech temporal lobe, 15f, 18–19
localization of, 7–8, 8f Subcortical substrate, 204–7
processing applications, 260–62 Subdural electrodes (SDEs), 94, 212
Subdural grids, 94
Stereotactic radiosurgery, 50, 50f Subdural strips, 94
Stereotactically implanted depth electrodes, Subject preparation methods
153 extraoperative functional cortical
Stimulation mapping, 94
auditory, 43f, 137, 250 neuropsychological testing, 59
bipolar, 95 Wada testing, 80–81
cortical, 271 Subparietal sulcus, 24
electrical, 69 Superior frontal sulcus, 16, 16f
Superior temporal sulcus, 16–17
Hemifield, 123 Supplementary motor area, 24
monopolar, 95 Surface electrical recordings, 249–51
motor cortical, 199 Surgical navigation, 46–47, 48f
sensorimotor, 105 Surgical planning, 46, 47f
single quadrant, 123 Sylvian fissure, 4
tactile, 123 Sylvian opercula, 13–15, 14f
visual, 37, 43f
Storage, 269 T
Striate visual cortex, 23 Tactile stimulation, 123
Stroke, 141–43 Taylor–Haughton lines, 4, 4f
Structural brain imaging regions TBI. See Traumatic brain injury
anterior speech area, 17f, 20–21 Temporal lobe
calcarine sulcus, 23 cerebral hemisphere, 15f, 18–19
central sulcus, 15, 15f neuropsychological testing
cingulate sulcus, 22, 22f episodic nonverbal memory, 63–64,
gyri 64t
and anterior basal orbitofrontal sulci, episodic verbal memory, 62–63, 63f
24f, 25 face processing, 65
and posterior basal temporal sulci, implicit memory, 64–65
24f, 25 language, 65
gyri of mesial surface olfaction, 65, 66t
cingulate gyrus, 22f, 24 Temporal lobe epilepsy (TLE), 79
cuneus, 22f, 25 Tertiary brain sulci, 13, 14t
gyrus rectus, 23, 24f TLE. See Temporal lobe epilepsy
lingual gyrus, 22f, 25 TMS. See Transcranial magnetic stimulation
medial frontal gyrus, 24 Tongue sensory function, 5, 7f
284 INDEX
Tonotopic organization, 241
Tractography, 227f, 234f
Traditional connectionists, 56
Traditional generalists, 56
Traditional localizationists, 56
Transcranial magnetic stimulation
(TMS)
sensorimotor cortex, 197
visual cortex, 229–30, 234–35
Traumatic brain injury (TBI), 143–45
V local field potential recordings, 230–31
VEFs. See Visual evoked magnetic fields
VEPs. See Visually evoked potentials
Verbal fluency, 66–67
Verbal IQ (VIQ), 59, 62
Verbal memory, 62–63, 63f
Vertical ramus, 15
Video-EEG, 96, 98t
VIQ. See Verbal IQ
Vision
definition, 219
localization, 8, 9f
Visual adaptation, 231
Visual cortex
advantages and pitfalls, 235–36
clinical applications
direct cortical stimulation, 235
event-related scalp visual evoked
potential, 233–34
functional MRI, 232–33
local field potential recordings, 235
magnetoencephalography, 233
positron emission tomography, 233
transcranial magnetic stimulation,
234–35
concordance across methods, 231
direct cortical stimulation, 230
electrocorticographic spectral analysis,
156–57
historical perspectives, 219–20
neuroanatomy, 220–23
neurophysiology, 220–23
noninvasive neuroimaging techniques
functional MRI, 227–28
magnetoencephalography, 229
positron emission tomography,
228–29
transcranial magnetic stimulation,
229–30
visually evoked potentials, 229
operative anatomy, 225–27
optical imaging in animals and humans,
134–35
organizational principles, 223–24
structural imaging, 225–27
Visual evoked magnetic fields (VEFs), 123
Visual perception, 60
Visual stimulation, 37, 43f
Visually evoked potentials (VEPs), 229,
233–34
Volatile anesthetic neuropharmacology, 113,
113t
W
Wada testing
advantages and pitfalls, 87–88
applications, 86
in clinical practice, 87
data acquisition and data analysis
language, 84–85
memory, 85–86
historical perspectives, 79–80
instrumentation methods, 81–83
invasive pediatric brain mapping,
177
principles, 79–80
recording techniques, 83–84
strengths and weakness, 87
subject preparation methods, 80–81
validation techniques, 86–87
Warrington’s recognition memory test, 59
Wechsler adult intelligence scale, 59
Wernicke’s area, 8, 8f
Wisconsin card sorting test, 61
Working memory, 60, 66, 269
Y
Young children, language mapping, 212