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FUNCTIONAL NEUROLOGY
NEUROPLASTICITY IN LEARNING
AND REHABILITATION
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GERRY LEISMAN AND JOAV MERRICK – SERIES EDITORS –
ISRAEL
Neuroimmunity and the Brain-Gut Connection

Aristo Vojdani
2015. ISBN: 978-1-63483-969-3
Considering Consciousness Clinically

Gerry Leisman and Joav Merrick (Editors)
2016. ISBN: 978-1-63484-260-0
Neuroplasticity in Learning and Rehabilitation

Gerry Leisman and Joav Merrick (Editors)
2016. ISBN: 978-1-63484-305-8

NEUROPLASTICITY IN LEARNING
AND REHABILITATION
GERRY LEISMAN
AND
JOAV MERRICK
EDITORS
New York

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CONTENTS
Introduction vii
Chapter 1 Neuroplasticity in learning and rehabilitation 1
Gerry Leisman and Joav Merrick
Section one: Learning and rehabilitation 5
Chapter 2 Neuroeducational networks 7
Gerry Leisman
Chapter 3 Plasticity and functional connectivities in rehabilitation 21
Gerry Leisman
Chapter 4 Persistent primitive reflexes and childhood
neurobehavioral disorders 65
Robert Melillo
Chapter 5 Neuroplasticity of asymmetric cortical function 101
Randy W Beck
Chapter 6 Traumatic brain injury: Neuropsychological rehabilitation 121
Nazareth P Castellanos, Elisa Rodríguez-Toscano,
Javier García-Pacios, Pilar Garcés, Nuria Paúl,
Pablo Cuesta, Ricardo Bajo, Juan García-Prieto,
Francisco del-Pozo and Fernando Maestú
Chapter 7 A computational model of cognitive deficits in medicated
and unmedicated persons with Parkinson‘s disease 133
Ahmed A Moustafa
Chapter 8 Outcomes in traumatic brain injury,
mild traumatic brain injury and concussion 155
Joel Brandon Brock, Samuel Yanuck, Michael Pierce,
Michael Powell, Steven Geanopulos, Steven Noseworthy,
Datis Kharrazian, Chris Turnpaugh, Albert Comey
and Glen Zielinski

vi Contents
Chapter 9 Connectivity cognition and psychosis in the physical brain 201

Avi Peled
Chapter 10 Auditory, visual, spatial, aesthetic, and artistic training facilitates
brain plasticity 211
Gerry Leisman
Chapter 11 The plasticity of neural network sensory-substitution object
shape recognition 229
Ella Striem-Amit, Ornella Dakwar, Uri Hertz, Peter Meijer,
William Stern, Alvaro Pascual-Leone and Amir Amedi
Section two: Acknowledgments 237
Chapter 12 About the editors 239
Chapter 13 About the National Institute for Brain and Rehabilitation Sciences,
Nazareth, Israel 241
Chapter 14 About the National Institute of Child Health and
Human Development in Israel 243
Chapter 15 About the book series ―Functional neurology‖ 247
Section three: Index 249
Index 251

INTRODUCTION

In: Neuroplasticity in Learning and Rehabilitation ISBN: 978-1-63484-305-8
Editors: Gerry Leisman and Joav Merrick © 2016 Nova Science Publishers, Inc.
Chapter 1
NEUROPLASTICITY IN
LEARNING AND REHABILITATION
Gerry Leisman1-3,, MD, PhD

and Joav Merrick4-8, MD, MMedSc, DMSc
1
The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel
2
Biomechanics Laboratory, ORT-Braude College of Engineering, Karmiel, Israel
3
Institute for Neurology and Neurosurgery,
Universidad de Ciencias Médicas de la Habana, Facultad Manuel Fajardo, Havana, Cuba
4
National Institute of Child Health and Human Development, Jerusalem, Israel
5
Office of the Medical Director, Health Services, Division for Intellectual and
Developmental Disabilities, Ministry of Social Affairs and Social Services,
Jerusalem, Israel
6
Division of Pediatrics, Hadassah Hebrew University Medical Center,
Mt Scopus Campus, Jerusalem, Israel
7
Kentucky Children‘s Hospital, University of Kentucky College of Medicine,
Lexington, Kentucky, US
8
Center for Healthy Development, School of Public Health,
Georgia State University, Atlanta, Georgia, US
A neuroanatomical conceptualization is a non-starter for rehabilitation practice. It is

important to understand that what we are really attempting to achieve both in
rehabilitation as well as in understanding the neurological basis of cognitive and motor
improvement after trauma or stroke is not which brain area controls a given cognitive
function, but how efficiently brain regions cooperate with each other and how novel
connectivities may develop.

Correspondence: Dr. Gerry Leisman, The National Institute for Brain & Rehabilitation Sciences, Biomechanics
Laboratory, O.R.T.-Braude College of Engineering, 51 Snunit, POB 78, Karmiel, Israel. Email:
g.leisman@alumni.manchester.ac.uk

2 Gerry Leisman and Joav Merrick
INTRODUCTION
We possess as neurological adults, a high degree of localization of function, with now over
150 years since Broca, we still subscribe to the notion consistent with the model that
dysfunction or damage to specific regions of the brain and nervous system should result in
specific damage and deficits in the behavior and function of individuals. Unfortunately, that is
not enough to explain the capacity for plasticity, regeneration, spontaneous recovery, and
optimization in neurological terms and certainly not in its translation in clinical rehabilitation.
Among the difficulties we face in the application of rehabilitation science in practice is
less the need to understand how the nervous system functions, but rather how it recovers from
dysfunction, how can we effectively evaluate function, dysfunction and recovery, and how to
provide a rational basis for making economic decisions about which method or methodology
to invest.
We have learned what happens to the nervous system when infants learn to talk, sit down
and stand up, toddle, walk, and eventually run. We know how to teach a child how to grasp a
pencil and write, we also understand from the primitive reflex ―operating system,‖ how it is
that those reflexes combine to form complex behavior and how those behaviors break down
after a stroke. Complex behavior over normal development and experience combines activity
in various brain regions that after stroke, breaks down to result in more compartmentalized
functioning. We can see retained function in some areas and dysfunction in others that would
normally be combined in the neurologically intact adult, such as in alexia without agraphia
and with a color-naming deficit. In such a case, an individual could not read, but could write,
but could not read what he or she had written (1, 2).
The use of medical rather than a statistical ―production management‖ models in
examining human function creates for binary thinking that allows us to evaluate human
performance in the context of function-dysfunction, diseased-non-diseased, impaired-non-
impaired, but not contextualized in a linear fashion in the form of optimization and
efficiencies of function with one level of that scale being represented by elite sports
performers and on the opposite side of the spectrum to the brain-spinal cord injured, and to
those in a locked-in state, and the ―brain dead‖ (3, 4).
A two-year olds‘ motor and cognitive function is developmentally appropriate, but
neurologically highly inefficient. The task of infancy and child development is render the
individual more optimized. When a two and a half-year old descends a staircase, he examines
each step and progresses one step at a time. An older child, who has already learned how to
automate that descent like an adult, examines the first step, pays no further conscious
attention and descends automatically. In fact, the function of most integrated behavior is to
automate as much of our responses to the world as possible as the information content from
our environment is so high and our cognitive system‘s capacity to effectively interact with the
environment is so limited (2, 5, 6).
The function then of early development is training to be able to integrate what should
normally be independent reflex-based processes into meaningful systems with those systems
being less reliant on specific brain regions for their control and more so on the networks that
are created to optimize the processes for effective performance. Effective performance
directly relates to the ability of the brain‘s plasticity.

Neuroplasticity in learning and rehabilitation 3
It is for this reason, that one of the primary functions of neurological development of the
nervous system is the integration of developing systems so that function will be localized for
more efficiency. But that is not to say that the system must work by localized control (7, 8).
For example, the languages that are learned in early childhood prior to the development of
Broca‘s and Wernicke‘s areas, with their nominal control of expressive and receptive
language respectively, are learned fast as a consequence of the exuberant neuronal
connectivities present in early childhood development.
These abundant connectivities in childhood allow for the rapid acquisition of knowledge.
The childhood system of exuberant connectivities renders the nervous system less optimized
than the adult brain-state and its resultant localization of function. When that now optimized
localization of function has developed, the number of potential connectivities is significantly
reduced and thereby plasticity reduced as well. Specialization of cortical regions optimizes
the system but does so by concentrating the networks in a circumscribed area allowing for
more effective temporal as well as spatially represented responses. In short, more potential
connectivities in early childhood will lead to greater automatization of skill-development and
localized function in the normal adult and less of an ability of the adult to acquire information
with as much ease as in early childhood.
Specialization, however, is a result of a long process of development and training. One,
for example may have a neonate born with hydrocephaly and function quite normally.
Rasmussen‘s syndrome with its early onset, lateralized status seizures requiring
hemispherectomy, results in dysfunction significantly less than one would expect in the adult.
A neuroanatomical conceptualization is a non-starter for rehabilitation practice. It is
important to understand that what we are really attempting to achieve both in rehabilitation as
well as in understanding the neurological basis of cognitive and motor improvement after
trauma or stroke is not which brain area controls a given cognitive function, but how
efficiently brain regions cooperate with each other and how novel connectivities may
develop. This text has culled several papers from the journal Functional Neurology,
Rehabilitation and Ergonomics to provide a detailed overview of this principle; the reader is
also invited to review these concepts more comprehensively elsewhere (5, 6).
REFERENCES
[1] Sroka H, Solsi P, Bornstein B. Alexia without agraphia with complete recovery. Confin Neurologica
1973;35(3):167–76.
[2] Leisman G. The neurophysiology of visual processing: Implications for learning disability. In:
Leisman G, ed. Basic visual processes and learning disability. Springfield, IL: Charles C Thomas,
1976:124–87.
[3] Leisman G, Koch P. Networks of conscious experience: computational neuroscience in understanding
life, death, and consciousness. Rev Neurosci 2009;20(3-4):151-76.
[4] Gilchriest JA. A method for quantifying visual search scanpath efficiency. Funct Neurol Rehabil
Ergon 2011;1(2):181-96.
[5] Melillo R, Leisman G. Neurobehavioral disorders of childhood: An evolutionary perspective. New
York: Springer, 2010.
[6] Leisman G. Brain networks, plasticity, and functional connectivities inform current directions in
functional neurology and rehabilitation. Funct Neurol Rehab Ergon 2011;1(2):315-56.

[7] Leisman G, Rodriguez-Rojas R, Batista K, Carballo M, Morales JM, Iturria Y, et al. Measurement of
axonal fiber connectivity in consciousness evaluation. 2014 IEEE 28th Convention of Electrical and
Electronics Engineers in Israel, IEEE Cat. No: CFP14417-CDR; ISBN: 978-1-4799-5987-7, 2014.
[8] Leisman G. Children‘s language production: How cognitive neuroscience and industrial engineering
can inform public education policy and practice. Forum Public Policy 2012;1:1-14.

SECTION ONE: LEARNING AND REHABILITATION

Chapter 2
NEUROEDUCATIONAL NETWORKS

1
2
3
Universidad de Ciencias Médicas de la Habana,
Facultad Manuel Fajardo, Havana, Cuba
Little of the 150 years of research in Cognitive Neurosciences, Human Factors, and the
mathematics of Production Management have found their way into educational policy
and certainly not into the classroom or in the production of educational materials in any
meaningful or practical fashion. While more mundane concepts of timing, sequencing,
spatial organization, and Gestalt principles of perception are well known and applied, as
well as the maintenance of simplistic notions of developmental brain organization and
hemisphericity for language rather than the neurophysiology of embodied language, these
concepts still inform pre-K-3 curriculum and clinical neurological practice in both the
diagnostic and therapeutic modalities. The paper overviews the science of human
physiologic efficiencies to develop a fundamental understanding that the concept of
localization of function in the brain is a just reflection of plasticity and required for
optimized function, but understanding brain function by that alone would obscure the
understanding of the education and rehabilitation process from early childhood through
the older years. Diagnostic and therapeutic systems need to address pathways in the brain
and their changes as a result of intervention rather than examine more static notions of
localized function.


8 Gerry Leisman
INTRODUCTION
Recent spectacular advances in the neurosciences have stimulated the hope that efficient brain
organization is no longer about cerebral asymmetries and simplistic left-right differences but
more about complex applications of networks, and communication system principles. This
new understanding of brain organization for learning have led to newly developed concepts
and findings that have not, as yet, found their way into clinical thinking in an significant way.
We are at the cusp of developing breakthrough concepts in the understanding of educational
and rehabilitation processes, notably learning, memory, motivation and of course evaluation
methods that examine these functions. Gradually it is being appreciated that there is
considerable overlap between the problems of educational, sociological, and psychological
processes and those of neurobiology, biochemistry and neurophysiology, and there is every
possibility of reciprocal assistance. Researchers in these fields are willing to approach
complex functions such as memory and learning on a physiological basis. We believe that the
techniques and knowledge of neuroscience as well as Human Factors and Industrial
Engineering notions of efficiency and production management can provide a service for
treatment and educational interventions at all stages throughout life. There are findings of
relevance for educators and rehabilitationists from those in the most diverse biological fields.
Although the human brain - the most crucial part of the anatomy - is the most complex
mechanism known to man, it is now being analyzed in ways that are clearly significant for
education and rehabilitation. Recent research on the human brain has provided data relevant
to understanding the processes of human learning and therefore to improving teaching and
increasing the likelihood of recovery of function after brain damage.
This author sees no fundamental difference between the task of education and the mission
of the educational system, rehabilitation after neurological insult or developmental
disabilities, the task of parenting, the effects of social interaction, the effects on the nervous
system of sport, or even the ability to intervene in the natural consequences of cognitive
aging. The term education can then be used interchangeably with rehabilitation as all directly
relate to measurable dynamic plastic changes in neural connectivities.
Education has been grabbing at straws for a long time. Often when a preliminary finding
is reported in the neuroscience literature or presented at a conference, it is grabbed and
expounded upon with little consideration of the fundamental nature of biological processes
that underlie those changes. For better or worse, over the last 10 years, education has been
actively and aggressively looking to the biological sciences in order to inform education
policy and practice. A good example is that of the 1998 decision in Georgia to fund an
expensive program, to provide CDs of Mozart‘s music to all new mothers. In establishing this
policy, the governor of Georgia drew heavily on work in cognitive neuroscience conducted at
the University of California, Irvine. The actions were taken in the hope of ―harnessing the
‗Mozart effect‘ for Georgia‘s newborns—that is, playing classical music to spur brain
development.‖ Despite what the program implied, Mozart effect research, upon close
examination, had little to offer education. One study, reported in Nature (1), found that
listening to Mozart raised the IQs of college students for a brief period of time. Another study
found that keyboard music lessons boosted the spatial skills of three-year-olds (2). Cognitive
neuroscientists responsible for this work were baffled by Georgia‘s program and actions
based on their work. Since this debacle, major figures in the sciences have published articles

Neuroeducational networks 9
emphasizing caution and care as scientists, educators, and practitioners proceed down this
exciting, but pitfall-laden road. These cautionary articles have laid the groundwork for
relationships between neuroscience and education. However, there is a paucity of publications
that systematically examine an area of research where conservative but confident claims can
be made of the benefits of interdisciplinarity.
Most currently prevailing patterns of education are heavily biased towards left cerebral
functioning and are antithetical to right cerebral functioning. Reading, writing and arithmetic
are all logical linear processes, and for most of us are fed into the brain through our right
hand. Most educational policies have tended to aggravate and prolong this one-sidedness.
There is a kind of damping down of fantasy, imagination, clever guessing, and visualization
in the interests of rote learning, reading, writing, and arithmetic. Great emphasis is placed
upon being able to say what one has on one's mind clearly and precisely the first time. The
atmosphere emphasizes intra-verbal skills, ―Using words to talk about words that refer to still
other words‖ (3).
If there is any truth in the assertion that our culture stresses left hemisphere skills and
discriminates against the right hemisphere, this is especially true of school systems. Our
society's overemphasis on ―propositionality‖ at the cost of ―appositionality‖ does not only
result in adjustment difficulties but also in a lopsided education for the entire student body.
Our students are not being offered the education they require to understand the complex
nature of the world and themselves, an education for the whole brain. Sperry wrote: Our
education system and modern society generally (with its very heavy emphasis on
communication and on early training in the three R‘s) discriminates against one whole half of
the brain. I refer, of course, to the nonverbal, non-mathematical, minor hemisphere, which we
find has its own perceptual, mechanical and spatial mode of apprehension and reasoning. In
our present school system, the attention given to the minor hemisphere of the brain is minimal
compared with training lavished on the left, or major hemisphere (4).
Educational institutions have placed a great premium on the verbal/numerical categories
and have systematically eliminated those experiences that would assist young children's
development of visualization, imagination and/or sensory/perceptual abilities. The over-
analytic models so often presented to children in their textbooks emphasize linear thought
processes and discourage intuitivity, analogical and metaphorical thinking. These factors of
neural functioning among children have been left to modification by random environmental,
rather than systematic, institutional means. Education, which is predominantly abstract, verbal
and bookish, does not have room for raw, concrete, esthetic experience, especially of the
subjective happenings inside oneself. Education imposes a structure of didactic instruction,
right-wrong criteria and dominance of the logical-objective over the intuitive-subjective on
the learning child so early in the course of emergent awareness of his world and of himself
that, except in rare cases, creative potential is inhibited, or at least diminished. (cf. 5). This
leads us to affirm that our system of education is one, which leads to the underdevelopment of
the right hemisphere. As a result of excessive emphasis on intellectualizing, verbalizing,
analyzing and conceptualizing processes, ‗curriculum‘ has become equated with mere
‗understanding.‘ This imposes 'neurotogenic limitation' and binds mental processes so tightly
that they impede the perception of new data. In the words of Gazzaniga (6) a long time ago,
curriculum is ―inordinately skewed to reward only one part of the human brain leaving half an
individual's potential unschooled.‖ The traditional preoccupation with formal intellectual
education effectively blocks the possibility for the students to recognize and cultivate

10 Gerry Leisman
creativity and transcendence. It has been the adaptation by educators of applications of brain
sciences into the classroom and the culture of dichotomies of the Behavioral Sciences over
the past 150 years that have placed undo reliance by our educational systems on functional
brain models that may be irrelevant at best and damaging at worst to children‘s classroom
performance and its evaluation.
What emerges as the central proposition of this paper is that (A) the examination and
study of regional cerebral differences in brain function as a way of explaining and evaluating
the learning process within the educational system is a non-starter. (B) The evaluation of
students by standardized aptitude and achievement tests is not sufficient although probably
still necessary and (C) the educational systems would be better to examine student
performance and teach towards ―cognitive efficiency‖ rather than simply mastery v. non-
mastery with methods that employ both psychophysics that examine person-environment
interaction and mathematical means of examining optimization and the strategy used to get
there as well as how far or close a student is functioning from a mathematically derived
optimization regression line or, in fact, how quickly the learner is progressing in that
direction. Educators, although perhaps not palatable to conceive of early childhood education
as such, are producing product and production management techniques that should be useful
for evaluating not just the product but the process or ―manufacture‖ of that product as well.
BRAIN ANATOMY IS IRRELEVANT TO EDUCATIONAL PRACTICE

AND LIKELY TO REHABILITATION AS WELL
We possess, especially as adults, but with children as well, a high degree of localization of
function, but that is not enough to explain the capacity for plasticity, regeneration,
spontaneous recovery, and optimization in neurological terms and certainly not in its
translation into educational practice. On the other hand, educational gains are measured
largely by achievement and also by aptitude testing. Achievement testing deals with
educational gains and not necessarily with the concept of optimization, and aptitude testing
again largely deals with the probability of success but does not give a comprehensive view of
the tools skills, both physiological and cognitive, that would directly relate to that educational
success that would be better measured psychophysically and through the tool skills of project
management, in the same way that cognitive optimization of pilots or air traffic controllers
might be measured or evaluated and that product evaluation might be achieved.
In attempting to understand why neuroanatomic conceptualization is a non-starter for
educational practice it is important to understand that what we are really attempting to
achieve both in educational practice as well as in understanding the neurological basis of
cognitive development is not which brain area controls a given cognitive function, but how
efficiently it is operating. Whilst not the scope of this paper to provide a detailed overview of
this principle, the reader is invited to review these concepts more comprehensively elsewhere
(5). To illustrate how it is that localization has less relevance to our point, Figure 1(A) below
presents a CT-Scan of the brain of Terry Schiavo while in a persistent vegetative state and
1(B) of a young lady of normal intelligence born with hydrocephalus where no significant
anatomic difference is evidenced between the PVS patient and the normally functioning
young lady, but clear functional differences are noted during language processing.

The concept of ‗‗cortical efficiency‘‘ that we have earlier described (7-11) that higher
ability in a cognitive task is associated with more efficient neural processing and not
necessarily a particular brain region that is involved in that processing. Whereas intuitively,
we would expect higher performance to correlate with more activity, for the cerebral cortex
the contrary is the case.
Figure 1. (A) CT of normal (l.) and that of the brain of Terry Shiavo (r.) when the latter was in
Persistent Vegetative State. (B) CT of normally functioning teenager with congenital hydrocephalus
and a CT similar to that of the patient. (C) Regional Cerebral Blood Flow image of individual in (B)
while performing language-based cognitive tasks.
Higher performance in several tasks, including verbal (12), numeric, figural, and spatial
reasoning (13, 14) is consistent with the reduced consumption of energy in several cortical
areas. This phenomenon has also been studied with EEG techniques in different frequency
bands. The amount of a background power (7.5–12.5 Hz) decreases during cognitive activity
compared with a resting state. This decrease has been observed to correlate with higher
performance in subjects with higher IQ scores (9) or with higher performance after training,
indicating a more efficient processing strategy for a cognitive task (15). Most of these studies
come from the psychological literature, focusing mainly on the domain of intelligence but
drawing relatively little attention to the investigation of task performance in second language
learners or bilinguals.
In an EEG coherence study on second language (L2) processing/bilingualism, an
extension of the ‗‗cortical efficiency‘‘ paradigm was examined. Coherence, the amount of
shared activity between any two electrode pairs and taken over the entire scalp surface, gives
an index of inter-regional communication effectiveness. The acquisition of an L2 is
equivalent to the training of a cognitive–behavioral skill, and some individuals respond to this
training more efficiently than others. If an L2 is acquired before a certain age or critical
period, even native speaker proficiency is achieved easily (early bilingualism).
If training starts later in life, the proficiency level achieved depends on the amount of
training, exposure, and on some kind of ‗‗predisposition‘‘ or aptitude of the individual.
Whereas, in general, L2 processing involves the same language-specific cortical areas (with
left hemisphere preference) as native language (L1) processing (cf. review 16), neuroimaging
studies have repeatedly shown that lower L2 proficiency is correlated with more widespread
cortical activity. Perani et al., (17) was tacitly in line with the ‗‗cortical efficiency‘‘ concept,
but not explicitly investigating it.
Reiterer and colleagues (18) applied this concept in studying late bilinguals/second
language learners, comparing, with EEG recording techniques, the recruitment of cortical
areas during L2 processing in two groups of individuals differing profoundly in L2
proficiency (although both had started to learn L2 at the same age).

12 Gerry Leisman
In using coherence analysis or the amount of sharing between any two wave trains and
thus reflective of brain integration of functioning and efficiency, the coherence brain maps
(exemplified in Figure 2) revealed more pronounced and widespread increases in coherences
in the α1-band (8–10 Hz) in low-proficiency than in the high-proficiency L2 speakers.
Surprisingly, this difference was obtained also during L1 processing and corroborated for
both languages by multivariate permutation tests. These tests revealed additional differences
between the low- and the high-proficiency group also for coherences within the β1- (13–18
Hz) and the β2-band (18.5–31.5 Hz).
The point is that greater activity is demonstrated with less proficiency and vice versa. The
function of childhood neurological development is precisely to facilitate the creation of
localized function and it is dynamic. It can be changed and is therefore plastic. This
localization of function is not the explanation of a process, but rather the end-result of
training. The efficiency of cognitive function is directly a consequence of the effectiveness of
networks that now can be measured. Fewer brain regions necessary to accomplish a single
task in one individual compared to another for the same task is a measure of efficiency. These
networks, active during learning and problem solving of all kinds, are plastic and can be
changed as a direct consequence of experience and training.
In attempting to apply graph theory concepts to child and adolescent neurocognitive
performance to create a fundamental change in the educational training and evaluation
paradigm, we can characterize the organization & development of large-scale brain networks
using graph-theoretical metrics as represented in Figure 3 below.
Figure 2. Coherence, or the amount of shared activity between EEG electrode sites, demonstrates
significant coherence differences in high-proficiency versus low-proficiency bilinguals relative to the
default condition (silence, noisy screen) in the δ frequency band (0.5–3.5 Hz) during processing of
visual and acoustic signals (A), and in the θ-band (4.0– 7.5 Hz), during processing of visual and
acoustic signals (B), and of visual signals only (C). The text was either in British English (1st row),
American English (2nd row), or in Austrian German (3rd row). (18).
What we can learn from the characterization, organization and development of large-
scale brain networks in children using graph-theoretical metrics is that small-world networks

are characterized by an increased clustering coefficient or an average node-to-node distance

(also known as average shortest path length) and a decreased characteristic path length (and
represented in Figures 4).
Figure 3. Functional connectivity along the posterior-anterior and ventral-dorsal axes showing
increased subcortical connectivity (●), decreased paralimbic connectivity (●) in children, compared to
young-adults. Brain regions plotted using y and z coordinates of centroids (in mm), 430 pairs of regions
show increased correlations in children & 321 pairs showed significantly increased correlations in
young-adults.
Functional brain networks in children and young-adults show small-world properties. In

mathematics, physics and sociology, a small-world network is a type of mathematical graph
in which most nodes are not neighbors of one another, but most nodes can be reached from
every other node by a small number of steps. Specifically, a small-world network is defined
to be a network where the typical distance L between two randomly chosen nodes (the
number of steps required) grows proportionally to the logarithm of the number of nodes N in
the network that is (19):
L α log N
In the context of a social network, this results in the small world phenomenon of
strangers being linked by a mutual acquaintance. Many empirical graphs are well modeled by
small-world networks. Social networks, the connectivity of the Internet, Wikipedia, and gene
networks all exhibit small-world network characteristics (20).
These findings suggest sub-networks of densely connected nodes, connected by a short-
path. Functional connectivity networks of brain from EEG (21) as well and MEG (22) have
also been shown to possess small-world architecture. Large-scale brain networks in 7-9-year-
old children show similar small-world, functional organization. Functional brain networks in
children show lower levels of hierarchical organization compared to young-adults. Children
and young-adults possess different interregional connectivity patterns, stronger subcortical-
cortical connectivities in young adults and weaker cortico-cortical connectivities in children.
Large-scale brain connectivity involves functional segregation and integration, stronger short-
range connections in children, and stronger long-range connections in young-adults.
In taking this concept further, we note that represented in Figure 4(a) and (b) below is a
representation of functional connectivity along the posterior-anterior and ventral-dorsal axes

14 Gerry Leisman
showing elevated subcortical connectivity and decreased paralimbic connectivity in children,

compared to young-adults. This clearly demonstrates that the wiring and connectivities of
young children are significantly different than teenagers and beyond and the change in
organization of these connectivities directly speaks to the issue of optimization of pathways
and is a direct consequence of training and therefore of education. In attempting to apply
graph theory to an understanding of language acquisition, Figure 4(b) below shows the
responses of both typically developing (TD) and of at-risk, late-talkers (LT).
Figure 4. (a) Characterization, Organization & Development of Large-Scale Brain Networks in

Children Using Graph-Theoretical Metrics. (b) The graph on the left is a typically developing (TD)
child (17 mo., 40%) and the graph on the right is of an at-risk, late-talker (LT) (24 mo., 10%). The
network of the TD child includes the 60 words in the child's productive vocabulary and the network of
the at-risk LT child includes the 61 words in the child's productive vocabulary. The apparent visual
differences in the networks are supported by the differences in the corresponding table, with the typical
talker's network showing higher clustering coefficient and higher median in-degree, but lower geodesic
distance, than the LT. These differences are consistent at both the individual and population level.

Figure 5. Demonstration of computational modulations in connectivity resulting from lesions in the (a) frontal cortex and (b) sensorimotor cortex. Red lines
indicate strength in connectivity. Note the widespread disruption caused by lesion in prefrontal cortex compared with relatively constrained, intrahemispheric
changes resulting from a lesion of the sensorimotor cortex.

16 Gerry Leisman
There is exists a significant and apparent visual difference in the networks with the TD's
network showing higher clustering coefficient and higher median in-degree, but lower
geodesic distance, than the LT. These differences are consistent at both the individual and
population level.
Figure 5 demonstrates clearly the computational modulations in connectivity resulting
from lesions in the (a) frontal cortex responsible for executive function, decisions, and
therefore associations and (b) the sensorimotor cortex. Red lines indicate strength in
connectivity. Note the widespread disruption caused by lesions in the prefrontal cortex
compared with relatively constrained, intrahemispheric changes resulting from a lesion of the
sensorimotor cortex.
It has been thought since the time of both Broca and Wernicke that there exists a high
degree of localization of function with an area anterior to the Sylvian fissure of the temporal
lobes being responsible for expressive language and Wernicke‘s area responsible for
comprehension.
Today we better understand that there no longer exists the localization of receptive
functions in one area (cf. Figure 6(a)). Multiple stream models are more likely. Receptive
language functions are organized into multiple self-organizing simultaneously active
networks. It appears also as represented in Figure 6 (b) that the meaning of words and
sentences has been grounded indicating that there is an ―embodiment‖ of meaning in brain
networks as previously described.
Figure 6. (Continued)

Figures 6. (a) Bye to the good old days: No more receptive functions in one (Wernicke's) area. Multiple
stream models are more likely. Receptive language functions are organized into multiple self-
organizing simultaneously active networks. (b) Grounded meaning indicates that the meaning of words
and sentences have been claimed to be ―embodied.‖
Figures 7. (A) and (B) represent the effect of brain on early as opposed to late exposure to a second
language. The figures clearly indicate the nature of the optimization and efficiency of brain function
connections when notions that related to early training and critical periods are applied.

18 Gerry Leisman
DISCUSSION
The paper has attempted to give an overview of the nature of neurologic processing
efficiencies in engineering terms in an attempt to develop novel approaches and thinking to
classroom-based practice and subsequently leadership and policy informed by current neuro-
scientific realities and by production management and optimization principles now applied to
schools, and their consumers.
We have known that small-world networks are characterized by an increased clustering
coefficient and a decreased characteristic path length. Applying this notion to brain networks
in children; we note that functional brain networks in children and young-adults show small-
world properties. This suggests sub-networks of densely connected nodes, connected by short
path. The functional connectivity networks of the brain from EEG-based systems demonstrate
they possess small-world architecture. Large-scale brain networks in 7-9-year-old children
show similar small-world, functional organization. Functional brain networks in children
show lower levels of hierarchical organization compared to young-adults and children and
young-adults have different interregional connectivity patterns, stronger subcortical-cortical
connectivities in young adults and weaker cortico-cortical connectivity in children. Large-
scale brain connectivity involves functional segregation and integration. Children possess
stronger short-range connections as opposed to younger adults who demonstrate stronger
long-range connections.
We have seen that brain connectivities are variously organized efficiently or inefficiently
in systems that can be relatively easily measured. It is possible to evaluate optimized changes
in brain connectivities after training and learning with applications ranging from progress in
early child development, classroom instruction, and bilingualism. These brain connectivities
are different and delayed in some as a direct consequence of experience. The measurement of
skill and function based on grade level or binary considerations such as a child possesses or
does not possess certain skills ―medicalizes‖ the learning paradigm. The focus should be less
on binary thinking and more on strategy and optimized performance most easily measured by
processing speeds, and strategic solutions. For example, individuals learning a second
language late possess brain activity in regions that are not optimally coordinated and
synchronized. As the brain continues to develop, more distant but simultaneously active areas
require synchronization. It is the developmental lack of effective synchrony that we
hypothesize speaks to the connections between motor and cognitive function and to the very
nature of learning itself.
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development. Ann NY Acad Sci 2005;1060:219–30.
[3] Bruner J. The relevance of education. London: Allen Unwin, 1971:89.
[4] Sperry RW. Right brain-left brain. Sat Rev 1975 Aug 9:30-3.
[5] Melillo R, Leisman G. Neurobiological disorders of childhood: an evolutionary approach. New York:
Springer, 2009.
[6] Gazzaniga MS. Editorial: Review of the split brain. J Neurol 1975:209(2):75-9.

[7] Ertl JP, Schafer EWP. Brain response correlates of psychometric intelligence. Nature
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[8] Grabner RH, Stern E, Neubauer AC. When intelligence loses its impact: neural efficiency during
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systems: evidence of neural efficiency in alpha band ERD. Cog Brain Res 2004:20(2);212–25.
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2011;1(2):181-96.
[11] Leisman G, Machado C, Melillo R, Mualem R. Intentionality and ―free-will‖ from a
neurodevelopmental perspective. Front Integrat Neurosci 2012;6:36. doi: 10.3389/ fnint.2012.00036.
[12] Parks RW, Loewenstein DA, Dodrill KL, Barker WW, Joshii F, Chang JY, et al. Cerebral metabolic
effects of a verbal fluency test: a PET scan study. J Clin Exp Neuropsychol 1988;10:565–75.
[13] Lamm C, Bauer H, Vitouch O, Gstattner R. Differences in the ability to process a visuo-spatial task
are reflected in event-related slow cortical potentials of human subjects, Neurosci Lett
1999;269(3):137–40.
[14] Vitouch O, Bauer H, Gittler G, Leodolter M, Leodolter U. Cortical activity of good and poor spatial
test performers during spatial and verbal processing studied with slow potential topography, Intern J
Psychophysiol 1997;27(3):183–99.
[15] Neubauer, AC, Grabner, RH, Freudenthaler H, Beckmann H, Jens F, Guthke J. Intelligence and
individual differences in becoming neurally efficient. Acta Psycholgica (Amsterdam) 2004;116(1):55–
74.
[16] Perani D, Abutalebi J. The neural basis of first and second language processing, Curr Opin Neurobiol
2005;15:202–6.
[17] Perani D, Abutalebi J, Paulesu E, Brambati S, Scifo P, Cappa SF, Fazio F. The role of age of
acquisition and language usage in early, high-proficient bilinguals: an fMRI study during verbal
fluency. Hum Brain Map 2003;19(3):170-82.
[18] Reiterer S, Hemmelmann C, Rappelsberger P, Berger ML. Characteristic functional networks in high-
versus low-proficiency second language speakers detected also during native language processing: an
explorative EEG coherence study in 6 frequency bands. Brain Res Cogn Brain Res 2005;25(2):566-78.
[19] Watts, Duncan J, Strogatz SH. Collective dynamics of 'small-world' networks. Nature 1998;393:440-2.
[20] Howard N, Leisman G. DIME (Diplomatic, information, military and economic power) effects
modeling system: Applications for the modeling of the brain. Funct Neurol Rehabil Ergon 2013:3:2-3.
functional neurology and rehabilitation. Funct Neurol Rehabil Ergon 2011;1(2):315-56.
[22] Stam CJ. Functional connectivity patterns of human magnetoencephalographic recordings: a 'small-
world' network? Neurosci Lett 2004;355(1-2):25-8.

Chapter 3
PLASTICITY AND FUNCTIONAL

CONNECTIVITIES IN REHABILITATION

1
The National Institute for Brain and Rehabilitation Sciences,
Nazareth, Israel
2
Biomechanics Laboratory, ORT-Braude College of Engineering,
Karmiel, Israel
3
Universidad de Ciencias Médicas de la Habana,
Facultad Manuel Fajardo, Havana, Cuba
While the clinical and neuropathological evaluation of neurological compromise has

traditionally concentrated upon the focal distribution of brain disease, ignored have been
the changes in the complex connections that link brain areas that are crucial for cognition
and optimized human performance. An overview of some recent developments in the
field of Rehabilitation Engineering will be provided that will indicate why successful
solutions to fundamental human function deficits in the disabled result from attempts to
find solutions to these difficulties by optimizing human performance and by asking the
right questions.
We will examine the nature of nervous system plasticity, man-machine interactions,
the nature of functional connectivities in the nervous system, and the application of
systems theory to highlight potential solutions to intractable problems such as persistent
vegetative and minimally conscious states, Parkinson‘s disease, Tourette‘s syndrome,
Major Depression and motor function and dysfunction in general from a systems
standpoint informing the nature of R&D in applications that include deep brain
stimulation, prosthetic limb and orthotics development to better understand the concept of
functional neurology both developmentally and in adult populations.


22 Gerry Leisman
INTRODUCTION
We now know more than ever before that we humans are more resilient to early, often quite
negative experiences. Developmental damage, dysfunction, or disease does not necessarily
constrain developments later on in life. Also, individuals sustaining head trauma or acute
disease later in life also demonstrate a fair degree of plasticity.
The direct application of an effective built-in system of plasticity is the rehabilitation of
traumatic injury to and disease of the nervous system. Functional Neurology is a field of
application and while the clinical neurosciences is generally a field of description and
explanation; there exists a requirement for tools for modification and optimization of the
nervous system after disease or trauma. Functional Neurology then requires data-based theory
to inform value judgments about what constitutes progress but more importantly how such
progress can be achieved. Functional Neurology requires the study of the function of the
nervous system and how that looks, but also development and aging, how each arise and what
would be if conditions were different and how that understanding would inform the
rehabilitation process. Therefore, the search for the nature of plasticity in all aspects of our
function from metabolic to physical to connections and disconnections collectively form the
cornerstone of scholarship in Functional Neurology.
To better understand the context for a neuroscience of rehabilitation, we must understand
that of necessity, organismic plasticity must be both multidimensional and relativistic in its
nature. A fundamental understanding of the nature of plasticity requires us to move beyond
the dichotomous right-left brain paradigm or the concept of localization of function so
prevalent in the development of neuropsychological thinking since Broca and beyond that
absolutist view of physiological and anatomical constancy towards a better understanding of
the dynamics of organismic change. We are not simply talking about one brain area‘s control
of a particular independent function, but we require an understanding of how brain trauma, or
developmental disabilities, for example, has manifestations in metabolic, digestive,
immunological and of course behavioral systems. Tunnel vision yields tunnel understanding –
we need a more fundamental understanding of the nature of balance versus change. The
malleable and unmalleable travel together. They are bonded together not as opposites but are
rather complementary.
On all levels from biological to cultural, our fundamental processing of information is
open to change. It has to be as how could we behave as adaptive organisms if we were not
capable of change, of rewiring, of making new associations, and of effecting change in
reciprocal relations with new processes. We are not only dealing with a trivial issue and we
state that if all levels of life are open to change, then much optimism exists for a functional
neurology to provide intervention and enhance human development.
Roger Sperry (1) cogently summarized the implications of a view of human development
based on plasticity and arising from his own work on ―split-brain‖ that allowed him to revise
a concept of consciousness evidenced by his having stated, ―The key development is a switch
from prior noncausal, parallelist views to a new causal, or ―interactionist‖ interpretation that
ascribes to inner experience an integral casual role in brain function and behavior.
In effect, and without resorting to dualism, the mental forces of the conscious mind are
restored to the brain of objective science from which they had long been excluded on
materialist-behaviorist principles.‖

Plasticity and functional connectivities in rehabilitation 23
Plasticity implies that the environment can modify a living organism and that unlike the
traditional view in modern western psychology, when we measure a response to a stimulus,
we are mostly not measuring a fixed action pattern but rather that which is reflective of the
concept of plasticity. Gollin (2) wisely indicated that plasticity is a reflection of systematic
―structural and/or functional changes in a process, and may involve ‗variations that lie on a
continuum of variation around some hypothesized average value, and variations that entail
structural and functional changes of a qualitative nature.‖
It has been variously observed quite in the past already (3) that among species that reach
their ultimate level of neurobehavioral organization relatively early in life, their behaviors
tend to be relatively stereotyped. Alternatively, members of a species that take longer to reach
their final level of neuro-behavioral organization are relatively more flexible being better able
to moderate their behaviors, and this being more representative of plastic function and thereby
having a greater capacity to modify behavior to adjust or fit with contextual demands.
Plasticity is not gene-coded and thus pre-formed. Organisms must develop their plasticity.
The fact that humans have a greater capacity than rats or even chimps for plastic or rather
flexibility of behavior, does not imply that we are either all stereotyped or flexible in our
behavior and brain organization. Stereotypy creates for efficiencies but plasticity or flexibility
allows for adaptation due to the exigencies of one‘s environment. We, given the notions of
stability and flexibility (4), have a basis for rehabilitation and effective adaptive function. The
concept of the interplay between stability and flexibility and it implications for rehabilitation
in brain and nervous system disorders or injury needs to be viewed as a relativistic notion,
viewed against the features of the organism that are not plastic. In order to identify flexibility
or plasticity, one must be able to identify the invariant and constant. The identification of
plasticity requires us to be able to know the constraints of the system. The fact, however, that
we are more plastic than other organisms is expressed even in our adult lives as organisms.
This suggests that our capacity for systematic change and the fact that we retain flexibility
across our later developmental periods allows application of rehabilitation thinking and the
measurement of optimization throughout the life span.
HOW MIGHT NEURAL FIRINGS LEAD TO INTEGRATION?

Conventional (i.e., functionalist, reductionist, materialist, physicalist, computationalist)
approaches to understand the nature of nervous system organization argue that neurons and
their synapses are the fundamental units of information in the brain, and that conscious
experience emerges when a critical level of complexity is reached in the brain's neural
networks (5).
In attempting to portray consciousness, thinking and memory and their constituent skills
as we have elsewhere (6-9) we could easily demonstrate how imaging technologies show
brain locations appearing to correlate with consciousness, although not directly responsible
for it. This is exemplified in Figure 1.
We have theorized earlier about how neural firings lead to thoughts and feelings (7). The
conventional approaches reached at that critical level of complexity is exemplified in
Figure 2.

24 Gerry Leisman
Figure 1. Imaging technologies show brain locations appearing to correlate with consciousness but
perhaps not directly responsible for it. Technology reveals brain activity associated with consciousness
but is that activity equivalent to it.
The difficulty with a pure neuronal model in attempting to provide a context for plasticity
is the fact that there are so many issues not adequately accounted for. For example, neuronal
complexity is not accounted for. Many motile single-celled organisms, for example, lack
neurons, swim, find food, learn, and multiply through an internal cytoskeleton. Furthermore,
assuming that the mind is computer-like (brain = mind = computer), there exists incompatible
neurophysiological details omitted from traditional assumptions of brain organization for
information transmission such as the widespread apparent randomness at all levels of neural
processes (is it really noise, or underlying levels of complexity?); glial cells (account for
some 80% of brain) what do they have to do with learning or plasticity? What is the nature of
dendritic-dendritic processing and of electrotonic gap junctions? What roles do
cytoplasmic/cytoskeletal activities play in learning, re-learning and plasticity? There is the
absence of testable hypotheses in emergence theory. No threshold or rationale is specified but
rather, consciousness and awareness ―just happens.‖
In attempting to address some of these concerns at the outset of this paper at least on a
micro-structural level, in our previous thinking, we had examined activity waves in a layered
neural continuum. With arborization facilitating synaptic connectivities, upon stimulation,
neural cells become active and trigger excitatory and inhibitory signals through synaptic
connectivities. If a given cell receives a sufficient preponderance of excitatory over inhibitory
synaptic inputs it fires in turn and sends signals to other cells.
Recent years have seen a proliferation of work in neuroscience, computer science,
physics, and biology concerning neurons and their connections. This stems from the dual
motivations of understanding mental function in terms of its material constituents and
emulating its aspects artificially. The latter effort has achieved some success (11, 12), but
progress in the larger endeavor has been slower, up against the size discrepancy between
artificial neural networks (about 104 cells at most (13) and mammalian brains (109-1011 cells)
(14, 15). It is clear that the type of analysis used to design, for example, conditionable pattern
recognizers must be supplemented by an approach that can account for the organization of
large numbers of neurons into what we call the ―mind.‖

Figure 2. Electrophysiological consequences of consciousness as a function of increasing levels of

system complexity. Is this how and when consciousness occurs? (after Tononi and Edelman (10)).
Our model of brain organization does not conceive, as do other theories, especially neural
network models, that the mind is a computer-like entity. Other models dealing with
interconnectivities omit details including: widespread apparent randomness at all levels of
neural processes (is it really noise, or underlying levels of complexity?); glial cells account
for approximately 80 percent of the brain; the effects of dendritic-dendritic processing; the
effects of electrotonic gap junctions; the effects of cytoplasmic/cytoskeletal activities. Single
cell paramecia swim and avoid obstacles with their cytocytoskeletons for example. Neuronal
complexity is generally not accounted for. Many motile single-celled organisms lacking
neurons swim, find food, learn, and multiply through internal cytoskeleton and the brain‘s
living state (the brain is alive!). Invariably, no threshold or rationale is specified, rather,
consciousness ―just happens.‖
Our approach, which can be conveniently called continuum neural dynamics, was first
proposed by Wilson and Cowan (15). They stated that a differential element of neural tissue
(which in the continuum approximation still contains many cells) could be characterized
completely by the connections it has with other such elements. Neural continuum can be
described as an assembly of cells, either excitatory (e-species) or inhibitory (i-species). Cells
of each species within a continuum element send their respective collective signals to the
other elements. Communications between individual cells are provided by axons. While
axons can be long, their average length less than 1 nm. In continuum approximation this fact

26 Gerry Leisman
is represented by a mean connection range, where the probability of connection between

continuum elements decreases exponentially. As a consequence of the neglect of the details of
near-neighbor connections interior to the elements, neurons themselves can be replaced by
figurative ―cells‖ which are of two species, ―excitatory‖ (e-cells), and ―inhibitory‖ (i-cells).
Then neural activity on the macroscopic level is described by a field variable A(s,x,t) (s = e,i),
which is the active fraction of species s at position x and time t. The properties of the neural
material are described in Figure 4 in the context of connection ranges.
Connections are of four types, viz. e-e, e-i, i-e, i-i, where in each case the first-named is
the afferent or pre-synaptic species and the second is the efferent or post-synaptic species;
these connections are probabilistic, the probabilities decreasing with distance. (It is essential
to this theory that the probabilities and their spatial ranges be different for the different
connection types). The activity field A obeys an integro-differential equation (7), which
expresses the fact that the change in activity in a region of the continuum is a nonlinear (i.e.,
sigmoid) function of synaptic input. This in turn is proportional to the algebraic sum of the
activity in all other regions, weighted by the connection probabilities as is exemplified in
Figures 3 (A) and (B).
We consider here the application of this theory to a model, which we believe is a first
approximation of cortical tissue. It consists of two identical layers, each containing both types
of cell. Connections between cells in different layers are subject to a time delay without
dissipation.
The presence of e-e connections denotes a source of free energy in the medium, which
can thus be described as ―active.‖ Active media amplify small signals, and this work concerns
itself with determining the characteristics of disturbances that are preferentially amplified, the
―fastest-growing normal modes‖ in other words.
Because the signals under consideration are initially small, a linear analysis suffices; the
growing disturbances can then be described in terms of waves. For example, for relatively
small delay the response of the two-layer system to an impulsive (delta-function) stimulus at
one of the layers is a growing, propagating wave with narrowly determined wavelength and
frequency. As delay increases the structure of the response becomes more complex, with two
or more such waves being simultaneously excited.
The delay acts as a control, determining both the spectral location of the resonances and
the qualitative nature of the response (16). The preferentially amplified wavelengths are
always large compared with the synaptic connection ranges.
Linear theory predicts that growth proceeds without limit. Therefore limitation to the
growth must come from factors outside the theory. Nonlinear saturation, which has been
studied to some extent (12, 17-22), is one possible limiting factor. It suits our purposes
instead to postulate that growth at a particular wavelength stops when the delay time changes,
so that growth at that wavelength is no longer favored. (The presence of a uniform decay
ensures the disappearance of non-growing disturbances.) A change in delay, over times long
compared with itself (and the periods of the resonant waves), can come about if the delay
results from reentrant neuronal circuits (23).
Karl Pribram's holonomic theory reviews evidence that the dendritic processes function
to take a ―spectral‖ transformation of the ―episodes of perception.‖ This transformed
―spectral‖ information is stored distributed over large numbers of neurons. When the episode
is remembered, an inverse transformation occurs that is also a result of dendritic processes. It
is the process of transformation that gives us conscious awareness.

a)
b)
Figure 3. The Neural continuum (A) As we zoom out, our field of vision contains more and more,
seemingly smaller and smaller cells. Eventually the distinctions among the individual cells blur.
We (1-5) have analyzed the properties of the material as a neural continuum. (B) Schematic of
simplified cortical model: Two layers each consisting of excitatory and inhibitory cells. Synaptic
connections within a layer are instantaneous; those between layers are subject to a (variable) delay,
without dissipation in activation strength. There is a simplifying assumption of axial uniformity where
the connection probabilities, ranges, time delays depend on axial or interlayer distance only. The neural
continuum can be described as an assembly of cells, either purely excitatory (e-species) or purely
inhibitory (i-species). The cells of each species within a continuum element send their respective
collective signals to the other elements. Communications between the individual cells are provided by
axons. Although many of these axons are quite long, their average length is less than 1 mm. In the
continuum approximation this fact is represented by a mean connection range, over which the
probability of connection between continuum elements decreases exponentially.
We suggest below a mental phenomenology in which various aspects of ―consciousness‖

consist of the simultaneous activation of elements of the continuum distant from each other
by a multiple of some currently favored wavelength. At small delays this large-scale
organization by wavelength is reproducible as a function of delay only. For larger delays,
phase relations among the several activated modes cause the details of the resonant pattern to
be functions as well of the spatiotemporal location of the initial signal. The elements under

28 Gerry Leisman
discussion contain enough cells to be complex neural networks, and a single ―neural cascade‖
can involve, from inception to termination, some millions of neurons.
The Figures 4 and 5 depict how resonantly growing waves simultaneously activate distant
modules into patterns of greater or lesser complexity. These patterns, the normal modes of our
model of cortical tissue, may well be expressions of ―mental‖ phenomena. For example,
consider a case where the modules contain feature-recognition information. At low delays,
when a single wavelength is resonantly excited, modules spaced at a distance equal to an
integral multiple of the resonant wavelength will be simultaneously active or inactive. They
can thus represent information that associates perhaps a face a voice and a name. A memory
search then would involve changing the delay until the correct pattern is achieved.
Figure 4. Properties of the neural continuum. The neural continuum is described as an assembly of
cells, either excitatory (e-species) or inhibitory (i-species). Cells of each species within a continuum
element send their respective collective signals to the other elements. Communications between
individual cells is provided by axons. While axons can be long, their average length less than 1 nm. In
continuum approximation this fact is represented by a mean connection range, where the probability of
connection between continuum elements decreases exponentially.
As previously indicated, the longer the delay remains constant, the greater the
exponential growth in the proportion of cells firing that is the number recruited into the
search. Note that the Figures depict the response to a single small local disturbance; there is
no reason why it should occur in isolation unless there exists a fundamental dys-
communication or functional disconnection between parts of the system. Several disturbances
separated from each other in space and time can give rise to a pattern more like a standing
than a propagating wave. Growing standing waves may be useful in explaining ―Tip-of-the-
Tongue‖ and related phenomena in relatively normal situation and conditions such as
persistent vegetative states or minimally conscious states in more egregious compromises to
the status of brain functional integration.

When the delay is such that several wavelengths are simultaneously resonant, the location
of the original disturbance is significant, since the phase relations among the excited waves in
any particular region lead to interference patterns. For example at T = 1.25 (see Figure 5d),
there are several adjacent modules simultaneously active near x = 150 and t = 25. Since the
spatial origin of the Figure represents the disturbance location, change in this location would
change the position at which the large activity occurs. It is not far-fetched to draw a
connection between this feature of the theory and the Proustian observation that memories of
the same experience are never exactly the same.

30 Gerry Leisman
Figure 5. The neural medium contains stored electro-chemical energy and therefore can be described as
active. Under a wide range of conditions, neural tissue amplifies initially small increments in collective
neuronal activity; when this occurs, the amplified signal takes the spatio-temporal form of waves, and
the amplification occurs at selected wavelengths. In our model the delay time T is the parameter most
instrumental in determining the dominant wave or waves, whose wavelengths are about an order of
magnitude greater than the average synaptic connection ranges. In our model the delay time T is the
parameter most instrumental in determining the dominant wave or waves, whose wavelengths are about
an order of magnitude greater than the average synaptic connection ranges. In this Figure we see the
spatiotemporal response of the model in Figure 3B to a unit impulsive stimulus to one layer at lateral
position x = 0 and time t = 0. (Distances are normalized to the excitatory connection range and times to
the uniform neural activity decay rate.) The response of the stimulated layer is shown for various values
of interlayer time delay T: (a) T = 0.50, (b) T = 0.75, (c) T = 1.00, (d) T = 1.25, (e) T = 1.50, (f) T =
1.75. To avoid showing the infinite (delta function) stimulus, the earliest time shown is t = 0.5. For
purposes of scaling, the graphs in this Figure terminate at t = 15. The responses at later times are shown
in Figure 6. Parameters are given in Koch and Leisman (3).

Furthermore, in the cortex, which can be represented by six layers (24), there are in
general six waves that can be activated, so that the number of possible simultaneous
resonances is larger than depicted here. This allows for enough complexity to explain some
aspects of intelligence and certainly conscious awareness.

32 Gerry Leisman
Figure 6. Spatiotemporal response of the model in Figure 3B to a unit impulsive stimulus to one layer at
lateral position x = 0 and time t = 0. (Distances are normalized to the excitatory connection range and
times to the uniform neural activity decay rate.) The response of the stimulated layer is shown for
various values of interlayer time delay T: (a) T = 0.50, (b) T = 0.75, (c) T = 1.00, (d) T = 1.25, (e) T =
1.50, (f) T = 1.75. For purposes of scaling, the graphs in this Figure start at t = 15. Parameters are given
in Koch and Leisman 1996 (3).
The sudden ―insight‖ shown by Kohler's (25) chimpanzee, that put together a platform
and a stick to retrieve a banana inaccessible with either alone can be explained by the
simultaneous activation of resonant patterns representing the two pieces of the puzzle. For
this to be accomplished delay must be controlled, but an uncertainty is introduced through a
disturbance and that effects the positions of the interference patterns. In general large delay

with its consequent complication of the resonant pattern is likely to be a favorable condition
for such ―creative thinking‖ to occur and its opposite for functional disconnectivities.
The assumption that the delay changes before nonlinear effects set in is an expression of
the familiar mental phenomenon of shifting attention.
The wave forms in Figure 5 terminate at t = 30 decay periods, at which time the
maximum amplitude shown is about 500 times the amplitude of the initial delta function
disturbance. By then the wave has propagated about 200 excitatory connection lengths from
the point of disturbance, so that about 107 cells (26), 0.1 to 1 percent of the (two-layer) cortex
(27), have been involved. This is reasonable for a typical ―mind moment.‖
In connection with attention shifts, we point out that in previous work (7-10, 19-21) we
have modeled the attentional center of the brain, and concluded that it communicates with the
higher centers through a spatial-frequency signal. Attention integrates systems, and functional
disconnectivities reflect impairment in that spatial frequency signal or signals. We speculate
that shifts in attention occur as the delay in the cortex adjusts itself so that one of the cortical
resonant wavelengths is equal to the wavelength of the attentional signal. The inability to
adequately perform such operations to varying degrees creates functional disconnectivities.
The neural medium has stored electro-chemical energy and can be described as active.
Neural tissue amplifies initially small increments in collective neuronal activity; when this
occurs, the amplified signal takes the spatio-temporal form of waves, and amplification
occurs at selected wavelengths.
Combined with the widely accepted theory that information storage is spatially
distributed in the cortex and hippocampus this universal property led us to the hypothesis that
implantation and retrieval of such stored information is based on the wavelength(s) of the
amplified activity wave(s) controlled mainly by the delay. The amplified mode structure
becomes more complex as delay increases As the favored modes grow and propagate they
associate, through simultaneous activation. Thus it can be argued that the delay-controlled
waves provide a mechanism by which ―memories‖ can be reproducibly recalled, and
―thoughts‖ generated and developed. It is also by means of this theoretical understanding that
we may have a better context for the notion of neural plasticity.
ENRICHMENT EFFECTS RESULT FROM

NEUROBEHAVIORAL PLASTICITY
Hebb had postulated in 1949 that, when one cell excites another repeatedly, a change takes
place in one or both cells such that one cell becomes more efficient at firing the other (28). It
is this view that is not only limited to a particular cell and its arborized neuronal connections
but to definable anatomical regions. It is this notion that forms the basis of our concept of
plasticity. The basis for this behavior of brain regions is of course, biochemically based, and
possibly a function of the hypothesized neural continuum described in the previous section.
Hebb was the first to propose the ‗enriched environment‘ as an experimental concept. He
reported anecdotally that laboratory rats that nurtured at home as pets were behaviorally
different than their litter mates kept at the laboratory (28).
Hebb was not the only one who conceptualized the effects of enriched nurturance having
an effect on nervous system structure and function. Hubel and Wiesel examined the effects of

34 Gerry Leisman
selective visual deprivation during development on the anatomy and physiology of the visual
cortex (29, 30) and Rosenzweig and colleagues introduced enriched environments as a
testable scientific concept (31-33) by measuring the effects of environment on ‗total brain
weight,‘ ‗total DNA or RNA content,‘ or ‗total brain protein‘ were measured (34-36).
Numerous researchers have demonstrated a significant linkage between enrichment and
neurological plasticity that have included biochemical changes, gliogenesis, neurogenesis,
dendritic arborization, gliogenesis, neurogenesis and improved learning and memory (37, 38).
An example is provided below in Figure 8.
Figure 7. The total activity within a lateral region of the model in Figure 3B caused by a unit impulsive
stimulus at time t = 0, as a function of distance L of the boundary of the region from the location of the
impulse. (Distances are normalized to the excitatory connection range and times to the uniform neural
activity decay rate.) The response of the stimulated layer between times t = 11 and t = 26 is shown for
two values of interlayer time delay T: (a) T = 0.50, (b) T = 1.25. Parameters are given in Koch and
Leisman 1996 (3).

Figure 8. Dentritic morphology of pyramidal neurons in layer III of the somatosensory cortex in rat
housed in (Left) standard and (right) enriched environments. Bar = 25 µm. The enrichment significantly
increases dendritic branching as well as the number of dendritic spines (from Johansson and
Belichenko (39)).
In an experimental setting, an enriched environment is ‗enriched‘ in relation to standard

laboratory housing conditions in that experimental animals in larger cages than their non-
enriched peers have greater opportunity at social interaction with nesting material, toys and
food locations frequently changed. The enriched animals were also given opportunities for
voluntary activity on treadmills. These experiences have allowed researchers to formulate a
definition of enrichment as ―a combination of complex inanimate and social stimulation‖ (40,
41).
Experiments since Hebb have collectively concluded that there exists no single variable
accounting for the consequences of enrichment (42).
Consequences of enrichment on the intact brain
Numerous studies over the past ten years have clearly demonstrated the relationship between
environmental enrichment, voluntary exercise, and positive changes in both brain state and in
learning and memory. In one such study, mice were assigned to groups with a learning task,
wheel running, enrichment or standard housing. Voluntary exercise in a running wheel
enhanced the survival of newborn neurons in the dentate gyrus, which is similar to the effects
of environmental enrichment, whereas none of the other conditions had any effect on cell
genesis (43).
This finding led to a comparison of the effects of enrichment and exercise on behavioral,
morphological and molecular changes in the brain.
Voluntary exercise and environmental enrichment produce notably similar effects on the
brain. We know that environmental enrichment and voluntary exercise massively increase
neurogenesis in the adult hippocampus via dissociable pathways (43). Environmental

36 Gerry Leisman
enrichment and voluntary exercise have consistently been shown to increase adult
hippocampal neurogenesis and improve spatial learning ability.
Although it appears that these two manipulations are equivalent in this regard, evidence
exists that enrichment and voluntary exercise affect different phases of the neurogenic process
in distinct ways. It has been suggested that enrichment increases the likelihood of survival of
new cells, whereas exercise increases the level of proliferation of progenitor cells.
Table 1. The effects of an enriched environment (69)
Olson and colleagues (44) have provided a model showing that voluntary exercise leads
to the convergence of key somatic and cerebral factors in the dentate gyrus (DG) to induce
cell proliferation, although insufficient evidence exists to provide a similar model for
environmental enrichment. These authors have also suggested that environmentally-induced
cell survival in the DG involves cortical restructuring as a means of promoting survival and
additionally concluded that environmental enrichment and voluntary exercise both lead to an
increase in overall hippocampal neurogenesis via dissociable pathways, and should therefore,
be considered distinct interventions with regard to hippocampal plasticity and associated
behaviors.
Neurogenesis is a constitutive activity in the adult dentate gyrus whereby new cells are
created in the subgranular zone, before becoming neurons in the dentate gyrus granule cell
layer (45). New granule cells are thought to migrate from the subgranular zone outwards to
the edge of the cell layer as they mature. In their experiments Redila and Christie (45)
examined the dendritic morphology of granule cells in the subgranular zone, and the inner
and outer regions of the granule cell zone in rats with low and high rates of neurogenesis. In
animals with lower rates of neurogenesis, the number of primary dendrites, degree of
dendritic complexity and total dendritic length was lowest in cells located in the subgranular
zone, higher in inner granule cell zone neurons, and highest in outer granule cell zone granule
cells. Subgranular zone granule cells typically extended one primary dendrite and had a
simple, immature dendritic tree, while granule cells in the outer granule cell zone had an
increased number of primary dendrites, greater dendritic complexity, and greater total
dendritic length.

Animals that engaged in voluntary exercise showed increased neurogenesis, and the
proportion of cells with one or two primary dendrites was increased in all of the granule cell
zones. Despite having fewer primary processes, these cells showed enhanced dendritic
complexity and an overall increase in their total dendritic length. These results indicate that
granule cell dendritic morphology may be indicative of the age and position of a cell in the
granule cell layer, but that in animals with increased rates of neurogenesis, the proportion of
cells exhibiting what is considered an immature phenotype is increased throughout the all
regions of the dentate gyrus cell layer.
Henriette Van Praag and colleagues (46) further confirmed these notions by noting that
while aging causes changes in the hippocampus that may lead to cognitive decline in older
adults, in young animals, exercise increases hippocampal neurogenesis and improves
learning. They investigated whether voluntary wheel running would benefit mice that were
sedentary until 19 months of age. Specifically, young and aged mice were housed with or
without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn
cells. After one month, learning was tested in the Morris water maze. Aged runners showed
faster acquisition and better retention of the maze than age-matched controls. The decline in
neurogenesis in aged mice was reversed to 50 percent of young control levels by running.
Moreover, fine morphology of new neurons did not differ between young and aged runners,
indicating that the initial maturation of newborn neurons was not affected by aging. Thus,
voluntary exercise ameliorates some of the deleterious morphological and behavioral
consequences of aging according to these authors.
In discussing the effects of voluntary physical activity and exercise training on the ability
to favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and
neuroprotective processes, Dishkan and colleagues (47) indicate that at least some of the
processes are mediated by neurotrophic factors. Motor skill training and regular exercise
enhance executive functions of cognition and some types of learning, including motor
learning in the spinal cord. These adaptations in the central nervous system have implications
for the prevention and treatment of obesity, cancer, depression, the decline in cognition
associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's
dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical
activity also attenuates neural responses to stress in brain circuits responsible for regulating
peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that
could plausibly contribute to reductions in clinical disorders such as hypertension, heart
failure, oxidative stress, and suppression of immunity. Mechanisms explaining these
adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal
muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help
explain effects of physical activity and exercise on the central nervous system.
In another paper in this text, Melillo (48), makes reference in the negative to toxicities of
presently unknown sorts that can allegedly create an epigenetic effect on the incidence of
autism and reduced plasticity. Gomez-Pinella and associates (49) evaluated the possibility
that the action of voluntary exercise on the regulation of brain-derived neurotrophic factor
(BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of
epigenetic regulation. They studied the BDNF promoter IV, as this is highly responsive to
neuronal activity. They found that exercise stimulates DNA demethylation in BDNF promoter
IV, and elevates levels of activated methyl-CpG-binding protein 2, as well as BDNF mRNA
and protein in the rat hippocampus. Chromatin immuno-precipitation assay showed that

38 Gerry Leisman
exercise increases acetylation of histone H3, and protein assessment showed that exercise
elevates the ratio of total for histone H3 but had no effects on histone H4 levels. Exercise also
reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of
the Bdnf gene (50), but did not affect histone deacetylase 9. Exercise elevated the
phosphorylated forms of calcium/calmodulin-dependent protein kinase II and cAMP response
element binding protein, implicated in the pathways by which neural activity influences the
epigenetic regulation of gene transcription, i.e., BDNF. These results showing the influence
of exercise on the remodeling of chromatin containing the BDNF gene emphasize the
importance of exercise on the control of gene transcription in the context of brain function
and plasticity.
Reported information about the impact of a behavior, inherently involved in the daily
human routine, on the epigenome opens exciting new directions and therapeutic opportunities
in the war against neurological and psychiatric disorders.
Enrichment improves learning and memory
Enrichment has been shown to enhance memory function in various learning tasks (51).
Enriched mice also did better on a water maze task (a test of spatial memory) than did
controls in standard housing (38, 52-54). Similarly, voluntary wheel running and treadmill
training have been shown to enhance spatial learning (55-57). In the exercise studies,
differences between sedentary and active animals were best observed when tasks were made
more challenging (56, 57). In addition, when tested on a different spatial memory task (a T-
maze), enriched rats did better than isolated rats with a running wheel (41). So, the degree of
learning improvement might be greater following enrichment that includes exercise than
exercise alone.
Anatomical Changes: There has been a long debate about whether environmental
enrichment influences cell proliferation in the adult brain going back at least to 1964 when
Altman (the first researcher to describe adult neurogenesis in the hippocampus (58))
investigated whether enrichment could affect the production of neurons but found only
enhanced gliogenesis (59). In this study, the focus of the analysis was on cortex rather than
hippocampus, which might be why no new neurons were observed. Subsequent studies
reported that the increase in glia was attributable to oligodendrocytes (60), and increases in
astrocytes (54) in enriched animals. As we had noted earlier, both enrichment and exercise
enhance the number of new neurons in the dentate gyrus. However, the mechanisms by which
new cells are generated might differ between the two conditions. Enriched living only
affected cell survival and not cell proliferation. By contrast, running increased cell division
and net neuronal survival. Cell proliferation and survival might therefore be regulated
differently by different behavioral or environmental manipulations within a constant genetic
background (61).
Enriched living rodents have been observed to have increased brain weight and size (34,
62) as well as enhanced perikaryonal and nuclear sizes in the cortex (63). The literature now
supports enrichment resulting in enhanced gliogenesis, neurite branching and synapse
formation in the cortex (55). Specifically, dendrite branching in occipital cortex pyramidal
neurons has been quantified. Upon bifurcation in the first dendrite, a second order dendrite is
created, and subsequent bifurcation results in higher order dendrite branches. It was found

that enriched rats have more higher order dendritic branches than controls. Synaptogenesis
has also been reported to be increased in enriched animals. Reducing neuronal density but
increasing synapse-to-neuron ratios (37), with similar findings specifically found in the
hippocampus (64, 66). Separately, motor skill learning has been shown to increase cortical
thickness and synaptogenesis (53) as well as the number of synapses per neuron in the
cerebellum (67).
Effects of Growth Factors: During development, growth factors provide important
extracellular signals regulating proliferation and differentiation of stem and progenitor cells in
the central nervous system (68). Several investigations have been made into the role of these
factors in the adult brain. Researchers have found that, in the mature organism, these factors
might function in synaptic plasticity, learning, enrichment, exercise and neurogenesis.
Consequences for damaged or diseased brains
In attempting to extrapolate the animal laboratory findings of neural plasticity associated with
environmental enrichment developed since the 1960s to the concept of human rehabilitation,
the literature generally indicates favorable outcome in conditions such as stroke, epilepsy and
even the aging process.
One group of investigators reported that three weeks of enrichment reduced apoptotic cell
death in the hippocampus by 45 percent and also prevented the development of motor
seizures after injection with kainic acid (70). Previous studies showed that recovery from
brain lesions was facilitated by pre- and postoperative enrichment (71).
Even a short enrichment can be effective. In addition, enrichment can facilitate recovery
when applied after a delay. For example, rats that were transferred to an enriched cage 15
days after middle cerebral artery ligation showed notable improvement in postural reflexes
and limb placement compared with rats in standard housing when tested 7 weeks later (72).
Interestingly, voluntary wheel running has also been shown to provide protection against
ischemia.
Apart from effects in the above-mentioned pathologies, enrichment might have beneficial
effects on genetic conditions. Deficits in non-spatial memory associated with disruption of the
hippocampal N-methyl-D-aspartate (NMDA) receptor 1 subunit could be rescued by
enrichment for three hours daily for two months. In mice carrying the Huntington‘s disease
transgene, enrichment delays the onset of behavioral deficits such as loss of motor
coordination, even though neural symptoms such as the formation of striatal inclusion bodies
were not changed (73).
Furthermore, enrichment has been shown to affect memory function and neurogenesis in
mouse strains that are known as poor learners (74). Exposure to an enriched environment
stimulated neurogenesis and improved learning in these mice (38). Taken together, the
findings indicate that an enriched environment may override some genetic constraints.
In attempting to apply the animal model to an understanding of human neuronal
plasticity, Faherty and colleagues (29) noted that idiopathic Parkinson's disease affects at least
2 percent of adults over 50 years of age. These affected individuals demonstrate a progressive
loss of dopamine neurons in the substantia nigra pars compacta (SNpc). One model that
recapitulates the pathology of Parkinson‘s disease is the administration of 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP). These investigators demonstrated that exposure to an

40 Gerry Leisman
enriched environment consisting of a combination of exercise, social interactions and learning

or exercise alone during adulthood, protected against MPTP-induced Parkinsonism.
Furthermore, changes in mRNA expression would suggest that increases in glia-derived
neurotrophic factors, coupled with a decrease of dopamine-related transporters (e.g.,
dopamine transporter, DAT; vesicular monoamine transporter, VMAT2), contributed to the
observed neuro-protection of dopamine neurons in the nigrostriatal system following MPTP
exposure.
Applications of this literature to the human condition have of late been noted. Besides our
extensive review (32), Halperin and Healey (33) have suggested that despite the most
effective and widely used treatments for ADHD being medication and behavior modification.
These empirically supported interventions are rarely maintained beyond the active
intervention. As such, they suggest that it would be highly beneficial if treatments would have
lasting effects that remain after the intervention is terminated. They propose approaches that
employ directed play and physical exercise to promote brain growth which, in turn, could lead
to the development of potentially more enduring treatments for the disorder.
Plasticity as a facilitator of integration
We have described elsewhere at great length (5) and in the chapter in this text by Machado
(75), Persistent Vegetative State (PVS) can be superficially described as eyes-open
unconsciousness first reported by Jennet and Plum in 1972 (76). Eyes open unconsciousness
is dissociation between aware and awake states. The upper brain fails to receive or project
information as well as evidence that exists of a lack of integration between the upper and mid-
brain. The brainstem, however, is generally intact. In the human condition, this state would be
more characteristic of the well-known states of Karen Ann Quinlan, Nancy Cruzan, and Teri
Schiavo.
An individual with PVS demonstrates sleep-wake cycles without the awareness of self or
of others when awake. There appears to be no apparent comprehension or expression of
language, and no sustained and reproducible voluntary or purposeful response to external
stimuli. The individual may demonstrate limb spasticity, but those movements are likely to be
non-purposeful. Reports of some emotive events have been made including smiles and
grimaces but not reproducible response to stimuli.
The cause of injury, co-morbid conditions and the length of time in the vegetative state
determine the recovery from PVS. ―Persistent‖ is defined as duration of greater than one
month (5) or when the cause in non-traumatic (e.g., anoxic brain injury post CPR), a duration
of greater than three months is termed ―permanent.‖ Duration of greater than 12 months post
traumatic injury is considered ―permanent.‖
One might think that the anatomy itself might define a comatose, persistent, or permanent
vegetative state when one sees an individual who is in that state and has the attendant
anatomical or structural involvement. Immediately, additional explanations are necessary to
counter the following situations.
Figure 9A left indicates a CT of a ―normal‖ brain and the rightmost image of 8A
indicates a CT of the well-known Terry Schiavo case indicating hydrocephalus and central
loss of brain tissue. However, Figure 9B represents a CT of a high normally functioning yet

congenitally hydrocephalic female with an anatomical presentation not significantly distant

from that represented in Figure 9A except fort he type of tissue affected.
Figure 9C represents the same young lady‘s rCBF indicating areas of function. The
functional differences between these two cases are likely the result of one case being
congenital and the other being the result of adult-onset trauma.
a)
b)
c)
Figure 9. Does the anatomy define the PVS or is there a case for plasticity? (A) (left) CT of normal
brain (right) Terry Schiavo's 2002 CT showing hydrocephalus and loss of brain tissue. (B) CT of
congenitally hydrocephalic female aged 18 (C) Image of rCBF of congenitally hydrocephalic female
aged 18.

42 Gerry Leisman
An additional view of why the Shiavo case was functionally different than the case of
congenital hydrocephalus reported in Figures 8 is largely a result of connectivities represented
in Figure 10.
Figure 10. Elevated CMRGlc during 3-10 yrs. corresponds to era of exuberant connectivity needed for
the energy needs of neuronal processes. This is greater by a factor of 2 compared to adults. PET scans
show the relative glucose metabolic rate. We also see the complexity of dendritic structures of cortical
neurons consistent with the expansion of synaptic connectivities and increases in capillary density in
the frontal cortex.
The elevated CMRGlc observed during ages 3-10 yrs. corresponds to an era of exuberant
connectivity that is needed for energy needs of neuronal processes. In childhood it is
measurably greater by a factor of 2 compared to adults. PET scans show the relative glucose
metabolic rate. We see the complexity of dendritic structures of cortical neurons consistent
with the expansion of synaptic connectivities and increases in capillary density in the frontal
cortex. During early childhood cross-modal plasticity is more evident (77) with, as seen in
Figure 10, exuberant connectivities between auditory and visual areas that will gradually
decrease in most children between 6 and 36 months of age (78).
PET and fMRI studies have shown that elderly people are more less ―optimized,‖
activating greater regions of the brain than younger individuals for a variety of motor tasks
including simple one. Accuracy is not affected, but the results of greater areas of brain
involved in motor tasks among the elderly is highly associated with increases in reaction time,
with greater surface area activation, and with the recruitment of additional cortical and
subcortical regions as compared to that found in younger individuals (79-81).
In congenitally blind humans, speech processing and auditory localization will activate
the visual cortex (82) and we know that blind human will localize sound better than non-blind

individuals (83). Cerebral organization for language is different in deaf and hearing
individuals. The cortical sensorimotor representation of the reading finger is expanded in
Braille readers (84) and we also know that tactile acuity is superior in the blind (85).
Additionally, the elderly tend to employ bilateral neurological strategies at problem solving as
compared to the young, indicating the development of functional neurological compensatory
strategies at certain type of problem solving and therefore plasticity being evidenced but of a
different kind than that seen in younger individuals.
Exposure to musical training in childhood has been studied extensively as models of
neuroplasticity (86-88). The long-term motor training and continued practice of complex bi-
manual motor sequences are highly associated with changes in brain structure and cortical
motor maps compared with individuals without such training. For example, the anterior
corpus callosum, with fibers connecting frontal motor regions and pre-frontal areas
coordinating bimanual activity is larger in musicians who started training prior to age seven
than in either controls or even in musicians who did not receive the early start (89).
Additionally, auditory experiences during early postnatal development shape the functional
neurology of auditory cortical representation resulting in increased functional areas of the
auditory cortex (90).
The developing brain is far more plastic than the adult brain explaining the results that we
see in recovery of function after brain damage in childhood; neuronal connections are being
continuously remodeled by experience, enrichment, and by performance on specific and
complex movements during motor and cognitive learning. New skill acquisition, present to a
much greater degree in childhood is highly associated with structural changes in the
intracortical and subcortical networks in motor skill training.
Maguire and colleagues (91) provide a clear example of structural plasticity in the normal
adult human brain that furthermore supports the nature of the mechanism of recovery of
function after brain damage. These investigators examined the right posterior hippocampi of
London Taxi drivers after a two year training period in the spatial localization of the streets of
Greater London. They found significant differences when compared to controls of greater
gray matter volume in the right posterior hippocampus to such a degree that they claimed that
the volume increase was proportional to the amount of time in training. This clearly indicates
that we are here not dealing with genetic differences but rather the results of training.
While we are still not clear on the nature of plasticity, but have noted the differences
between, animal, early childhood and human adult models, we do know that strength training
is less related to plasticity than skill learning, the latter indicating cortical reorganization.
Exercise induces angiogenesis but does not alter movement representation in the cortex (92).
We also now know that cortical synaptogenesis and motor map reorganization occur
during late but not during the early phases of motor skill learning with synaptogenesis
preceding motor map reorganization. Motor map reorganization and synapse formation
represent the consolidation of motor skills occurring at the late stages of skill-training but do
not contribute to the initial acquisition of that skill (93).
Plasticity as a solution to adult onset functional disconnections
Figure 10 represents the comparison on rCBF in the left superior temporal gyrus compared
with activity in the left prefrontal cortex and demonstrates areas with more ―efficient‖

44 Gerry Leisman
connectivity with the auditory cortex in individuals with PVS as compared to those with
Minimally Conscious States (MCS). The relationship is presented as representative of the
concept of functional disconnection and follows from the notion earlier reported by Leisman
and Ashkenazi (94) and reviewed by Leisman and Melillo (95).
We therefore see PVS as a functional disconnection syndrome represented in a way
similar to neonatal normal activation and similar to our functional disconnection syndromes
(e.g., autism) (96, 97). There also exists in PVS a non-activation of higher-order association
cortices, with impaired functional connections between distant cortical areas, including the
thalamus and cortex, with the recovery of consciousness paralleled by the restoration of
cortico-thalamo-cortical interaction.
We can actually see these functional disconnectivities in sleep (98). In sleep, brain areas
loose ability to communicate with each other as compared to awake subjects who create
responses in different destinations unlike sleep subjects who are more likely to create
responses to single or fewer destinations. Reduced brain consciousness is associated with
breakdown into non-coherent activity. Consciousness then could be considered to be the
ability of the brain to integrate information with consciousness being the coherent
communication between brain areas. PVS as well as all other neurological dysfunctions that
relate to functional disconnectivities seems to be a compromise in that integration process.
The unity of consciousness is based on a ―centrencephalic system‖ that includes the
reticular formation and thalamus. While it is not known which portions of the brain are
responsible for cognition and consciousness; what little is known points to substantial
interconnections among the brainstem, subcortical structures and the neocortex. Thus, the
'higher brain' may well exist only as a metaphorical concept, and not in reality. The role of
cortex allows for the interface between world, the individual‘s body and the conscious self as
well as well as in the integration of sensory input and motor output. Functional
disconnectivities represent the behavioral traits observed and reconnection may be
engineered.
To emphasize this point, we can provide a gedanken experiment on the so-called Sprague
Effect (99). The complete removal of posterior visual areas of a hemisphere in the cat (parietal
areas too) renders the animal profoundly and permanently unresponsive to visual stimuli in
the half of space contralateral to the cortical tissue removal. The cat is blind in the same way
as would a human with radical damage to the geniculostriatal system. If one were then inflict
additional damage on such a severely impaired animal at midbrain level, then the ability of
the cat to orient and localize stimuli in the formerly blind field would be restored. This would
be accomplished by removing the contralateral superior colliculus or by severing fibers in the
central portion of the collicular commissure. Adding damage in the brainstem to the cortical
damage ―cures‖ a behavioral effect of massive cortical damage. Similarly, in the auditory
system, unilateral ablation of auditory cortex results in severe sound localization deficits, as
assessed by acoustic orienting, to stimuli in the contralateral hemifield. Sprague and
colleagues (100) found that auditory orienting responses can also be restored into the
impaired hemifield during deactivation of the contra-lesional superior colliculus.
The Sprague Effect is a consequence of secondary effects generated at the brainstem level
by unilateral cortical removal. The damage deprives the ipsilateral superior colliculus of its
normal cortical input. Damage unbalances collicular function via indirect projection
pathways, those chiefly from the substantia nigra to the colliculus, which cross the midline in
a narrow central portion of the collicular commissure. The ―restorative‖ interventions

partially correct this imbalance, allowing the collicular mechanism to resume at least part of
its normal functional contribution to behavior, with partial restoration of vision as a result.
Minimally Conscious States (MCS), plasticity and functional disconnection
MCS has recently be shown to be alterable by physiological manipulation providing us with

an additional gedanken experiment this time on elucidating the nature of MCS with deep
brain stimulation. Electrodes receive pulses from pacemaker surgically placed (101) under the
skin of patient‘s chest. Electrodes transmitted pulses from pacemaker to thalamus, for 12
hours after which the patient became significantly more alert and aware and had the capacity
to express pain return. The individual reportedly kept his eyes open most of the time during
the day and followed others with his eyes as they moved. The MCS patient, according to
Schiff and colleagues communicated reliably with gestures and audible phrases of up to six
words. He also took all meals orally and drank from a cup.
Schiff and colleagues have assumed and we support the notion that widespread loss of
cerebral connectivity is assumed to underlie the failure of brain mechanisms that support
communication and goal-directed behavior following severe traumatic brain injury. We know
(5) that disorders of consciousness persisting for longer than 12 months are considered to be
immutable and no treatment is likely to accelerate recovery or improve functional outcome.
Schiff and colleagues have shown otherwise. Recent studies have demonstrated unexpected
preservation of large-scale cerebral networks in patients in MCS indicating residual
functional capacity in some that could be supported by therapeutic interventions. These
individuals were thought by Schiff‘s group to be limited by chronic under activation of
potentially recruitable large-scale networks. Schiff and colleagues had demonstrated that in a
6-month double-blind alternating crossover study, bilateral deep brain electrical stimulation
(DBS) of the central thalamus modulated behavioral responsiveness in a patient who
remained in MCS for 6 years following traumatic brain injury before the intervention.
The frequency of specific cognitively mediated behaviors (primary outcome measures)
and functional limb control and oral feeding (secondary outcome measures) increased during
periods in which DBS was on as compared with periods in which it was off. Logistic
regression modeling demonstrated a statistical linkage between the observed functional
improvements and stimulation history.
Neglect, plasticity, and functional disconnection
Individuals with right hemisphere damage often show signs of left unilateral neglect, an
inability to take into account information coming from the left side of space (102-104).
Neglect patients do not eat from the left part of their dish, they bump with their wheelchair
into obstacles situated on their left, and when questioned from the left side they may either
fail to answer or respond to a right-sided bystander. When presented with bilateral stimuli,
they may immediately look toward the rightmost stimulus, as if their attention were
―magnetically‖ attracted (105).
Most studies of the anatomical basis of neglect indicate involvement of the temporal–
parietal junction (TPJ) and the inferior parietal lobule (IPL) (106), consistent with the role of

46 Gerry Leisman
the posterior parietal cortex in spatial attention (107). Other investigators have implicated
more rostral portions of the superior temporal gyrus (108), emphasizing the importance of the
ventral visual stream in spatial awareness originally hypothesized by (109). Still others have
indicated the involvement of yet other brain structures in neglect including the thalamus, the
basal ganglia, and the dorsolateral prefrontal cortex (108). However, at variance with
interpretations of neglect stressing the role of damage to local brain modules, it has long been
proposed that attentional spatial processes that may be disrupted in neglect do not result from
the activity of single-brain areas but rather emerge from the interaction of large-scale
networks (102, 103). If so, then damage to the connections making up these networks is
expected to impair their integrated functioning and consequently bring about signs of neglect.
Within each hemisphere, large-scale cortical networks coordinate the operations of
spatial attention (102, 110). Important components of these networks include the dorsolateral
prefrontal cortex and the posterior parietal cortex.
Physiological studies indicate that these 2 structures show interdependence of neural
activity. In a groundbreaking study in the monkey (111), showed that severe neglect may
arise after a unilateral section of the white matter between the fundus of the intraparietal
sulcus and the lateral ventricle, interrupting long-range communication pathways between the
parietal and the frontal lobes. Analogous findings have been reported in humans (112), where
the anatomical correlates of neglect were investigated in a large sample of right brain–
damaged patients not selected for the presence or absence of concomitant visual field defects.
Figure 11. Functional disconnectivities in PVS and MCS. MCS states have less functional
disconnectivity.
These authors found that the main correlate of chronic neglect was the combined lesion
involvement and hypofunctioning of fibers connecting the parietal and temporal lobes (ILF),
as well as those linking the parietal and frontal lobes (SLF), loaded in the white matter
beneath the TPJ reflected in computed tomography (113) provided compelling evidence from
individuals awakened during surgery for resection of low-grade gliomas. Neurosurgeons
often awaken patients in order to assess function and minimize cognitive impairment,
allowing investigators to map cognitive functions in humans with unrivaled spatiotemporal
resolution (∼5 mm by 4 s).
The authors asked two patients with gliomas in the right temporoparietal region to mark
the midpoint of 20-cm horizontal lines. The electrical stimulation of either the right IPL or the

caudal STG but not its more rostral portions determined rightward deviations on a line
bisection task. The strongest shifts occurred when one of the patients was stimulated
subcortically. The authors concluded that damage to the frontoparietal pathways is important
in produce neglect, consistent with the postulated role of this pathway in space perception
(114). The pathways alluded to are exemplified in Figure 12 below.
The demonstration of the role of frontoparietal disconnections in neglect supports models
of neglect postulating impairment of large-scale right hemisphere networks (118), including
prefrontal, parietal, and cingulate components. The parietal component could determine the
perceptual salience of extrapersonal objects, whereas the frontal component might be
implicated in the production of an appropriate response to behaviorally relevant stimuli (118),
in the online retention of spatial information (119) or in the focusing of attention on salient
items through reciprocal connections to more posterior regions (120). As a consequence of
frontoparietal disconnection, inaccurate or slowed communication between posterior and
anterior brain regions, whether coupled or not with a general deficit in responding to
unattended stimuli, might also delay the information transfer from sensory-related areas to
response-related regions to the point of exceeding an elapse of time after which this
information is no longer useful for affecting behavior (121).
Figure 12. Lateral view (A) and coronal sections (B) of a normalized brain showing a 3-dimensional
reconstruction of white matter pathways (red, corpus callosum; dark blue, AF; orange, SLF III; blue,
SLF II) and the maximum overlap of neglect patients' subcortical lesions from 4 studies (pink, (115);
yellow, (106); light blue, (108); green, (116) all after (117).

48 Gerry Leisman
How functional disconnection manifests clinically
The huge number of neurons in the human brain is connected to form functionally specialized
assemblies. The brain's amazing processing capabilities rest on local communication within
and long-range communication between these assemblies. Even simple sensory, motor and
cognitive tasks depend on the precise coordination of many brain areas. Recent improvements
in the methods of studying long-range communication have allowed us to examine the
common mechanisms that govern local and long-range communication and how they relate to
the structure of the brain? How does oscillatory synchronization subserve neural
communication? And what are the consequences of abnormal synchronization or functional
disconnection?
While it is not the purpose to provide an exhaustive overview of the broad clinical
ramifications of functional disconnection syndromes here, an excellent example is provided
by alexia without agraphia following stroke as represented in Figure 13.
Figure 13. Alexia without agraphia: A classical disconnection syndrome.

Figure 14. Average processing speeds and response latencies for a visual stimulus requiring a choice
and a button push response.
Alexia without agraphia has also been termed pure agnosic alexia or pure word blindness
resulting from a disruption of the splenium and associated with a right homonymous
hemianopsia. It is characterized by deficit in word but preservation of letter reading. Such an
individual is able to write spontaneously, but cannot read what has been written. The
individual can identify words spelled aurally and number reading may be preserved.
We have examined elsewhere the relationship between general neurological dysfunction
as manifested in autistic spectrum disorder (95) and non-intuitive associations with Persistent
Vegetative and Minimally Conscious States. All share commonality with normal neonatal
activation. All have activation of primary cortices but non-activation or dysfunctionality of
higher-order association cortices, and all demonstrate impaired functional connections
between distant cortical areas and the impairment in connectivities between the thalamus and
cortex. All may theoretically have plastic changes associated with enrichment, skill training
or recovery paralleled by restoration of cortico-thalamo-cortical interaction.
Impairment in the function of networks is often most easily measured by increases in
response time. This is most obvious in the word finding latency reported in dyslexics (122),
disorders of conduction velocity in clinical electromyography, sensory evoked response
latency changes and so on.
Processing speeds as well as response latencies are well documented and one such
example is provided in Figure 14. A visual stimulus that requires a choice and a button push

50 Gerry Leisman
response, for example, involves pathways from the primary visual cortex to the prefrontal
cortex to the premotor and primary motor cortices then to spinal motor neurons and ultimately
to the muscles in the finger. That choice is related to higher cognition function (learning
experience, memory, planning) is self-evident.
Another condition in which the notion of functional disconnection plays an important role
with a resultant network disruption is amyotrophic lateral sclerosis (ALS). Seeley and
colleagues (123) have shown a direct and potentially unique correlation between disease and
affected brain networks, and thus suggest that disease state can be characterized by
quantitative descriptors of network metrics such as functional connectivity.
Resting-state functional connectivity analysis has identified ten prominent networks.
(124) Mohammadi and associates (125) examined five of these, including the default mode,
sensorimotor, parietal–temporo-frontal, posterior, and ventral networks, using independent
component analysis (ICA) in patients with ALS. Sensorimotor network differences were
observed, showing decreased functional connectivity in the premotor cortex.
Jelsone-Swain and colleagues (126) demonstrated an overall reduced functional
interhemispheric connectivity between parceled motor cortices in the M1 network in ALS
patients. Additionally, a pronounced difference was observed between groups in the dorsal
half of the motor cortex – the half that corresponds to limb and trunk body regions of the
homunculus. It was found that the greater the disparity between right and left hand strength,
the less functionally connected ROIs were in the dorsal motor cortex. Additionally, reduced
functional connectivity was found in the prefrontal cortex, posterior/ventral-anterior areas of
the cingulate cortex, and bilateral inferior parietal cortices, hence demonstrating decreased
functional connectivity between core regions of the default mode network.
Rowe et al. (127) studied attention to action in individuals with Parkinson‘s disease by
functional MRI (fMRI) during performance of a simple paced overlearned motor sequence
task, with and without an additional attentional task. Structural equation modeling of fMRI
time series was used to measure effective connectivity among prefrontal and premotor areas.
In both Parkinson‘s and controls, the motor task was associated with activation of a
distributed network including the premotor, motor and parietal cortex, striatum and
cerebellum. In control subjects, but not patients, attention to action (relative to execution of
an overlearned sequence) was associated with further activation of prefrontal, parietal and
paracingulate cortex, and the supplementary motor area (SMA). Parkinson‘s individuals
showed greater than normal activation of the SMA during execution of the simple
overlearned motor sequence, but less augmentation when attending to their actions. In control
subjects, attention to action, but not attention to the visual distractor task, increased the
effective connectivity between prefrontal cortex and both the lateral premotor cortex and the
SMA. These findings represent a specific increase in effective connectivity. Attentional
modulation of effective connectivity between the prefrontal, premotor cortex and SMA was
not observed in patients. This deficit indicates a context-specific functional disconnection
between the prefrontal cortex and the supplementary and premotor cortex in Parkinson‘s
disease.
Elliot (128) noted that while executive processing is intimately connected with the intact
function of the frontal cortices, attempts to link specific aspects of executive functioning to
discrete prefrontal foci have been inconclusive. She suggested that executive function is
mediated by dynamic and flexible networks that can be characterized using functional
integration and effective connectivity analyses. She adds that while the neuropsychological

literature converges on the view that successful performance on tests of executive function is
critically dependent on the frontal cortex, the terms ‗executive‘ and ‗frontal lobe‘ function are
often used synonymously. However, recent theories have suggested that this view is
simplistic and subcortical regions may also be critically involved. Neuropsychological
deficits of patients with Parkinson's disease, for example, suggest that striatal structures play a
role in the mediation of executive processes. Unsurprisingly, it appears that these complex
processes are subsumed by distributed circuitry rather than discrete structures.
The disorder where executive dysfunction has been most extensively studied using
functional imaging is probably schizophrenia. There have been many studies demonstrating
hypofrontality associated with executive impairments in schizophrenia, although many of
these studies are plagued by confounds (129). In the absence of a clear focal pathology,
theories of disordered connectivity in schizophrenia are particularly appealing (130).
Prefrontal disconnectivity has also been associated with verbal fluency (131) and working
memory (132). Neuroimaging evidence for impaired connectivity has provided the insights
that underpin a new generation of neuropathological and neurodevelopmental theories of
schizophrenia (133, 134).
The dynamic network approach to understanding executive function also has implications
for understanding how the brain recovers from trauma. Executive function is frequently
compromised as a result of brain injury, but, like language and motor functions, executive
functions may recover to at least some extent. Functional imaging provides an exciting tool to
study recovery. Both PET and fMRI have been used to demonstrate that there is extensive
functional re-organization following a head injury or stroke (135, 136). Neighboring or
contralateral regions may be recruited to subserve the original function; the extent to which
this occurs is dependent on age, neurological status and exact task demands (137). The
processes of recovery and reorganization are conceptually more plausible in a dynamic and
flexible network model.
The question emerges of whether it is possible to ―jump-start‖ reconnectivities that will
ultimately have plastic effects of brain function after a cerebral insult or dysfunction.
Overly developed functional connectivities explained by integrated

control networks
In attempting to answer the question, we might want to look at ―disorders‖ of sensory

integration where independent sensory systems tend to leak into each other. While
localization of function is a widely accepted principal of brain organization leading,
developmentally to ―optimized‖ performance, it is not the only principle of brain
organization. Due to the requirement for integration, networks of activity are necessary to
allow for the organism to function quickly and efficiently. This principle of integration we
term functional connectivity. At times, increased crosstalk between regions specialized for
different functions may account for a condition called synesthesia.
Some, for example, create an additive experience of seeing color when looking at
graphemes. This may well be the effect of cross-activation of the grapheme-recognition area
and the V4 color area of the occipital cortex (138). This and similar effects may be the result
of a failure to prune synapses that are normally formed in great excess during the first few
years of life as indicated earlier in Figure 10.

52 Gerry Leisman
An alternate possibility is disinhibited feedback, or a reduction in the amount of

inhibition along normally existing feedback pathways (139). Normally, excitation and
inhibition are balanced. However, if normal feedback were not inhibited as usual, then signals
feeding back from late stages of multi-sensory processing might influence earlier stages such
that tones could activate vision. Cytowic and Eagleman find support for the disinhibition idea
in the so-called acquired forms (140) of synesthesia that occur in non-synesthetes under
certain conditions: temporal lobe epilepsy, head trauma, stroke, and brain tumors. It can
likewise occur during stages of meditation, deep concentration, sensory deprivation, or with
use of psychedelics such as LDS or mescaline, certain prescription medications or even, in
some cases, marijuana.
Functional neuroimaging studies using PET and fMRI demonstrate significant
differences between the brains of synesthetes and non-synesthetes. fMRI shows V4 activation
in both word-color and grapheme-color synesthetes (141-143). Diffusion tensor imaging
allows visualization of white matter fiber pathways in the intact brain. This method
demonstrates increased connectivity in fusiform gyrus, intraparietal sulcus and frontal cortex
in grapheme-color synesthetes (144).
The degree of white matter connectivity in the fusiform gyrus correlates with the
intensity of the synesthetic experience.
Autism and epilepsy occur with synesthesia more often than chance predicts. Daniel
Tammet, the savant who set a European record for reciting the digits of pi, has all three
conditions indicating that they might share an underlying genetic cause. Synesthesia has so
far been linked to a region on chromosome 2 that is associated with autism and epilepsy
(145).
Figure 15. Multisensory disintegration and the temporo-parietal junction.

If there existed a localized cortical region responsible for integration, and by extension, in
its dysfunction responsible for some types of functional disconnection and again by
extension, compromises to some forms of plasticity, then it would be likely the temporo-
parietal junction or TPJ a core region of vestibular cortex situated at the TPJ including the
posterior insula.
The TPJ is implicated along with cortical areas along intraparietal sulcus in combining
information from tactile, proprioceptive, and visual input in coordinated reference frames.
The TPJ permits perception of the entire body and its parts, biological motion, and mental
body self-imagery proving its role in multisensory perception. The TPJ is responsible for
egocentric visuo-spatial perspective taking, agency, and self-other distinction. Figure 15
indicates the TPJ‘s role in a variety of important integrative functions.
Deep brain stimulation jump-starts functional connectivities
Deep brain electrical stimulation (DBS) has become a recognized therapy in the treatment of
a variety of motor disorders and has potentially promising applications in a wide range of
neurological diseases.
It has been variously observed that electrical high-frequency stimulation of a given brain
area induces an effect similar to a lesion suggested a mechanism of functional inhibition. In
vitro and in vivo experiments as well as intra-operative recordings in patients have revealed a
variety of effects involving local changes of neuronal excitability as well as widespread
effects throughout the connected network resulting from activation of axons, including
antidromic activation. This methodology has been applied to individuals with Parkinson‘s
disease employing high-frequency stimulation of the subthalamic nucleus with the result of
motor restoration.
Houeto and Colleagues (146) reported in an ―N = 1‖ study, a patient with a severe form
of Tourette‘s syndrome treated with bilateral high frequency stimulation of the centromedian-
parafascicular complex (Ce-Pf) of the thalamus, the internal part of the globus pallidus (GPi),
or both. Stimulation of either target improved tic severity by 70%, markedly ameliorated
coprolalia, and eliminated self-injuries by the stimulation of neuronal circuits within the basal
ganglia, confirming the role of the dysfunction of limbic striato-pallido-thalamo-cortical
systems. Ackermans and associates (147) also described the effects of bilateral thalamic
stimulation in one patient and of bilateral pallidal stimulation in another patient. Both patients
suffered from intractable Tourette‘s syndrome. Electrodes were implanted at the level of the
medial part of the thalamus (centromedian nucleus, the substantia periventricularis, and the
nucleus ventro-oralis internus) in one patient and in the posteroventral part of the globus
pallidus internus (GPi) in the other patient.
In both cases, deep brain stimulation (DBS) resulted in a substantial reduction of tics and
compulsions. Servello et al. (148) also reported on 18 cases of Tourette‘s treated by DBS.
DBS was placed bilaterally in the centromedian–parafascicular (CM–Pfc) and ventralis oralis
complex of the thalamus. The comorbid symptoms of obsessive–compulsive behavior,
obsessive–compulsive disorder, self-injurious behaviors, anxiety and premonitory sensations
decreased after treatment with DBS.
DBS has also been applied to individuals suffering from dysfunctional network function
implicated in major depression.

54 Gerry Leisman
Figure 16. Location of nucleus accumbens and position of deep brain stimulation electrodes. (a)
topographical location of the nucleus accumbens in relation to other brain structures on a horizontal
plane 3 mm below the AC-PC plane. (b) The location of the lowest contact of the stimulation electrode
in a horizontal and coronal plane with projections of the left (green) and right (yellow) electrode path in
the surgical planning stage. Stereotaxic coordinates are 1.5 mm rostral to the anterior edge of the
anterior commissure, measured at the crossing point, 4 mm ventral and 7–8 mm lateral of the midline of
the third ventricle. Burr holes were placed deep fronto-laterally. (c) The actual location of the electrode
leads in the post-operative control X-ray. (From Schlaepfer et al., 2007) (149).

Figure 17. One week after onset of bilateral stimulation to the nucleus accumbens, metabolism in a
distributed network of limbic and prefrontal brain regions was altered. Increases in metabolism
following stimulation (shown in yellow) were observed in the nucleus accumbens, amygdala,
dorsolateral, and dorsomedial prefrontal cortex. Decreases in metabolism (shown in blue) were
observed in medial prefrontal cortex and caudate. Graphs on the right display normalized PET units
from each subject from before and after implantation in the nucleus accumbens (NAcc), the medial
prefrontal cortex (mPFC), and the dorsal cingulate cortex (dCC). (From Schlaepfer et al., 2007) (149).
A clinical feature of depression is anhedonia—the inability to experience pleasure from

previously pleasurable activities—and because there is clear evidence of dysfunctions of the
reward system in depression, DBS to the nucleus accumbens was applied in treatment-
resistant depressive individuals. Three patients suffering from extremely resistant forms of
depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive
therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens.
Clinical ratings improved in all three patients when the stimulator was on, and worsened
in all three patients when the stimulator was turned off. Effects were observable immediately,
and no side effects occurred in any of the patients. Using FDG-PET, significant changes in
brain metabolism as a function of the stimulation in fronto–striatal networks were observed.
The methods are represented in Figure 16 and the results in Figure 17.
CONCLUSION
Nervous system function can be changed by many manipulations, perturbations, and stressors
that include enrichment, experience and learning, direct brain stimulation, hormones, stress,

56 Gerry Leisman
trauma and virtually any repetitive stimulus impinging upon the organism. In the negative,
disease, injury, disease, drugs, and developmental disorders likewise are mediated by
neuroplasticity.
While we have not successfully explained how neuroplasticity functions we have
demonstrated that it does. Principles that allow us to describe the nature of the process include
―kindling‖ that describes a progressive increase in neural responsivity that result in either
response potentiation or response damping.
Another principal of neuroplasticity involves a kindling-like increase in one modality
seems to transfer among neural structures. Some of these responses may be adaptive while at
other times may be maladaptive. For example a ―stress response may be associated with
―fight or flight mechanisms‖ that includes immune changes in one situation, beneficial with
the stressor being an infectious agent, or maladaptive in a traffic jam.
Homeostatic regulation acting to balance Hebbian plasticity preventing neural
dysfunction involves as we had indicated earlier the scaling up or down of synaptic
connection strengths to preserve previously encoded relative differences in strengths and in
the control of intrinsic excitability of the neural continuum.
There seems to exist both feed-forward and feedback systems. Responses to the sensory
environment and experience can affect genetic mechanisms to potentially change gene
expression and thus give expression to epigenetic phenomena in brain organization and
function. Those levels both directly above and below the others can act upon any given level
of brain function.
The alteration of neural activity generated at any level is a ―perturbation‖ in that activity
that can be either acute or chronic, reflecting either internally or externally generated stimuli.
These perturbations can be responses to beneficial stimuli leading to learning or the effects of
pathological stressors. They can be activity-dependent producing long-term modifications of
neural activity by restructuring relationships among levels of organization. Alternatively,
artificially induced perturbations, such as deep brain stimulation can induce a response
potentiation (e.g., Long Term Potentiation or ―kindling‖) that might not normally be
maintained but occurs because the circuit is ―tricked‖ by overriding the normal inhibitory
feedback mechanisms.
The relative strength of any perturbation will depend on relevance to the individual.
Therefore diffuse stimuli (e.g., multisensorial) will be associated with inhibition diminishing
the strength of the perturbation. In contrast, focused relevant stimuli (e.g., visual object
identification matched with hand movement) will be associated with reinforced neural
associations and will therefore be reinforcing rather than inhibitory.
Therefore a narrow path of activity achieves the specificity of neural modification across
levels. The more focused the trajectory, the greater the specificity and ability to bypass
homeostatic mechanisms and to be able to traverse levels. Wider trajectories, on the other
hand, will be more likely to generate negative feedback within and across levels.
Related to the issue of plasticity and age, neural instructions in early child development
are more widespread across the CNS than those arising in the adult CNS. The trajectory is
wider in childhood than in adulthood affecting large numbers of neurons (e.g., instructions for
synaptogenesis). The fewer inhibitory mechanisms of the developing brain and nervous
system would allow wider trajectories to alter circuitry more easily in the younger than in the
adult brain. Alternatively, alterations in the adult CNS would have a narrow trajectory

regulated by the already well developed inhibitory mechanisms that impact on specific and
limited numbers of neurons.
The spread of activity within and across levels will depend on the balances of positive
and negative feedback among elements. Weaker alterations in activity will be damped by
homeostatic mechanisms. More appropriate or stronger alterations will propagate by
overcoming lateral inhibition in any single level. This lateral inhibition will limit lateral
spread more within rather than across levels.
The longevity of any potential modification depends on stimulus strength and by the
reinforcement from other levels that would include: durability, number of repetitions, or
strength of the inducing stimulation. We have learned that during early development, genetic
information contributes more than environmental in the neuronal sprouting, arborization, and
synaptogenesis. Existing though are critical periods when neuroplastic modifications are
greatest that environmental influences can combine with the laid-down genetic instructions
providing long-term modifications in neural activity. It is during these critical periods that we
have a relevant peak of synaptogenesis and receptor proliferation, both regulated by external
stimuli. It is up to these critical periods that inhibitory feedback mechanisms remain relatively
weak providing less homeostatic feedback. The greater number and contributions of larger
brain areas driving and maintaining changes in the developing CNS that may in part explain
why the brains of children demonstrate greater plasticity than those of adults as indicated
earlier.
So, the level of recovery that can be attained appears to be age-dependent, differing from
the adult CNS in the amount of reorganization possible. Such age dependent factors are
highly associated with the extent of the exuberant connectivities present (see Figure 10). It is
beyond this point that a framework for ―jump-starting‖ connections may be evidenced with
both the ―Sprague effect,‖ ―enrichment,‖ and with deep brain stimulation.
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Chapter 4
PERSISTENT PRIMITIVE REFLEXES AND CHILDHOOD

NEUROBEHAVIORAL DISORDERS
Robert Melillo, PhD

Persistent primitive reflexes have been noted in a number of neurobehavioral disorders

and are thought to be related to delayed or absent developmental milestones in this
population of children. This is also associated with the presence of clumsiness,
incoordination, awkward posture, gait and other motor disturbances. The degree of motor
incoordination seems to be related to cognitive dysfunction as well. ADHD, autism,
dyslexia as well as almost all neurodevelopmental disorders have been associated with
anatomical and functional effects that correlate with the motor incoordination, motor
disturbance, cognitive delays and the presence of persistent primitive reflexes. For some
time researchers have debated if the structural anatomic and volumetric differences in
disorders such as ADHD and autism represent deviant developmental changes or whether
they reflect a maturational delay. We review the literature that clearly demonstrates that
these disorders and the structural differences represent cortical maturational delays not
deviant development. We also note that persistent primitive reflexes are the earliest
markers for this delay and that this delayed maturation will eventually lead to the
presence of autism, ADHD, and other neurobehavioral disorders. We also note that these
disorders and their recent reported increased incidence is related to a combination of
genetic and epigenetic factors mostly driven by environmental and lifestyle changes
affecting early motor development, sensory stimulation and activity dependent
synaptogenesis and neuroplasticity. Symptom variations between these neurobehavioral
disorders may be related to asymmetrical maturational differences resulting from
different rates of maturation of the right and left hemisphere. Asymmetric persistent
primitive reflexes may also be an early marker related to this maturational imbalance.
This abnormal pattern of hemispheric asymmetry may lead to desynchronization,
underconnectivity, and ultimately a functional disconnection between regions of the brain
and cortex. Lastly we comment of the possibility of exercises that can inhibit and

Correspondence: Dr. Robert Melillo, The National Institute for Brain and Rehabilitation Sciences, Biomechanics
Laboratory, ORT-Braude College of Engineering, Snunit 51 Street, POBox 78, IL-21982 Karmiel, Israel. E-
mail: drrm1019@aol.com.

66 Robert Melillo
remediate persistent primitive reflexes as one possible target for early treatment of these
disorders.
INTRODUCTION
ADHD is thought to be the most prevalent childhood disorder. In 2010 the National Institute
of Mental Health stated that ADHD is the most prevalent mental disorder among the youth in
the US (1). The US Center for Disease Control recently stated that ADHD now affects 10%
of all children in the United States (2). Although some of the increased prevalence may be
related to changes in diagnostic criteria and increase awareness that is not sufficient to explain
the geometrically increased incidence. Autism two decades ago was diagnosed in 1-10,000
children, most recent statistics from the CDC now stated the prevalence as 1-110 or 1% of the
population (2). Although some genetic differences have been identified between ADHD and
non-ADHD children, these differences are only present in a relatively small percentage, the
relationship to ADHD symptoms has not been demonstrated, and their mechanisms of action
is speculative at best (3). For the vast majority of cases of ADHD and autism there is no clear
genetic cause. Although ADHD and autism both seem to have a relative high concordance
within families, many researchers think that environmental epigenetic influences are the
primary driving forces behind the rapid increase in ADHD and other neurobehavioral
disorders such as autism, Tourette‘s and others (3).
Recent research has attempted to clarify whether specific differences in the size and
function of the brains of those with ADHD and autism are related to deviant developmental
changes or whether they reflect a maturational delay (4). In this chapter we review the
literature in regard to this question and identify other markers of development, specifically
persistent primitive reflexes and delayed or absent motor milestones, that might reflect
maturational delay. We will also identify particular targets of therapeutic intervention based
on these markers. We will also discuss this maturational delay and its relationship to the
concept of functional disconnection, which we hypothesize to be the neurophysiologic
mechanism associated the symptoms of ADHD.
Human executive functions are unique among all organisms. Humans have achieved a
level of ―intelligence‖ which is reflected in self-consciousness or self-awareness beyond the
degree achieved by other species. These unique cognitive abilities do not appear to be a
product of genetic differences since we share 85% of the same genes as mice and 99% of the
same genes as chimpanzees yet our cognitive abilities or intelligence is arguably
exponentially different than that of a chimpanzee. Many neurobehavioral disorders of
childhood are thought to be partly the result of the delayed maturation or development of
executive functions. Tannock and Schachar (5) note, ―that there is a growing consensus that
the fundamental problems in (ADHD) are in self-regulation and that ADHD is better
conceptualized as an impairment of higher-order cognitive processing known as (executive
function).
What is clear in the literature is that the main functions that are affected have been termed
executive functions and it is known that executive functions seem to primarily reside in the
frontal lobes. In fact, ADD is considered a name for a spectrum of deficits of cognitive
executive functions that may respond to similar treatments and are often comorbid with a
wide variety of psychiatric disorders, many of which may also be spectrum disorders.

Persistent primitive reflexes and childhood neurobehavioral disorders 67
Therefore understanding how executive functions arose through the course of evolution
may provide insight as to why delays in development may occur during the course of
childhood. Ontogeny recapitulates phylogeny, also known as the ―Biogenetic Law‖ was
proposed by Ernst Haeckel in 1866. Although this theory has been discredited there are many
similarities between development of the human brain during childhood and its development
during the course of evolution. To explore this concept further we must explore the question,
when and how brains developed the way that they did through the course of evolution which
can then provide insight into the developmental aspects of the human brain and its executive
functions.
According to Llinaes (6, 7), brains and a nervous system are only necessary for
multicellular creatures that can orchestrate and express active movement, a biological
property known as (motricity). For movement to be beneficial it must be purposeful or goal
directed otherwise it will not be beneficial and will not be selected out by natural selection.
Once one moves, one must make a choice to move either toward or away requiring a choice
which requires some level of prediction. For movement to purposeful and beneficial it must
be able to predict the outcome of movement before it occurs. This requires what we refer to as
thinking. Prediction or goal directed behavior is thought to be the foundation of all executive
function. Approach or avoidance is the foundation of all behavior and has been present from
the very beginning; this is the beginning of asymmetry in the brain. There is a simple rule in
evolution: simple movement simple brains, complex movement complex brains.
Movement allows us to interact with the environment in more sophisticated ways and can
help improve our chances of survivability. Interacting with the environment in a purposeful
and beneficial way requires the development of sensory organs which supply us with
information about our environment allowing us to negotiate our environment and develop a
sensory motor map of the world that we can use as the basis of prediction and goal directed
adaptive behavior.
As we interact with our environment developmentally in progressively more
sophisticated ways, we develop our sensory systems through feedback with the outside world.
This in turn will activate genes that will cause activity-dependent neuronal plasticity
increasing the size, complexity and integration of the brain to allow for a more accurate
picture of the environment and more accurate predictions of the outcome of movement
allowing for greater survivability. The nature of the relation of enrichment on plasticity has
been more fully described in another paper by Leisman (8) in this issue.
Organisms developed brains because they moved and as they moved they interacted with
their environment. Human beings, as a species, have a large brain that is capable of a high
cognitive intelligence, and an upright body position that is propelled by bipedalism. Walking
upright allows for less leeway in size and structure in the human pelvis than exists for those
animals that walk on all fours. Large headed infants are born to mothers with relatively
constrained birth canals. If both mother and neonate are to survive the birth process
unscathed, the infant's brain cannot be fully developed in size or complexity at birth. No
matter how precocious we may fancy that our children are, no human infant is as precocious
as a horse's newborn foal or a duckling recently hatched, that can run or swim when only
hours old, humans are unable to do much more than feed and interact with their caregivers
until after several months of life have passed.
Our newborn skull is only a quarter the size that it will become in the adult. It weighs
approx. 370 grams at birth and will nearly triple to 1080 grams by age 3, and quadruple to

68 Robert Melillo
1350 grams by six to 14 years. ―The brain comprises 100 billion neurons at birth, with each
neuron developing on average 15,000 synapses by 3 years of age‖ (9). Much of the growth of
the brain; and the concomitant expansion of the head will have occurred by the age of 2 years
at which age the cranium is 75% of its adult size and volume, and the brain is about 80% of
its adult weight. By approximately 10 years of age, the brain (and skull) reaches
approximately 95% their ultimate adult size. Overall, the human brain more than triples in
size from birth to adulthood. Therefore, humans are born with considerably less than their
ultimately fully developed brains. Our brains are ―built‖ during child and adolescent
development.
To stimulate growth and development of the brain an infant needs to be able to move and
interact with his environment. However, the process of movement is impeded by a brain and
nervous system that is not effectively developed at birth and when little functioning motor
cortex exists that can control volitional movement. What makes some volitional movement
possible are the infantile ―primitive reflexes‖ already intact at birth that allow for reflexogenic
movement and interaction with the environment in basic ways that help increase the chances
of survival. These reflexes appear prenatally and are thought to aid in the birth process. Most
of these reflexes are present at birth and then become inhibited within the first few months
with the longest (the plantar reflex) remaining until the end of the first year post-natally.
These reflexes allow for basic reflexogenic movement thought to contribute to early motor
milestones such as rolling over, creeping, crawling, grasping, sucking and eventually
crawling and walking.
Postural reflexes that allow for more sophisticated individualized movements are
themselves replaced with voluntary movement. Primitive reflexes allow for basic movements,
which allow for simple interaction with the environment and form the basis of early
movement. This movement allows the infant to interact with his environment and engages
and stimulates his sensory organs and receptors. This increase in sensory feedback and
stimulation is thought to result in the expression of genes that are related to protein synthesis
and the building of functional connections and the stimulation of glial cell proliferation and
increasing the size and connectivity of neurons (10). As neurons grow in size, density and
connectivity they will eventually inhibit, through propriospinal projections, lower or more
primitive areas of the brain and will stimulate the growth and activation of higher more
sophisticated areas in higher and higher rostral areas of the brainstem and cortex (11).
Primitive reflexes eventually become inhibited but they are never completely eliminated.
Eventually all reflexes seem to come under control of the frontal lobe (12).
In patients with frontal lobe damage, dysfunction, or degeneration there is often the
reappearance of primitive reflexes known as frontal release signs (12). Upper motor lesions
also often result in the reappearance of primitive reflexes such as the Babinski reflex or
plantar reflex. This is thought to be due to the loss of the inhibitory descending connections
from the cortical spinal tract, which is a reflection of the maturation and growth of the frontal
lobe and the sensory motor cortex (13). Primitive and postural reflex testing is part of a
typical pediatric neurological examination and it is commonly known that the persistence of
these reflexes is associated with brain damage or injury.
However it has also been noted (14) that the presence of these reflexes is a common
feature of children with neurodevelopmental disorders of childhood such as ADHD and
autism. In most of these disorders there no observable damage, injury, lesion or degeneration
is present resulting in our here hypothesizing that the persistence of these primitive reflexes

reflects a maturational delay of areas of the brain that would normally inhibit these reflexes
especially those in feedback with the frontal lobes.
The maturational delay of the frontal lobes is reflected by the persistence of primitive
reflexes and delay in the development of postural reflexes, which in itself leads to the delay of
various motor and sensory milestones like crawling and walking. Maturational delay is also
related to the lack of development of executive functions, a hallmark of ADHD and other
neurodevelopmental disorders. This maturational lag is thought to be a product of abnormal
or absent environmental influences that will alter gene expression resulting in smaller, more
immature neurons associated with underconnectivity, decreased activation, coordination and
synchronization of cortical networks which we think underlies the symptoms and functional
deficits seen in children with ADHD and other neurodevelopmental disorders.
One of the other unique features of the human brain is its degree of lateralization or
asymmetry. Humans have the most asymmetrical and lateralized brains of any species (15).
This is thought to be another factor that leads to the significant differences in cognitive
intelligence between humans and other species. Having a more lateralized brain allows for the
development of a greater variety of centers that can individually process and control various
functions, being able to combine these unique individual centers together into various
combinations leading to the unique cognitive abilities of humans. This lateralization becomes
more developed with increasing age and development of the brain and nervous system.
A small child does not have the same degree of laterality as an adult (16). Laterality is in
many ways a product of maturity of the brain and especially of the neocortex and the frontal
lobes (16). The development of laterality and asymmetric control of functions increases
cognitive potential but also requires greater coordination and synchronization of cortical
networks (17). For various functions to bind together there must be activation of all of these
areas and their networks simultaneously. This coordination is also a byproduct of maturity.
As the brain grows and as neurons become interconnected, the speed and coordination of
cortical networks inter- and intra-hemispherically increases, allowing for synchronization and
integration of greater numbers of functions. The two hemispheres of the brain do not develop
at the same time (18); the right hemisphere is thought to develop more rapidly and earlier than
the left with the greatest development being prenatal and for the first 2-3 years of life. Then
the left hemisphere is emphasized in development for the next 2-3 years. Development will
continue this back and forth development between the two hemispheres until adolescence.
Environmental influences that appear during different time courses of development are
thought to contribute to the growth and development of the brain and the cerebral
hemispheres. The type of environmental and sensory stimulation available during a particular
phase of development will influence the receptors that are activated and the cortical networks
that will ultimately process that information. The hemisphere that is being emphasized during
a particular phase of development will be the hemisphere that will ultimately have an
advantage for processing that type of information and will develop as a product of that
incoming flow of sensory information.
The absence or reduction of environmental influences that would normally promote the
growth and development, and neuroplasticity within higher centers, would normally lead to
the inhibition of primitive reflexes and the expression of postural reflexes. The persistence of
these primitive reflexes is a reflection of a maturational lag, which, in turn, is a result of not
activating gene expression that would ultimately lead to the growth and development of
neurons and their connections. Depending on when during development primitive reflexes are

70 Robert Melillo
―turned off‖ will influence hemispheric development and specialization as well. The
persistence of primitive reflexes especially asymmetric persistence will be a reflection of not
only maturational delay of the brain but, depending on the timing, may indicate an abnormal
asymmetrical development of the hemispheres.
If this happens in the first two to three years of life, it will be more likely to result in a
maturational delay of the right hemisphere. This will result in a physical immaturity of the
brain and brain stem that may be measured as a volumetric difference, but, we hypothesize,
will also lead to under connectivity and lack of coordination and synchronization with other
cortical networks both within the right and left hemisphere and between the two hemispheres.
The long range cortical connections, exemplified in Figure 1, form later in development (19)
and are thought to contribute to the temporal coherence of cortical networks especially
between the two hemispheres.
Figure 1. The Reticular Activating System and its connections. The Reticular Activating System
appears to be intimately involved in the neural mechanisms which produce consciousness and focused
attention, receiving impulses from the spinal cord and relaying them to the Thalamus, and from there to
the Cortex, and back again in a feedback loop to the Hippocampus/Thalamus/ Hypothalamus and
participating neural structures in order for learning and memory to take place. Without continual
excitation of cortical neurons by reticular activation impulses, an individual is unconscious and cannot
be aroused. When stimulation is enough for consciousness but not for attentiveness, ADD or LD
results. If too activated, an individual cannot relax or concentrate (and is over-stimulated or
hyperactive) often resulting in ADHD.
These long range cortical networks forming after the shorter range connections, are found
more between the two hemispheres and are expected to be more affected and underdeveloped
with maturational delays (16). This may lead to greater coherence within the hemisphere

while there will be less coherence between the hemispheres (16, 20). This is the foundation of
a functional disconnection, which we think is basis of many of the symptoms of
neurodevelopmental disorders of childhood. The difference in symptoms is dependent on the
hemisphere that is underdeveloped and the timing of the epigenetic influences that affect that
development.
PRIMITIVE REFLEXES
Primitive reflexes are considered adaptive reactions that appear in neonatal life and disappear
or are inhibited as the brain matures. Their persistence and or reappearance in childhood,
adolescence and adulthood is thought to indicate cortico-subcortical neuronal loss or possibly
neuronal developmental delay that may be associated with normal aging or dementia (21-28).
Some authors have stated that these reflexes are found in normal populations. Even in young
adults the palomental reflex was found in 6% to 27% of subjects aged 20 to 50 years, and
28% to 60% of those above 60 years; snouting in 13% of subjects between 40 and 57 years
and 22% to 33% of those above 60 years of age; (29) and suck reflex which some authors
associate with ―frontal lobe disease,‖ has been found in 6% or more of normal subjects aged
73 to 93 years (22). Therefore the prevalence of these reflexes is considered to be variable
and there is disagreement on the pathological significance of these reflexes, and on their
increasing frequency with aging.
The grasp reflex and the extensor plantar response (Babinski sign) are two reflexes that
are well established as indicators of disease in the central nervous system. It is possible that
some of the controversies may be explained by differences in opinion and interpretation of the
reflexes which can vary significantly from clinician to clinician (30), leading to variability in
what is considered ―normal.‖ It may be that an individual with early functional neurological
impairments or children with subtle developmental delays may still fall within the ―normal‖
range for the majority of tests yet actually be showing the beginnings of what may later
develop into a pathological state. Perhaps then these signs can be viewed as early markers for
developmental delay or for neurological dysfunction.
The relationship between cognitive deficits and primitive reflexes has also been
controversial. Some authors (22, 23) consider these reflexes as predictive of diffuse cerebral
dysfunction, since these signs are significantly correlated with cognitive deficits in a wide
age-range of individuals as determined by the Halstead-Reitan neuropsychological test
battery. On the other hand, other authors found no correlation between snout, glabellar, and
grasp reflexes and the presence of cerebral atrophy by CT-scan or by the results of
psychometric tests (Wechsler Memory Scale) in patients with Alzheimer‘s disease (31). In
another study, the relationship between primitive reflexes (PRs) and cognitive functioning
was examined in aging individuals with and without dementia, to verify what items of
neurological examination and cognitive testing were the most predictive of brain dysfunction.
Using the Cognitive Abilities Screening Instrument-Short Form (CASI-S), Teng and
colleagues (32), concluded that in those with dementia, the highest primitive reflex scores
tended to associate with the lowest cognitive scores and in particular to SPECT scan pattern.
Therefore, these researchers concluded that the presence of multiple PRs and their scores
could be useful predictors of diffuse cerebral dysfunction. In particular the presence of the

72 Robert Melillo
grasp and Babinski responses, or the combination of paratonia, snout, suck, and palomental
reflexes are strong indicators of diffuse brain dysfunction, especially when these signs are
marked and accompanied by deficits of one or more of the cognitive subsets. If the presence
of multiple primitive reflexes is an indicator of diffuse brain dysfunction in elderly
populations, it is possible that their persistence and presence in children and adolescence may
be indicative of diffuse cortical maturational delay, and correlate with cognitive, and
executive developmental absence or delay?
Primitive reflexes and delayed cognitive and motor development
There has been a correlation shown between retained primitive reflexes and delayed motor
development in very low birth weight infants (33). The asymmetrical tonic neck reflex, tonic
labyrinth reflex and Moro reflex were assessed in low birth weight children. They observed
the children‘s ability to roll and measured their performance on the gross motor scale of the
Denver Developmental Screening Test. Marquis and colleagues (33) noted that very low birth
weight (VLBW) infants retained stronger primitive reflexes and exhibited a significantly
higher incidence of motor delays than did full-term infants. They confirmed a high incidence
of motor delays among VLBW infants and demonstrated a clear association between retained
reflexes and delayed motor development in VLBW infants. It is important to note that this
was in the absence of any overt pathology in the brains of these children.
In another study (34) the relationship between extreme low birth weight infants, motor
and cognitive development at one and at 4 years was studied. The authors note that a
relationship between motor ability and cognitive performance. Their study investigated the
association between movement and cognitive performance at one and 4 years corrected age of
children born less than 1000g, and whether developmental testing of movement at one year
was predictive of cognitive performance at four years. Motor assessment at both ages was
performed using the neurosensory motor developmental assessment (NSMDA). Cognitive
performance was assessed on the Griffith Mental Developmental Scale at one year and
McCarthy Scales of Children‘s Abilities at four years. A significant association was found
between NSMDA group classification at one year and cognitive performance at both one and
at four years and between the subscales of each test. They also noted that group classification
of motor development at one year was predictive of cognitive performance at four years and
this was independent of biological and social factors and the presence of cerebral palsy.
In yet another study (35), the relationship between a normal intact cerebellum and
primitive reflexes was examined. Tonic labyrinth and neck reflexes were studied separately
and in combination in the decerebrate cat before and after acute cerebellectomy. The
investigators noted clear changes in these reflexes both before and after surgery. They
concluded that the presence of the cerebellum is required for the occurrence of the normal
asymmetric labyrinth reflexes. As we will show later, decreased size and immaturity as well
as dysfunction of the cerebellum and the inferior olive are seen in almost all children with
neurobehavioral disorders and these factors are thought to play a critical role in the
development of normal coordination and synchronization of the motor system and the brain.
Romeo and associates (36) examined the relationship between the acquisition of a
postural reflex, the forward parachute reaction (FPR), and the age of acquisition of
independent walking. They noted that most of the infants they examined had a two step

development pattern. The infants at first showed an incomplete and then a complete FPR
which was observed more frequently at nine months. An incomplete FRP only, without
successive maturation to a complete FPR was present in 21% of the whole sample. Infants
with a complete FPR walked at a median age of 13 months, whereas those with an incomplete
FPR only walked at a median age of 14 months. The investigators observed, in those with
incomplete pattern, a trend toward delayed acquisition of independent walking.
Teitelbaum and associates (37), hypothesized that movement disturbances in infants can
be interpreted as ―reflexes gone astray‖ and may be early indicators of autism. They noted
that in the children they reviewed, some had reflexes that persisted too long in infancy,
whereas others first appeared much later than they should. The asymmetric tonic neck reflex
is one reflex that they noted may persist too long in autism. Head verticalization in response
to body tilt they noted is a reflex that does not appear when it should in a subgroup of
―autistic-to-be‖ infants. They suggested that these reflexes may be used by pediatricians to
screen for neurological dysfunction that may be a markers for autism.
In their earlier work (38), they showed that infants destined to become autistic showed a
characteristic cluster of disturbances in movement patterns detectible by our methods as early
as 4-6 months of age. Teitlebaum et al. Eshkol-Wachman Movement Analysis (EWMN) (39),
in conjunction with laser disc still-frame analysis. They suggested that the movement
disturbances noted in autism can be understood as reflexes gone astray in infancy.
Relationship between motor incoordination and ADHD/Autism
We have elsewhere described how abnormal motor development can accurately be used as a
marker to predict autism in later development (8). Many authors have noted a relationship
between incoordination and clumsiness, especially of posture and gait, and autism as well as
with other neurodevelopmental disorders. The type of gait and motor disturbance has been
compared mostly to those that are either basal ganglionic and most commonly cerebellar in
origin (40). The most common of all comorbidities in practically all neurobehavioral
disorders of childhood is DCD, developmental coordination disorder, or more simply put
―clumsiness‖ or motor incoordination. In fact, practically all children in this spectrum have
some degree of motor incoordination. The type of incoordination is also usually of the same
type primarily involving the muscles that control gait and posture or gross motor activity.
Sometimes to a lesser degree, we find fine motor coordination also affected.
Although it has been fairly well known that attention deficit disorders are comorbid with
psychiatric disorders such as the ones described above, what is less known and what is more
significant is the association between ADD and motor controlled dysfunction (clumsiness) or
developmental coordination disorder (41). In the past, motor clumsiness had not been viewed
as a psychiatric disorder, but rather as being neurological. Motor control problems were first
noted in what were then called minimal brain dysfunction syndromes or MBD. MBD was the
term used to describe children of normal intelligence, but with comorbidity of attention deficit
and motor dysfunction or ―soft‖ neurological signs. Several studies by Denckla and others
(42-48) have shown that comorbidity exists between ADHD and OCD, dyscoordination
and/or motor perceptual dysfunction. Several studies have shown that 50 percent of children
with ADHD also had OCD (49).

74 Robert Melillo
In a Dutch study (50), 15 percent of school age children were judged to have mild neural
developmental deviations and another 6 percent demonstrated severe neural developmental
deviations (occurring in boys twice as often as in girls). Minor developmental deviations were
reported to consist of dyscoordination, fine motor deviations, choreiform movements, and
abnormalities of muscle tone. Researches that have dealt with these minor neural
developmental deviations tend to look at motor dysfunction as a sign of neurological disorder
that may be associated with other problems such as language and perception dysfunction.
Motor dyscoordination has also been noted as a significant sign in autistic spectrum disorders
and in Asperger‘s syndrome. In fact, it has been speculated that the type of motor
incoordination might be able to differentiate high functioning autistic from Asperger‘s
syndrome individuals (51-53).
In Asperger‘s syndrome, it has been noted that individual‘s have significant degrees of
motor incoordination. In fact, in Wing‘s original paper, she noted that of the 34 cases that she
had diagnosed based on Asperger‘s description, ―90 percent were poor at games involving
motor skill, and sometimes the executive problems affect their ability to write or draw.‖
Although, gross motor skills are most frequently affected, fine motor and specifically
graphomotor skills were sometimes considered significant in Asperger‘s syndrome.‖ (54, 55)
Wing (55) noted that posture, gait, and gesture incoordination was most often seen in
Asperger‘s syndrome and that children with classic autism seem not to have the same degree
of balancing and gross motor skill deficits. However, it was also noted that the agility and
gross motor skills in children with autism seem to decrease as they get older and may
eventually present at similar or at the same level as those with Asperger‘s syndrome.
Gillberg (56) also reported clumsiness to be almost universal among children that she had
examined for Asperger‘s syndrome. The other associated symptoms she noted consisted of
severe impairment and social interaction difficulties, preoccupation with a topic, reliance on
routines, pedantic language, comprehension, and dysfunction of nonverbal communication. In
subsequent work, Gillberg included clumsiness as an essential diagnostic feature of
Asperger‘s syndrome (57-59).
It has been reported (59) that children with ADHD and autism spectrum problems,
particularly those given a diagnosis of Asperger syndrome, have a very high rate of comorbid
Developmental Coordination Disorders. Klime and colleagues (60) noted that a significantly
higher percentage of Asperger‘s rather than non-Asperger‘s autistic individuals showed
deficits in both fine and gross motor skills either relative to norms or by clinical judgment.
They further noted that all 21 Asperger‘s cases showed gross motor skill deficits, but 19 of
these also had impairment in manual dexterity which seems to suggest that poor coordination
was a general characteristic of Asperger‘s. With studies like these, many researches have
noted dysfunction of fine motor coordinative skills as a feature of autistic spectrum disorders.
However, when we examine the condition from the perspective of the interaction of the
cerebral hemispheres, as we will note later, gross motor skill dysfunctions are more typical of
right hemisphere involvement whereas fine motor skill dysfunctions are more typical of left
hemisphere involvement. We will demonstrate later that both classic autism and Asperger‘s
syndrome are associated with right hemisphere deficits, and thereby, would be expected to
show a greater involvement of gross motor skill deficits. It might seem somewhat confusing
initially when fine motor skills seem to be disrupted at almost equal levels. According to a
neuropsychological model, this type of weakness would be more indicative of a left
hemisphere deficit. However, when examining the literature closely, it has been noted (61)

that manual dexterity is less effective for high functioning autistics than for Asperger‘s, but
only for the non-dominant hand. This suggests a lateralized difference. This would show that
although fine motor coordinative skill is decreased in autistics, it is primarily decreased in the
left hand, associated with right hemisphere function. This is consistent with a hemispheric
imbalance model and specifically a right hemisphericity.
Manjiviona and Prior (62) noted that 50 percent of autistics and 67 percent of their
Asperger‘s individuals studied presented with significant motor impairment as defined by
norms on a test of motor impairment. Szatmari and colleagues (61, 63) also noted that autistic
groups did not differ from Asperger‘s groups with respect to dominant hand speeds on type
boards although both were slower than psychiatric controls. Vilensky and associates (64)
analyzed the gait pattern of a group of children with autism. They used film records and
identified gait abnormalities in these children that were not observed in a control group of
normally developing children or in small groups of ―hyperactive/aggressive children.‖
Reported abnormalities were noted to be similar to those associated with Parkinson‘s. Hallet
and colleagues (65) assessed the gait of five high functioning adults with autism compared
with age matched normal controls. Using a computer assisted video kinematic technique, they
found that gait was atypical in these individuals. The authors noted that the overall clinical
findings were consistent with a cerebellar rather than a basal ganglionic dysfunction.
Kohen-Raz and colleagues (66) noted that postural control of children with autism differs
from that of matched mentally handicapped and normally developing children and from
adults with vestibular pathology. These objective measures were obtained using a
computerized posturographic technique. It has been also noted that the pattern of atypical
postures in children with autism is more consistent with a mesocortical or cerebellar rather
than vestibular pathology. Numerous investigators (67) have provided independent empirical
evidence that basic disturbances of the motor systems of individuals with autism are
especially involved in postural and lower limb motor control.
Makris et al. (68) examined attention and executive systems abnormalities in adults with
childhood ADHD. They noted that ADHD is hypothesized to be due, in part, to structural
defects in brain networks influencing cognitive, affective, and motor behaviors. Although the
literature on fiber tracts is limited in ADHD, they note that gray matter abnormalities suggest
that white matter connections may be altered selectively in neural systems. A prior study (69),
using diffusor tensor magnetic resonance imaging showed alterations within the frontal and
cerebellar white matter in children and adolescents with ADHD. In this study of adults the
authors hypothesize that fiber pathways subserving attention and executive functions would
be altered. To this end, the cingulum bundle (CB) and superior longitudinal fascicle II (SLF
II) were investigated in vivo in 12 adults with childhood ADHD and 17 demographically
comparable unaffected controls using DT-MRI. Relative to controls, the fractional anisotropy
(FA) values were significantly smaller in both regions of interest in the right hemisphere, in
contrast to a control region (the fornix), indicating an alteration of anatomical connections
within the attention and EF cerebral systems in adults with childhood ADHD. The
demonstration of FA abnormalities in the CB and SLF II in adults with childhood ADHD
provides further support for persistent structural abnormalities into adulthood.

76 Robert Melillo
ADHD, EXECUTIVE FUNCTION AND CORTICAL MATURATION

McAlonan et al. (70) noted that children with attention-deficit hyperactive disorder (ADHD)
have difficulties with executive function and impulse control which they postulate may
improve with age which would seem to correlate to a maturational delay rather than structural
damage. In this study they compared ADHD and control groups on the change task measures
of response inhibition (stop signal reaction time SSRT) and shifting (change response reaction
time, CRRT). Voxel-wise magnetic resonance imaging correlations of reaction times and grey
matter volume were determined, along with bivariate correlations of reaction times, brain
volumes and age. Results showed that individuals in the ADHD group had longer SSRTs and
CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with
SSRT. Striatal and cerebellar volumes strongly correlated with CCRT. Older children had
faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial
temporal and cerebellar volumes correlated with CCRT but not SSRT. The authors concluded
that this evidence supports delayed brain maturation in ADHD and implies that some features
of ADHD may improve with age.
Shaw et al. (71) noted that there is a controversy over the nature of the disturbance in
brain development that underlies ADHD. They note that it is unclear to some whether the
disorder results from a delay in brain maturation or whether the disorder results from a
deviation from the template of typical development. Since its earliest description, there has
been debate as to whether the disorder is a consequence partly of delay in brain maturation or
complete deviation from typical development (72). Several studies find that brain activity at
rest and in response to cognitive probes is similar between children with ADHD and their
slightly younger but typically developing peers, evidence that would seem to be consistent
with a maturational lag in cortical development (73-74). Others report a quantitatively distinct
neurophysiology, with a unique architecture of the electroencephalogram and some highly
anomalous findings in functional imaging studies which would seem to imply that ADHD is a
deviation from typical development (75-79).
Using computational neuroanatomic techniques, Shaw and colleagues (71) estimated
cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired
prospectively on 223 children with ADHD and 223 typically developing controls. With this
sample size, they could define the growth trajectory of each cortical point, delineating a phase
of childhood increase followed by adolescent decrease in cortical thickness (a quadratic
growth model). The findings are exemplified in Figure 2. From these trajectories, the age of
attaining peak cortical thickness was derived and used as an index of cortical maturation.
They found maturation to progress in a similar manner regionally in both children with and
without ADHD, with primary sensory areas attaining peak cortical thickness before
polymodal, high-order association areas. However, there was a marked delay in ADHD
individuals in attaining peak thickness throughout most of the cerebrum: the median age by
which 50% of the cortical points attained peak thickness for this group was 10.5 years, which
was significantly later than the median age of 7.5 years for typically developing controls. The
delay was most prominent in prefrontal regions important for control of cognitive processes
including attention and motor planning. Neuroanatomic documentation of a delay in regional
cortical maturation in ADHD has not been previously reported.

Figure 2. The age of peak cortical thickness in children with ADHD compared with normals. (A) dorsal
view of cortical regions of peak thickness by age (ages 7–12) in ADHD (Upper) and normal controls
(Lower). Darker colors indicate regions where a quadratic model was not appropriate (non-calculated
peak), or the peak age was estimated to lie outside the age range covered. ADHD group showed
significant delay in reaching this developmental marker. (B) Right lateral view of cortical regions of
peak thickness by age (ages 7–13) in ADHD (Upper) and normals (Lower). (From Shaw et al. (71)).
Immaturity in functional connectivity measures had previously been reported in studies

of other developmental disorders including autism (80-85). At present it remains unclear
whether these immaturities are common across different developmental disorders or whether
or not they involve the same or similar brain regions.
It may be that functional connectivity studies are documenting immaturities in different
functional networks or different parts of the same networks (86). ADHD is commonly
comorbid with Tourette‘s syndrome and it is possible that the two disorders share a common
connectivity deficit that becomes apparent in both in studies that examine at both ADHD and
Tourette‘s (87, 88). It has been suggested more generally that long–range functional
underconnectivity could be related to deficits in the integration of information (87, 88). The
decrease in long range connections observed in Tourette‘s adolescents relative to their age–
matched peers is consistent with this idea as well (86). In this scenario functional
underconnectivity could affect communication and coordination between the cerebellum,
frontal cortex, and parietal cortex. Different patterns of functional connectivity might explain
distinctive symptoms in different developmental disorders. Some authors (86) have noted that

78 Robert Melillo
the connectional immaturity observed in TS is not due to a general functional

underconnectivity, but rather to a more specific pattern of increasing and diminishing
functional connections that appear to mimic the pattern observed in studies of typical
development (88).
ADHD and underconnectivity: Its relationship to desynchronization
Cortical underconnectivity has been correlated in various neurodevelopmental and psychiatric

disorders with desynchronization of large cortical networks. Dockstader et al. (89) note that
convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-
striatal-cerebellar circuitry as the source of the behavioral deficits. They also note that recent
studies have shown that regions governing basic somatosensory processing show
abnormalities in those with ADHD suggesting those processes may also be compromised. In
this study they used event-related magnetoencephalography (MEG) to examine patterns of
cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response
to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were
brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two
counterbalanced conditions: unpredictable and predictable. They measured changes in
strength, synchronicity, and in the frequency of cortical rhythms. Their results showed that
the normal controls showed strong event-related desynchronization and synchrony in SI and
SII. By contrast, those with ADHD showed significantly weaker event-related
desynchronization and event-related synchrony in the alpha (8–12 Hz) and beta (15–30 Hz)
bands, respectively. This was most striking during random presentation of median nerve
stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both
SI and SII except for when the onset of the stimulus event could be predicted. In this case, the
rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls. Their
findings suggested that somatosensory processing is altered in individuals with ADHD.
The general assumption of cortical oscillations is that populations of neurons exist in
varying states of synchrony as they respond to externally or internally generated events.
Event-related desynchronous (ERD) and event-related synchronous (ERS) phenomena are
thought to represent decreases and increases, respectively, in synchronization within a
specific frequency range in relation to an event (90). Previous MEG studies of cortical
activity following median nerve stimulation in healthy adults report brief suppression of mu
(an alpha wave variant oscillating at approximately 10 Hz) and beta (15–30 Hz) cortical
activity over the primary and secondary somatosensory cortex (ERD) followed by a marked
increase in beta band activity above baseline (late-ERS, known as beta rebound) (90). Basic
or complex sensory processing requires a dynamic interaction between groups of neurons
oscillating at particular frequencies and differing degrees of coupling. Oscillations in the
alpha and beta bands are of particular interest in ADHD research as these frequencies are
thought to mediate perception (91, 92) and attention (93, 94).

PATHOPHYSIOLOGY OF ADHD AND AUTISM: A COMBINATION

OF GENETIC AND ENVIRONMENTAL FACTORS
The pathophysiology of ADHD remains unclear, although converging evidence suggests that
alterations in brain structure, function, and physiology likely arise from an interaction of
genetic and environmental causes and experience (95-98). For example, structurally,
prominent volumetric decreases are evident in the posterior-inferior lobules of the cerebellar
vermis in both male and female children with ADHD (99). There are decreases in prefrontal
volume, particularly the right prefrontal cortex (100). Also reported are regional differences
in cerebral blood flow in the cerebellum, striatum (101), and prefrontal cortex (PFC) (102).
Moreover, differences in baseline oscillatory activity between those with ADHD and controls
have been observed in frontal regions, particularly the PFC (103). Consistent with the
neuroimaging findings, psychological research indicates clearly that subtle impairing
environmental problems are historical correlates of ADHD, regardless of gender or age (104).
Epigentics and autism
Schanen (105) indicated that many think that the autism spectrum disorders (ASD) that
include autism, Asperger‘s disorder, childhood disintegrative disorder and pervasive
developmental disorder-not otherwise specified (PDD-NOS) are largely genetic in origin,
with a polygenic, epistatic model best fitting the family, twin and epidemiological data for
non-syndromic forms. The number of interacting loci contributing to susceptibility has been
estimated to range between two and 15 genes of varying effect (106). Despite considerable
effort over the past decade, these underlying risk alleles have been remarkably elusive, with
the exception of a handful of rare, large effect genes (107) and several single gene disorders
associated with an increased risk for autism or ASD (108).
Although this likely reflects the underlying genetic heterogeneity within and among the
diagnostic categories in the ASD, the obstacles encountered in mapping the risk alleles have
led a number of investigators to rethink the model of inheritance to include contributions of
new mutations and/or epigenetic mechanisms such as genomic imprinting or epimutations in
the underlying genetic susceptibility to ASD (109, 110).
Epigenetic modifications including cytosine methylation and post-translational
modification of histones provide a mechanism for modulation of gene expression that can be
influenced by exposure to environmental factors and that may show parent of origin effects.
Epigenetic effects can be related to sensory-motor based activity. Over the past two decades
one of the most dramatic lifestyle changes has been related to early motor activity. Children at
earlier and earlier ages have reduced motor activity and spatial exploration that is thought to
be the single most important factor in gene expression and early synaptogenesis of functional
connections in the developing brain. This can be compounded by the persistence of primitive
reflexes and delay of postural reflexes which will further alter motor acquisition and spatial
exploration.
Neurons can change their gene expression patterns according to the inputs they have
received. This activity-dependent gene regulation mechanism plays an important role in the
formation of neural circuits during development. Further, by regulating the synaptic plasticity,

80 Robert Melillo
this mechanism may function as an essential one for each organism to adapt flexibly to its
environment. Abe (111) summarizes the current knowledge about the activity-dependent gene
regulation mechanism in neurons, focusing on the transcription factors and signaling
pathways involved in this mechanism.
Epigenetics and synaptogenesis
As we stated earlier primitive reflexes are necessary for early movement to occur in the
absence of a fully formed neocortex. This movement allows for interaction and exploration of
environment and basic survival behaviors such as feeding and approach and avoidance
behavior. This interaction then engages the sensory receptors and activates the neural
pathways which is thought to stimulate gene activity and synaptogenesis which creates
neuroplasticity which will eventually lead to inhibition of primitive reflexes and the activation
of postural reflexes. The postural reflexes then will engage the sensory systems, especially
muscle spindle activation of postural muscles, which will then, through relevant feedback,
create increasing synaptogenesis and neuroplasticity.
Flavell et al. (112) have noted how sensory experience and the resulting synaptic activity
within the brain are critical for the proper development of neural circuits. Experience-driven
synaptic activity causes membrane depolarization and calcium influx into select neurons
within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the
synaptic connectivity within the neural circuit. One way in which calcium influx leads to the
remodeling of synapses made by neurons is through the activation of new gene transcription.
Recent studies have identified many of the signaling pathways that link neuronal activity to
transcription, revealing both the transcription factors that mediate this process and the
neuronal activity–regulated genes (a review in the context of enrichment is provided by
Leisman in this text. These studies indicate that neuronal activity regulates a complex
program of gene expression involved in many aspects of neuronal development, including
dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in
several key regulators of activity-dependent transcription give rise to neurological disorders
in humans, suggesting that future studies of this gene expression program will likely provide
insight into the mechanisms by which the disruption of proper synapse development can give
rise to a variety of neurological disorders.
As the neurons become larger and more insulated by glial cells, they increase the speed of
their impulse transmission; more networks can be activated simultaneously increasing the
coordination and integration of large cortical networks. Initially this increased coordination
occurs with short range intracortical connections to increase integration and coherence within
the individual hemispheres. As this coordination and synaptogenesis continues, long range
connections will form and this will increase the size of the corpus callosum where many of
these fibers will cross to connect with areas on the opposite hemisphere. This is all part of the
normal process of cortical maturity. We think this is the process that is affected and delayed
in most if not all neurobehavioral disorders.

Brain maturation and increases in cortical synchrony
Brain development is characterized by maturational processes that span the period from
childhood through adolescence to adulthood, but little is known whether and how
developmental processes differ during these phases. Uhlhaas and associates (113) have
analyzed the development of functional networks by measuring neural synchrony in EEG
recordings during a Gestalt perception task in participants ranging in age from 6 to 21 years.
Until early adolescence, developmental improvements in cognitive performance were
accompanied by increases in neural synchrony. This developmental phase was followed by an
unexpected decrease in neural synchrony that occurred during late adolescence and was
associated with reduced performance. After this period of destabilization, they observed a
reorganization of synchronization patterns accompanied by pronounced increases in gamma-
band power and in theta and beta phase synchrony. These findings provide evidence for the
relationship between neural synchrony and late brain development that has important
implications for the understanding of adolescence as a critical period of brain maturation
(114).
Synchronization and cortical development
Recent data indicate that the synchronization of oscillatory activity is relevant for the
development of cortical circuits as demonstrated by the involvement of neural synchrony in
synaptic plasticity and changes in the frequency and synchronization of neural oscillations
during development. Analyses of resting-state and task-related neural synchrony indicate that
gamma-oscillations emerge during early childhood and precise temporal coordination through
neural synchrony continues to mature until early adulthood. The late maturation of neural
synchrony is compatible with changes in the myelination of cortico-cortical connections and
with late development of GABAergic neurotransmission. These findings highlight the role of
neural synchrony for normal brain development as well as its potential importance for
understanding neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and
schizophrenia (115).
Oscillations and the generation of synchronized neuronal activity play a crucial role in
the activity-dependent self-organization of developing networks (116-118). The development
and maturation of cortical networks critically depends on neuronal activity, whereby
synchronized oscillations play an important role in the stabilization and pruning of
connections (118). For example, in spike-timing dependent plasticity, pre- and postsynaptic
spiking within a critical window of tens of milliseconds has profound functional implications
(118). Stimulation at the depolarizing peak of the theta cycle in the hippocampus favors long-
term potentiation, whereas stimulation in the trough causes depotentiation (119). The same
relationship holds for oscillations in the beta- and gamma- frequency range (120), indicating
that oscillations provide a temporal structure that allows for precise alignment of the
amplitude and temporal relations of presynaptic and postsynaptic activation that determine
whether a strengthening or weakening of synaptic contacts occurs. Accordingly, the extensive
modifications of synaptic connections during the development of cortical networks are
critically dependent upon precise timing of neural activity.

82 Robert Melillo
Synchronization of oscillatory activity is an important index of the maturity and

efficiency of cortical networks. Neural oscillations are an energy efficient mechanism for the
coordination of distributed neural activity (115) that is functionally related to anatomical and
physiological parameters that undergo significant changes during development. Thus,
synchronization of oscillatory activity in the beta- and gamma-frequency range is dependent
upon cortico-cortical connections that reciprocally link cells situated in the same cortical area,
across different areas or even across the two hemispheres (121). In addition to chemical
synaptic transmission, direct electrotonic coupling through gap-junctions between inhibitory
neurons also contributes to the temporal patterning of population activity and, in particular, to
the precise synchronization of oscillatory activity (122).
Gap-junctions are functionally important during early brain development (123).
Postnatally, changes in both GABAergic neurotransmission (124) and the myelination of long
axonal tracts (125) occur. Thus, changes can be expected in the frequency and amplitude of
oscillation as well as in the precision with which rhythmic activity can be synchronized over
longer distances at different developmental stages.
The literature on resting state activity as well as neural activity during cognitive tasks
indicates that important changes occur in the parameters of neural synchrony during
childhood and adolescence. Although high-frequency activity emerges during early
development, cortical networks fully sustain precise synchrony only during the transition
from adolescence to adulthood, which is compatible with concurrent changes in anatomy and
physiology.
Csibra et al. (126) measured gamma band responses in EEG data in 6- and 8-months-old
infants during the perception of Kanisza squares that require the binding of contour elements
into a coherent object representation. Based on prior behavioral studies that showed that
infants up to six-months of age are unable to perceive Kanisza figures, the authors
hypothesized that perceptual binding in 8-month-old infants is related to the emergence of
gamma band oscillations. This was supported by an induced oscillatory response between 240
and 320 ms over frontal electrodes that was not present in the younger group, indicating that
the emergence of gamma band oscillations during infancy is correlated with the maturation of
perceptual functions. The development of induced oscillations and their synchronization was
examined by Uhlhaas and associates (113, 114, 127) in a study that investigated children,
adolescent, and young adult‘s perception of Mooney faces. The data represented in Figure 3
indicated that in adult participants, perceptual organization of upright Mooney faces was
associated with prominent gamma band oscillations over parietal electrodes as well as long-
range synchronization in the theta and beta band. During development, profound changes in
these parameters occurred that correlated with improved detection rates and reaction times.
Accordingly, the development of induced oscillations and their synchronization from late
adolescence to early adulthood reflect a critical developmental period that is associated with
a rearrangement of functional networks and with an increase of the temporal precision and
spatial focusing of neuronal interactions. Changes in neural synchrony during development
are also present in the motor system in which beta band oscillations are associated with the
preparation and execution of motor commands (128). Synchrony of spinal inputs to motor
neurons can be investigated by measuring the covariation of signals from electromygraphic
(EMG) recordings over abductor muscles. Farmer et al. (129) analyzed the coherence of
EMG-signals in the 1 to 45 Hz frequency range during development in a sample of 50
participants (4–59 years). Pronounced developmental changes in beta band coherence were

found between 7–9 and 12–14 years, with adolescent participants showing elevated levels of
beta band coherence relative to children.
Figure 3. Phase synchrony in the beta and gamma bands in the Mooney face condition. All values are
expressed in standard deviations in reference to the baseline. (Left) Phase synchrony (13–75 Hz) across
all electrodes. (A–E) Adult (A); late adolescence (B); early adolescence (C); late childhood (D); early
childhood (E). (Middle Column) Topography for 13–30 Hz frequency band between 100-300 ms. (F)
Adult group. Synchrony between electrodes is indicated by black lines. (G–J) Difference maps for
younger age groups relative to adult participants. Black lines indicate a significant increase (P _ 0.0003)
in synchrony in adults compared with the younger group. Green lines indicate a significant increase
(P _ 0.0003) in synchrony for the younger group relative to adults. (K) Group comparison for all
electrodes of phase synchrony in the 13–30 Hz frequency range between 100 and 300 ms. (L) Group
comparison for all parietooccipital electrodes in the 13–30 Hz frequency range between 100 and 300
ms. (130).

84 Robert Melillo
In addition to the increase in the synchrony of EMG signals, there is evidence that long-
range synchronization of oscillations between the primary motor cortex and muscles
undergoes significant changes during development. James and colleagues (130) examined
EEG recordings over primary motor cortex and EMG data from the contralateral wrist
extensor muscle in a sample of 48 participants (0–58 years). In the youngest age groups (0–3
and 4–10 years) coherence values between EEG and EMG signals were randomly distributed
across different frequencies indicating that the drive from corticospinal pathways to motor-
neurons is not oscillatory.
Uhlhaas et al. (113), in a different study, reviewed evidence on developmental changes in
neural synchrony during childhood and adolescence highlighting the relationship between
brain maturation and changes in the frequency, amplitude and synchronization of neural
oscillations. These data indicated that, in addition to providing a mechanism for the
coordination of distributed neural responses that underlies cognitive and perceptual functions,
neural synchrony is closely related to the development of cortical circuits. This is indicated by
the relationship between the emergence of specific patterns of oscillatory activity and certain
cognitive functions and by the correlation between the appearance of certain brain disorders
at different developmental periods and electro- graphic signs of abnormal temporal
coordination. Accordingly, such data support the view that neural synchrony is not
epiphenomenal but plays a role in the functions of cortical networks.
FUNCTIONAL DISCONNECTION AS A RESULT OF

UNDERCONNECTIVITY, DESYNCHRONIZATION, AND POOR TEMPORAL
COHERENCE AND IMMATURE CORTICAL NETWORKS
We have proposed previously (for a complete overview see (16)) the concept of functional
disconnection as a unifying model that can describe all of the symptoms and characteristics of
the full spectrum of neurobehavioral disorders including ASD, ADHD, dyslexia, obsessive–
compulsive disorder, Tourette‘s syndrome, nonverbal learning disability as well as possible
relationships with other psychiatric disorders such as schizophrenia and bipolar disorder.
Other authors have discussed similar mechanisms under different labels, desynchronization
and underconnectivity (71), weak central coherence (131), temporal binding deficit (132),
developmental disconnection (133), and recently a new term, temporo-spatial processing
disorders of multi-sensory flow and multi-system brain disconnectivity-dissynchrony (see
131).
In their review (134), Gepner and Féron propose that temporo-spatial processing
disorders (TSPDs) of multi-sensory flows represent a common neuropsychological basis for
the main behavioral, cognitive and motor disturbances observed in people with ASD.
According to this hypothesis, ASD individuals would present various degrees of disability in
processing dynamic multi-sensory stimuli online, associating them into meaningful and
coherent patterns, and producing real-time sensory-motor adjustments and motor outputs. We
also present results demonstrating that slowing down the speed of facial and vocal events
enhance imitative, verbal and cognitive abilities of some ASD children. Then, we propose
that TSPDs are based on multi-system brain disconnectivity-dissynchrony (MBD), i.e.,
disorders of functional connectivity and neural synchrony within/between multiple brain

regions, and review the recent fMRI and electrophysiological data supporting MBD. Finally,
we list the suspected neurobiological mechanisms underlying TSPDs and MBD.‖ All of these
models essentially are all similar in where they focus on the inability of large cortical
networks to bind in time and space. They note that the TSPD hypothesis emerged from data
indicating that in ASD patients exhibit various degrees of disability in perceiving and
integrating environmental dynamic multisensory stimuli online and producing real time
sensory –motor coupling, postural adjustments and adequate verbal and nonverbal outputs.
Autistic children have been shown to have weak postural reactivity to visually perceived
environmental motion (135). It has also been noted that children with low functioning autism
are posturally hyporeactive to environmental movements especially when the speed of
movement is high, whereas children with Asperger‘s syndrome display normal or even
greater postural reactivity to the same type of stimuli (136). It has been postulated that this
under or over visuo-postural coupling in children with ASD may in part explain executive
dysfunction in ASD patients (137) and sensory-motor, motor disturbances such as poor motor
coordination, poor or enhanced postural control, gross or fine motor clumsiness (138-142). It
has also been shown that high functioning autistic subjects display a deficit in the perception
of second order radial, translational and rotational direction of movement (143).
ASD children also have difficultly perceiving the motion of small squares on a computer
screen especially at high speed and when the direction was less predictable (144) all implying
a temporal processing deficit for particular types of stimuli. Other research supporting a
temporal processing deficit comes from observed impairments in children and adolescents
with ASD who were tested for their ability to extract online relevant information among noisy
stimuli, through three types of tasks and measurements (a) occulomotor reactivity to global
movements of coherent pattern of lighting points through optokinetic nystagmus, (b) speech
flow perception and segmentation through categorization of simple and complex phonemes
and (c) proprioception and motor anticipation in a bimanual load lifting task (145). Results
showed that the ASD subjects showed weak oculomotor reactivity in response to global
motion (i.e., higher motion coherence thresholds, when compared to controls (146).
Weaker occulomotor reactivity was observed in reaction to higher motion velocities
(146). It was speculated that this deficit which was assessed as a defect in rapid temporal
analysis of visual motion stimuli embedded in noise is a strong argument for a deficient
temporo-spatial integration in the visual modality. It is also thought that this difficulty to
integrate single points into a global coherent motion is also the argument used for weak
central coherence (146). In the auditory realm, similar temporal processing deficits have been
documented for rapid auditory processing. In a group of ASD patients they were shown to
have a deficit in speech phoneme categorization. Compared to control children, who
categorize ambiguous phonemes such as MNA in an MA or a NA random response, autistic
children over categorize MNA in a NA response. This abnormal over–catagorization
specifically appeared in autistic subjects when speech phonemes were displayed at normal
speed, whereas their phoneme categorization was normalized when phonemes were slowed
down by a factor of 2. It was speculated that phoneme categorization deficit may be due in
part to a difficulty in rapid speech flow processing and therefore to a temporal integration
deficit in the auditory modality (147). This is thought to in part explain the receptive and
expressive language and verbal communication deficits noted in individuals with ASD
especially noting that the same deficit was found in children with Language learning
impairments (148) and was improved by slowing down the speed of speech flow (149, 150).

86 Robert Melillo
Researchers think that deficient rapid temporal processing may contribute to impaired
language development by interfering with the processing of brief acoustic transitions, critical
for speech perception. It was also shown that in the rapid processing of proprioceptive inputs
(151) autistic children mostly use a feedback mode of control as opposed to feed forward in
normal controls. This results in a slowing of the movement of autistic children. Autistic
children react instead of predicting. It is thought that this impairment along with the visual-
proprioceptive processing deficit (i.e., deficit of visual-postural and visuo-occulomotor
reactivity), contribute to executive dysfunction in ASD individuals and particularly to slowed
sensory-motor processing speed. This could also be viewed as immature processing of
particular information relative to the performance of non-impaired children of the same age. It
was found that ASD individuals who perform poorly in facial recognition tasks involving
processing of facial dynamics (152), perform equally as well as typical developing children of
the same developmental age in emotional and facial speech recognition tasks when the stimuli
are slowed down (153).
Gepner and Féron (134) note that In regard to motor development, babies who will later
exhibit typical autism (153) or Asperger syndrome (154) show disturbances in some or all of
the milestones of development, including lying, righting, sitting, crawling and walking. In
addition, Adrien and associates (155) and Sauvage (156) observed that they frequently exhibit
deficits of postural adjustment, a lack or a delay in anticipating attitudes as well as in oculo-
manual coordination, all of these symptoms being possibly due to a distorted proprioceptive
and visuo-postural integration, and stereotyped behaviors like swinging, rocking and swaying,
possibly aimed at compensating it.
The time course of autistic symptoms during infancy may appear as succession and
intrication of maldevelopmental cascades, in which early temporo-spatial processing
disorders of visual, auditory and proprioceptive stimuli impact secondarily on (a) sensory-
motor development, (b) verbal and emotional communication and social interactions between
an infant and his physical and human environment (156). One of these maldevelopmental
consequences has been named E-Motion Mis-sight, i.e., various degrees of disability in
perceiving and integrating motional and emotional stimuli on time (157). E-Motion Mis-sight
has been proposed to be an early precursor of mindblindness (158) and empathizing deficit
(158).
In summary, TSPDs of multi-sensory stimuli may account for numerous clinical and
neuropsychological findings in ASD. The cerebellum (160) is known to play a crucial role in
all these stages. First, visual inputs, especially dynamic ones, travel through mossy fibers via
the pontine nuclei before reaching the cerebellum (160). Second, the cerebellum plays a
major role in speed and temporal coding and therefore in integrating multi-sensory dynamic
inputs (161). Thirdly, the cerebellum exerts a real-time fine tuning of movement (162).
Fourthly, the cerebellum contributes with the basal ganglia to motor control as well as to
learning (163), via projections on motor and premotor cortices as well as on prefrontal,
temporal and parietal cortices. Yet, some of the most consistent neuroanatomic anomalies
affecting people with ASD are likely to affect the cerebellum (164). Visuo-cerebellar
pathways, among other sensory-cerebellar pathways, are therefore highly suspected to be
involved in the neurophysio-pathology of ASD (165), that could explain the unusual visuo-
motor reactivity and, possibly, the bizarre cognitive style and higher order cognitive
peculiarities observed in these individuals.

Numerous investigators have linked the neuroanatomic abnormalities of the cerebellum

with cognitive impairments in ASD, supporting the notion that disturbances in the inferior
olive found in autism (166-168), and consequently in olivo-cerebellar pathways, would
disrupt the ability of inferior olive neurons to become electrically synchronized and generate
coherent rhythmic output. These anomalies of synchronization would (a) impair the ability of
individuals with ASD to process rapid information (e.g., their ability to use rapid sequences
of cues for the development of normal language skills), and (b) result in slowing their
perceptual and cognitive processing speed. Rapid received sensory information (rapid sensory
flows) would arrive too quickly to be processed on time by the autistic brain. Appropriately, a
neuromimetic model (i.e., a mathematic model simulating brain functioning) of brain
connectivity found that the speed of synchronization depends on the dynamical and network
parameters, and is most probably limited by the network connectivity (169). Functional
connectivity is the mechanism allowing the achievement of a cognitive task or perceptual
process by coordinating and spatio-temporally correlating activities between different neural
assemblies (170). Studies using functional magnetic resonance imaging (fMRI) during the
past 5 years have confirmed that functional brain connectivity could either be decreased (171,
172), or sometimes increased (173) in ASD individuals during either resting state and simple
or complex cognitive tasks.
Asymmetric development leads to underconnectivity, desynchronization and

functional disconnection
A global immaturity of the function of cortical networks in childhood would be associated

with a reduction in motor activity, spatial exploration, experience-dependent plasticity,
persistent primitive reflexes, and delayed postural reflexes. A more specific imbalance in
maturity would be expected if there was an asymmetric development of primitive reflexes. If
there existed unilateral persistence of primitive reflexes and unilateral delay of postural
reflexes, we would expect an asymmetric development and maturity of the brain and nervous
system.
Futagi et al. (174) examined the relationship between asymmetry in the plantar grasp
response during infancy. They reviewed the neurologic outcomes of 61 children with
asymmetric plantar grasp responses during infancy during a follow up period of 2.8 – 11.9
years. All children had perinatal risk factors and/or neurologic signs except for asymmetric
plantar grasp responses recorded during infancy. The outcomes consisted of cerebral palsy in
38, delayed motor development in 6, mental retardation in 3, borderline intelligence in 9, and
normal in 5. Most patients demonstrated concordance between side of abnormal response,
laterality in motor function, and abnormal CT findings. The asymmetry they observed in the
plantar grasp response strongly suggested the existence of brain dysfunction. This study
showed that a relationship between asymmetric development of primitive reflexes is related to
persistence of motor abnormalities related to the same side. As we stated earlier, the plantar
response is thought to be one of the reflexes that is most related to brain development whether
due to injury or functional developmental delays. This type of asymmetrical development of
the developing brain is something that has been very commonly seen and noted in almost all
neurobehavioral disorders, especially ADHD, autism, Tourette‘s and dyslexia. Along with

88 Robert Melillo
anatomical asymmetries there have also been functional asymmetries noted with
―unevenness‖ of skills characteristic of all of these disorders, to varying degrees.
One of the most interesting features of those with neurobehavioral disorders is the
―unevenness‖ of cognitive abilities. We have proposed elsewhere (8, 175) that the best way to
explain the diverse behavioral effects noted in autistic spectrum disorders is by understanding
the basis of the condition as a functional disconnection syndrome, not unlike what is seen in
sleep, minimally conscious states, or as reported in dyslexics (176). Functional asymmetry
within widespread cortical networks could result in decreased temporal coherence in certain
networks while also resulting in enhanced temporal coherence in other functional networks
(177). It would also make sense that enhanced skills are found in the networks with enhanced
coherence and reduced skills be associated with networks with reduced coherence.
Optimized brain function implies more efficient neural processing than non-optimized.
One might expect optimized performance to correlate with more activity. For the cerebral
cortex the contrary seems to be the case: higher performance in several tasks has been noted,
including verbal (178), numeric, figural, and spatial reasoning (179, 180), is associated with
reduced consumption of energy in several cortical areas. This phenomenon has also been
studied with EEG techniques in different frequency bands. The amount of a background
power (7.5–12.5 Hz) decreases during cognitive activity compared with a resting state (event-
related desynchronization, ERD); this decrease has been observed to correlate with higher
performance in subjects with higher IQ scores (181, 182) or with higher performance after
training, indicating a more efficient processing strategy for a cognitive tasks (183). Yet the
issues should include not only the expenditure of energy but also the nature of the functional
connectivities between brain regions.
Associated with these functional asymmetries or imbalances also seem to be anatomical
asymmetries noted only in these individuals and not in others that seem to mirror the
functional imbalances (177). Physically smaller areas of activation have been found
consistently in various areas of the brain in individuals with neurobehavioral disorders. These
smaller areas seem to represent brain regions that are delayed in development rather than
representing any specific form of damage, pathology, and or atrophy (8, 16) There has also
been noted reduced connectivity between various areas of the brain in individuals with autism
and other neurobehavioral disorders (8, 16, 184, 185).
The most significant reduction of cortical connectivity appears to be in the corpus
callosum (186). This seems to imply that the most common type of functional disconnection
seen in these children is one that involves the two hemispheres. What we also think is that the
hemisphere with reduced coherence is the side responsible for the reduced skill level in
various cognitive, motor and sensory abilities which is controlled by that side of the brain,
whereas the enhanced capabilities are seen associated with the side of greater within
hemisphere coherence (184) We have also reported reduced connectivity and coherence
observed in the longer interhemispheric connections with increased connectivity and
coherence with shorter intrahemispheric connections (184, 185) that we theorize leads to the
enhanced capabilities such as those seen in savantism.
In Autism it seems that reduced coherence as well as connectivity is associated with
underactivation of the right hemisphere. This also seems to be consistent with the reduced
cognitive, motor, sensory and autonomic functions that are primarily controlled by the right
hemisphere. This is also consistent with research that shows increased neuroendocrine
function of the dopamine systems in the brain (8, 187). This hyper-dopamine activity is also

associated with an enhanced function of the left hemisphere that has a greater concentration
of dopamine (188). Dopamine, the most widely studied of all neurotransmitters, is thought to
play a crucial role in motivation (189) and higher-order intelligence (190) and in most major
clinical disorders—including attention-deficit/hyperactivity disorder (ADHD) (191), autism
(8, 187), bipolar disorder (especially its manic phase) (192), obsessive-compulsive disorder
(OCD) (193), Parkinson‘s disease (194), schizophrenia (195), and Tourette‘s syndrome (196).
Most of these hyperdopaminergic disorders show a very high co-morbidity (197) and many
disorders besides autism have shown varying degrees of increased incidence in recent decades
(198).
We think that this asymmetric development of primitive and postural reflexes is
associated with the asymmetric activation of genes responsible for synaptogenesis especially
of the long range connections between the two hemispheres. This, in turn, is associated with
an underconnectivity and a desynchronization of large cortical networks. All are related
ultimately producing a functional disconnection between brain regions.
Primitive Reflexes are Biomarkers and a Target of Treatment
The persistence of primitive reflexes may actually be one of the earliest markers of abnormal
or delayed cortical maturation and by extension of neurobehavioral disorders. The rooting and
sucking reflexes as well as many other primitive reflexes are present at birth. The inability to
latch on and breast feed, which is often seen in children with developmental delays, as well as
delays or asymmetry of rolling over at 3-5 months of age may be the earliest signs of autistic,
ADHD as well as other neurodevelopmental delays. There are various therapists who
recommend specific exercises that are thought to stimulate or reproduce primitive reflexes as
a way of remediating various neurobehavioral disorders. Although the mechanism of how
these exercises inhibit these reflexes and affect or improve neurobehavioral disorders has not
been previously described to our knowledge. We speculate that utilizing these reflexes
increases the sensory stimulation and feedback to the nervous system that stimulates genes
responsible for synaptogenesis and neuroplasticity of more rostral and complex areas of the
brain. This is associated with inhibition through descending propriospinal connections that
inhibit these reflexes that would under normal circumstances lead to more complex
individualized volitional control of movement that will stimulate growth and cortical
maturity.
CONCLUSION
The persistence of primitive reflexes through childhood and adulthood has been associated
with brain injury and various developmental disorders. They have also been documented in a
number of functional neurological disorders of childhood that are not associated with any
specific neurological insult or pathology. We think that the presence of persistent primitive
reflexes is representative of a maturational delay which is also reflected in structural and
functional changes and various motor and cognitive delays. ADHD, autism and most
neurobehavioral disorders are increasing at epidemic levels and we think that the driving

90 Robert Melillo
force behind this increase is a combination of genetic and environmental factors with the
emphasis being on environmental factors. The most significant epigenetic factors we think
relate to lifestyle changes over the past two decades especially reduction of early motor
activity and spatial exploration of children. We think that this reduces the activation of
activity and experience dependent genes that stimulate synaptogenesis and neuronal plasticity
of central neurons and glial cells that help to build and increase the size and complexity of the
brain during the especially the first 3 years of life. This is the basis we think of both the
maturational cortical delay that has been identified in almost all neurobehavioral disorders
and also the basis of the persistent primitive reflexes.
Normally after the first few months of life, the feedback created by primitive reflexes
generated movement leads ultimately to the inhibition of these reflexes and to the activation
of more complex subsequent postural reflexes, resulting in a more complex interaction with
the environment, that in turn leads to greater sensory feedback thereby activating genes that
allow for the creation of integration and coordination between various cortical networks. As
these cortical networks become more connected and integrated they increase the speed of
their interaction and their synchronization improves allowing more areas to be activated
simultaneously. If cortical maturity and motor coordination are delayed, which may happen as
a result of the abnormal persistence of primitive reflexes, the brain will not continue to grow
and develop at a normal rate thereby delaying the emergence of its more mature functions.
Since the brain‘s hemispheres develop at different rates and at different times, with the
abnormal asymmetric persistence of primitive reflexes a maturational imbalance can be
produced where one hemisphere may mature at a normal rate while the other may be delayed
in its maturity. This can create large imbalances in synchronization and temporal coherence
decreasing the ability for large cortical networks between the two hemispheres from binding
in time and space. This can result in a functional disconnection syndrome which can present
with varied symptoms depending on the time, hemisphere and degree of the maturational
delay and imbalance.
In conclusion, we hypothesize that most neurobehavioral disorders of childhood are a
result of maturational delays and imbalances and not a result of actual structural damage or
pathology, that they are primarily a result of environmental influences, and are therefore
amenable to remediation. We think that the presence of persistent primitive reflexes and the
developmental milestones that might be delayed or absent as a result of those reflexes may be
the earliest markers of developmentally delayed children and also can be a target of early
intervention along with multimodal hemispheric specific intervention.
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Chapter 5
NEUROPLASTICITY OF ASYMMETRIC
CORTICAL FUNCTION
Randy W Beck, BSc, DC, PhD, DACNB, FAAFN

Institute of Functional Neuroscience and Division of Health Sciences,
Murdoch University, Perth, Western Australia
Considerable evidence exists to suggest that a variety if not all cortical systems can
undergo some type of plastic reorganization. Modulation of afferent input (sensory
deprivation or sensory increase) to the cortical areas represents at least one factor that
determines the type of reorganization observed. This innate plastic response is probably
determined to a certain extent by the central integrative state of the neurons and glial
components of the functional projection networks involved. The central integrative state
(CIS) of a neuron is the total integrated input received by the neuron at any given
moment and the probability that the neuron will produce an action potential based on the
state of polarization and the firing requirements of the neuron to produce an action
potential at one or more of its axons. In some instances neuro-plastic responses and the
resultant changes in activity lead to asymmetric functional levels in cortical projection
networks. At some point of asymmetrical dysfunction a critical level of imbalance of
activity or arousal levels between one cortical hemisphere and the other can result in a
functional disconnect syndrome. This paper explores the processes of development and
correction of neuro-plastic induced cortical asymmetry.
INTRODUCTION
Considerable evidence exists to suggest that a variety if not all cortical systems can undergo
some type of plastic reorganization. Modulation of afferent input (sensory deprivation or
sensory increase) to the cortical areas represents at least one factor that determines the type of
reorganization observed. Sensory deprivation leads to the consequence of down regulation for
connectivity and function of the target areas of the cerebral cortex. The pioneering work of

Correspondence: Dr. Randy W Beck, Director, Institute of Functional Neuroscience, Perth, Australia, 146
Fanstone Ave, Beeliar, WA 6164, Australia. E-mail: randywbeck@yahoo.ca.

102 Randy W Beck
Wiesel and Hubel (1, 2) involving the visual cortex has been especially well documented.
Binocular visual occlusion at birth, which prevents all pattern vision, renders the majority of
neurons in the visual cortex either unresponsive to light or unselective to oriented contours.
The resulting situation which has developed from disuse down regulation renders the cortical
system essentially dysfunctional. Increased use, on the other hand, leads to a strengthening of
synaptic connections and an expansion of cortical tissue activated by the corresponding
stimuli. This has been demonstrated particularly well in the somatosensory cortex, where
increased stimulation of particular body parts results in their expanded cortical representation.
This adaptive plastic response of the cortex to afferent stimulus seems to remain throughout
the life of the animal (3, 4). The overall size of the cortical surface does not seem to change,
this leads to the assumption that the expansion of certain body-part representations occurs at
the expense of others. Thus, while the relative size of cortical representations is determined
innately by the number or density of afferent fibers from the sensory periphery, the actual size
of these maps is modulated constantly as a function of sensory experience (5). Changes in
cortical map size do not necessarily mean an increase in functional performance. For instance,
in the development of the visual cortex occlusion of one eye during a critical period ends up
driving fewer neurons and innervating less cortical tissue than the non-occluded eye (1).
However, apart from small improvements in hyperacuity, the non-occluded eye does not seem
to garner any advantage from its vastly expanded control of visual cortical neurons. It seems,
therefore, that the visual cortical system is already working at some predetermined optimum,
which prevents it from improving beyond its innate capability regardless of the stimulus
received (5). This innate capability is probably determined to a certain extent by the central
integrative state of the neurons and glial components of the functional projection networks
involved. The central integrative state (CIS) of a neuron is the total integrated input received
by the neuron at any given moment and the probability that the neuron will produce an action
potential based on the state of polarization and the firing requirements of the neuron to
produce an action potential at one or more of its axons (6, 7).
In some instances the development of expanded cortical maps and the resultant changes
in activity lead to asymmetric functional levels in cortical projection networks. At some point
of asymmetrical dysfunction a critical level of imbalance of activity or arousal levels between
one cortical hemisphere and the other can result in a functional disconnect syndrome (8, 9).
The critical level at which this functional disconnect first becomes symptomatic seems to
vary between individuals. The symptomatic presentation of functional disconnection
syndrome varies widely but can include conditions including attention deficit disorder and
attention deficit hyperactivity disorder (10), autism (11), depression (12), asymmetric control
of the autonomic nervous system, immune system dysfunction, and asymmetric modulation
of sensory perception, as well as cognitive, learning, and emotional processes (12).
In this chapter these concepts are discussed as well as a variety of treatment options for
functional disconnection syndrome secondary to asymmetric cortical function.
Asymmetric Cortical Function
The fact that the human brain functions in an asymmetric manner has been fairly well
established in the literature (13-17). The exact relationship between this asymmetric design
and the functional control exerted by each hemisphere remains controversial.

Neuroplasticity of asymmetric cortical function 103
The concept of asymmetric hemispheric function of the cortex involves the assumption
that the two hemispheres of the brain control different asymmetric aspects of a diverse array
of functions and that the hemispheres can function at two different levels of activation. The
level at which each hemisphere functions is dependent on the central integrative state of each
hemisphere, which is determined to a large extent by the afferent stimulation it receives from
the periphery as well as nutrient and oxygen supply. Afferent stimulation is gated through the
brainstem and thalamus, both of which are asymmetric structures themselves, and indirectly
modulated by their respective ipsilateral cortices (18). Imbalances may develop between the
activation of one hemisphere and the other with a number of different etiological pathways
including aberrant patterns of activation or arousal (19), acute or chronic ablative lesions (20-
22), asymmetric afferentation excesses or deficits (23), inter or intra hemispheric transmission
imbalances (24, 25), circulation deficits, diffuse axonal injury (concussion), asymmetric
neurotransmitter concentrations (26, 27) or asymmetric metabolic dysfunction. Often a
combination of these factors contributes to the state of asymmetry between the hemispheres.
At some point of asymmetrical dysfunction, a critical level of imbalance of activity or arousal
levels between one cortical hemisphere and the other can result in a functional disconnect
syndrome (8, 9). The critical level at which this functional disconnect first becomes
symptomatic seems to vary between individuals. Neuro-plastic changes may be maladaptive
in cases of asymmetric cortical stimulation or inhibition resulting in a chronic state of
disequilibrium in lateralized cortical systems. For example in stroke survivors ablative injury
to areas of cortex may result not only in disruption of functional activities related to the site of
the injury but also in a lack of inhibitory projections to the contralateral hemisphere. This sets
into motion the chronic state of over excitation in the contralateral hemisphere (21, 22). The
chronic disinhibition of the contralesional cortical area may result in a vicious cycle in which
the lesioned area experiences a chronic increased inhibition due to the over excitation of the
contralesional site which in turn inhibits the lesioned site to even greater degree. This same
cycle may develop from any of the etiologies listed above.
Asymmetries in cortical function based on fMRI, BOLD, PET and qEEG studies have
been found in a number of different symptomatologies and conditions including attention
deficit disorder and attention deficit hyperactivity disorder (10), autism (11) approach versus
withdrawal behavior, maintenance versus interruption of ongoing activity, tonic versus phasic
aspects of behavior, positive versus negative emotional valence, asymmetric control of the
autonomic nervous system, and asymmetric modulation of sensory perception, as well as
cognitive, learning, and emotional processes (12) and depression (28).
Hemispheric asymmetries in function have also been shown to exist under normal
physiological conditions such as in the control of movement. For example, the dynamic
dominance hypothesis of movement control in which the left hemisphere is proposed to have
a greater contribution to dynamic control and the right hemisphere a greater contribution to
positional control involved in movements of the limbs (29, 30). Blood (31) has proposed that
motor and postural control exhibit opposite hemispheric dominance and may be involved with
the development and maintenance of dystonias (31).
Functional hemispheric asymmetries have also been shown to exist with respect to
cortical control of cardiovascular function. The research suggests that asymmetries in brain
function can influence the heart through ipsilateral pathways. It is quite clear from the
literature in this area that stimulation or inhibition at various levels on the right side of the
neuraxis results in greater changes in heart rate, while increased sympathetic tone on the left

104 Randy W Beck
side of the neuraxis results in a lowered ventricular fibrillation threshold. This occurs because
parasympathetic mechanisms are dominant in the atria, while sympathetic mechanisms are
dominant in the ventricles (32, 33).
Neurotransmitter asymmetries in the cortex have also been discovered. Quite consistent
results have been reported in a number of studies that have suggested that noradrenergic
innervation, the biological substrate of arousal shows a clear right hemispheric asymmetry
(27, 34, 35). Several studies have also shown strong indications that the neurotransmitter
serotonin shows a right hemispheric dominance (36, 37, 38), which may occur from birth as
an inborn feature of cortical function (39). The role of gating signals, such as acetylcholine, in
the enhancement of cortical plasticity (40, 41) may also play a role in the development of
asymmetric activation.
Cortical asymmetries have also been documented with respect to hormonal regulation.
Cortisol secretion has been associated with the right hemisphere with predominance of
control demonstrated in this hemisphere during emotionally-related situations (42, 43).
Various studies have shown that right hemispheric chemical dominance was associated with
up-regulation of the hypothalamic-mediated isoprenoid pathway and was more prevalent
among individuals with various metabolic and immune disorders including a high body mass
index, various lung diseases including asthma and chronic bronchitis, increased levels of lipid
peroxidation products, decreased free radical scavenging enzymes, inflammatory bowel
disease, systemic lupus erythematosis (SLE), osteoarthritis, and spondylosis. Left
hemispheric chemical dominance was associated with a down-regulated isoprenoid pathway
and was more prevalent among individuals with low body mass index, osteoporosis, and
bulimia.
A number of studies have indicated that cortical asymmetries may exist when different
emotional states are activated. The left frontal cortex appears to be activated during the
expression or experience of positive emotional states, whereas the right frontal cortex seems
to be activated during the expression or experience of negative emotional states (44-47). The
severity of symptoms in depression has been linked to the activation levels in the left frontal
cortex (48). Those patients with left frontal cortex lesions with sparing of the right frontal
cortex showed the most severe depressive symptoms.
Cortical asymmetry has also been shown to be important in immune regulatory functions.
Natural killer cell activity was significantly increased in human females with extreme left
frontal cortical activation when compared to females with extreme right cortical frontal
activation (49). The level of hemispheric activation in these women was determined by
electro-encephalographic (EEG) determinants of regional alpha power density. This
measurement has been shown to be inversely related to emotional or cognitive brain
activation (44). A variety of animal studies have also provided direct evidence of the
relationship between cerebral asymmetry and immune system function (50, 51). Partial
ablation of the left frontoparietal cortex in mice, which results functionally in relative right
cortical activation, resulted in decreased immune responses and partial right cortical ablation,
which would result functionally in a left cortical activation showed no change or a reduced
immune response (52, 53). Other studies have shown that the development of the lymphoid
organs including the spleen and thymus occurs with left cortical lesions, whereas increased
development of the spleen and thymus occurs with right cortical lesions and activation of T
cells is significantly diminished in lesions involving the left cortex and elevated with lesions
of the right cortex (54-56). These findings indicate that T-cell-mediated immunity is

modulated asymmetrically by both hemispheres with each hemisphere acting in opposition to

the other. Increased activity of the left cortex seems to enhance the responsiveness of a
variety of T-cell-dependent immune parameters, whereas increased right cortical activity
seems to be immunosuppressive. B-cell activity was found not to be affected by cortical
activation asymmetry (51, 57).
It appears from the findings of the above studies that changes in hemispheric activation
because of either ablation of cortical areas or modulation in physiological activation levels
result in changes in immunological response activity. Both hemispheres seem to be active in
the modulation of immune response, with the left hemisphere enhancing cellular immune
responses and the right inhibiting those responses. Some evidence does suggest that the
involvement of the right hemisphere may not act directly on immune components but may
modulate the activity of the left hemisphere which does act directly to regulate immune
function (52).
Fundamental functional projection systems
The cortical asymmetries outlined above become even more important clinically when
we consider some of the basic fundamental functional projection systems utilized by the
cortex to modulate activity in wide-ranging areas of the neuraxis. About 90% of the output
axons of the cortex are involved in modulation of the neuraxis. About 10% of the cortical
output axons of the cortex are involved in motor control and form the corticospinal tracts. Of
the 90% output dedicated to neuraxis modulation about 10% projects bilaterally to the
reticular formation of the mesencephalon (MRF) and 90% projects ipsilaterally to the
reticular formation of the pons and medulla or pontomedullary reticular formation (PMRF).
The cortical projections to both the MRF and the PMRF are excitatory in nature. The neurons
in the MRF and some of those in the PMRF project bilaterally to excite neurons in the
intermediolateral (IML) cell columns located between T1 and L2 spinal cord levels in the
grey matter of the spinal cord; however, the majority of the PMRF remain ipsilateral (58).
These neurons in the IML form the pre-synaptic output neurons of the sympathetic nervous
system, and project to inhibit neurons in the sacral spinal cord regions that form the pelvic or
sacral output of the parasympathetic nervous system. Following the stimulus flow through the
functional system it can be seen that high cortical output results in high PMRF output, which
results in strong inhibition of the IML, which in turn results in disinhibition of the sacral
parasympathetic output. The bilateral excitatory output of the MRF is overshadowed by the
powerful stimulus from the cortex to the PMRF (Figure 1).
To further illustrate the impact that an asymmetric cortical output could potentially have
clinically, consider the effects of an asymmetric cortical output on the activity levels of the
sympathetic and parasympathetic systems on each side of the body. Autonomic asymmetries
are an important indicator of cortical asymmetry as this reflects on fuel delivery to the brain
(sympathetic system) and the integrity of excitatory and inhibitory influences on sympathetic
and parasympathetic function throughout the rest of the body. The PMRF has other
modulatory effects in addition to modulation of the IML neurons. All of the modulatory
interactions of the PMRF have clinical relevance and include:

106 Randy W Beck
 Inhibition of pain ipsilaterally;

 Inhibition of the inhibitory interneurons which project to ventral horn cells (VHCs)
ipsilaterally which acts to facilitate muscle tone—this is another example of
inhibition of inhibition in the neuraxis as discussed above; and
 Inhibition of the ipsilateral anterior muscles above T6 and the posterior muscles
below T6.
Figure 1. Functional Projection Systems from the Cortex to the Reticular Formations of the Brainstem.

A sense of the clinical impact that asymmetric stimulation of the PMRF can produce
symptomatically in a patient becomes apparent when it is considered that all of the following
can result:
 Increased blood pressure systemically or ipsilaterally to the side of decreased PMRF

stimulation, which results in differences in blood pressure between right and left
sides of the body;
 Increased vein-to-artery ratio, which is most apparent on examination of the retina;
 Increased sweating globally or ipsilaterally to the side of decreased PMRF
stimulation;
 Decreased skin temperature globally or ipsilaterally to the side of decreased PMRF
stimulation;
 Arrhythmia if decreased left PMRF stimulation occurs or tachycardia if decreased
right PMRF stimulation occurs;
 Large pupil (also due to decreased mesencephalic integration) to the side of
decreased PMRF stimulation;
 Ipsilateral pain syndromes to the side of decreased PMRF stimulation;
 Global decrease in muscle tone ipsilaterally to the side of decreased PMRF
stimulation;
 Flexor angulation of the upper limb ipsilaterally to the side of decreased PMRF
stimulation; and
 Extensor angulation of the lower limb ipsilaterally to the side of decreased PMRF
stimulation.
Clinical presentation of ipsilateral flexor angulation of the upper limb and extensor
angulation of the lower limb is known as pyramidal paresis, and is an important clinical
finding in many patients with asymmetric cortical function.
Measuring cortical function
Another method used to identify cortical asymmetric activity involves the measurement of the
electrophysiological activity in the cortex itself. To measure the complex patterns of brain
activity tools are needed with the appropriate temporal and spatial resolution. This task is not
as simple as it sounds because ―appropriate resolution‖ varies with different types of analysis
and utility expectation of the information. The measurement tool must measure the particular
activity we are interested in without interfering with it to any great extent.
Neurons function through the production of two fundamentally different activities
involving analogue (local field potentials) and digital (action potentials) components (59).
Both of these activities are continuously changing over time and involve multiple frequencies
and amplitudes. Therefore the perfect measurement tool would be able to provide a time-
frequency analysis algorithm that would provide a perfect picture of all changes in all
frequencies continuously over time in whatever spatial dimension we choose to explore. All
of the current methods of measuring brain function involve a compromise between the
desired temporal and spatial resolution necessary for complete analysis. The desired temporal

108 Randy W Beck
resolution is in the order of the operation speed of the neuron, or at very least neuron systems,
which is in the millisecond arena. The desired spatial resolution varies between molecular
interaction to global brain activity depending on the processes being investigated and the
questions being asked. No current method exists that can continually and instantaneously
monitor between decimeter and molecular spatial scales (59). Obviously, the methods
available at this time differ in their spatial and temporal resolution, and none of them achieve
the highest resolution in both domains. For example what fMRI gains in spatial resolution it
loses in temporal resolution and vice versa for EEG. Quantitative electroencephalography
(QEEG) has been shown to be a valid instrument in the evaluation of a variety of components
of cognitive function (60, 61). Computer-assisted EEG analysis and interpretation offers
multiple advantages over visual inspection of raw EEG tracings, including the ability to
derive measures, perform data transforms, and identify subtle shifts in the types and patterns
of EEG activity.
The most commonly used qEEG measures of these types include: frequency composition
of the EEG over a given period (spectral analysis); absolute and relative amplitude
(μV/cycle/second) and power (μV2/cycle/second) within a frequency range or at each
channel; coherence (analogous to cross-correlation in the frequency domain between activity
in two channels); phase (relationships in the timing of activity between two channels); and
symmetry between homologous pairs of electrodes. Data of these types may be mapped over
the scalp surface (historically referred to as brain electrical activity mapping, or BEAM,
among other terms). Statistical probability mapping of such data may be used to construct
topographical maps for visual inspection.
Among qEEG measures, frequency analyses and coherence are of particular interest in
the study of mild TBI and post-concussive symptoms. The scalp-measured frequency of the
electrical energy generated by groups of cortical neurons varies with: their numbers (i.e., as
neurons are lost, the amplitude (and therefore power) of electrical energy recorded at the
scalp diminishes); the integrity of the thalamocortical circuits in which they participate (i.e.,
injury to and/or dysfunction of those circuits results in a shift to slower frequencies recorded
at scalp electrodes); and the influence of ‗bottom-up‘ activation from the reticular system
(i.e., with increases in reticular activating system activity, shifts toward higher frequencies are
observed, whereas decreases in the activity of this system shifts cortical activity towards
lower frequencies). Coherence evaluates the correlation between EEG activity (in the
frequency domain) between scalp electrodes, and therefore may serve as an indicator of
neural network connectivity and dynamics (61).
Low resolution brain electromagnetic tomography (LORETA) (62) is another functional
imaging method based on electrophysiological and neuroanatomical constraints. LORETA
and its variants have been employed by many studies seeking to analyze spectral components
of EEG activation (63). LORETA also promises to be a useful method for the localization of
neural generators in the study of long-distance neural synchronization and in identifying
asymmetries in cortical function (see Figures 2 and 3).
Treatment of cortical asymmetry
The treatment of cortical asymmetry centers on the understanding of neuroanatomy and the
application of the concepts of central integrative state and neuro-plasticity.

Figure 2. QEEG produced Topographic head maps and a LORETA brain image demonstrating a left
hemisphere infarction in a patient.
Figure 3. LORETTA images demonstrating asymmetrical cortical activation following concussion.
Central Integrative State (CIS) of a neuron
The central integrative state (CIS) of a neuron is the total integrated input received by the
neuron at any given moment and the probability that the neuron will produce an action
potential based on the state of polarization and the firing requirements of the neuron to
produce an action potential at one or more of its axons. The physical state of polarization
existing in the cell at any given moment is determined by the temporal and spatial summation
of all the excitatory and inhibitory stimuli it has processed at that moment. The complexity of
this process can be put into perspective when you consider that a pyramidal neuron in the

110 Randy W Beck
adult visual cortex may have up to 12,000 synaptic connections, and certain neurons in the
prefrontal cortex can have up to 80,000 different synapses firing at any given moment (64,
65).
The firing requirements of the neuron are usually genetically determined but
environmentally established and can demand the occurrence of complex arrays of stimulatory
patterns before a neuron will discharge an action potential. Some examples of different
stimulus patterns that exist in neurons include the 'and/or' gated neurons located in the
association motor areas of cortex and the complex rebound burst patterns observed in
thalamic relay cells. ‗And‘ pattern neurons only fire an action potential if two or more
specific conditions are met. ‗Or‘ pattern neurons only fire an action potential only when one
or the other specific conditions are present (66). The thalamic relay cells exhibit complex
firing patterns. They relay information to the cortex in the usual integrate and fire pattern
unless they have recently undergone a period of inhibition. Following a period of inhibition
stimulus, in certain circumstances, they can produce bursts of low-threshold spike action
potentials referred to as post-inhibitory rebound bursts. This activity seems to be generated
endogenously and may be responsible for production of a portion of the activation of the
thalamocortical loop pathways thought to be detected in encephalographic recordings of
cortical activity captured by electroencephalograms (EEG) (67). The neuron may be in a state
of relative depolarization, which implies the membrane potential of the cell has shifted
towards the firing threshold of the neuron. This generally implies that the neuron has become
more positive on the inside and the potential difference across the membrane has become
smaller. Alternatively, the neuron may be in a state of relative hyperpolorization, which
implies the membrane potential of the cell has moved away from the firing threshold. This
implies that the inside of the cell has become more negative in relation to the outside
environment and the potential difference across the membrane has become greater (68).
The membrane potential is established and maintained across the membrane of the
neuron by the flux of ions; usually sodium (Na), potassium (K), and chloride (Cl) ions are the
most involved although other ions such as calcium can be involved with modulation of
permeability. The movement of these ions across the neuron membrane is determined by
changes in the permeability or ease at which each ion can move through selective channels in
the membrane. When Na ions move across the neuron membrane into the neuron, the
potential across the membrane decreases or depolarizes due to the positive nature of the Na
ions, which increases the relative positive charge inside the neuron compared to outside the
neuron. When Cl ions move into the neuron, the neuron membrane potential becomes greater
or hyperpolarizes due to the negative nature of the Cl ions, which increase the relative
negative charge inside the neuron compared to outside the neuron. The same is true when K
ions move out of the neuron due to the relative loss of positive charge that the K ions possess.
The firing threshold of the neuron is the membrane potential that triggers the activation of
specialized voltage gated channels, usually concentrated in the area of the neuron known as
the axon hillock or activation zone, that allow the rapid influx of Na into the axon hillock
area, resulting in the generation of an action potential in the axon (69).
The concept of the CIS described above in relation to a single neuron can be loosely
extrapolated to a functional group of neurons. Thus, the central integrative state of a
functional unit or group of neurons can be defined as the total integrated input received by the
group of neurons at any given moment and the probability that the group of neurons will

produce action potential output based on the state of polarization and the firing requirements
of the group (6, 7).
The concept of the central integrative state can be used to estimate the status of a variety
of variables concerning the neuron or neuron system such as the probability that any given
stimulus to a neuron or neuron system will result in the activation of the neuron, or neuron
system; the state of pro-oncogene activation and protein production in the system; and the rate
and duration that the system will respond to an appropriate stimulus (6, 7).
Neural plasticity
Neural plasticity results when changes in the physiological function of the neuraxis occur in
response to changes in the internal or external milieu (70). In other words the development of
synapses in the nervous system is very dependent on the activation stimulus that those
synapses receive. The synapses that receive adequate stimulation will strengthen and those
that do not receive adequate stimulation will weaken and eventually be eliminated. The
organization of the synaptic structure in the neuraxis largely determines the stimulus patterns
of the nervous system and hence the way in which the neuraxis functions. Neural plasticity
refers to the way in which the nervous system can respond to external stimuli and adjust
future responses based on the outcome of the previously initiated responses. In essence, the
ability of the nervous system to learn is dependent on neural plasticity.
The processes of neuro-plasticity can be expressed at two interacting levels of nervous
system function such as at the level of motor or sensory representations of body parts in the
cortex which corresponds to representational or map plasticity; or at the neuronal level which
can involve synaptic plasticity or changes in neuron activation levels or morphology (71). In
the somatosensory cortex some forms of plasticity can occur very rapidly within minutes to
hours (72). For instance, cortical neurons deafferented by peripheral nerve lesion or
amputation rapidly become responsive to sensory input from adjacent functioning sites (23,
73, 74). In the motor cortex neurons can also rapidly reorganize their representative maps in
response to nerve lesions or ischaemic nerve block (75) or during motor practice (76-78). It is
now well documented that changes in somatocortical activation can be directly linked to both
direct and indirect somatosensory input from peripheral receptors including joint receptors
and muscle spindle afferent projections (79-81). Several mechanisms have been suggested to
explain these plastic changes in the cortex. These include changes in synaptic efficacy
(Hebbian plasticity) or by reducing or modifying protein synthesis and proteinase activity in
nerve cells via receptor activation of immediate early genes. These processes are controlled
by the central integrative state of the neuron and are thus strongly influenced by the
stimulation status of the neuron.
Synaptic efficacy and Unmasking of Latent Horizontal Connections
Synaptic connections are maintained by neurons when they are active and produce activity
(action potentials) in the primary neurons. These connections modulate the neurons output
through temporal and spatial summation characteristics at any given moment. Mechanisms

112 Randy W Beck
responsible for this type of plasticity include long-term potentiation (LTP) and long-term
depression (LTD) (82). An intriguing example of this process has been proposed as a reason
for our need to sleep and dream. The Hebbian principal of synaptic maintenance due to
activation also suggests that synapses or connections between inactive neurons are being
constantly degraded due to spontaneous down regulation of molecules and substrates
necessary for maintenance of synaptic function. In circuits were activity levels are high these
processes are refreshed by the constant activation and expression of the genes that code for
the necessary substrates. Circuits that are infrequently utilized refresh their synaptic strength
during sleep and dreaming (83). During sleep the maintenance of synaptic fitness in long term
memory circuits and circuits not frequently utilized while we are awake is stimulated by
spontaneous slow (delta) wave oscillations and via fast wave stimulus during the REM
component of sleep (84). The activation of new and old memory circuits during REM sleep
may result in what we perceive as dreams (85).
It seems that many synaptic connections that are maintained in the system have a
moderate to low efficacy for individually inducing a large enough change in a neurons‘
membrane potential to result in the generation of an action potential. Some of these pre-
existing but semi dormant projection fibres have been referred to as horizontal fibres.
Should the firing characteristics of other more primary firing inputs to the neuron change
say through functional dysfunction, trauma or stroke then the effect of these synapses on the
system become ―unmasked‖ and may change their effects on the system drastically.
The effects may be either beneficial or harmful to the individual depending on a complex
set of circumstances including the functional area of the brain involved and the increase or
decrease in inhibitory influences on the system.
For example, in the case of a stroke, survivors typically experience an acute increase in
perilesional excitability due to, for the most part, increases in excitatory neurotransmitters,
followed by chronic changes that include changes in intracortical and interhemispheric
inhibitory imbalances that manifest in a variety of physical symptoms that could facilitate or
hinder recovery depending on the functional systems involved (20).
Immediate early gene activation of protein synthesis
It is now commonly accepted that the brain controls mental, physiological and behavioural
processes and that brain function is controlled by gene activation. It is also accepted that
social, developmental and environmental factors can alter gene expression and that alteration
in this gene expression induces change in brain function (86). This process is accomplished
by special transmission proteins called immediate early genes (IEG) which are activated by a
variety of second messenger systems in the neuron in response to membrane stimulus (87,
88). Two types of IEG responses have been recognized and include Type 1 IEG responses
which are specific for the genes in the nucleus of the neuron and type 2 IEG responses which
are specific for mitochondrial genes (89). These genes are activated by a complex interaction
involving receptor stimulation and the biochemical status of the neuron.

Regeneration
Regeneration involves the re-sprouting or new formation of dendrites and or axons that form
new synapses. This re-growth is usually associated with the release of various nerve growth
factors. This type of neural plasticity can be stimulated by ablative lesions such as stroke (90).
Redirection, reorganisation or rerouting of nerve transmission
This type of plasticity includes creation of new anatomical connections (sprouting of axons
and dendrites) or elimination of existing connections or by altering synapses morphologically
(91). A typical example of this type of plastic change is recovery after ischemic strokes.
Mechanisms of plasticity result in re-organization of the nervous system in such a way as to
allow other parts of the CNS take over some of the functions that were impaired from the
ablative loss of neural tissue. For example, injury to cortical areas elicits a sequence of self-
repair mechanisms, including redirection of tasks to other cortical areas. This reorganization
may include functional circuits far removed from the original site of injury. This injury-
induced reorganization may include enlargement of the cortical areas representative of the
new circuits involved, and it may provide the neural substrate for adaptation and recovery of
motor behaviour after injury (92). This type of reorganization seems to occur spontaneously
in response to injury and training can facilitate the shift of processing from damaged parts of
the CNS to more functionally intact areas. Focused rehabilitation that facilitates expression of
neural plasticity is presently the most effective form of reorganization stimulus but additional
methods are under investigation and include stimulation of the cerebral cortex utilizing both
direct current in the form of transcranial direct current stimulation (tDCS) (93, 94) and
magnetic currents in the form of transcranial direct magnetic stimulation (TMS) (95, 96).
Apoptosis
This type of plasticity involves elimination of neurons through pre-programmed or

chemically induced cell death. Most neuronal systems undergo a phase of substantial neuron
death at some phase of their development. In most neuron systems about 50% of the initial
neurons formed undergo cell death. This process usually occurs temporally at the same time
that the axons of the system have formulated contacts with their destination areas. This
suggests that a certain amount of the stimulus for neuron death may actually arise or be
initiated from the axon destination field through some form of feedback system (97). The
feedback mechanism may be in the form of tropic growth factors produced at the destination
site tissues. Active competition by axons for these growth factors may determine which axons
and thus which neurons remain alive.

114 Randy W Beck
Afferent Modulation of Cortical Function
The development and maintenance of functional projection systems of the neuraxis is

dependent on the central integrative state of the neurons supporting the projection fibres of
the system. This is dependant to a large degree on the afferent input and efferent output
transmitted by the system. Changes in cortical activation can result from changes or
attenuation of afferent information arriving in the cortex from peripheral or subcortical
structures. The changes resulting from attenuation of the afferent input that are manifested
both morphologically and functionally in the cortex seem to also occur at all levels within the
projection system involved (98). For instance, changes in cortical somatotopic maps in cats
also show acute and chronic changes at the level of the spinal cord, dorsal columns and the
thalamus following nerve transsection (99, 100). Similar findings have also been found in
monkeys (23, 98, 101).
There is extensive evidence that alterations in motor activities which involve both
afferent and efferent projection systems can induce structural and functional plasticity within
the cortex, basal ganglia, cerebellum and spinal cord in humans (102-105). Novel movement
performance induces changes in cortical synaptic number, strength, and topography of
cortical maps in the projection systems and neural assemblies involved in the performance of
the movements (106). Peripheral sensory stimulation has also been shown to induce long
lasting modulation of cortical activation and cortical motor output (107). Cortical
representation of cranial nerves has also been shown to modulate with alterations in afferent
input. Hamdy, 1998, reported an increase in excitation levels in the pharynx cortical
representation maps following short term (10 min) stimulation of the pharynx (108). These
changes lasted 30 minutes following the cessation of the initial stimulus. In a similar study,
Ridding, 2000 showed that repetitive mixed nerve stimulation of the ulnar nerve increased the
excitability of the cortical projections to the hand muscles of the same hand lasting at least 15
minutes longer than the stimulus (107). The rapid development of these plastic changes
suggests that the mechanism involves unmasking or disinhibition of pre-existing weak
(horizontal) projections (71).
APPROACHES TO TREATMENT OF CORTICAL

ASYMMETRIC FUNCTION
Spinal manipulation
Spinal manipulation of dysfunctional joints may modify transmission in neuronal circuitries

not only at a spinal level as indicated by previous research but at a cortical level, and possibly
also deeper brain structures such as the basal ganglia.
Spinal manipulation of dysfunctional cervical joints can lead to transient cortical plastic
changes, as demonstrated by attenuation of cortical somatosensory evoked responses.
Cervical spine manipulation may alter cortical somatosensory processing and
sensorimotor integration (109, 110). The pathways involved in the modulation of the cortex
and supraspinal structures remain controversial however Holt, Beck and Sexton have
proposed the following potential mechanisms (111):

1. Cervical manipulations excite spinoreticular pathways or collaterals of dorsal column

and spinocerebellar pathways.
2. Cervical manipulations cause modulation of vestibulosympathetic pathways.
3. Cervical manipulations cause vestibulocerebellar activation of the nucleus tractus
solitarius (NTS), dorsal motor nucleus of vagus, and nucleus ambiguous.
4. Manipulations may result in brain hemisphere influences causing descending
excitation of the pontomedullary reticular formation (PMRF). The PMRF will exert
tonic inhibitory control of the IML.
5. Lumbosacral manipulations may result in sympathetic modulation due to direct
innervation of the RVLM via dorsal column nuclei or spinoreticular fibers that
ascend within the ventrolateral funiculus of the cord.
6. Spinal manipulation may alter the expression of segmental somato-sympathetic
reflexes by reducing small-diameter afferent input and enhancing large-diameter
afferent input. This may influence sympathetic innervation of primary and secondary
organs of the immune system.
7. Spinal manipulations may alter the expression of suprasegmental somato-
sympathetic reflexes by reducing afferent inputs on second order ascending
spinoreticular neurons. This may influence sympathetic innervation of immune
system organs at a more global level.
8. Spinal manipulations may alter central integration of brainstem centres involved in
descending modulation of somato-sympathetic reflexes. This may occur via
spinoreticular projections or interactions between somatic and vestibular inputs in the
reticular formation.
9. Spinal manipulations may alter central integration in the hypothalamus via
spinoreticular and spinohypothalamic projections and the influence of spinal
afferents on vestibular and midline cerebellar function.
10. Spinal manipulations may influence brain asymmetry by enhancing summation of
multi-modal neurons in the CNS, monoaminergic neurons in the brainstem or basal
forebrain regions, cerebral blood flow via autonomic influences, or by influencing
the hypothalamic-mediated isoprenoid pathway.
CONCLUSION
It seems clear that a great deal of research has documented that the brain often works in an
asymmetric fashion in order to produce accurate and efficient processing and integration of
information. It also appears clear that if these asymmetric processes become unbalanced they
can result in unwanted thoughts, actions and behaviors.
The recognition and correction of these cortical asymmetries in clinical practice offers the
great hope of reducing the afflictions experienced by humankind as a result of these
dysfunctional states.

116 Randy W Beck
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Chapter 6
TRAUMATIC BRAIN INJURY:

NEUROPSYCHOLOGICAL REHABILITATION
Nazareth P Castellanos*, PhD1

Elisa Rodríguez-Toscano1,
Javier García-Pacios1, Pilar Garcés1, Nuria Paúl2,
Pablo Cuesta1, Ricardo Bajo1, Juan García-Prieto1,
Francisco del-Pozo1 and Fernando Maestú1,3
1
Laboratory of Cognitive and Computational Neuroscience
(Centre of Magnetoencephalography), Centre of Biomedical Technology (CBT).
Universdiad Politécnica de Madrid, Madrid, Spain
2
Department of Basic Psychology I – Basic Process,
Universidad Complutense de Madrid, Madrid, Spain
3
Department of Basic Psychology II – Cognitive Process,
Universidad Complutense de Madrid, Madrid, Spain
Brain plasticity is understood as the capacity of the brain to evolve, or recover after an
aggression. Even in the adult brain, plasticity plays an important role in functional
recovery after acquired brain injury, which might have significant relevance to the
practice of neurorehabilitation. It is of special interest to identify the mechanisms
underlying plasticity for functional improvement after injury. A very appropriate
platform to study the principles followed by brain plasticity is the study of brain activity
changes after brain injury and posterior recovery. To reach this goal we analyzed the
magnetoencephalographic recordings from 15 traumatic brain injured patients before and
after neuropsychological rehabilitation and 14 healthy controls, in resting state condition.
We compared the entropy and complexity in these three conditions to estimate how the
brain injury impact alters the dynamical pattern of the brain activity. After traumatic
brain injury the brain is globally more complex and entropic, principally in frontal and
occipital areas. These values were restored after rehabilitation, statistically approaching
*
Correspondence: Dr. Nazareth P Castellanos, Laboratory of Cognitive and Computational Neuroscience, Centre
for Biomedical Technology, Campus de Montegancedo 28660, Universidad Politécnica de Madrid, Madrid,
Spain. E-mail: nazareth@pluri.ucm.es.

122 N P Castellanos, E Rodríguez-Toscano, J García-Pacios et al.
to the healthy control reference. Change in patient complexity negatively correlates with
PCRS, reflecting the patient‘s current ability to adapt to daily living activities. The
characterization of neurophysiological changes would allow us to know the mechanism
of recovery and the possible identification of recovery markers.
INTRODUCTION
Traumatic brain injury (TBI) is one of the most common causes of disability in the world.
After TBI, the impairment in essential functions for routine activities, such as movement
programming and execution, sensorimotor integration, language and other cognitive functions
have a deep and life-long impact on life's quality. The brain‘s capacity to recover and adapt to
new environments, which is called neuroplasticity or brain plasticity, is also a crucial
neurophysiological mechanism after brain lesions. Growing evidence shows that the brain is
capable of significant spontaneous functional recovery after brain injury due to plastic
mechanisms that can be enhanced by the use of therapies. In order to treat cognitive deficits,
neuropsychological rehabilitation has been developed as a systematic, functionally oriented
therapeutic intervention, based on: the assessment and understanding of patient‘s cognitive
deficits, emotional or behavioural regulation problems and functional disabilities. The term
―Neuropsychological Rehabilitation‖ can be applied to any intervention, programme or
technique carried out with the purpose of enabling people and their relatives to live with,
manage, by-pass, reduce or come to terms with cognitive deficits caused by a neurological
alteration or disease (1). Therefore, the practice of this discipline is not only concerned with
cognitive deficits of these patients but also with emotional, behavioral and psychosocial
consequences of their condition, as well as the impact of this condition on family members,
attempting to provide them with tools that achieve the best possible quality of life. Currently,
it is possible to find a large amount of literature supporting the benefits of various types of
cognitive interventions with traumatic brain injury patients (2-6). Nevertheless, the scientific
study of the effectiveness of rehabilitation is limited not only by the heterogeneity of subjects
and interventions, but also by the ethical principles that guide its practice, as well as the
different measures of outcomes available and the varied methodologies used for this purpose.
A common measure of treatment effectiveness refers to changes observed on psychometric
tests of cognitive function, before and after the rehabilitation process (7). This method is
mainly used in clinical settings by neuropsychologists and corresponds to what Carney and
colleagues (8) call ―indirect evidence‖ of effectiveness, while measures of employment and
real-life function are considered ―direct evidence.‖ Within the latter, there is a wide range of
tools for evaluating outcomes (e.g., Glasgow Outcome Scale (GOS), the Disability Rating
Scale (DRS), Functional Independence Measure (FIM), the Functional Assessment Measure
(FAM) or the Barthel Index) as well as a lack of consensus about the most appropriated ones
for scientific purposes.
Notwithstanding, the mechanisms that take place within the brain during the
rehabilitation process and the way in which cortical reorganization occurs have not been
completely unveiled yet, although the increased use of functional neuroimaging methods is
enhancing our understanding of brain damage and neuronal plasticity (9). Research has
shown that practice and experience can produce changes in the organization of the cerebral
cortex as well as some evidence about neuronal reorganization following rehabilitation have

Traumatic brain injury: Neuropsychological rehabilitation 123
already been provided. Some of these studies have found a decrease of activation in specific
brain regions associated with better functional recovery outcomes, such as the activation
pattern became similar to ones observed in normal subjects (for reviews, see 10, 11). In
contrast, other studies have reported an increase in the activation pattern after rehabilitation,
especially in contralesional areas. On the other hand, a combination of increases and
decreases has been also observed, either reflecting a quantitative change in the pattern of
activation within the same areas, redistribution of functional activations, or a qualitative
reorganization to different cortical areas, ―process switching‖ (12). Considering that cognitive
processes require a functional interaction between specialized multiple, local and remote
brain regions, a new approach has been used based on the idea that these interactions can be
strongly altered in brain injury. Very recently, in Castellanos and her colleagues (13, 14)
evaluated the impact of brain injury on functional connectivity patterns, showing a correlation
between changes in the brain functional connections and the neuropsychological
improvement of the patients after rehabilitation. We showed that the functional connectivity
pattern was restored to healthy-control ones after recovery, specifically in delta and alpha
bands, and we designed a model that could give some hints about how the functional
networks modify their weights in the recovery process. These results might indicate that the
structure of the functional networks evolves in parallel to brain recovery with correlations
with neuropsychological scales.
Functional connectivity, which can be estimated from non-invasive techniques as MEG
or EEG, refers to the functional association between recording brain sites (15, 16). However,
due to technical limitations we cannot easily infer in the local underlying synchronization of
the brain activity recorded with a scalp-sensor. Indirect measures of such synchronization
could reflect the dynamic properties of the brain activity and its alteration due to brain injury.
Very recently used measures to characterize brain signals are the complexity and the entropy.
The definition of complexity is still today a matter of debate in the scientific community (17).
Formally, complexity is defined as ―the state of being formed of many parts; the state of
being difficult to understand.‖ But intuitively we could define complexity as a measure which
increases when the variety (distinction) of components increases, and it is directly related to
the dependency (connection) of parts. For example Tononi et al. (18) proposed a measure,
called ‗neural complexity (CN),‘ which can be defined as a balance between functional
segregation and integration in the brain. The majority of these measures can be defined as an
estimate of the regularity/variability of brain oscillations and an attempt to evaluate the
number of independent oscillators or frequency components underlying the observed signal
(Figure 1). Therefore, the higher the level of complexity, the more components oscillating
independently, with lower degree of communication between one another. Complexity is
determined in several dimensions, as the three spatial dimensions, geometrical structure,
spatial scale, time and dynamical scale (17). Nowadays, complexity is receiving a growing
interest in different scientific fields (19, 20), as for example in the field of signal processing
(21) and dynamical systems, where several measures of complexity are available (Hausdorff
dimension to Lyapunov exponent, and Kolmogorov-Smirnov entropy). (For a comparison of
different measures in the Neuroscience (multichannel EEG) see (23)).

Figure 1. Complexity can be defined as the number of independent oscillatory components in the brain
signal (measured by scalp recording sites). The lack of synchronization between components produces
an increase of complexity.
In this work we aim to study for first time how complexity and entropy of brain activity
change as a consequence of traumatic brain injury. To this end, we estimated entropy and
complexity of MEG signals from a TBI patients group, before and after cognitive treatment,
and from an age-matched healthy controls group, in resting state condition. With the
following hypothesis: 1) If complexity values increase with disintegration of the global
network, patients before cognitive rehabilitation will show higher levels of complexity than
healthy volunteers; 2) if cognitive rehabilitation affects the functional brain network, in
accordance with previous studies (13, 14), complexity values in patients after rehabilitation
will be lower than before rehabilitation. Moreover, cognitive rehabilitation will approximate
patients‘ complexity values to those showed by healthy controls; and 3) changes in
complexity due to cognitive rehabilitation will correlate with improvement in measures of
daily living competency.
OUR STUDY
29 adults took part in the experiment: 15 traumatic brain injured (TBI) patients and 14 healthy
controls. All TBI patients were included in a neurorehabilitation program (mean age 32.13
years; age range, 18 to 51 years; mean level of education, 13.7 years; range, 8 to 18 years;
mean time since stroke, 3.8 months; range, 2 to 6 months; neurorehabilitation program period,
9.4 months; range, 7 to 12 months; Table 1).
All TBI patients showed severe cognitive impairments in several domains such as
attention, memory and executive functions. Experimental and healthy control groups were
matched for age (31.93), educational level (15.57) and gender. None of them had previous
history of psychiatric disease or extended psychoactive drug consumption.
We took MEG recordings and neuropsychological assessments before (―pre‖) and after
(―post‖) neuropsychological rehabilitation program. However, control subjects were

measured once, assuming that brain networks do not change in their structure in less than one
year, as demonstrated previously in young (23) and elderly subjects (24).
Informed consent was obtained from each subject or a legal representative after full
explanation of the study. The Research Local Ethics Committee approved the study.
Neuropsychological assessment of both groups included a number of standardized test
and functional scales in order to provide their cognitive and functional status concerning
attention skills, memory processes, language, executive functions, visuospatial abilities and
some daily activities. The subjects of experimental group received individual
neuropsychological treatment during 1 hour, for 3-4 times per week. In some cases, cognitive
intervention was coupled with other types of neurorehabilitation therapies according to the
patient´s profile (physiotherapy, speech therapy or occupational therapy). For more detailed
description see (13).
MEG and data preprocessing
Cortical magnetic signals were recorded with a 148-channel whole-head magnetometer (4D-
MAGNES 2500 WH, 4-D Neuroimaging) confined in a magnetically shielded room. The
recording was bandpass filtered between 0.1 and 50 Hz and raw data were submitted to a
noise reduction procedure. Magnetic fields were measured during resting state with opened-
eyes condition, at a sampling rate of 169.45 Hz. Time-segments containing eye movements,
blinks, other myogenic or mechanical artifacts were visually rejected by experienced
investigators, reaching to 12s length segments. Digitized MEG data were imported into
MATLAB Version 9.1 (Mathworks, Natick, MA, USA) for analysis with custom-written
scripts.
Entropy, complexity (SMC index) and statistics
Entropy can be defined as the average amount of code necessary to encode the draws of a
discrete variable X with M possible outcomes Xi, each of them with probability pi. The
Shannon entropy (25) of this set of probabilities is:
This entropy is positive and is measured in bits (when log 2 base is used). Entropy can be
interpreted as a measure of the uncertainty of the outcome. Thus the largest entropy
corresponds to a uniform distribution in which all the states have the same probability, while
a peaked delta distribution will have minimum entropy. Complexity measures are mostly
based on either information from theoretic approaches (i.e., in terms of entropy and
predictability) or on topological properties (i.e., correlation or fractal dimension). We
complementarily use SMC (signal mode complexity) (26) as a measure aimed at assessing the
complexity of a time series, based on the distribution of the strengths of its orthogonal
oscillatory modes and it is based on singular value decomposition. SMC does not require any

prior assumption on the nature (such as determinism or nonlinearity) of the analyzed time
series, and is completely data-adaptive. After scaling, the averaged singular value profile is
able to distinguish chaotic from random structure in a time series. The complexity index is
calculated as the weighted mean average of this averaged singular value profile, where a
weight inversely proportional to the singular value dominance is applied. A non-parametric
Kruskall-Wallis test (p <0.001) was used to check for statistical differences.
FINDINGS
Patients before cognitive rehabilitation obtained statistically lower scores in the
neuropsychological assessment (cognitive and functional scores) than control reference, and
importantly also lower than those obtained by the same patients after rehabilitation. This
suggests an improvement in global cognitive status of patients due to clinical intervention
(better performance and faster reaction times). For a detailed evaluation of the
neuropychological evaluation see Castellanos et al, 2010 (13). In this work we focus in a
global measure of functional competency (total score), the Spanish version of PCRS (Patient
Competency Rating Scale, Prigatano et al. 1998), that was completed by a third person or
observer person with the aim of obtaining a measure of functional ability. This scale is
formed by 30 items related to different daily living activities, between which are included
basic and instrumental activities as well as social skills, cognitive and emotional issues.
Entropy and complexity
Entropy is estimated in every channel (148 magnetometers) in free of artifacts segments in

controls as well as TBI patients before and after rehabilitation. The grand average of the
entropy is calculated (Figure 2A) per condition. The entropy increases as a consequence of
the TBI, being the entropy maximum in patients before rehabilitation. The highest increase of
entropy is localized in fronto-temporal areas and in lower degree in occipital areas. Although
entropy values in post-rehabilitation condition are higher than the control reference, we can
observe a decrease of entropy with respect to the pre-treatment condition. In general, entropy
restores up to controls values.
Figure 2. A) Topographic representation of the entropy per channel (brain recording site) in control,
after and before rehabilitation, respectively. Color codes for entropy values. B) Global entropy
(averaged in all the channels) in three conditions.

Statistical test confirm the hypothesis of restoring of entropy (Figure 3). No statistical
differences (p < 0.001) are found when comparing control entropy and post-rehabilitation
condition. The statistical increase of entropy due to TBI is spatially localized in frontal-
temporal areas, where the negative sign of the difference indicates an increase of entropy in
favor of pre-rehabilitation patients. The comparison of the entropy in patients before and after
rehabilitation shows a statistical decrease after treatment (negative sign in the difference),
spatially located in frontal and occipital areas.
Figure 3. Statistically significant changes of entropy. A) No statistical differences were found in

entropy between controls and post rehabilitation patients. B) Entropy is significantly higher in patients
with TBI before rehabilitation, principally in temporal areas. C) Statistical changes in pre- and post-
rehabilitation, the reduction of entropy after rehabilitation is spatially located in frontal and occipital
areas.
The average of the entropy in all the channels gives us a quantification of the global
entropy in the 3 conditions (Figure 2B), where we observe a gradual increase of entropy with
the influence of the brain injury, being statistically different both the entropy in control and
pre-rehabilitation and the comparison before and after treatment. No significant differences
were found between global entropy in controls and post-rehabilitation condition.
In order to give a more detailed description of the change in the brain activity after TBI,
we complement the characterization of the brain reorganization with a measure of the
complexity. We estimate the SMC index in pre- and post-rehabilitation condition to study the
plastic brain changes. In this case we observe a decrease of complexity after rehabilitation
(Figure 4A). Both entropy and complexity increase as a consequence of the TBI but they
decrease in recovery. Statistical tests show that complexity changes principally occur in
frontal and occipital areas (Figure 4B). The distribution of the complexity indexes (Figure
4C) shows the increase of the complexity values in pre-rehabilitation condition, where
however, the distribution is narrower than in post condition, indicating a global increase of
complexity after a TBI.
A post hoc analysis was performed to explore whether the improvements in the global
neuropsychological status of patients were related to changes in complexity. The correlation
was computed for changes between pre- to post-rehabilitation complexity and the PCRS
change from pre- to post-rehabilitation score. Subsequently, Pearson‘s correlation coefficients
were calculated and t-tests were performed (P < 0.01). Figure 5 shows the negative statistical
correlation (r = -0.67, p = 0.008). Those patients with traumatic brain injury that showed
greater improvement in PCRS were those that showed greater loss complexity.

Figure 4. A) Negative change of complexity from pre- to post-rehabilitation and significant sites (B). C)
Distribution of complexity index in pre- and post-rehabilitation condition.
Figure 5. Correlation between changes in complexity (Post-rehabilitation Cs – Pre-rehabilitation Cs)

and improvement of PCRS (Patient Competency Rating Scale).
DISCUSSION
In this work we have characterized from a new point of view the neurophysiologic
mechanisms underlying brain plasticity. To end this, we recorded the biomagnetic activity
(MEG recordings) from patients following a traumatic brain injury (pre-rehabilitation) and
after (post-) rehabilitation, as well as activity from age-matched control subjects. For the first
time, we have described the changes in entropy and complexity in neurophysiologic signals
and we correlated them with those changes observed at the behavioral level. After a TBI we
observe a global increase of entropy and complexity with respect to control references and
also in comparison with the same patients after rehabilitation, principally in frontal and
occipital areas. Change in patient complexity negatively correlate with PCRS, reflecting the
patient‘s current ability to adapt to daily living activities.

As shown in previous papers (13, 14) the functional networks are altered as a
consequence of a TBI. Not only the level of synchronization but also the topology is affected
and posterior recovered. The previous measures of functional connectivity estimate the
association between different brain regions. However, entropy and complexity (by means of
SMC method) allows us to study the local organization of the brain. These methods estimate
the number of oscillatory components in a signal, and hence provide a quantification of how
the brain is organized or the modification of neural cell assemblies. Our results prove the lack
of functional coupling or the disruption of the healthy networks after TBI. The increase of
entropy could reflect a loss of the regularity of the signal and an increase of oscillatory
independent components, which can be interpreted as a decrease of the organization. After
rehabilitation, the local networks recover, understanding recovery as an approach to control
values of organization. The increase in the complexity of the signal after TBI is spatially
localized in frontal and occipital areas. In the current study most of the patients showed
impairment over the frontal lobe and the lesion on this brain region influences the difference
between controls and patients pre-rehabilitation. Also occipital areas are altered in TBI
patients where the impact was located in frontal sites. Those areas are the ones with show the
higher decrease (and then, restoration) of the complexity from pre- to post-rehabilitation
condition.
In this work we have employed a very recently proposed method, SMC, of quantifying
the complexity of a time series, by studying the constituent oscillatory components. This
method is based on singular value decomposition and estimate the energy associated to each
oscillatory mode. SMC does not require that the data are deterministic, nonlinear or
stationary. This property is especially advantageous for neural data, normally short lasting
and non-stationary signals. Recently different works have studied how the organization of the
brain can be reflected in the complexity. It has been proved (27) that the information
transferred between one source to the rest of the network is related to changes in entropy of
the sources composing the functional network. The propagation of information could be
explained as the sum of the complexity of every signal. The role of a region of interest in a
cerebral network has been studied by means of the change of topological properties of the
network (28). The authors investigated resting state EEG signals and showed that the
centrality of the signals (more connected brain regions) predict the content of information of
brain activity.
As a potential use of complexity measures at clinical level, we could establish an
evolutional profile at behavioral, cognitive, motor, and functional level, supporting our
predictive and prognostic capability to, for example, support the assignment of a certain
program (strength degree, length), as well as the election of optimal pharmaceutics strategies
among different possibilities.
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[26] Bhattacharya J, Pereda E. An index of signal mode complexity J Comput Neurosci 2010;29(1-2):13-
22.

[27] Vakorin VA, Misic B, Krakovska O, McIntosh AR. Empirical and theoretical aspects of generation
and transfer of information in a neuromagnetic source network. Front Syst Neurosci 2011;5:1–6.
[28] Misic B, Vakorin VA, Paus T, McIntosh AR. Functional embedding predicts the variability of neural
activity. Front Syst Neurosci 2011;90:1–6.

Chapter 7
A COMPUTATIONAL MODEL OF COGNITIVE DEFICITS

IN MEDICATED AND UNMEDICATED PERSONS WITH
PARKINSON‟S DISEASE
Ahmed A Moustafa*, PhD

Center for Molecular and Behavioral Neuroscience, Rutgers University-Newark,
Newark, New Jersey, US
We present a neural network model of behavioral performance in medicated and

unmedicated Parkinson‘s disease (PD) patients in various behavioral tasks. The model
extends existing models of the basal ganglia and PD and further simulates the role of
prefrontal dopamine (PFC DA) in behavioral performance, including stimulus-response
learning, reversal, and working memory (WM) processes. In this model, PD is associated
with decreased DA levels in the basal ganglia and PFC, whereas DA medications
increase DA levels in both brain structures. Simulation results show that DA medications
impair stimulus-response learning, which is in agreement with experimental data. We
also show that decreased DA levels in the PFC in unmedicated patients is associated with
impaired WM performance, as found experimentally. Increase in tonic DA levels in the
PFC, due to DA medications, enhances WM performance, in line with modeling and
experimental data. Furthermore, we show that DA medications impair reversal learning.
In addition, this model shows that extended training of the reversal phase leads to
enhanced reversal performance in medicated PD patients, which is a new prediction of
the model. Overall, the model provides a unified account for performance in various
behavioral tasks using the same computational principles.
INTRODUCTION
In this chapter we present a neural network model of behavioral performance in medicated
and unmedicated Parkinson‘s disease (PD) patients in various behavioral tasks. The model
*
Correspondence: Dr. Ahmed A Moustafa, School of Social Sciences and Psychology & Marcs Institute for
Brain and Behaviour, University of Western Sydney, Sydney, New South Wales, Australia. E-mail:
a.moustafa@uws.edu.au

134 Ahmed A Moustafa
extends existing models of the basal ganglia and PD and further simulates the role of
prefrontal dopamine (PFC DA) in behavioral performance, including stimulus-response
learning, reversal, and working memory (WM) processes. In this model, PD is associated
with decreased DA levels in the basal ganglia and PFC, whereas DA medications increase
DA levels in both brain structures. Simulation results show that DA medications impair
stimulus-response learning, which is in agreement with experimental data (1, 2). We also
show that decreased DA levels in the PFC in unmedicated patients is associated with impaired
WM performance, as found experimentally (3-6). Increase in tonic DA levels in the PFC, due
to DA medications, enhances WM performance, in line with modeling and experimental data
(7-9). Furthermore, as reported in Cools et al. (10), we show that DA medications impair
reversal learning. In addition, this model shows that extended training of the reversal phase
leads to enhanced reversal performance in medicated PD patients, which is a new prediction
of the model. Overall, the model provides a unified account for performance in various
behavioral tasks using the same computational principles.
Parkinson‘s disease (PD) is a neurodegenerative disorder associated with reduced
dopamine (DA) levels in the basal ganglia, particularly the dorsal striatum (11, 12). In
addition to motor dysfunction, PD patients show impairment performing various cognitive
tasks such as planning (13, 14) and cognitive set shifting (15). PD patients also show
impairment performing various working memory (WM) tasks, including delayed-response
tasks (16), the Wisconsin Card Sorting Task (17-21), object and spatial span tasks (22), as
well as other WM tasks (23).
Dopamine medications (both precursors and agonists) are used to treat motor symptoms
of PD (tremor, akinesia, and bradykinesia), but can either enhance or impair cognitive
function (10, 24-26). For example, various studies show that DA medications and agents
impair stimulus-response learning in both PD patients (1, 27, 28) and healthy subjects (2, 29).
In stimulus-response learning tasks, subjects learn to associate the presentation of different
stimuli with different responses, based on corrective feedback. Unlike stimulus-response
learning, many studies found that DA medications enhance WM performance in PD patients
as well as in Parkinsonian animals (4-6, 30). It was also found that dopamine agonists
enhance WM performance in healthy subjects. Unlike WM, experimental studies show that
dopamine agonists impair reversal learning performance in monkeys, PD patients, and
healthy subjects (10, 25, 31). In reversal learning tasks, subjects initially learn to associate
different stimuli with different responses, and subsequently learn to associate the same stimuli
with the opposite responses (i.e., reversal). Cools et al. (10) found that medicated PD patients
are more impaired at reversal learning performance than unmedicated patients (25).
Furthermore, Jentsch et al. (31) found that the administration of cocaine (DA agonist) to
monkeys lead to impairment performing reversal learning tasks. Similar results were found
with administering quinpirole (DA agonist) to rats (32). It is argued that dopamine
medications perhaps overdose the PFC and thus impair performance in reversal tasks (10). In
line with this hypothesis, our model argues that increase of DA levels in the PFC impairs
reversal performance (see Experimental Procedures section for more details).
The model we present here builds on our earlier models (33, 34), and addresses how PD
and DA medications affect performance in stimulus-response learning, reversal, and WM
tasks. Below, we briefly discuss experimental studies of the role of the PFC and basal ganglia
in each of these tasks.

A computational model of cognitive deficits … 135
Stimulus-response learning, WM, and reversal
Experimental studies support the findings that the basal ganglia subserve stimulus-response
learning. Graybiel (35) noted that stimulus-response learning is (a) acquired very slowly and
(b) usually occurs without awareness, processes that have been ascribed to the basal ganglia
function (36). Lesion and physiological studies show that the basal ganglia subserve stimulus-
response learning. For example, Packard, Hirsh, and White (37) found that lesioning the basal
ganglia in rats impairs stimulus-response learning, but not long-term memory tasks. Jog et al.
(38) recorded striatal neurons‘ patterns of activity while rats performed a stimulus-response
task, namely a T-maze task. Jog et al. (38) found that striatal neurons increased their
activations while learning different motor plans in this task. These changes in firing patterns
were associated with better performance, mainly a decrease in movement time and an
increase in performance accuracy. The model we present here assumes that the basal ganglia
is key for stimulus-response learning, as argued by several experimental and modeling
studies.
As for reversal learning, various studies show that the basal ganglia and PFC are
important for reversal learning performance (10, 39-41). For example, Pasupathy and Miller
(42) recorded from both the striatum and PFC while a monkey performed a reversal task.
They found that, within a trial, the striatum increased its activation before that of PFC
neurons, suggesting that both basal ganglia and PFC are engaged during reversal learning
processes.
Like reversal learning, WM processes recruits the basal ganglia and PFC. Though the
basal ganglia has traditionally been associated with motor processes, it has also been found to
subserve cognitive processes, such as WM (13, 22, 43-47). For example, Gabrieli et al. (22)
tested WM capacity in PD patients and healthy controls using verbal and arithmetic span
tasks. In the verbal span task, subjects were instructed to remember the last word of a given
sentence. Subjects were given up to seven sentences, and were instructed to report the words
in the same order they were presented. The arithmetic span task used in the study was very
similar with the only difference that subjects had to remember digits instead of words.
Gabrieli et al. found that PD patients showed a lower WM span than that of normal subjects.
PD patients reported a maximum of about three or four items in both tasks, while the control
subjects reported all the items. Gabrieli et al. suggest that the basal ganglia is key for WM.
Furthermore, several studies reported that the PFC is important for maintenance of info in
WM (48, 49). Sawaguchi and Iba found that inactivating PFC with muscimol interferes with
performing WM processes, while it had a minor effect on performing a stimulus-response
control task. Sawaguchi and Iba found that increasing the length of the delay interval, from 2
to 4 s, was associated with an increase in the number of errors in the WM task. This finding
suggests that PFC subserves the active maintenance of information in WM. Based on these
studies, the model we present here argues that the PFC is important for WM maintenance and
the basal ganglia is key for memory-guided motor responses.

MODEL
Here, we briefly describe our model (see Figure 1). Model architecture and learning equations
are described in detail in the Experimental Procedures section below. The model attempts to
explain how PD and dopamine medications either impair or enhance cognitive performance in
stimulus-response, WM, and reversal learning tasks. As similar to our earlier models (33, 34),
here, we use an extended actor-critic model to address these questions. Actor-critic models
are systems-level models concerned with modeling reinforcement-learning-based motor
actions (i.e., learning to make motor actions that are followed by rewards). Here, we assume
that PFC is important for stimulus selection and maintenance of information in working
memory, whereas the basal ganglia is key for stimulus-response learning. In the model, PD is
associated with reduced DA levels in the basal ganglia and PFC (12). DA medications
increase DA levels in both brain structures (see Table 1 for a summary). In our model, we
simulate changes in phasic dopamine signaling by changing learning rate values. We simulate
increase in tonic DA levels by increasing the gain parameter value, as previously proposed by
Cohen and colleagues (50, 51).
FINDINGS
Below, we show how computational principles described in the Experimental Procedures
section explain PD patients‘ behavioral performance in stimulus-response learning, WM, and
reversal tasks.
Table 1. Simulation of the effects of Parkinson‟s disease and dopamine medications.

Parkinson‟s disease is associated with decreased phasic and tonic dopamine levels in the
basal ganglia and prefrontal cortex. Dopamine medications increase tonic dopamine
levels but further decrease phasic signaling in the basal ganglia and prefrontal cortex.
See Experimental Procedures section for description of all parameters. DA = Dopamine
Simulation 1: Dopamine medications impair stimulus-response learning
In the stimulus-response task, the model is presented with two stimuli, and on each trial, the
model learns to predict which of two stimuli is associated with reward. The model is
presented with eight different pairs of stimuli (trial types). The task design here is similar to

the task used by Shohamy et al. (28). On each trial, only one stimulus is associated with
reward presentation. The number of trials in this task is 96 trials.
40
35
30
Total # Error 25
20
15
10
0
HC PD on PD off
(a) experiment
40
35
30
Total # Error
25
20
15
10
0
HC PD on PD off
(b) model
Figure 1. PD performance in stimulus-response learning task. (a) experimental results from Shohamy et
al. (28). (b) Modeling results. Formerly 3.
Simulation results show that medicated PD patients are more impaired at learning the
stimulus-response task than unmedicated patients (see Figure 1), which is in agreement with
Shohamy et al. and other findings (2, 28, 31). Decreasing the learning rate value (which
simulates medicated PD patients, see Table 1) slows down stimulus-response learning, and
thus explains medicated patients‘ impaired performance in this task (see Figure 1).

Simulation 2: Dopamine medications enhance working memory
The model simulates performance in the AX-CPT working memory task. This task was
originally used to test WM function in schizophrenic patients by Cohen and colleagues (52-
55, 56). Recently, we used the AX-CPT task to test WM function in PD patients on and off
medications (3). Here, we show how our model simulates PD patients ‗performance in this
task.
In this task, the model is presented with sequential letter stimuli (coded as A, B, X, Y in
the human version). The model is trained to select a motor response when A is followed by X
(AX ―target‖ trials) and to select a different motor response otherwise (AY, BX, and BY
trials). The task requires the model (and the subjects) to remember which cue (A or B) was
presented before which probe (X or Y) so they can respond correctly (hence it is a WM task).
Successful maintenance of contextual information in working memory allows the model (and
presumably human subjects) to perform well at detecting the AX target sequence but will
likely make more false positive errors on the AY sequence (due to prepotent anticipation of
an X). Context maintenance should improve performance on the BX case, because one can
use the B to know not to respond to the X as a target. Accordingly, as in the original Moustafa
et al. study, we measure WM performance using the WM context index, which is the average
performance in AY trials subtracted from average performance in BX trials.
Simulation results show that PD patients off medications are impaired at performing the
AX-CPT task (Figure 2). In the model, this is due to decreased tonic DA levels in the PFC,
which we simulate by decreasing the gain parameter value in the PFC module. Consequently,
input to the PFC module is less likely to pass the threshold and thus is less likely to be
maintained in WM. Conversely, increasing DA levels in the PFC in the model, as in
medicated PD patients, enhances performance in WM, as found in experimental studies (3).
0.4
0.3
BX-AY Percent Accuracy
0.2 PD on
0.1
PD off
HC
-0.1
-0.2
Block 1 Block 2
(a) experiment

0.4
0.3
BX-AY Percent Accuracy

0.2 PD on PD on
0.1
HC
Block 1
0
PD off
-0.1
-0.2
Block 1 Block 2
(b) model
HC
Figure 2. PD performance in the AX-CPT task. (a) experimental results from Moustafa, Sherman,
Frank (3). (b) Modeling results. WM context index (BX-AY) is the average performance in AY trials
subtracted from average performance in BX trials (see text for description). Higher index values
represent enhanced WM performance.
Simulation 3: Dopamine medications impair probabilistic

reversal performance
The probabilistic reversal task consists of two phases: acquisition and reversal. The
acquisition phase involves probabilistic classification of stimuli. On each trial of this phase,
the model learns to select one of two stimuli. One stimulus is designated as the correct
stimulus, which is associated with 80% of positive feedback (and 20% negative feedback).
The other stimulus is designated the opposite ratio of reinforcement. As in Cools et al., this
phase has 40 trials. The second phase is the reversal phase in which reinforcement
contingencies are reversed so that the previously incorrect stimulus is now correct and vice
versa. As in the initial learning phase, the reversal phase has 40 trials. Following Cools et al.
(10), the learning criterion of any of the phases in our simulations is correct responses in eight
trials. In addition to simulating the probabilistic reversal task, we further ran the model on the
exact same task but by increasing number of trials in the reversal phase to test extended
learning on reversal performance. We assume that each run of the model corresponds to a
different subject (each simulation run has different initial random values; see Experimental
Procedures section for details).
In the original reversal task, we found that many of the simulation runs of the medicated
PD network did not reach criterion performance in the reversal phase (see Figure 3b). In other
words, medicated PD patients are more impaired at the reversal phase than unmedicated PD
patients and controls. In the model, DA medications impair performance in the reversal phase.
In the beginning of the reversal phase, the model receives negative feedback, and because of

an increase DA tonic function in the PFC, the model shifts attention to other cue instead of
learning to reverse responses. This in turn lead to an increase number of errors in the reversal
phase in many of the simulation runs of the medicated PD patients network. This delays
correct reversal learning, and thus explains medicated PD patients‘ impaired performance in
this phase. In the extended reversal task, we found that many of the runs of the medicated PD
patients network were able to reach performance criterion in the reversal phase (Figure 3c).
The model here shows that impaired performance in medicated PD patients in the original
reversal task as reported by Cools et al. is perhaps due to the use of a few number of trials in
the reversal phase, which did not allow patients to learn the task.
100 PD off
Reversal
90
Percentage of subjects Passing
80
70 PD on
60
50
40
Acquisition Reversal
(a) experiment
100
Percentage of simulation runs Passing
90 HC
PD off
80
70
PD on
60
50
40
(b) model

100
Percentage of simulation runs Passing

HC
90
PD off
80
PD on
70
60
50
40
(c) model (extended reversal training)
Figure 3. PD performance in the probabilistic reversal task. (a) experimental results from Cools et al.
(10). (b) Modeling results of the original reversal task. (c) Modeling results in the extended reversal
learning tasks (see text). Increasing number of training trials of the reversal phase shows that PD
patients can learn the reversal task.
DISCUSSION
Our model provides an account for how the basal ganglia, PFC, and DA interact in stimulus-
response learning, WM, and reversal learning tasks. In our model, the basal ganglia is key for
motor learning while the PFC is key for stimulus selection and maintenance of information in
WM. Our model argues that basal ganglia output to the motor cortex is responsible for the
initiation of motor responses. We argue that tonic DA levels control the initiation of motor
responses and maintenance of information in WM, whereas phasic DA responses facilitate
learning to select correct motor responses via changes in synaptic plasticity in the basal
ganglia, as reported experimentally (57, 58). In agreement with many computational models
(34, 36, 59-63), we argue that mesolimbic dopamine phasic signals projected to the striatum
are important for reinforcing motor responses that lead to reward.
In our model, PD is associated with decreased phasic and tonic dopamine levels in both
the PFC and basal ganglia, as reported in several experimental studies (11, 64-68). We also
argue that dopamine medications increase tonic dopamine levels (beyond those of healthy
normals) in both the basal ganglia and PFC, but decrease the magnitude of phasic dopamine
signaling in these brain structures which is in agreement with various experimental studies
(68-73). We simulate decrease (increase) in tonic dopamine by decreasing (increasing) gain
value of a sigmoidal activation function, as previously proposed in models of schizophrenia
(50, 51, 74). (See Experimental Procedures below for details.) In our model, increase of tonic
dopamine levels increases the activity of postsynaptic cells (75). On the other hand, we use

learning rate parameters to simulate changes in phasic dopamine signaling (for experimental
support see (58, 76)).
Now, we explain how the model simulates performance in stimulus-response, WM, and
reversal learning tasks in healthy controls and PD patients. For stimulus-response learning, as
we mentioned above, various studies show that DA medications and agents impair stimulus-
response learning performance in both PD patients (1, 27, 28) and healthy controls (2, 77).
The model shows that decreasing learning rate (due to increase of dopamine levels in the
basal ganglia and PFC) leads to impairment performing the stimulus-response learning task.
As for WM, the model shows that increase in dopamine levels in the PFC, as in medicated PD
patients, leads to enhanced WM function. In the model, increase in DA levels leads to an
increase in PFC function and thus enhanced gating and maintenance of information in WM.
This is in agreement with various experimental studies showing that DA medications enhance
WM performance in PD patients (3, 5, 6, 30, 78, 79), but see (80) for an exception. As for
reversal learning, the model shows that medicated PD patients are impaired at performing
reversal tasks, due to increase of DA levels in the PFC. Simulation results show that during
the reversal phase, increase of DA levels in the PFC made the model shifts attention to
different stimuli instead of learning to reverse responses, which delays learning. Interestingly,
the same mechanism explains enhanced attentional performance in medicated PD patients as
we showed in our earlier work (33) and as reported experimentally (10, 25). Furthermore, the
model shows that increasing the number of training trials in the reversal phase enhances
performance of medicated PD patients, which is a new a prediction of the model. We
conclude that impaired performance of medicated PD patients in the reversal task in Cools et
al. study is perhaps due to the use of few numbers of trials in the reversal phase. Future
experimental research should confirm (or disconfirm) model prediction.
The model presented here, along with our earlier Moustafa and Gluck model, shows that
the same computational principles can simulate performance in attentional and WM
processes. This is in agreement with experimental studies reporting a positive correlation
between performance in attentional and WM tasks (81-83). Our models show that PFC, along
with dopaminergic modulation, is essential for both attentional and WM processes. In
summary, we use the same computational principles to simulate performance in various tasks,
including stimulus-response, reversal, and WM, and provide a theory of the effects of PD and
DA medications on these tasks.
Relation to other models
Our model bears similarity to many of the existing models of the basal ganglia and PFC.
Below, we discuss models of stimulus-response, WM, and reversal learning tasks.
Many basal ganglia models simulate performance in stimulus-response learning tasks.
The most common framework for simulating the role of the basal ganglia in stimulus-
response learning is the actor-critic model. These models assume that there are two different
systems responsible for reinforcement-based stimulus-response associations: (a) critic (which
is responsible for reward-prediction learning) and (b) actor (which is responsible for stimulus-
response learning) (84). These systems are interrelated: the critic sends a reinforcement signal
to the actor to either increase the likelihood of selecting the action it has just made if it has
desirable consequences or not to select the action just made if it does not have desirable

consequences. The critic, on the other hand, is not informed about what action the actor has
made. However, it is informed about whether the action made had rewarding consequences.
As in our model, existing actor-critic models simulate the learning of stimulus-response tasks
(60, 85-87). We are not aware of any model that simulates effects of dopamine medications
on stimulus-response learning. Our model assumes that dopamine medications increase tonic
DA levels. This in turn reduces phasic signaling of dopamine cells, and thus impairs learning.
Reversal learning is arguably more complex than stimulus-response learning. Frank (36)
proposed a model that simulates performance in probabilistic reversal tasks. Unlike our
model, Frank (36) assumes that reversal deficits in medicated PD patients are due to
dysfunctional learning in the basal ganglia indirect pathway (which we did not incorporate in
the model). A more recent model by Frank and Claus (88) incorporates the orbitofrontal
cortex and simulates performance in reversal tasks. Assuming that dopamine medications
might perhaps overdose and thus impairs the function of the orbitofrontal cortex, the Frank
and Claus model can readily simulate reversal learning performance in medicated PD
patients.
Unlike reversal learning, there are a larger number of basal ganglia-PFC models of WM.
One of the earliest models of WM is that of Dehaene and Changeux (89). This model
simulated the role of PFC in active maintenance of information in WM and the occurrence of
perseverative responses as related to PFC damage. The model had two modules. The first
consisted of an input layer directly connected to an output layer, which is key for associating
stimuli with motor responses. The second module subserved maintenance of information in
WM. This module‘s performance was modified by learning that depended on reward
presentation. The Dehaene and Changeux model showed that damage to or not incorporating
the PFC, led to the occurrence of perseverative responses in WM tasks. One limitation of this
model is it does not incorporate a basal ganglia module and does not simulate performance in
PD patients.
Frank, Loughry, and O‘Reilly (90) proposed a model that simulates performance in a
WM task, known as 1-2-AX task. This task requires the subject to maintain two cues in WM
in order to correctly select a response to a target sequence. Specifically, the subject is
presented with a sequence of stimuli, one at a time, consisting of the stimuli 1, 2, A, B, X, or
Y. If the subject last saw a 1, then the target sequence is an A followed by an X. If the subject
last saw a 2, then the target sequence is a B followed by a Y. The Frank model assumed that
the function of the basal ganglia is to gate information into WM, while the function of PFC is
active maintenance of information in WM. O‘Reilly and Frank (91) proposed a similar model
that incorporated the basal ganglia indirect pathway. The Frank models assume that PD and
DA medications mainly affect DA levels in the basal ganglia, whereas our model assumes
that the PFC is also affected by PD and DA medications. Furthermore, Braver and Cohen (53)
proposed a model that simulates performance in the AX-CPT task. This model incorporated
interactions between sensory association cortex, PFC, the ventral tegmental area, and cortical
motor areas. The model assumes that DA neurons of the ventral tegmental area subserve
gating of information into WM. One limitation of this model is that it did not incorporate the
role of basal ganglia in behavioral performance. The Braver model did not simulate
performance in PD patients and did not simulate performance in stimulus-response or reversal
learning tasks.
As similar to our model, Suri and Schultz proposed a model that simulates performance
in delayed-response tasks. In these tasks, a stimulus is presented to the subject (e.g., A or B),

and after a delay period in which this stimulus is no longer present, the subject must select a
motor response (e.g., R1 or R2) depending on which stimulus was presented before the delay.
As in our model, this model incorporated an actor-critic architecture and was trained using the
temporal difference (TD) algorithm. Like our model, Suri and Schulz assume that the striatum
subserved motor responses, and that lateral connectivity of striatal neurons, simulated by a
winner-take-all network, subserve action selection. Moreover, Monchi and colleagues (92)
built a model that simulates the role of the basal ganglia and PFC in different working
memory tasks. These models assume that basal ganglia input to the PFC is key for
maintenance of information in WM. Monchi and colleagues simulate PD by decreasing
values of weights connecting PFC and striatal units. Unlike our model, Monchi and
colleagues did not simulate the role of dopamine in learning.
Cohen and Servan-Schreiber (50) provided a computational model of the role of PFC and
DA in behavioral performance. As in our model, the PFC is key active maintenance of
information in WM and dopamine projected to the PFC module is increases the signal-to-
noise ratio. As similar to the Cohen model, Amos (17) proposed a computational model that
simulated interactions between PFC and basal ganglia in the Wisconsin Card Sorting Task.
As in our model, Amos argues that PFC maintains the sorting rule (card, color, or shape) in
WM. The sensory association cortex encoded representations of input stimuli and the striatum
integrated cortical information and decided what action to perform. Feedback to PFC from the
basal ganglia informed PFC whether to maintain or change the sorting rule (not modeled).
The model simulated the occurrence of perseverative responses in PFC-damaged subjects and
random responses in PD patients. Dopamine reduction (as in PD) was simulated by
decreasing the gain parameters of the sigmoidal activation function and lesioning was
simulated by decreasing the output of neurons representing the lesioned area. One limitation
of the model is it did not simulate learning processes, and does not simulate dopamine
medication effects on behavior.
Model limitations
Though our model simulates performance in various behavioral tasks, it has some limitations.
One limitation of the model is that it does not simulate performance in more complex WM
tasks. Unlike the O‘Reilly and Frank models, our model does not simulate the effects of
distractor presentation on WM performance and does not simulate the maintenance of more
than one item in WM. Future modeling work will address the simulation of these processes as
well the effects of changing delay length on WM performance. Another limitation of the
model is that it does not simulate differential effects of PD and DA medications on learning
from positive or negative feedback, as reported in various experimental studies (3, 24, 93-95).
Furthermore, unlike the Frank‘s and Cohen‘s model‘s (7, 36), our model did not simulate
functional contributions of different dopamine receptors to performance. As in our model,
Cohen et al. argue that tonic DA projected to the PFC is key for maintenance of information
in WM. It is perhaps the case that tonic dopamine effects occur via D1 receptors in the PFC
(7).
Furthermore, it was found that the administration of levodopa to healthy subjects
enhances associative learning performance (96, 97). This is different from experimental
studies and simulation results presented here showing that DA agents impair stimulus-

response learning (27, 29, 96). It is likely the case levodopa and dopamine agonists have
different effects on behavioral performance. Levodopa is converted to dopamine by dopamine
cells and thus might balance phasic signaling of dopamine. This enhancement of phasic
signaling of dopamine might enhance stimulus-response learning, as found in the Knecht et
al. (96) study. On the other hand, dopamine agonists act on postsynaptic cells and increase
tonic firing of dopamine. According to our model, increase in tonic DA reduce phasic
signaling of dopamine cells, and thus might explain slow learning associated with dopamine
agonists. Future experimental and computational studies should investigate differential effects
of levodopa and DA agonists on behavioral performance.
Despite its limitations, our model provides a unified account for PD patients‘
performance in various behavioral tasks and provides new theories regarding how PD and
dopamine medications might affect stimulus-response, WM, and reversal learning processes.
Based on simulation results, we posit that reversal deficits in medicated PD patients are
perhaps due to the low number of training trials used in the experimental studies (10). The
model shows that increasing the number of trials in the reversal phase leads to enhanced
performance in medicated PD patients. The model also extends our previous Moustafa and
Gluck model of attentional and category learning, and further simulates PD patients‘
performance in WM and reversal tasks.
Experimental procedures
Here, we describe the model architecture and the learning algorithm used in the simulation
results presented above. The model architecture and learning rules are the same as in
Moustafa and Gluck (33) model, except the model here incorporates a WM mechanism in the
PFC module and simulate performance in various reversal and WM tasks.
Model architecture
The model takes the form of an actor-critic architecture, in which the critic is important for
reward and feedback-based learning and the actor is key for stimulus and action selection
learning and WM (Figure 4). The critic and actor influence each other in that the critic sends a
teaching signal to the actor to strengthen or weaken stimulus and action selection learning.
The critic is not informed about what action the actor has selected, but it is informed about
whether the action made had rewarding consequences. The model is trained using the
temporal difference (TD) model, which we describe in the learning algorithm section below.
The model has four modules: Input, PFC, motor response, and dopamine module (see
Figure 4). The PFC layer is fully connected to the Motor response layer (Striatum module).
Each unit in the Input module represents a cue presented to the network. The Input and PFC
modules have the same number of nodes. The motor module has three nodes, each
representing a different motor response. Input patterns presented to the network activate their
corresponding units in the Input module. The Input module sends topographic projects to the
PFC layer. Here, we use a winner-take all network to simulate inhibitory connectivity among
PFC neurons. For simplicity, in the current simulations, we allow only one PFC node to be
active at each time step. Here, we argue that competitive dynamics among PFC neurons is the
brain mechanism underlying limited working memory processes. We also assume that a
negative feedback decreases the activity of most active PFC neurons, as simulated in the

Amos model. As mentioned above, an increase in tonic dopamine levels increase activity and
competition among PFC neurons, which in turn enhance the selection of different stimuli
following negative feedback.
Figure 4. The basal ganglia-PFC model showing relevant brain structures. The model has four modules:
Input, PFC, motor response, and dopamine module. The critic corresponds to dopamine neurons
whereas the actor corresponds to the prefrontal-striatal system. Learning (i.e., synaptic modification)
takes place in both the PFC and Striatum modules. Learning is modulated by dopamine phasic
responses projected from the critic. The Input layer sends topographic projections to the PFC layer. The
PFC layer is fully connected to the Striatum (Motor) layer (i.e., every PFC unit is connected to every
striatal unit). Activation of a unit in the Input layer represents input received from the environment;
activation of a unit in the PFC layer represents attended-to stimuli; activation of a unit in the Striatum
module represents a selected motor response. Dotted lines represent dopaminergic modulatory effects.
Abbreviations: PFC, prefrontal cortex.
The model has four parameters that are manipulated depending on the simulation of PD
and dopaminergic medications. These parameters are two learning rate parameters (one each
for the Striatal and PFC modules) and two gain parameters (Striatal and PFC modules).
Learning rate parameters simulate changes in phasic dopamine signaling (58, 76), whereas
gain parameters simulate changes in tonic dopamine levels in the corresponding simulated
brain structure. We simulate PD by decreasing learning rate and gain values in the basal
ganglia and PFC modules. In addition, we simulate the effects of dopaminergic medications
by increasing gain values while concurrently decreasing learning rate values, beyond those
used for healthy normals (see Table 1).
The simulated striatum in the proposed model learns to map input stimuli to responses
(for similar ideas see (60-63)). Like the PFC module, we use a winner-take-all network to
simulate inhibitory connectivity among simulated striatal neurons. At the cognitive level, the
winning node represents the selected motor response (61, 63). Unlike most existing basal
ganglia models (36, 60, 61, 98, 99), the basal ganglia, in our model learns to map
representations of selected stimuli and WM information to motor responses.

Sigmoidal function
1
0.9
0.8
0.7
Activation Level 0.6
0.5
Small Gain
0.4 Large Gain
0.3
0.2
0.1
0
-1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1
Input
Figure 5. An example showing sigmoidal activation function with small and large gain values. Tonic
dopamine effects in a simulated brain area in the model is simulated by increasing gain value in
sigmoidal activation function representing that area, as initially proposed by Cohen (see (74)).
Based on experimental findings (72), it is likely that dopaminergic medications increase

dopamine levels in the PFC. Specifically, we simulate increase in PFC tonic dopamine levels
by increasing the gain value of the sigmoidal activation function, as previously proposed by
various computational models (17, 50, 51, 74).
Learning algorithm
We assume that learning in the PFC and basal ganglia modules relies on phasic dopamine
signals projected from the midbrain (60, 61). In this model, phasic dopamine signals are key
for both stimulus selection and stimulus-response learning. The model is trained using the TD
algorithm, which simulates various characteristics of phasic dopamine firing (100-102). Let
TD(t ) be the temporal difference error signal at time t (also known as the effective
reinforcement); R(t ) be the reward presented at time t (reward is 1 when reward is presented
after correct feedback and is 0 otherwise); P(t ) be the reward prediction at time t; γ be the
discount factor (which determines how future reward affect reward predictions; is set to 0.99
in all simulation runs presented here). The TD error is computed as follows:
TD(t )  R(t )   P(t )  P(t  1) (1)
Let wi be the weight connecting unit i to the critic node; n be the number of Input nodes;
and xi be activation of input units (which take binary (0,1) values). Reward prediction P(t ) is
computed by the critic node as follows:

n
P(t )   wi (t ) xi (t ) (2)
i 1
Now, we describe the equations of the actor module. Let w ji be the weight connecting
unit i to unit j;  ji (t ) be the Gaussian noise associated with the weight w ji (with zero mean
and standard deviation of 0.025).
All weights are perturbed using Gaussian noise, which is included to induce exploration
in the system. Let u ji be the perturbed weight connecting unit i to unit j. Perturbed weight
values are computed as follows:
u ji (t )  w ji (t )   ji (t ) , (3)
Activations of all units in the network are computed using a sigmoidal function (Figure
5):
1
f ( x)  (4)
1  e  Gm x
where Gm is the gain parameter (Gpfc for PFC and Gbg for basal ganglia module). Let n be the
number of Input (or prefrontal) units. The input units take binary (0,1) values. The activation
of a unit j is computed as:
n
Aj (t )  f ( u ji (t ) xi (t )) (5)
i 1
In the model, a winner-take all network computes the unit with the highest activation in
both the PFC and striatal modules. We assume that winner-take all competition among striatal
neurons is assumed to be the mechanism underlying the choice of motor responses. Similarly,
we assume that winner-take all competition among PFC neurons is the mechanism underlying
stimulus selection processes.
1 if A j   & A j  Ai for all i  j

A jp   (6)
0 otherwise
p
where β is a threshold; A j is the activation of unit j; A j is the activation of unit j resulting
from winner-take all computations (for similar ideas see (60, 61, 84, 85, 100)).
We simulate WM as in our earlier model (34), but see Frank et al. models for similar
ideas. We assume that each PFC unit can maintain a different stimulus in WM. A PFC unit
maintains a cue in WM if input passed the threshold (β). Maintained information in WM in
PFC influences motor learning in the striatal module (see Figure 4).

Learning in the model is based on the three-factor rule of learning—also known as the
dopamine-based Hebbian learning rule (for similar ideas, see (63)). According to this rule, the
phasic dopamine signal is essential for strengthening weights linking active nodes. It is also
important for weakening weights linking an active node and another inactive node. Numerous
computational models also incorporate this learning rule (53, 60, 61, 63).
Let LRm be the learning rate. There are two learning rate parameters in the model, one
for the PFC (stimulus selection) module and one for the basal ganglia (motor) response
module. Let xi represents the activation level of the presynaptic node. The weight update
rule is,
w ji (t  1)  w ji (t )  LRmTD(t ) xi (t ) Ajp (7)
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Chapter 8
OUTCOMES IN TRAUMATIC BRAIN INJURY, MILD

TRAUMATIC BRAIN INJURY AND CONCUSSION
Joel Brandon Brock1,2,4*, Samuel Yanuck3,4,

Michael Pierce1,5, Michael Powell2,6,
Steven Geanopulos7, Steven Noseworthy8,
Datis Kharrazian9, Chris Turnpaugh3,11, Albert Comey1,12
and Glen Zielinski2,3,13
1
Cerebrum Health Centers (Dallas Campus), Irving TX, US
2
FR Carrick Institute for Clinical Ergonomics, Rehabilitation and Applied Neurosciences,
Garden City, New York, US
3
The Yanuck Center, Chapel Hill, North Carolina, US
4
Cogence, LLC, Chapel Hill, North Carolina, US
5
Integrated Health Systems, Denver, Colorado, US
6
Powell Chiropractic Clinic, Cedar Rapids, Iowa, US
7
New Heights Integrated Health, New York, US
8
Essential Medicine, Lakewood Ranch, Florida, US
9
Bastyr University, San Diego, California, US
1
Brain Balance Center of Mechanicsburg,
Mechanicsburg, Pennsylvania, US
12
Comey Chiropractic Clinic, Largo, Florida, US
13
Northwest Functional Neurology, Lake Oswega, Oregon, US
The need for effective clinical interventions in chronic neurological diseases such as TBI
and other variants of chronic neurological conditions have been called for in the
literature. The cellular and neurochemical mechanisms addressed in recent literature have
focused around three common themes that traverse all of these condition classes: immune
and autoimmune mechanisms, inflammatory pathways and oxidative phosphorylation or
other energy production damage. Limits to the effectiveness of pharmaceutical and
surgical approaches are apparent, and complicated by the physiological
*
Correspondence: Dr. Joel Brandon Brock, 105 Decker Court, Suite 120 Irving, TX 75062, United States. E-mail:
drjbbrock@gmail.com.

156 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al.
interconnectedness of such pathways. A growing call for non-drug, non-surgical options

has evolved due to the dangers of poly-pharmacy, the lifestyle illnesses, and emerging
evidence pointing to functional measures and methods. This paper surveys and links
selected studies of specific, measurable effects of brain injury on several body systems,
and it indicates an emerging path toward outcome-based multifactorial functional
neurological assessment and treatment of some of the sequelae of chronic TBI and mTBI)
(mild traumatic brain injury).
INTRODUCTION
While many people recover from common brain injuries during the first year of recovery,
those who are left with chronic problems have been told to accept their fate according to the
dogma of permanence. Brain plasticity research has brought this notion under scrutiny.
Studies on the neurochemistry and sensorimotor consequences of chronic brain injury have
revealed wide ranging and cross-disciplinary mechanisms. These measurable phenomena
have increased the understanding of both pathological and dysfunctional syndromes within
this category of illness. An increasing need for strong generalist thinking is therefore
demanded in order to comprehend and utilize this bounty, and to avoid the traps of heuristic
decision making and specialist-dumping in a clinical setting. Careful examination of many
wide-ranging patient measures must be integrated in order to progress, such as reflexive eye
movements, hormone panels, sensorimotor changes, immune and inflammatory markers, and
mental and emotional states. History taking will need to expand to include lifestyle factors
previously thought unrelated. The compartmentalization of diagnosis and treatment and the
wanton medication of these populations of chronic brain injury may not be their only fate.
Part I of this paper will survey mechanisms that span much of the above chronic
neurological illness spectrum; first, through intracellular, and then, endocrine and tissue
effects. This includes the underlying milieu prior to the injury, neurochemistry and receptors,
fuel, immunity and inflammation, barriers, and endocrine effects. The CDC defines
concussion as a subset within TBI and many sources consider it a form of mTBI (mild
traumatic brain injury). There are several criteria for mTBI and concussion, so the reader is
warned that each reference may define these with slightly different symptoms. Part II includes
trauma effects, clinical neurological rehabilitation applications and mental health related to
persistent post-concussion syndrome (PPCS).
PART I: MOLECULAR, RECEPTOR,

SECRETORY AND CELLULAR DYNAMICS
Accumulated neuroinflammation and neurodegeneration from multiple concussions cause

deleterious effects that are well established. The fact that non-traumatic mechanisms can
create pro-inflammatory influences on the brain that influence the same cellular signaling
mechanisms to those seen with trauma suggests that, in order to understand the total burden of
brain pathology in a given patient, both traumatic (injury) and non-traumatic (insult) sources,
and their interactions, must be considered. Non-traumatic sources of brain insult may be

Outcomes in traumatic brain injury, mild traumatic brain injury … 157
instigators of microglial priming in advance of TBI or mTBI, therefore worsening TBI or

mTBI outcome.
Neuron-microglial interactions in the healthy brain
In the adult brain, there is a decline in gray matter density over time. Thus neurons die every
day. They need to be cleared, or they will drive damage associated molecular pattern (DAMP)
mediated immune system activation, instigating a pro-inflammatory response in the brain.
Hormonal Issues Multiple

Connections Death of Vestibular,
Damage to BBB – Presentation Progesterone in TBI
Cerebellar, Mesencephalic,
of Brain Self-Antigenic Neuronal Thyroid Requirements
Systemic Inflammation PM, Vagal and other neurons
Markers to Systemic Immune NFkB inhibition by estrogen
& Alteration of Total Brain
System Adrenal/Cortisol Inhibition of IL-6 causes NTIS…
Integrity
Inflammation ↓T4 & T3; ↑rT3 →
↓ Metabolism including
Neuronal Metabolism
TBI / mTBI
IL-6 Elevation
Central Nervous
Changes in Microglia / Neuron System-Induced
Redox Chemistry Issues Promotion of Pro-Inflammatory Relationship and/or Immunodepression
Leading to Neuronal Necrosis Cytokines or other Signaling Excitotoxic Status Death of Cortical Neurons Syndrome (CIDS) &
Instead of Apoptosis Increased Mesencephalic / Shift Toward Th2
Molecule Changes / of Brain Environment & Alteration of
Sympathetic Activation Dominance in Brain
Increased ON Signals Favoring Total Brain Integrity
Decreased OFF Signals Death of Neurons / & Body
Loss of Cortical Integrity
Has
Decreased Neuronal FOF Neuroprotective
(a primary OFF signal) Aspects
Hepatic Biotransformation Issues
Neuropsychiatric
 Altered biotransformation of Consequences
endogenous compounds Fuel: Increased Peripheral Vascular
(cortisol, sex hormones, etc.) - O2 Resistance – Affects Brain O2?
 Haptens - Glucose
 Chemicals Neuronal Fuel Exhaustion -> Low FOF Faster Use of Glucose
Insulin Resistance -> Inflammation
Glycation -> Induction of
Inflammatory Inflammatory and AI Potential Systemic Pathogens
Promotion of Diminished Th1 Surveillance
Respiratory Infection
MDSC-Based &
UTI
Immune Diminished Innate Immune
GI Dysbiosis
Suppression Response
Viral Infections
Figure 1. Chronic TBI sequelae © Samuel Yanuck 2013.
Microglia are the predominant immune cells in the healthy brain (1). In the normal,
resting state, it is the job of ramified microglia to phagocytize the dead neurons, much like
macrophages phagocytize apoptotic cells and tissue debris in peripheral tissues. In both cases,
this housekeeping level of phagocytic activity drives the creation of anti-inflammatory
mediators like IL-10 and TGFß. Phagocytosis of apoptotic cells provides immune regulation
through anti-inflammatory cytokines and regulatory T cells (2).
However, since there is no appreciable drainage of lymph from the brain, except
minimally at the cribriform plate, the option of clearing phagocytized debris from tissue via
the lymph system, as occurs in the periphery, is not available in the brain. Therefore,
microglia must fully degrade dead neurons and recycle them as building blocks and fuel.
Given billions of neurons and an estimated ten microglia per neuron, and given a motif of
continuous surveillance, the number of instantaneous events of microglial cells being
activated or inhibited in the decision flow to instigate phagocytosis of a neuron is very large
indeed. How do the microglia decide which neurons are dead? How is this process between

microglia and neurons regulated in non-neutral circumstances like trauma, infection,

inflammation, or neurodegeneration?
Neurons control microglial activity (3). ‗Off‘ signals from neurons keep microglia in
their resting state and reduce pro-inflammatory activity, while ‗On‘ signals from neurons are
inducible, including purines, chemokines, and glutamate. Thus, neurons should be envisaged
as key immune modulators in the brain (3).
Table 1. Inhibition of Glial Phagocytosis of Neurons (“OFF” Signals) (3)
OFF Signals Signal Effect

Released TGFβ Inhibition of effector T cells; Promotion of immune
tolerance & inflammatory resolution; loss of anti-
CD22 pathogenic vigilance
CX3CL1 Inhibition of B cell activity
Neurotransmitters Inhibition of microglial neurotoxicity
NGF Multiple functions
BDNF Nerve growth factor
NT-3 Brain derived neurotrophic factor
Neurotrophin-3
Membrane CD200 Inhibition of glial inflammation
Bound CD22 Inhibition of B cell activity
CD47 Inhibition of glial inflammation
CX3CL1 Inhibition of microglial neurotoxicity
Table 2. Activation of glial phagocytosis of neurons (“ON” Signals) (3)
ON Signals Signal Effect

Released CCL21 Glial chemoattraction
CXCL10 Glial chemoattraction
ATP & UTP Glial chemoattraction & IL-1β release
Glutamate TNFα release & Neuroexcitotoxicity
MMP3 Induces glial release of TNFα, IL-1β, IL-6 (inflammatory)
Membrane TREM2 ligand Promotes glial phagocytosis of neurons
Bound
In a healthy brain, the interplay of neurons and microglia is balanced. Healthy, viable
neurons produce adequate OFF signals to repel microglial phagocytic interest. In addition,
healthy neurons produce abundant electrical activity. The electrical activity of neurons is
itself a potent inhibitor of microglial activation (4).
In the healthy, non-inflamed brain, ramified microglia secrete TGFß, which promotes a
tolerogenic and anti-inflammatory tissue environment (5). In addition, in a healthy brain,
microglia and astrocytes express FasL, which induces apoptosis in T cells that migrate from
the periphery into the brain (6). Neurons and glia express cellular death signals, including
CD95Fas/CD95L, FasL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
and TNF receptor (TNFR), through which they can trigger apoptosis in T cells and other
infiltrating cells (2).

Factors affecting neuronal-microglial „On‟ or „Off‟ signaling
The capacity of neurons to maintain robust frequency of firing (FOF) is essential for sustained
electrical activity and neurotransmitter (NT) output, two essential ‗OFF‘ signals. The central
integrative state (CIS) of the neuron depends on presynaptic stimulation, neuronal oxygen and
neuronal glucose. Physiological factors that have the capacity to impair these three factors can
contribute to changes in neuronal FOF, thereby changing the neuron-microglial ON/OFF
equation. The capacity of neurons to maintain robust FOF also depends on the metabolic
integrity of the neurons themselves. A host of factors contribute to neuronal metabolic
integrity. Among the variables that can perturb function and lead to diminished FOF are a
lack of exercise, excessive accumulation of mitochondrial ROS, diminished thyroid hormone
signaling, and CoQ10 deficiency (statin-induced or other). The accumulation of ROS in
mitochondria depends on the balance between electron accumulation from excessive caloric
consumption versus the utilization of electrons via exercise. Too much caloric intake
combined with a lack of exercise yields an overabundance of electrons (general biology).
They react with oxygen, creating superoxide. If this occurs in amount in excess of what can
be cleared by mitochondrial antioxidant mechanisms, the mitochondria are damaged.
Mitochondrial damage from ROS may be more common in patients with single nucleotide
polymorphisms (snips) for glutathione or SOD. Approximately half the population has a snip
for GSTM-1, the primary gene for the production of glutathione s-transferase).
Sensory stimulation factors like lack of exercise, destruction of joint mechanoreceptors in
arthritic conditions, poor muscular tone, diminished rib movement with respiratory disorders
and other such changes can alter the neurosensory environment.
Glycemic dysregulation in diabetes, hypoglycemia, insulin resistance and other such
conditions can impair systemic and consequently CNS glucose levels. Many of these patients
have microcirculatory problems exacerbating inadequate blood glucose levels with poor
delivery to brain. Likewise, CNS oxygen levels can be impaired by respiratory disorders,
disorders of microcirculation and other such problems.
Clearance and inflammation in injury
When the brain is injured, however, the resulting inflammatory chemistry can change the
equation. With inflammation, neurons and microglia both change in ways that promote
microglial phagocytosis of neurons. As with any cell, inflammation compromises metabolic
integrity. In neurons, this yields diminished production of neurotransmitters and reduced
electrical activity. Thus, two potent ―Off‖ signals are lost. Meanwhile, inflamed microglia
change their morphology. Brain inflammation differs from inflammation in the periphery by
the relative absence of leukocytes and antibodies. There is a limited traffic across this barrier
and this traffic can be increased by inflammation which can recruit leukocytes into the brain
(1).

Neuron Microglial Cells

Glycemic ↓ Neuronal
Microglial Insulin Resistance
Dysregulation Glucose
Phagocytosis of
Neuron
↓ Exercise or
↓ Neuronal
↓eNOS or
Perfusion Autoimmune
↑ Vasoconstriction OFF ON Disease, Stress,
Mucosal
Dysregulation,
Infection, Toxicity,
T Cell Polarization
↓ Respiratory
↓ Neuronal O2
FOF, Trauma (TBI, mTBI)
Problems
Function
NT’s
Inflammatory
↑ IL-6 → Neuronal Metabolic Systemic
↓ Rib Mechanics Cytokines Inflammation
↓T3 & ↑rT3 Integrity
in Brain
↑ Electron
↓CoQ10 from Mitochondrial Combination with Physiological
↓ Afferent Barrage
Statin Use Dysfunction O2 →↑ Superoxide Inflammation
Radical
↓Muscular Tone, ↑ Electron

Sensory Efficiency ↓Exercise Accumulation in SNIPs for GSH, SOD Caloric Abundance
of Joints, etc. Mitochondria © Samuel F
Yanuck 2013
Figure 2. Factors potentially affecting the neuron-microglial ON/OFF equation.
However, in the inflamed brain, microglia (which are after all a specialized form of
macrophage) acquire antigen presenting cell capacity (4). Instead of inducing apoptosis in
invading T cells, inflamed microglia present antigen to invading T cells. Antigenic material
can be fragments of processed pathogens. This is a useful antimicrobial effect, favoring
clearance of pathogen. However, microglia can also present fragments of neuronal tissue
debris as antigen, promoting a self-antigenic response in the T cells to which the antigen is
presented. A mild and transient form of this T cell self-antigenic activation appears to be
reparative. However, prolonged or overly exuberant self-antigenic T cell activation can cause
irreversible damage to brain (4). It is noteworthy that some of the research in this field
occurred before there was a full appreciation of the role of TH17 polarization in T
cell/microglial interactions.
Inflammation is known to induce mitochondrial uncoupling, diminishing mitochondrial
integrity in all cells. Inflammation is therefore also a driver of diminished mitochondrial
integrity and FOF of neurons. In a variety of inflammatory and neurodegenerative diseases,
glial cells such as microglia gain antigen-presenting capacity through the expression of MHC
molecules. The pro-inflammatory cytokines stimulate microglial MHC expression in the
lesioned CNS areas only (4).
Neuronal signaling, a strong ―Off‖ signal, works to suppress the immune system‘s
inflammatory activation in the brain so that induction of brain immunity is strongly counter
regulated in intact CNS areas. The signaling activity of neurons also constitutes an inhibitory
signal. The control of MHC expression by neurons is dependent on their electrical activity.
Immunity in the CNS is inhibited by the local microenvironment, in particular by

physiologically active neurons, to prevent unwanted immune mediated damage of neurons (4)
(emphasis not original).
Research on the role of T cells and peripheral innate immune cells in the brain is
evolving. Most authors suggest that maintenance of the non-inflamed CNS environment
depends on the ability of microglial cells to induce apoptosis in peripheral T cells that gain
access to the brain. However, the failure of systemic anti-inflammatory medications to yield
improvement in neuroinflammatory disorders has led some authors to a view that CNS-
infiltrating T cells provide crucial anti-inflammatory cytokine signals that are essential for the
resolution of neuroinflammation (7).
It is noteworthy that non-steroidal, anti-inflammatory medications have been described in
the literature as ―resolution toxic‖ because they inhibit signaling mechanisms involved in the
resolution of inflammation (8). This insight may prove useful in understanding the failure of
anti-inflammatories as a viable therapy to address chronic neuroinflammation.
In the presence of systemic inflammation, T cells invading the CNS are likely to be
influenced by pro-inflammatory cytokines and other factors into a pro-inflammatory
morphology, as they are in the periphery. Once so influenced, they are likely to produce pro-
inflammatory cytokines, further promoting the pro-inflammatory CNS environment.
Pathogens in tissue create pathogen associated molecular patterns (PAMPs). Damaged
tissue creates damage associated molecular patterns (DAMPs). Microglial pattern recognition
receptors (PRRs) sense PAMPs and DAMPs, triggering phagocyte NADPH oxidase (PHOX),
which turns molecular oxygen into reactive oxygen species (ROS). This conversion depletes
the tissue of molecular oxygen, yielding hypoxia, driving hypoxia inducible factor 1α (HIF-
1α), driving NF-κB, driving IL-1ß and TNFα, which increase gene expression of NF-κB. NF-
κB drives iNOS (inducible nitric oxide synthase) expression. Though nitric oxide (NO) is
cytoprotective, the combination of NO and hypoxia impair cellular respiration, yielding
excitotoxicity. Though balanced amounts of ROS are normal to microglial function, ROS in
combination with NO yields peroxynitrite, driving neuronal apoptosis. In patients with
antioxidant depletion, from glutathione (gsh) snips or other factors, the likelihood of
microglia producing neurotoxic amounts of ROS is increased.
↑ PHOX →
PAMP or DAMP → ↑ HIF-1α
↓ Molecular O2 Hypoxia ↑ IL-1β, TNFα
↑ Microglial PRR → ↑ NFκB
to ↑ ROS
Cellular
Antioxidant Microglial ↑ iNOS
↑ O2- & H2O2 Respiratory
Depletion Activation → ↑ Nitric Oxide
Inhibition
↑ Apoptosis /
Neurotoxicity ↑ ONOO- Cytoprotection Excitotoxicity
Phagocytosis
Figure 3. Factors contributing to perpetuation or resolution of neuroinflammation (1, 11).

Microglial priming and the contribution of non-traumatic influences to

neuroinflammation
Microglial priming is a condition in which microglia move from the ramified state in which
they perform housekeeping functions and reduce neuro-inflammation to a state in which they
swell and fill with pro-inflammatory cytokines (9-12). Priming can be induced by aging,
trauma, infection, or other stimuli. Microglia can remain in this state for long periods of time,
without returning to the ramified state, but without releasing their bolus of cytokines.
However, further insult to the brain will cause a flooding release of pro-inflammatory
cytokines that can be damaging to the brain (9-12). It has been established that increases in
pro-inflammatory cytokines in the periphery yield upregulation of brain inflammation and
potentiate neuronal death (13, 14). It has also been shown that increasing the peripheral LPS
(lipopolysaccharide) level can induce the activation of central pro-inflammatory mechanisms,
even when the amount of LPS used for stimulation is minimal or when the peripheral
inflammatory cytokine levels are suppressed artificially. Both central and peripheral
inflammation can exacerbate local brain inflammation and neuronal death (15). Once
neuroinflammation occurs, the key question is whether it will resolve quickly or yield a
chronically activated state, in which greater neuronal loss occurs.
Microglia alter their morphology and activate in response to pathophysiological brain
insults. Microglial phenotype is also modified by systemic infection or inflammation. Chronic
systemic inflammatory components are risk factors for Alzheimer disease. This implies that
crosstalk occurs between systemic inflammation and microglia in the CNS (16). Pathogens,
protein aggregates, or damaged neurons may inflammatorily activate glia, which may then
kill neurons. IL-1b has been shown to be the main activator of microglia during brain
disturbances. Systemic IL-1b can cause CNS inflammation once it enters the brain, thus
linking systemic inflammation and immune activation (12).
Microglia can become over-activated through two mechanisms. First, microglia can
initiate neuron damage by recognizing pro-inflammatory stimuli, such as lipopolysaccharide
(LPS)). Second, microglia can become overactivated in response to neuronal damage (11).
LPS can directly activate the brain endothelium even at relatively low doses, obviating the
need for systemic cytokine stimulation (9, 10). Many of the pathological events described in
traumatic brain injuries can also be seen with excitotoxicity (12).
Receptor stimulation by pathogens or neuron damage contributes to nuclear factor-
kappaB (NF-κB) activation. Simultaneous activation of PHOX (Phagocyte NADPH oxidase)
and iNOS (inducible nitric oxide synthase) in microglia resulted in the disappearance of NO,
appearance of peroxynitrite and apoptosis. However, the chronic state of activation may
progress to ―resolution phase‖ where microglia are amoeboid, highly phagocytic, and produce
anti-inflammatory cytokines (including IL-10 and TGFb) in order to resolve the inflammation
and clear up the mess (1).
With successful, non-phlogistic microglial phagocytosis of apoptotic neurons, the neuron
is engulfed and digested without release of additional damage associated molecular patterns
(DAMPs) into the tissue environment. This favors the production of anti-inflammatory
cytokines and a movement toward resolution of tissue inflammation in the brain parenchyma.
If instead the neuron dies by necrosis through direct or indirect trauma, or is triggered into
necrosis by a pathogen or toxin, its death releases cell fragments and cytosolic contents into
the tissue environment, triggering a pro-inflammatory response in surrounding microglia.

Neuroinflammation favors a more aggressive microglial cell phenotype and a more exuberant
phagocytosis of neurons, yielding neuronal loss in excess of that necessary to bring about
resolution of the initial condition.
SIDS, SIRS and CARS
Acute neuroimmunological syndromes such as central nervous system injury-induced

immune deficiency syndrome (SIDS), systemic inflammatory response syndrome (SIRS) and
compensatory anti-inflammatory response syndrome (CARS) have been reviewed elsewhere
(17). It is unclear in the literature, however, whether a gradient of severity exists in these
syndromes. For example, it is unclear whether a patient with mTBI (mild traumatic brain
injury) might be expected to manifest a modest version of the apoptosis of innate immune
cells and TH1 cells seen in SIDS. If this were the case, the patient might be incrementally
more susceptible to chronic infection, promoting systemic and therefore neuroinflammatory
mechanisms.
From a clinical perspective, whether or not mild forms of these syndromes pertain, the
clinician faced with a patient with a TBI or mTBI should be alert for indications of
suppressed immune vigilance against pathogens. Such a circumstance would have the
potential to yield chronic infection, a known driver of microglial priming and
neuroinflammation.
The injured neuron
In the realm of traumatic brain injury, the neuron is the center point of the physiological story
(18). Factors including the preexisting central integrated state of various neuronal pools, the
integrity of existing neuronal circuitry, peripheral receptor integrity, level of circulating
cytokine populations, polarization status of a dynamic immune system, level of glial priming
and function, balance and integrity of the endocrine system, various underlying infectious
organisms, genetic predisposition, associated comorbidities and the extent of damage
sustained as well as related biomechanics of a given injury all determine neuronal integrity
and probability of recovery post-injury (19). Other factors that can impact the neuron are the
nutritional and digestive status of the patient as well as vascular perfusion and autonomic
integrity. The neuron‘s ability to survive and maintain optimum functional capacity and
appropriate cellular plasticity is vital to recovery and sustaining humanism and vitality post-
neurological insult. Understanding and evaluating all converging physiological scenarios that
can impact the health of the neuron and how it relates to head injury and damage to the CNS
is vital when determining the extent of injury, creating appropriate treatment plans and care of
patients suffering from traumatic brain injury or neurodegeneration (20).
The intracellular cascade after head injury is complex and involves organelle function,
metabolic and ionic fluctuations and surface receptor interplay. This gross level interplay
impacts cellular plasticity, immunoexcitotoxicty, intracellular calcium and binding proteins,
caspase cascades, apoptosis, cerebral blood flow, glucose metabolism, phospholipase and free
radical production, protease and cytoskeleton breakdown, endonuclease and DNA damage,
nitric oxide isomers and superoxide anions (12). On a smaller intracellular scale, organelle

involvement includes changes in mitochondrial function, neurofilaments and microtubules,

lysosomes, epigenetic function, protein replication, secretory vesicle production and synaptic
capacity. The eventual consequence of intracellular and organelle variations will impact
cellular energy, axonal and myelin integrity, cellular swelling, synaptic transmission, lipid
membrane stability, synaptic transmission, and cellular summation capabilities. When
damage occurs in the CNS, neurons are impacted, glial cells are altered, glutamate receptors
can become sensitized, GABA receptors can become internalized, the immunological system
is impacted, vasculature is compromised and the blood-brain barrier becomes damaged. This
combination of events can lead to cellular damage, microglial priming and sustained
inflammation within the CNS, antigen presentation of neural tissues and possible
autoimmunity and compromise in the resolution process post-injury (21).
Surface receptor types, densities and their sensitivities also contribute to metabolism (22).
There are many receptor types; however, of particular interest are the ionotropic receptors
including NMDA, AMPA, Kainate and voltage gated calcium channels. These receptors types
allow a regulated influx of calcium into the cell that impacts multiple intracellular pathways
allowing for intracellular cascades, cellular function, cellular plasticity and long term
potentiation. The ultimate promotion of NMDAr(define) (N-methyl-D-aspartate, a specific
type of ionotropic glutamate receptor) promotes the extracellular influx of calcium and
calcium stores within the cell. The increase and appropriate regulation of cytosolic calcium
leads to the proper activation of kinase dependent signaling cascades leading to cAMP (cyclic
adenosine monophosphate) element binding protein activation. The activation of CREB
(cAMP Response Element-Binding protein) ultimately generates the phosphorylation at SER
133 (serine 133) leading the generation of protein synthesis within the nucleus. This generates
the ability for the cell to innately generate more surface receptors, intracellular structures,
cytokines, neurotrophic factors, cellular efficiency, dendritic development and repair cycles
vital for cell survival. The ultimate outcome of this process is synaptic plasticity and long
term potentiation. This process is a large part of learning and memory and is a major
mechanism of repair after damaged neural circuitry is created after head injury or in a
neurodegenerative process (23).
The dysregulation of intracellular calcium, however, can lead to degenerative and
excitotoxic mechanisms that are damaging. Under certain circumstance, cell surface receptors
become more permeable to calcium while intracellular calcium-buffering proteins become
aberrant thus causing the intracellular calcium levels to become dysregulated. Multiple
neurodegenerative conditions, inflammatory scenarios and disease processes as well as
excitotoxin loads and glutamate levels have the ability to alter NMDA receptors activation
and skew AMPA:NMDA receptor ratios allowing a greater influx of extracellular calcium
into the cell (18). The resultant intracellular calcium dysregulation triggers pathology. The
triggering of intracellular lipases causes cell membrane damage. Triggered nucleases destroy
DNA. Calcium induced phospholipase activation promotes prostaglandins, arachidonic acid
and leukotrienes which generate inflammation, vascular dysfunction, white matter disease,
myelin damage, axonal damage and further free radical generation (24). Energy uncoupling
allows for protein phosphorylation, which alters gene expression and ion channel activity and
changes the central integrated state and firing capacity of the neuron. Calcium induced
proteolysis occurs which breaks down the cytoskeletal structure of the neuron thus altering
transporting mechanisms and supportive structures of the cell body and axonal projections.
This has the potential to alter antero- and retrograde function, which can alter the

transportation of synaptic vesicles thus reducing synaptic activity. Activation of reactive

oxygen and nitrogen species generates mitochondrial damage, NFκB activation and
ultimately cellular apoptosis if persistent. A continuation of inflammation, oxidative damage
and excitotoxicity can generate a situation where glial cells remain primed, neurons fail to
function, plasticity is diminished and the neurochemical environment is altered. This
continued process can lead to post concussive syndromes, second impact syndromes and
repeat concussive symptoms despite not having another physical injury.
During times of oxidative stress, inflammation or neurodegeneration, energetic failure
emerges among normal mitochondrial function and overall energy production of the cell (25).
This can lead to a breakdown in the electron transport chain and decrease mitochondrial
calcium loading capacity through an activated mitochondrial permeability exchanger. The
exchanger opens mitochondrial pores and allows the deposition of calcium within the
mitochondria into the cellular cytosol disrupting intracellular calcium regulation. Respiratory
chain uncoupling and the release of intermembrane space proteins as a result of MPT
(membrane permeability transition) activation causes multiple cascades to occur (26). These
include the release of intracellular caspases, caspase independent cell death effectors, NLRP3
inflammasomes, NF?B and interferon regulatory factors. The release of cytochrome C from
the mitochondria activates caspase three which programs cell death and apoptosis. These
cascades collectively lead to the development of inflammation, loss of cellular energy
production and perpetuate further mitochondrial and cellular dysfunction. Thus the milieu of
the cell primes the receptor sensitivity even before death or life receptors are triggered. This
phenomenon of ―setting receptor tone‖ is conceptually similar to how the tympanum tension
is preset to perceive or protect from sound prior to the event, and the muscle spindle tone is
preset before a perturbation. The implications of this for clinical prognosis and cellular
apoptosis indicate some potential for leverage through clinical cell mediator manipulation.
Such manipulation could be through substances administered as well as evoked potentials.
In a normal cell, when there is abnormal stress, organelle damage, accumulation of
misfolded proteins or damaged mitochondria, the cell removes the damaged organelles or
unwanted proteins (27). These processes include autophagy and mitophagy. Under periods of
aging, inflammation, oxidative stress, mitochondrial damage, intracellular calcium
dysregulation or a decrease in cellular activation, appropriate autophagy and mitophagy is
impaired. When these cellular processes are impaired after head injury, various diseases can
manifest, the health of the neuron can fail and ultimately lead to cellular death and premature
neurodegeneration.
Head injury or uncontrolled inflammation or imbalanced immunological responses can
trigger abnormal neuronal surface receptor activation. This can lead to dysregulated
intracellular calcium, which can cause oxidative stress, cell structure breakdown, energy
production loss and activation of inflammatory cytokines.
Inflammation and cellular apoptosis can ultimately lead to the released of glutamate and
proinflammatory cytokines that generate more surrounding excitotoxicity to nearby cells.
This can create plasticity related to abnormal circuitry activation and lead to seizure,
hyperkinetic function, ischemia and GABA receptor internalization. This mechanism is the
cornerstone to the onset and perpetuation of many neurodegenerative diseases that might arise
or be triggered post TBI.

Protein
trasncription
LTP
Plasticity Neurotrophic
Factors
CREB Healthy state
Ca Ca
Homeostasis Mitochondria
Disease state
Cytochrome C
Caspase
Diseases state Impact on

Ca
CA Dysregulated
Mitochondria
Inflammation
Protease NFKB activation
DNA Prostaglandins
Endonuclease Nucleus ROS
damage RNS
Vascular changes
Energy loss
Cytoskeleton
Phospholipase
breakdown
Free radical
production
Transporter
breakdown,
Synaptic
changes
Altered
plasticity
Figure 4. The balance of life and death receptors is epigenetically primed much like the muscle spindle
system © Joel Brandon Brock 2013.
Neuronal energetics and TBI
Traumatic brain injury alters neuronal membrane potentials amking them more sensitive thus
placing greater energy demand on a compromised system. Glucose is the obligate fuel source
of the mammalian brain. While the brain can use alternate fuels, such as lactate and ketones,
the efficiency with which the brain can do so varies with development stage/age as well as
whether or not the brain is operating under normal physiological conditions (28). While the
brain accounts for only 2% of a human‘s entire biomass it is responsible for 50% of total
glucose utilization (29). Under normal physiological conditions approximately 85% of brain
glucose utilization is directed toward fueling the Na/K pumps that restore resting membrane
potentials in active neurons (30). Like the periphery, cellular uptake of glucose in the brain
can be accomplished through both insulin-independent and insulin-dependent mechanisms.
And while central neurons can synthesize their own insulin the majority of brain-based
insulin is derived from peripheral supply (31).
The brain environment is sequestered and barriers exist to free flow of nutrients and
glucose from the periphery. The two main obstacles to delivering nutrients and glucose to
active neural tissue in the CNS are the blood-brain barrier (BBB) and the lack of local

carbohydrate storage in neurons themselves (31). Under conditions of concussion and

traumatic brain injury, energy demands increase while glucose utilization decreases resulting
in a significant neuroenergetic mismatch (32).
Copyright ©Joel Brandon Brock

2013
Mechanism of Injury
Will vary depending
Age / Sex / Other
PAST MEDICAL On time
bodily injury
HISTORY
Axonal damage Cellular damage Second impact /

Changes to CNS Post concussive
Depends on area of Synaptic Neurofilaments prone Will vary depending
trauma, extent of force Damage on severity
on the head, amount of
tissue ischemia, other Mechanical and ionic
comorbidities Deformation
Glial priming
Inflammation
Lysosome Energy loss Second impact /
Damage to Mitochondrial Intracellular Post concussive
Terminal or Relates to comorbidities
Twisting, Shearing, Compression Structural Damage Autophagy debris prone
transporters And number of injuries
Bleeding, Diffuse and Focal
Damage
Neurochemical
Biomechanical forces Damage
Apoptosis
Second impact /
Chemical NMDA PON
Knockout Post concussive
Cascade iNOS
Coup Caspase prone
Calpain SOA
Contra Coup Excitotoxicity
Rotational
Head Injury Shearing
Linear force Reuptake
Bleeding transporter loss Glutamate ↑
Unconscious GABA↓ Hyperkinetic Second impact /
Chemical TND Post
Cascade Excitotoxic concussiveprone
Bleeding / stroke / watershed Transmitter changes
Twisting
Rotation
Shearing force Golgi Depression
Blunt trauma ↓Fuel causes Vascular changes Packaging damage Serotonin ↓
Cellular Oxidative stress Pain Emotional changes
Traction Dopamine ↓
Failure Emotional Head and body pain
To Monoamine issue
changes
Peripheral Vestibular Synaptic vesicle loss
System
Reactive
Vasconstriction
Contusion or Ischemia
damage to the Excitotoxicty
To tissue
Decrease in
peripheral Decrease in fuel for Prone for loss in Without therapy
synaptic
vestibular delivery plasticity Recovery ↓
transmission
apparatus
Damage to
TM / round / oval Or Damage to hair cells
window Or Displacement of Fracture to temporal Inflammation
or Or
Otoconia bone Autoimmunity
Delineate vestibular
And Auditory loss or Damage to PVN
Hearing loss
both Fistula / TM BPPV Conditions Damage to PV Hydrops
Canal / Otoliths
apparatus
Figure 5. How physical forces transmute into cellular changes and clinical conditions.
Glucose transport across the blood-brain barrier
The neuronal cell membrane is an impermeable barrier that requires insulin for transport
across the cell membrane. Neurons express high amounts of insulin receptors, however the
majority of brain insulin is derived from peripheral production, although some evidence does
exist that neurons can produce small amounts of insulin themselves (33). Beyond the cell
membrane the neurovascular unit functions not only as a static barrier but can adapt to
physiological changes by altering transport systems in order to modify and facilitate ion and
nutrient flux. There are two primary classes of active glucose transporters that can express on
both luminal (blood facing) and abluminal (brain facing) surfaces of the neurovascular unit.
These two mechanisms are dedicated glucose transporters (GLUT1) and sodium-glucose co-
transporters (SGLT).

GLUT1 is a member of the glucose transport molecule family, is highly expressed in the
brain, and can upregulate or down-regulate nutrient transport depending on the
pathophysiological state of the system (33). It is a facilitated transport system that moves
glucose along a gradient and is both Na+ and insulin independent. SGLT, on the other hand,
is a Na-dependent symporter (integral membrane protein involved in transport of molecules
across phospholipid membrane), moving one glucose molecule along with two Na+
molecules in the same direction across the cell membrane in a co-transport relationship,
against the glucose gradient (31). SGLT is a secondary active transport mechanism that uses
ATP generated from ion gradients. SGLT can also function in reverse, moving accumulated
Na+ out of the cell into the extracellular space (34). While GLUT1 is considered the primary
glucose transport system studies have shown upregulation of the sodium-dependent glucose
transporter SGLT1 in conditions of ischemia-hypoxia (33).
Because of these limitations (cellular and tissue level barriers coupled with a lack of
passive diffusion and local neuronal glucose storage) the brain relies heavily on the
expression of glucose transporters on the blood-brain barrier as well as the storage capacity of
astrocytes. Both of these glucose transporters can be insulin sensitive or insensitive,
hormonally regulated or driven by glucose concentrations (31).
Other GLUT and SGLT isoforms (GLUT3, GLUT4, SGLT1, SGLT2) exist in the brain,
but in lower concentrations and contribute to a lesser degree to neuroenergetics (5).
Energy compartmentalization
In the brain, energy metabolism is highly compartmentalized (35). While neurons have both
aerobic and anaerobic pathways they have little capacity to store energy. As such neurons rely
heavily on glucose delivery from the periphery as well as the participation of astroglial cells,
which function as the brain‘s glycogen repository. This presents several problems since there
are significant barriers to consistent and stable glucose supply to the brain. Furthermore
astrocytic glycogenesis and glycogenolysis as well as neuronal mitochondrial function can be
influenced by TBI.
Since neurons do not store glycogen, neuronal glucose utilization is intimately yoked to
astroglial compartmentalization of glycogen. In the absence of its own localized glycogen
neurons must communicate energetically with astrocytes in order to replenish energy
substrates. This allows for resetting of membrane potentials and continued neuronal viability
and functionality. Astrocytes support neuronal energetics via multiple pathways, the most
notable and well-studied being the Glutamine-Glutamate Cycle and the Astrocyte Neuron
Lactate Shuttle (ANLS).
In the former, glutamate produced by neuronal Citric Acid Cycle (TCA) mechanics
passes into the extracellular space and is taken up by astroglial cells where it is converted to
glutamine (36). Astroglial glutamine then exits the astrocyte and can be taken up again by a
nearby neuron where it can resupply the neurotransmitter pool or reenter the TCA cycle by
being converted into either alpha-ketoglutarate or succinate (37).
The Astrocyte Neuron Lactate Shuttle provides substrate for neurons to engage the
glycolytic pathway. Extracellular glutamate, from active neuronal signaling, increases
astroglial uptake of glucose by upregulating GLUT1 (38). Astroglial cells then drive the
glycolytic process creating lactate as a metabolic byproduct. This lactate is transported out of

the astroglia into neurons by a monocarboxylate transporters, MCT1 and MCT 2 respectively.
Neurons express several isoforms of lactate dehydrogenase (LDH) causing the conversion of
lactate to pyruvate and the initiation of neuronal glycolysis, which eventually yields more
glutamate to continue the ANLS. These two systems, Glutamine-Glutamate Cycling and the
Lactate Shuttle, bind astroglial cells and central neurons in a symbiotic relationship that
ultimately determines the ATP potential of both functional and injured brains.
TBI alters brain energy metabolism
In 2001, Giza and Hovda outlined the neurometabolic cascade of concussion. The injured
brain shifts into ―hypermetabolism,‖ which increases the demand for ATP. At the same time
energy production pathways shift away from the highly efficient oxidative phosphorylation to
the much less efficient glycolysis. The net effect is neuronal acidosis, membrane dysfunction
and BBB permeability. In addition evidence suggests that in the context of TBI lactate-
consuming pathways that would otherwise drive ATP production via the ANLS are
compromised (32).
What follows is diminished cerebral blood flow, which may be reduced by as much as
50%. This cellular energy crisis predisposes the injured brain to second injury and prolongs
functional deficits associated with the injury (39). Beyond the direct effects upon ATP
producing pathways, post-injury depolarization and K efflux opens NMDA receptors.
Calcium influx further impairs neuronal ATP production by impairing both oxidative
phosphorylation and glycolysis. This promotes activation of apoptotic pathways,
neurofilament compaction, microtubule disassembly, axonotomy and increases the production
of inducible nitric oxide synthase (39).
Due to its high lipid content, the brain is highly susceptible to oxidative damage. TBI
leads to a significant decrease in glutathione and ascorbic acid, the two primary intracellular
antioxidants. Rat brains subjected to TBI showed a three-fold reduction in the reduced-to-
oxidized glutathione ratio. Concomitant reductions in cerebral NAD+ promote mitochondrial
dysfunction (32). Reduced glutathione has been shown to impair astroglial glucose
metabolism and glycogen utilization (40).
Hypoxia
Epidemiological studies reveal that up to 44% of severe TBI patients experience brain
hypoxia that is a direct consequence of hypoperfusion. Proinflammatory cytokine
upregulation induces BBB dysfunction via IL-6 and IL-1b and an overall significant
hypoglycemia, with brain glucose levels dropping by 50% in injury-induced hypoxia (41).
Peripheral metabolic impacts on injured brain fuel status
Ives et al. explored evidence of hypopituitarism following multiple concussions. Growth

hormone was the most vulnerable to successive brain injury followed by gonadotropins, TSH
and finally ACTH. Furthermore these hormonal imbalances may not be evident until well

after the initiating injury (42). Agha et al. (43) explored Glucagon Stimulation and Insulin
Tolerance tests in a population of brain injured patients with a median interval of 7 months
post-injury. Approximately 28% of patients exhibited at least one anterior pituitary hormone
deficiency, 22% showed isolated deficiencies involving either GH, LH/FSH (follicle-
stimulating hormone) or ACTH (adrenocorticotropic hormone) and 6% showed evidence of
multiple deficiencies. Both GH and ACTH exert significant influence over the action of both
glucagon and insulin, and GH deficiency can impair glucose tolerance by decreasing beta cell
mass and insulin production (44). These conditions can have impacts on the injured brain
primarily due to the brain‘s reliance on peripherally derived insulin for glucose uptake.
Post-synaptic contributions in TBI
Traumatic brain injury can lead to various mechanisms of gastrointestinal dysfunction. These
mechanisms include: impairment of digestive enzyme production, impairment of intestinal
motility, disruption intestinal autonomics related to circulation, promotion of intestinal
permeability, and altered interoceptive processing. Disruption of the brain-gut axis involving
the cortico-pontine circuit has been demonstrated with brain imaging studies as a central
mechanism of irritable bowel syndrome (45). Central integration of cortico-pontine circuit is
critical for proper vagal temporal summation and autonomic regulation necessary for
regulating proper intestinal afferent and efferent communication. Additionally, traumatic
brain injury can lead to significant changes of brain-gut peptides in both plasma and small
intestine, which may be involved in the pathogenesis of complicated gastrointestinal
dysfunction (46). These cortico-pontine and pontine-cortical central integrations may be
altered in TBI. Cortical integration is critical for proper bowel function and bowel disorders
associated with lack of cortical level integration of visceral inputs have been demonstrated
with percept-related fMRI (47). Therefore it appears that TBI may potentially lead to altered
gastrointestinal function from loss of cortico-pontine central processing.
TBI and intestinal permeability
One of the major consequences of TBI is lack of cortical activation of the pontine vagal
system leading to altered postsynaptic autonomic changes that promote decreased intestinal
autonomics and inflammatory reactions leading to intestinal permeability. Intestinal
permeability induced from TBI may be a consequence of lack of post-syanaptic activation of
the vagal nuclei. In a mouse model of TBI, vagal stimulation prevented TBI-induced
intestinal permeability and also increased enteric glial activity (48). This study supported the
notion that the vagal nuclei disruption from TBI was the central mechanism for intestinal
permeability development and that vagal activation has modulating activity on the enteric glia
neuroinflammatory responses. Additionally, TBI can induce an increase in intestinal
permeability, which may lead to bacterial translocation, sepsis, and system inflammation (49,
50). TBI induced intestinal permeability thus has the potential to promote a vicious
inflammatory cascade involving the brain to gut axis and the gut to brain axis. Intestinal
permeability has been found to increase proinflammatory cytokines at the intestinal mucosal
level and cause lipopolysaccharide translocation that can disrupt brain function (51, 52).

Therefore, the alteration of cortico-pontine integration from TBI can lead to gastrointestinal
inflammatory consequences from intestinal permeability that then potentially further suppress
brain function leading to chronic inflammatory vicious cycles between the brain and the
gastrointestinal system. Traumatic brain injury can also lead to pro-inflammatory immune
activation in the peripheral blood stream leading to systemic inflammatory response
syndrome (53).
TBI and intestinal mucosa compromise
At the intestinal level many changes take place in the intestinal mucosa directly after brain
injury including mucosal ischemia, mucosal atrophy, and activation of intestinal
inflammatory cascades. These reactions occur rapidly as early as 3 hours following brain
injury and last for more than 7 days with marked mucosal atrophy (54). Additionally, TBI
induces profound effects including gastrointestinal mucosa ischemia and motility dysfunction
(55). The inflammatory reactions that occur in the intestinal mucosa following traumatic brain
injury appear to increase the expression of intestinal nuclear factor kappa B and intercellular
adhesion molecule-1 in the intestine leading to acute gut mucosal injury following TBI (56,
57). There is also rapid and persistent up-regulation of myeloid differentiation primary
response protein 88 (Myd88) in combination with systemic inflammatory cytokine activation
(58). These inflammatory changes that occur after TBI are immediate and illustrate how
cortical injury can lead to inflammatory consequences in the peripheral gastrointestinal
mucosa lining.
TBI and breakdown of the blood-brain barrier
The blood-brain barrier plays a critical role in protecting the brain from immune activating
substances. However, widespread breakdown of the blood-brain barrier occurs immediately
after brain trauma leading to susceptibility of circulating proteins and the promotion of
inflammatory sequelae (59). It appears the blood-brain barrier breakdown occurs rapidly
within hours. TBI disruption of the blood-brain barrier occurs and cerebral vascular
permeability can increase fourfold within six hours of the initiating trauma. It was also found
that vagal nerve stimulation attenuated cerebral vascular permeability and decreased up-
regulation of perivascular aquaporin 4 after TBI (60). Therefore TBI loss of cortico-pontine
dysregulation of the vagal nuclei appears to be a central mechanism for both intestinal and
blood-brain permeability. Specifically TBI induces profound breakdown of the blood-brain
and blood cerebrospinal fluid barriers (BCSFB) and release into the CSF a major
chemoattractant for monocytes, CCL2, by the choroid plexus epithelium at the side of the
BCSFB (blood cerebrospinal fluid barriers) leading to post-traumatic invasion of monocytes
promoting the recruitment of inflammatory cells to the injured brain (61). These
inflammatory changes in the blood-brain barrier neurovascular network have been found to
ultimately lead to delayed neuronal dysfunction and degeneration (62). In summary, in TBI
loss of cortico-pontine processing disrupts vagal network integration and inflammatory
sequelea that promotes breakdown of the neurovascular blood-brain barrier network leading
to loss of brain barrier protection and susceptibility to further neuroinflammation.

Joel Brock © copyright2013

TBI
Supplements Dietary
Canals Plasticity
Vestibular input Diet Nutritional
Otoliths Receptor based
Concerns
therapy
PMRF Neuron
Autonomics MRF
Trigeminal
Brain Glial
Immune interaction
Glial Cells
Blood flow Control immune activation

Transmitters Can prime or turn off
Reticular Transmitters
Pyramidal
Glial Hypothalamic
Fuel Immune
Paraventricular Astrocytes
Muscle tone Inflammation Cerebellum
Delivery Left Right Mesencephalic Cytokines Microglial
Posture Brain activation Basal Ganglia
Efficiency Oligodendro
Proprioceptive Good and bad

Transmitters Feedback Needs balance
Brainstem output
Innate Immune Response Success

Gait
Inflammatory Astrocyte barrier
Parasympathetic Stability
Barriers Resolution Endocrine / Cortisol Non-inflam protection
Sympathetic balance Agility
Adaptive Response BDNF
Biomechanics
Success
Inflammation
Vagal output Pathogen Not Pathogen Barrier breakdown
Inadequate Excessive
Killed. Tissue Killed. Tissue
Non or inflammatory
Vestibulospinal Inflamed. Inflamed. Excitotoxic
Cytokines
Organ Glutamate↑ gaba↓
Splenic cytokines Gut
interaction
Brain
Tissue Becomes Neuroinflammation Tissue Becomes Stress
Lung
Antigen Neurodegeneration Antigen reactions Cell growth Central integrated state
Posture Glial cells
Inflammatory respons
Vestibulo Cell growth or death Immune activation

Vagal output
ocular Factors Influencing Neuroimmunological Outcomes...
Biotransformation Regulation of Control of hormone
Immune separation Neuron – Microglial Apoptosis vs. Necrosis Blood sugar output ROS / PON NMDA /
Vagal control over Ocular function Cytokine Interactions Mit failure Death receptors
LIver
T Cell Polarization
Death Caspase
Dynamic connectivity Cytokines, Hormones, NT’s Loss of brain mass
P450 Immune borders cascade
ROS, RNS, Other Tissue Factors Organ output
↓Inflammation & ↓Pathogen
Killing vs. Cytochrome
Gain and sensitivity Self / Alt-Self / Pathogen
Toxin removal ↑Inflammation & ↑Pathogen Apoptosis Caspase
Antigen
Killing
Biotransformation Glial health / NFKB or

Protection of tissues Adrenal- thyroid
Chemical sensitivity Epigenetic changes
insulin
Spindle feedback Tissue Health / death
Deafferentated Cellular health / death Energy failure
Ability to be plastic / TND
Glial Priming / Glial coding
Figure 6. Stepwise progression toward immune dysfunction in brain injury.
TBI dysautonomia
Various autonomic imbalances may occur after brain injury impaired cortico-pontine
integration called dysautonomia (63). It is a common consequence of TBI and has been found
in 8 to 33% of TBI individuals (64). Dysautonomia after brain injury is characterized by
episodes of increased heart rate, temperature, blood pressure, muscle tone, posturing, and
profuse sweating (65). A common presentation of dysautonomia is persistent sympathetic
overactivity in response to nociceptive stimuli and development of chronic pain after TBI (66,
67). In addition to chronic pain, many individuals that suffer from TBI also demonstrate
prolonged uncoupling of heart rate and heart rate variability postulated to occur from cortical-
pontine disconnection (68). These outcomes have also found to be worse with those that
suffer from post-traumatic hypertonia and have been linked to poor long-term outcome (69).
It appears that TBI leads may lead to altered cortico-pontine integrations leading to various
types of autonomic consequences such as chronic pain, hear rate variability, abnormal
sweating, and various types of imbalanced sympathetic and parasympathetic responses.

TBI and systemic immune dysregulation
Immune system dysregulation may occur from traumatic brain injury, specifically TBI can
lead to immunodeficiency and vulnerability to infections (70, 71). It appears brain injury
leads to systemic immune responses from which chemokine signals from the central nervous
system activate the production of hepatic immune responses and changes in systemic
immunity (72). TBI can alter immune homeostastis contributing to immunosuppression from
decreased phagocytic functions of neutrophils and macrophages as well as monocyte
deactivation resulting in decreased capacity of antigen presentation to lymphocytes (73).
These immune suppressive reactions may have long-term expressions. It was found that brain
injury leads to immunodepression for months and to chronic central nervous system and
systemic immune activation for years after the initial injury (74). Animal lesion studies have
been able to demonstrate the pre and post immunological changes that occur after brain
injury. Animal induced lesion studies of the cerebellum with localized kainic acid
microinjections resulted in reduction of lymphocyte percentage in peripheral white blood
cells and an inhibition on the number and functions of T-cells, B-cells, and natural killer cells
suggesting a role the cerebellum may play in neuroimmunomodulation (75, 76). These
immune compromise changes secondary to brain lesions were also evaluated with kainate
lesions of the vestibulocerebellum. The chemical lesion induced depressed secretion of
hematopoietic cytokines in tissue cultures of bone marrow and thymus (77). It appears that
the brain and immune system are intimately connected and neuroimmunomodulation may be
impaired after TBI leading to immunological compromise and susceptibility to infection.
The blood–brain barrier role in TBI
The term ―leaky brain‖ is the jargon used to describe the increased permeability across the
astrocytes that make up the blood-brain barrier. This is described as the increased passage of
molecules through pericellular and transcellular permeability (78). Shrinkage of endothelial
cells causes a mechanical disarray of the tight junctional complex. This is due to drastic yet
reversible changes in cell morphology leading to spatial reorganization of the junctions (78).
Brain infiltration of cells, ions, or molecules may initiate, amplify, procrastinate, repair
or disrupt a CNS response (78). It is also well understood that a fundamental principle of a
mTBI is a breach in the BBB. The severity or ability to recover from a TBI may be intimately
related to the pre-existing state or the severity of the breach of the BBB. Glial cell types are
all capable of producing typical proinflammatory molecules (78). Inflammatory cytokines
have been implicated as modulators of BBB function (79).
TBI induced breaches in the BBB cause an extravasation or movement of albumin from
the capillaries to the surrounding tissue in brain, changing the ion channels. This may be an
independent activator of astrocytes and result in long-term neocortical abnormalities and
functional decline (80).
The brain has a highly specialized glioneuronal system to buffer extracellular potassium
(81). Increased levels of potassium will cause massive reduction in blood flow. This reduction
will shift the brain toward hypoxia and loss of metabolic support.

Cellular
Cell Death excitotoxicity
Axonal Damage
Direct damage
Vascular
Traumatic Brain Injury BBB Breakdown
sensitization
Glial Priming Brain swelling

Intracellular damage
Figure 7. Cellular and barrier changes from TBI © Joel Brandon Brock 2013.
Glutamate is more concentrated in the blood. A breach in the BBB will lead to increased
glutamate in brain causing an excitotoxic response and an increase in firing. Adenosine helps
to maintain neurovascular control. When the BBB is breached, a complex synergy of
adenosine and glutamate transporters and catalytic enzymes is altered, leading to an overall
drop in adenosine availability to curb neuronal firing and increased glutamate (78). In these
examples it is reasonable to understand how a breach in the BBB, from multiple mechanisms,
can lead to chronic states of neuronal compromise and predispose the brain to TBI and inhibit
the recovery of a TBI.
Vagal nerve stimulation attenuates the effects of TBI by protecting hippocampal
neurons. Vagal nerve stimulation also attenuates the breakdown of the BBB post TBI. The
attenuation of the BBB breakdown may be the mechanism of hippocampal protection (60).
This mechanism may be further described as vagal nerve stimulation induction of the
cholinergic anti-inflammatory pathway, effectively inhibiting pro-inflammatory cytokines.
This has been partially confirmed by vagal nerve stimulation decreasing systemic tumor
necrosis factor alpha hours after TBI (82). Some disagree and state it is due to a more
localized central nervous system-specific effects of vagal nerve stimulation (83). What is
agreed on is the fact that vagal nerve stimulation attenuates post TBI BBB breakdown (82).
Not only is this a potential therapy, but also further implicates the importance of BBB
integrity as an independent risk factor with regard to TBI.
In adult brains, oligodendrocyte precursor cells (OPCs) are thought to maintain
homeostasis and mediate long term repair in white matter after disease (79). The activation of
OPCs is supposed to represent a protective response in the damaged or diseased brain.
Recently, however, reactive glia are now recognized to mediate complex mechanisms,
including both beneficial and deleterious effects after brain injury and neurodegeneration (84,
85). For example, depending on context, astrocytes can either promote neuroplasticity or
secrete inhibitory matrix molecules that inhibit axons (86, 87). Similarly, microglia are now
known to release both pro-recovery and neurotoxic factors 88-90). OPCs can also release
multiple factors to modulate neighboring cells and the microenvironment (91). These
intercellular signals may be especially important, since perturbations in the blood-brain
barrier (BBB) are known to be a critical part of white matter pathology in a wide range of

CNS disorders (92, 93). OPCs in adult brain are precursor cells for white matter remodeling,
and repair injury and demyelination. They can play a surprisingly deleterious role in
cerebrovascular injury and demyelination in white matter (79).
With TBI or other mechanisms causing inflammatory changes in brain, even before
demyelination occurs, BBB leakage and neutrophil infiltration can be observed (79). MMP2
(matrix metalloproteinase-2) and -9, are known to mediate BBB injury (94, 95). In studies
after an initiating trauma or event causing a BBB breach, the early phase of BBB leakage at 3
days, white matter MMP9 expression is increased, mostly in OPCs and at 7 or 14 days, a
secondary expression of MMP9 occurs in cerebral endothelial cells (79). No other glial cell
types (mature oligodendrocytes, astrocytes, microglia) appear to produce MMP9 in the model
of cerebral hypoperfusion and chronic hypoxic stress (82). No significant MMP9 increases
occur in blood neutrophils nor plasma at day 3. Importantly, MMP9 expressing OPCs were
located close to cerebral endothelial cells and OPCs existed near the BBB leakage areas at the
acute phase of white matter injury (79).
After brain injury and disease, progenitor/precursor cells in the adult brain are believed
to help compensate for lost brain function (96, 97). OPCs can be triggered to become mature
oligodendrocytes or cortical projection neurons after white matter injury (98). OPCs can
rapidly respond to white matter injury and produce MMP9 that appears to open the BBB and
trigger secondary cascades of cerebrovascular injury and demyelination (79). This could serve
as a model to explain a more severe consequence of a ―seemingly‖ mild injury/event causing
severe effects on brain function.
Inhibition of the early MMP9 phase in OPCs also prevented the secondary expression of
MMP9 in cerebral endothelium on day 7 and subsequently the development of white matter
injury and demyelination as well as cognitive deficits in cerebral hypoperfusion. OPC-derived
MMP9 in the acute phase may trigger further secondary cascades of cerebrovascular damage
in white matter (79).
BBB Breakdown
Injury / Stress OPC MMP-9
Neutrophil Infiltration
White Matter Damage

Cognitive Decline
Figure 8. Oligodendrocyte cascade (79).
OPCs do not produce MMP9 under normal conditions, but after treatment with nonlethal
levels of the inflammatory cytokine IL-1ß (similar to that in a TBI), MMP9 secretion is
markedly increased. IL-1ß–treated OPCs degrade the tight-junction protein ZO-1 in cerebral
endothelial cells without affecting cell survival. Consistent with this effect on tight junctions,
conditioned medium from IL-1ß–stimulated OPCs significantly increased endothelial

permeability and neutrophil transmigration (79). This effect is dependent on MMP. This
suggests that stimulated OPCs (potentially from TBI) release MMP9, which degrades the
BBB in white matter. This represents a mechanism for white matter disease at an early stage,
and creates further damage and downstream inflammation and demyelination. The state of the
BBB both prior to and immediately after injury plays a major role in the probability of, the
severity, and the long-term consequences a TBI.
TBI and its effect on the adrenals and hormones
Deficiencies in circulating hormones may not be apparent immediately after injury but can be
demonstrated days to weeks thereafter. Aimaretti et al. reported an incidence of pituitary
dysfunction in 33% of TBI patients 3 months after injury, complete panhypopituitarism in
5.7%, multiple defects in another 5.7% and a single hormone deficit in 21%. Secondary
hypoadrenalism was found in 8.5% but considering those with panhypopituitarism or multiple
hormone abnormalities that might include the adrenal hormones, this incidence may be as
high as 20% (99).
In a prospective comparison of 80 TBI patients to 41 trauma patients without TBI,
measuring cortisol and ACTH levels twice daily for 9 days after injury, adrenal failure, which
was defined as two consecutive cortisols of ≤ 15µg/dL or one cortisol of ≤ 5µg/dL, occurred
in 53% of the TBI patients at a mean time of 2.4 days and suggested a secondary cause.
Patients with adrenal failure were more severely injured, demonstrated more episodes of
hypotension and more often required vasoactive drug support (100). From such data, it would
appear that the risk of secondary hypoadrenalism after TBI is somewhat higher than 25%.
Recently published guidelines recommend acute endocrine evaluation only for patients
with documented fractures in the sella turcica or diabetes insipidus. Other authors, however,
suggest early endocrine assessment for all patients with moderate-to-severe TBI and routine
endocrine testing for all TBI patients at 3 and 12 months. It is also suggested that evaluation
be performed for primary and secondary adrenal failure in patients that demonstrate
continuing hyponatremia or hypoglycemia or require persistent vasoactive drug treatment
during acute care (99).
Endocrine evaluation should include a baseline blood cortisol concentration, a serum
ACTH measurement and thyroid studies before the administration of any preparation
containing steroids. Although some authors recommend a morning cortisol blood test, stress
decreases the normal diurnal variation in cortisol release, making random values acceptable.
In both primary and secondary adrenal failure this measurement should be low. The actual
concentration that defines a low value is somewhat controversial because of the expected
increase in cortisol during ‗stress‘ caused by TBI. Therefore, values between 200 and 700
nmol/l or over 15mgm/dl are suggested as minimal basal concentrations expected after trauma
(100).
HPA (hypothalamic-pituitary-adrenal) injury may also produce underproduction of
thyroid stimulating hormone (TSH) as ‗central‘ hypothyroidism, indicated by low TSH and
tetraiodothyronine (T4) blood concentrations. The ‗euthyroid sick syndrome‘ is expected in
such critically injured patients, but in that condition the TSH remains normal. Growth
hormone and the several gonadal hormones produced by the pituitary gland may also be low

but do not require acute replacement, although treatment during later recovery will be
important (100).
Utilization of the traditional ‗high-dose‘ (250 mg) versus ‗low-dose‘ (1 mg) ACTH
stimulation test remains controversial. The higher pharmacological amount may allow a
partially dysfunctional gland to release a sufficient amount of hormone to appear falsely
normal, while the lower dose is perhaps more difficult to accurately administer. Similarly,
criteria regarding the magnitude of response that confirms a responsive adrenal gland have
been controversial. Criteria include either a specific post-stimulation (usually 60 min) cortisol
concentration (e.g., above 500 nmol/l, or 25 mg/dl) or a specified incremental increase from
basal levels (e.g., >250 nmol/l or >9 mg/dl). Bernard et al. found 78% of their TBI patients
had a basal cortisol value of under 414 nmol/l, but after a 250 mg ACTH stimulation, only
13% failed to increase the serum cortisol concentration by less than 250 nmol/l (101). These
data again emphasize that the diagnosis of hypoadrenalism often depends upon the criteria
selected (100).
Cortisol is measured in the blood as both an unbound (‗free‘) form, which is the
biologically active hormone, and as cortisol bound with cortisol-binding globulin (CBG).
CBG is commonly low in critical illness/injury, especially when the serum albumin is less
than 2.5 gm/dl and may be one cause of an apparent low cortisol serum concentration.
Measurement of free-cortisol, therefore, has been suggested as the more accurate assessment
of adrenal output. Testing methods for CBG and free cortisol, however, are rarely available
(99).
Acute hypoadrenalism after TBI may contribute to hypotension, hyponatremia or
hypoglycemia during patient care. Its incidence remains unclear due to variable definitions
and testing methods, but appears to be approximately 25%, including both secondary causes
related to injury to the central hypothalamic-pituitary axis and primary adrenal failure. We
recommend serum testing of basal cortisol, ACTH, and post-ACTH stimulation cortisol at 60
min when hypoadrenalism is suspected. Basal cortisol below 15 mg/dl suggests either
primary or secondary adrenal failure and may warrant treatment. Failure of the cortisol
concentration to increase by at least 9 mg/dl after stimulation suggests primary adrenal gland
hypoadrenalism. Treatment with intravenous hydrocortisone during acute care should be
initiated if clinical circumstances warrant. Thyroid function should also be evaluated and, if
needed, hormone replacement should be provided if adrenal insufficiency is treated. It is
generally recommended that even if acute treatment is not given, all patients should be
evaluated for adrenal, thyroid and growth hormone deficiency 3 months after severe TBI (99).
It has been previously reported that experimental mild traumatic brain injury results in
increased sensitivity to stressful events during the first post-injury weeks, as determined by
analyzing the hypothalamic-pituitary-adrenal (HPA) axis regulation following restraint-
induced stress. This is the same time period when rehabilitative exercise has proven to be
ineffective after a mild fluid-percussion injury (FPI) [100]. These findings suggest that the
increased sensitivity to stressful events during the first post-injury weeks, after a mild FPI,
has an impact on hippocampal neuroplasticity (100).
An earlier paper described an increased sensitivity to restraint-induced stress during the
first two post-injury weeks as indicated by increases in corticosterone (CORT) and ACTH
compared to uninjured rats (100). The stress response involves the activation of the HPA axis
resulting in the release of ACTH from pituitary cells. ACTH stimulates the adrenal gland to

release glucocorticoids, such as CORT, which in turn results in the inhibition of ACTH
secretion (102).
It has been well characterized that stress decreases neuronal plasticity and favors
neurodegeneration (103). The effects of stress on the central nervous system are most notable
within the hippocampus where it substantially influences neuronal excitability and long-term
potentiation (LTP). The hippocampus has a high density of glucocorticoid receptors (104).
These receptors exert a variety of effects besides the autoregulation of the stress response,
such as influencing mood, learning and memory (105). Moreover, stress-related increases in
glucocorticoids have been associated with cell death and cognitive impairments (106).
Among the effects of stress is the inhibition of hippocampal brain-derived neurotrophic factor
(BDNF) (107). The anatomical and vascular characteristics of the hypothalamic-pituitary
complex increase its vulnerability during TBI. Particularly, diffuse TBI, where metabolism
and neural connectivity are compromised (108).
Given the above-mentioned effects of glucocorticoids on hippocampal synaptic plasticity
and BDNF expression, it is feasible that impaired neuroendocrine function interferes with
BDNF-mediated restorative processes after TBI. For example, a hyper-response to stress
following TBI may play a role in the inability to increase BDNF during the subacute period,
as seen in rats with a mild injury (109).
Affective disorders and cognitive impairments after TBI play a substantial part in
decreasing quality of life. A dysregulation of the stress response has been linked to affective
disorders in TBI patients. In effect, alterations in the regulation of the HPA axis contribute to
negative mood states associated with depression (110). In addition to showing a hyper-
responsiveness to stress after TBI, we now provide evidence that post-injury stress has an
effect on BDNF regulation within the hippocampus. The effects of stress on cognitive
abilities also need to be considered, particularly given BDNF‘s effects on plasticity. An
increase in glucocorticoids, in human subjects, is associated with impaired memory and
hippocampal deterioration (111). These data add some pieces to the puzzle in understanding
the hyper-response and the delay of exercise-induced increases in BDNF during the subacute
period. However, they also emphasize the need for more studies regarding HPA dysregulation
after a mild TBI. Understanding some of the molecular mechanisms influencing the response
to stress will allow us to better address posttraumatic affective and behavioral disorders as
well as enhancing rehabilitative therapies.
There were 113 charts that were retrospectively reviewed of traumatic brain injury
patients within 10 days of their injury. They all had a high-dose corticotropin stimulation test
performed because of haemodynamic instability. Blood cortisol concentrations were
measured at baseline, 30 and 60 minutes after the administration of high-dose corticotropin.
The incidence of adrenal insufficiency was determined according to various definitions used
in the literature (101).
Primary adrenal insufficiency defined by an abnormal baseline cortisol concentration and
an abnormal response to the high-dose corticotropin stimulation test was present in 13–28%
of patients according to the cut-off values used. The incidence of adrenal insufficiency varies
from 25 to 100% in the first 10 days after traumatic brain injury when the charts of 113
traumatic brain injury patients were reviewed (101).
Adrenal insufficiency has emerged in recent years to be a crucial and prevalent problem
in intensive care. Hypopituitarism has recently been reported to occur in 35–80% of patients
in rehabilitation following head injury. Adrenal insufficiency accounts for 30–50% of these

cases (101). Underestimation of the true incidence of adrenal insufficiency and potentially
under-treated patients may be occurring by using only the low-dose stimulation test to define
adrenal insufficiency (101).
A concentration of 414 nmol/l is considered to be the normal minimum value in response
to severe stress, particularly hypotension. Hence, it is viewed as the minimal appropriate
concentration for intensive care patients. A concentration below 690 nmol/l has been
suggested instead since patients undergoing surgery or sustaining trauma almost invariably
have cortisol concentrations above this value. The intensive care literature tends to support
this view. Response to high-dose corticotropin stimulation test, in a study by Annane and
colleagues, suggested a rise in plasma cortisol concentration by >250 nmol/l was the
appropriate response of the adrenal glands in intensive care patients with sepsis (112). This
definition is probably the most widely used cut-off to interpret a stimulation test in intensive
care. Classically, a rise above 500 or 550 nmol/l is considered normal based on the response
of non-critically ill patients to insulin-induced hypoglycaemia (101).
Primary adrenal insufficiency defined by an abnormal baseline and abnormal post high-
dose corticotropin stimulation test cortisol concentration was present in 13–28% of patients
depending on whether a 60 or 30 min sampling time after high-dose corticotropin was used,
respectively. Whichever definition was used, the incidence of primary adrenal insufficiency is
markedly reduced if the 60 min (rather than the 30 min) cortisol values were used to define
adrenal insufficiency (101). This study showed that the incidence of adrenal insufficiency in
severe traumatic brain injury varies enormously depending on the definition used. The
incidence of adrenal insufficiency defined by baseline cortisol concentrations may be as high
as 100%. Primary adrenal insufficiency accounts for 13–25% of the cases. It also
demonstrated that sampling for cortisol at 60 min after a high-dose corticotropin stimulation
test is more appropriate than doing so at 30 min. 414 mmol/l is probably a more useful cut off
in a traumatic brain injury population (103).
Although fatigue is a common experience in the general population it is particularly
bothersome to those with TBI (113). Depending on the scales used to measure fatigue and
time since injury, its prevalence has been reported in 16–80% of individuals after injury.
Associated symptoms include depression, sleep disturbance, pain, cognitive and motor
disturbances (113).
Neuroendocrine abnormalities as manifested by pituitary dysfunction can occur after
TBI. One-to-several hypothalamic-pituitary axes may be affected; posterior pituitary
dysfunction typically resolves during the first several months post-injury, whereas anterior
pituitary problems are more likely to persist (113).
Although several lines of evidence indicate that TBI may predispose the pituitary to
injury, neuroendocrine dysfunction is rarely considered in current TBI management. Autopsy
studies of fatal head-injury victims confirm that up to one third sustain anterior pituitary gland
necrosis. Moreover, numerous case reports, retrospective reviews, and recent prospective
cohort studies have documented acute and chronic posttraumatic hypopituitarism (100).
Activation of the HPA axis is an important protective response during critical illness.
Untreated adrenal insufficiency (AI) may lead to hemodynamic instability and poor outcome
(100). The molecular mechanism of the effects of glucocorticoids on chronic inflammation is
not well understood, but there is increasing evidence that they inhibit the action of
transcription factors such as AP-1 and NF-kB (114). Glucocorticoids are potent inhibitors of
the activation of NF-kB, which may account for most of their anti-inflammatory actions

(115). Glucocorticoids are effective inhibitors of NF-kB, but they have endocrine and
metabolic side effects when given systemically (115).
Activation of NF-kB, for example by cytokines, is blocked by glucocorticoids.
Glucocorticoid-receptor complexes bind to the p65 subunit of NF-kB, and this prevents NF-
kB activation of the inflammatory genes. Synthesis of nuclear factor of kappa light
polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα) is stimulated by the binding of
glucocorticoid-glucocorticoid-receptor complexes to a glucocorticoid response element in the
promoter region of the IkBα gene (115). It may be unwise to block the activation of NF-kB
for prolonged periods, because the factor plays such a critical part in the immune response
and other defensive responses 115.
Part I revealed a wide range and number of cellular and tissue/hormone processes that
can be measured and manipulated. Part II describes clinical level measures and interventions.
PART II: CLINICAL CONSEQUENCES AFFECTING SPECIFIC

BRAIN SYSTEMS
Evidence of anatomical brain damage has long been a hallmark in diagnosis of brain injury.
For the chronic post-concussion patient this has historically been elusive. Researchers
consider concussion to be the result of mechanical trauma to the head or neck that leads to
functional impairment without overt structural damage (115). This results in no gross changes
or brain abnormalities seen on imaging (116, 117). A traumatic head injury mechanism
combined with a lack of positive findings on imaging is the primary diagnostic scenario. This,
the symptom checklists, the opinion of a physician familiar with the patient and ongoing
observation by family, coaches or the patient themselves, are standard diagnostic tools. These
are commonly used strategies in identifying the presence of concussion and are relied upon
for clinical, return to activity and legal purposes in most settings (118-121).
Current neuroscience has reached a point where evidence of the neuroanatomical
consequences of concussion can be identified. The initiating structural damage appears to
result from stretching and disruption of neuronal, glial and axonal cell membranes; while cell
bodies and myelin sheaths are less affected (122, 123). These injuries are microscopic,
involving cellular structures, as well as microvasculature and the blood-brain barrier.
Although techniques to identify microscopic structural damage are not readily available to
clinicians, the pursuit of this information is clinically relevant. Investigators looking at extent
of tissue damage using advance imaging techniques have been able to use the data in
predicting individuals who will likely have an uncomplicated recovery from concussion
versus those who progress to chronic post-concussion syndrome (124).
Postmortem studies of individuals who survived concussion and later died due to
apparently unrelated circumstances have provided early evidence of microscopic brain
damage in concussion. These types of studies, performed as early as the 1950‘s and 1960‘s,
continue to provide evidence of damage post-concussion. Historically, the overall impression
has been that post-concussion brain damage occurs diffusely in the white matter (125-127).
More recently diffusion tensor imaging, tractography, perfusion studies and functional
neuroimaging have been utilized in identifying areas of damage in individuals with mild
traumatic brain injury. These advanced neuroimaging techniques support the notion of axonal

and vascular lesions (128-131). Additionally, a mouse model of concussion has provided
evidence that degeneration in the gray matter, involving extensive dendrite degeneration and
synapse reduction with very minimal cell death, may be a major neuropathological feature in
mTBI (132). Chronic head injury at the concussive or subconcussive level has been
associated with morphological change in the brain that is similar to those seen in Alzheimer‘s
disease and other neurodegenerative disorders. Cortical degeneration with neurofibrillary
tangles, neurite heads, neuronal dropout and accumulation of Tau and transactive response
DNA-binding protein 43 (TDP-34) proteins are found the human brain chronically after
repetitive concussion and subconcussion trauma (133-136).
Brain Damage
Structure
Changes in
damage Changes in
protein
Neurofilament
replication and
and microtubles
epigenetic factors
Changes in
Changes in
mitochondrial
secretory vesicles
function
Changes in Changes in
synaptic capacity lysosomes
Figure 9. Neuroanatomical damage at the cellular level © Joel Brandon Brock 2013.
Work has been done to identify which regions of the brain are most often affected in
concussion. In severe and moderate brain injury the location of damage is fairly consistent
with proximity to mechanical trauma, contrecoup deformation, areas of the brain in contact
with more rigid structures and those displaced by swelling (137, 138). For the chronic post-
concussion patient there is less predictability in the specific region of damage. Medial frontal,
dorsolateral frontal, occipital, subcortical and corpus callosum have all been reported as
damaged in this population (113, 139-141). In a subset of chronic post-concussion patients
with depression, the frontal and temporal white matter have been identified as injured (142).
Corticocerebellar circuitry disruption has been found as well (115, 124, 143). Structural
involvement of the thalamus was inferred using graph theory analysis and proposed as a
useful marker in identifying mTBI (144). Sheering stresses around the brainstem have been
investigated by recreating a series of recorded head to head collisions in football and
analyzing the threshold of force that may be necessary to produce a lasting concussion
syndrome (145). Additionally, the tissue stressor from concussive trauma has been associated

with vascular damage to both the small vessels and integrity of the blood-brain barrier (146,
147).
The immediate trauma associated concussion results in a host of other changes at the
cellular and molecular levels. They include involvement of the immune and endocrine
systems. They affect the metabolism and biochemistry of the brain, as well as distant sites in
the body (148, 149). There is very strong and growing evidence that both the immediate and
ongoing ―non-anatomical‖ consequences are associated with the vast majority of the
difficulties faced by the post-concussion patient (150-152).
Visual and vestibular dysfunction in the mTBI patient
Beyond neurocognitive testing, many additional methodologies have been evaluated to assess
the consequences and natural history of mTBI. These forms of functional analysis offer new
windows for the clinician to assess the severity of mTBI and monitor response to treatment
and level of recovery. Further, they imply promising new avenues of treatment for the mTBI
patient.
Vestibular dysfunction in mTBI
Vestibular impairment is a common consequence of mTBI. As many as 65% of mTBI

patients will experience some form of vestibular dysfunction during their recovery (153).
Vestibular lesions have been shown to directly produce central inflammatory changes.
Unilateral vestibular deafferentation has been demonstrated to result in significant microglial
and astroglial activation in the vestibular nuclei (154). Rat models of vestibular lesion via
arsanilate transtympanic injection manifest significant central vestibular inflammatory
changes. Elevations in the number of tumor necrosis factor alpha immunoreactive (TNFa-Ir)
cells in the bilateral medial and inferior vestibular nuclei can be seen as early as 4 hours after
vestibular lesion, with NF-kB upregulation following 8 hours after the lesion, and manganese
superoxide dismutase (MnSOD) elevation after 24 hours. Similar changes have been
demonstrated in rat models of mechanical unilateral vestibular deafferentation (140). As a
consequence, thorough evaluation and management of vestibular dysfunction in mTBI
patients may show promise as a means of limiting central inflammatory processes.
Benign paroxysmal positional vertigo is the most common form of posttraumatic vertigo
(139). As this is a relatively straightforward condition to evaluate via Dix-Hallpike testing,
and manage with canalith repositioning maneuvers, Dix-Hallpike testing should be employed
in all mTBI patients with vestibular complaints (139). Sherer et al. (155) evaluated blast-
induced mTBI patients reporting persistent dizziness via videonystagmography (VNG),
rotational chair, cervical vestibular-evoked myogenic potentials, computerized dynamic
posturography, and self-report measures.
Evidence of central and peripheral vestibular dysfunction was identified at a higher
frequency in symptomatic patients. Abnormal nystagmus or oculomotor findings were present
in 50% of symptomatic subjects. Rotational chair testing found evidence of peripheral
vestibulopathy in 25% of symptomatic patients, and central vestibular pathology in 17% of
symptomatic subjects (141).

Computerized dynamic posturography (CDP) has been proposed as a means to monitor

the status of vestibular function. CDP testing assesses the patient‘s ability to maintain
postural stability against a standardized series of balance and postural challenges.
Approximate entropy (ApEn), a measurement of how likely a postural correction is to recur
within a time series, is thought to decrease with mTBI [ ]. A person swaying in a predictable
manner represents a lowered capacity to adapt to subtle changes in environmental stability,
and thus lower postural control dynamics. ApEn has been shown to decrease with mTBI, and
shifts in stabilization strategies toward greater anterior-posterior and decreased medial-lateral
control [142]. This raises the likelihood that concussed patients have a chronic risk of falls
without appropriate neurorehabilitation.
Brain Trauma
Degeneration
Inflammation
Glutamate Decreases
upregulation and monoamine
NMDA turnover
Pathways tip, various cells die, various

circuits skew, symptoms present
Increased risk
of seizure, GABA Down Decreased
headache and regulates. Receptors Changes in
Increases risk serotonin and
metabolic internalize melatonin and
of cellular TND dopamine
failure. Cell Plasma Cat.
conversion
might not
summate
Saccades OPK
Loss of Changes in
inhibitory Loss in frontal striatal and
Increases risk Increases risk pathways gating and frontal systems
of Intracellular of ROS, PON
striatal and global
damage and caspase
summation cortical
function
Limb movement Changes in Posture

cerebellar,
Increases risk cortical, basal
Increases risk Depression,
of glial ganglionic and
of Limbic changes issues with
priming, mesencephalic
inflammation and emotional summation,
autoimmunity output
and BBB lability cognitive
and cellular
damage slowing
debris
Cortisol
Autonomic changes
Cytokines
Anxiety,
Basal
insomnia, Mesostriatal
ganglionic Pathway
perpetuates Mesocortical
Pathway changes, alteration
hyperkinetic Mesolimbic
alteration hyperkinesis
issues,
and cortical
changes
Figure 10. mTBI progression to visual and vestibular dysfunction © Joel Brandon Brock 2013.

Treven et al. (157) demonstrated the utility of CDP to assess and quantify balance deficits
in ambulatory mTBI. They revealed that standardized functional measures utilized for
determining release from acute mTBI rehabilitation settings do not consistently and
specifically assess balance. Many patients that have reached discharge level from acute rehab
setting maintain a high degree of balance deficit. This persistent instability raises the risk of
reinjury and further trauma.
Assessment of vestibular dysfunction has been effectively demonstrated through the use
of vestibular-visual-cognitive interaction tasks (158). Changes in static visual acuity,
perception time, target acquisition, target following (TF), dynamic visual acuity (DVA), and
gaze stabilization have been demonstrated in blast-induced mTBI patients. Rehabilitation
procedures involving the vestibulo-ocular reflex, cervico-ocular reflex, and depth perception,
as well as somatosensory balance exercises, dynamic gait, and aerobic function exercises
have been employed to effectively manage these systems (144).
Vestibular rehabilitation therapy (VRT) has been shown to be helpful for patients with
persistent dizziness and balance dysfunction for whom gait and balance dysfunction did not
resolve with rest alone [ ]. Subjective dizziness and objective measures of gait and balance
have shown to be improved after protocols of rehabilitation involving gaze stabilization
exercises, standing and dynamic balance exercises, and canalith repositioning maneuvers
where indicated (145). Similarly, target following and dynamic visual acuity scores returned
to normative levels after an 8-week vestibular physical therapy protocol. Gaze stabilization
similarly improved after 8 weeks of VRT (144).
Visual dysfunction in mTBI
Visual dysfunction has been shown to be extremely prevalent in the mTBI population.
Ciuffreda et al. assessed for frequency of occurrence of oculomotor dysfunction in TBI,
considering accommodation, version, vergence, strabismus, and cranial nerve palsy. They
found that oculomotor dysfunction is the norm in TBI (160).
Convergence insufficiency (CI) has been shown to be present in roughly 9% of the
visually symptomatic TBI population without simultaneous vestibular dysfunction, saccade or
pursuit dysfunction, cranial nerve palsies, visual field deficits, visuospatial neglect, or
nystagmus. In many cases it appears that CI may occur in the absence of obvious dysfunction
in visual and vestibular systems, rendering a thorough evaluation even more necessary (161).
The neural substrates of eye movements involve diffuse networks including the frontal
lobes, parietal lobes, and cerebellar cortices. These systems also serve within networks that
facilitate executive functions and higher cognitive experience. Impairments of eye
movements have thus been demonstrated to have considerable clinical utility in both
diagnosing and rehabilitating the mTBI patient.
TBI patients demonstrate aberrancies in predictive components of smooth pursuit eye
movements (162). These deficits in average target prediction, eye position error, and eye
position variability positively correlated with executive function and attentional measures on
the California Verbal Learning test (CVLT-II), without apparent reduction in IQ noted on the
Weschler Abbreviated Scale of Intelligence (WASI). Impairment of predictive smooth pursuit
eye movements thus may be a sensitive indicator of impaired attention processing.

Smooth pursuit movements coupled with target blanking, wherein the target being
pursued is intermittently obscured, necessitates the generation of greater predictive eye
movements (163). This process requires greater reliance on brain regions involved in
cognitive processing. Deficits in CVLT-II performance have been shown to more positively
correlate with oculomotor variability during target blanking than during target tracking (163).
Maruta et al. (164) demonstrated the presence of diffuse axonal injury (DAI) within the
frontal lobes in mTBI via diffusion tensor imaging. Fractional Anisotropy indicates frequent
involvement of the anterior corona radiata, the uncinate fasciculus, the genu of the corpus
callosum, and the cingulum bundle. They compared various measures of eye movement
performance to fractional anisotropy (FA) and diffusion tensor imaging (DTI), as well as to
neurocognitive tests. Variability of gaze position errors during predictive smooth pursuit
proved to be a sensitive measure that correlated with neurocognitive testing data and DTI
findings. The degree of variability correlated with the mTBI spectrum severity (164). They
determined that performance variability during predictive visual tracking is a valid and useful
indicator of damage to frontal white matter tracts, and is similarly indicative of impaired
cognitive function (164).
Similar correlations have been shown between dysfunction in saccade eye movements
and measures of neurocognition. Mulhall indicated that bedside tests of saccades utilizing
infrared oculography (IRO) produced saccadic impairment data that positively correlated with
impairments on neurocognitive tests (165). Recovering TBI patients were shown to have
decreased rates of self-paced saccades, impaired ability to suppress inappropriate saccades in
single memory-guided and antisaccade tests, prolonged saccadic latencies, and hypometric
saccades in visually guided reflex saccade tests. This implies that IRO testing should be part
of any mTBI management protocol (165).
Increased duration of reflexive saccade latencies has also been shown to be present in
mTBI (166). Portable saccadometry has been utilized to evaluate boxers pre- and post-bouts.
Latency distributions have been shown to be significantly altered after blows to the head, with
these effects reversible over a short period of time. Latency requires cortical decision
mechanisms, and is directly affected by processes that affect cerebral function (166).
Drew et al. (167) investigated the relationship between dysfunctional visuospatial
orientation processes and difficulty with orienting attention. Saccadic targets were presented
with varying temporal gaps and reaction times were assessed. They found that mTBI patients
demonstrated significantly longer saccadic reaction times than controls when the time gap
between saccades was short, but not when the temporal gap was long. Shifts in attention
require disengagement from the point of fixation, both cognitively and visually. This process
appears impaired in mTBI (167).
Heitger (168) found that eye movement function was impaired in post-concussion
syndrome, with eye movement deficits found on measures relating to motor functions
executed under both conscious and semi-conscious control, as well as on several eye
movement functions that are beyond conscious control and indicative of sub-cortical brain
function. They demonstrated specific deficits in antisaccade performance, a task that in non-
mTBI individuals that requires attentional focus, inhibitory control, working memory, and the
ability to generate voluntary goal-directed behavior (169). They recommended that eye
movement testing be utilized with post-concussion syndrome patients to evaluate for
incomplete recovery of function (169).

Given the interaction between visual and vestibular function within the maintenance of
balance and gait, it is perhaps unsurprising that TBI patients demonstrate abnormal caloric
irrigation and optokinetic circularvection testing, as well as lower anterior and posterior and
higher medial and lateral center of mass displacements and velocities during gait assessment
(170).
Rehabilitation of eye movement dysfunction has been shown to be effective in mTBI
patients. Ciuffreda et al. demonstrated a 90% rate of improvement from oculomotor
rehabilitation, with reduction in both symptoms and objective findings that persisted at a 2- to
3-month follow-up, demonstrating both the efficacy of optometric rehabilitation and
significant neural plasticity in mTBI patients (171).
Novel forms of rehabilitation have been shown to have efficacy in treating the visual and
vestibular dysfunction, and may hold promise in the treatment of those same dysfunctions in
mTBI patients. Optokinetic stimulation has been shown to activate areas often involved in
mTBI, including the prefrontal cortex/frontal eye fields, areas involved in generation of
saccades, and modulation of the parieto-insular vestibular cortex, an area involved in visual-
vestibular interaction (172). Repetitive optokinetic stimulation has been shown to be useful
for rehabilitation of vestibular deficits and in causing adaptive changes in locomotion in
healthy subjects (173-175). Optokinetic stimulation has shown efficacy restoration of
mobility in acute stroke patients (176, 177). Vagal nerve stimulation has been shown to be
effective in limiting the vasogenic edema that develops secondary to the disruption of the
blood-brain barrier in TBI, thus limiting central inflammation and neuronal damage (60, 178).
Within a virtual reality environment, combinations of optokinetic stimulation and habituation,
visual and physical perturbations, and postural stability exercises have been shown to
decrease visual and physical motion intolerance and impairment in static balance (179).
Further research is needed with respect to these interventions.
Given the interaction between the visual and vestibular systems, the frequency of
impairment noted in these systems, and their potential influence on central inflammatory
processes, thorough and sensitive evaluation of these systems is a prerequisite for effective
management of mTBI.
Neuropsychological effects: Multi-systems approach to persistent post-

concussion syndrome (PPCS)
Neurocognitive effects of concussion/TBI are unpredictable. Research to date has given us a

wealth of information concerning the mechanism of injury, acute pathophysiology, chronic
pathophysiology, imaging, neuro-immune and HPA axis contribution. With all of this
information there are still few tools available for clinicians to diagnose the extent of cognitive
impact and even fewer tools available for prognosis and treatment. Why is it that some who
have suffered more severe TBI have complete resolution of cognitive symptoms but those
with a relatively mild history of injury have such great difficulty with executive function,
attention, anxiety, pain, fatigue, and depression? This leaves clinicians with little choice but
to react to symptoms as they occur, thus allowing the potential harm of unrecognized,
undiagnosed chronic pathophysiology and dysfunction to fester.
The treatment for persistent post-concussion syndrome (PPCS) due to mTBI does not
address the cause, and mostly consists of rest and cognitive behavioral therapy with limited

results for those suffering from PPCS (180). Medications to treat concomitant depression,
attention deficit and anxiety are often prescribed.
There are two current sets of research criteria for the post-concussive disorder: the
International Classification of Diseases, 10th Edition (ICD-10), and the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). According to the DSM-IV
the individual with post-concussion syndrome will have trouble paying attention,
concentrating, changing focus from one activity to another, performing more than one mental
activity at the same time, remembering information, and learning new information. Three or
more of the following symptoms occur after the trauma and last at least three months: fatigue;
insomnia; headache; vertigo or dizziness; anger that occurs without a good reason; anxiety,
depression, or mood swings; and personality changes such as inappropriate behavior, apathy,
or lack of spontaneity. The impairment represents a significant decline from pre-trauma
functioning and causes significant difficulty with school or workplace performance.
According to the ICD-10, a person must have a history of ―head trauma with loss of
consciousness‖ preceding the onset of symptoms by a period of up to 4 weeks and at least
three of six symptom categories. These include:
• Headaches, dizziness, general malaise, excessive fatigue, or noise intolerance.

• Irritability, emotional lability, depression, or anxiety.
• Subjective complaints of concentration or memory difficulty.
• Insomnia.
• Reduced tolerance to alcohol.
• Preoccupation with these symptoms and fear of permanent brain damage.
The ICD-10 criteria do not require ―objective‖ evidence of cognitive problems. Both
models attempt to clearly state the symptoms and parameters for diagnosis, however they do
not offer much of a direction for understanding pathophysiology once the diagnosis has been
made. A clear understanding of the pathophysiology as it relates to multiple systems and
circuits will guide research toward better models of prognosis, care and prevention.
Complete or nearly complete recovery from concussion occurs in a timely manner in the
majority of individuals, however there is a minority of those who have symptoms that persist
for months to years (181). The research is not clear as to how to predict who will be more
likely to experience chronic symptoms. Bigler et al. described PPCS as it is related to
structural damage to specific predictable or likely brain regions impacted by brain injury
using biomechanical models. Recent advances in imaging using DTI have detected axonal
damage previously undetectable. The anatomical regions most likely to suffer structural
damage with concussion include the posterior frontal lobe, medial temporal lobe, midbrain
structures, fornix, hypothalamus, pituitary, cerebral peduncle, entorhinal cortex and
hypothalamus. So, within a few centimeters are critical brain structures that, if affected, could
represent the structural basis to many symptoms associated with concussion (182).
Rao and Lyketsos (183) indicated that the PPCS nomenclature is too vague and that the
more accurate description is ‗frontotemporal syndrome‘ as this better describes the regions
most affected by injury. There is considerable evidence linking the vestibular system and
objective findings utilizing digital posturography and videonystagmography for ocular
involvement and precise evaluation of central circuits involved.

Amnesia
Memory Tau / N degen
Confused
Brain fog Synaptic and cell Cortical

Cognitive Consciousness
Verbal delay capacity regions
Drowsy
Attention Metabolic capacity
Disoriented
Cytokines
Autonomics
Head pain Cellular function
Sensitization
Peripheral
Somatic Vestibular
Central vENG
Exam
Posurography
Visual Vision/Pur/Sac/OKN
Head Injury Met / summation Fuel / trans

Sleeping more
Fuel Glut / Gaba
Sleep Disorder Cell output and

Sleeping less Excitotoxicity
fatigue
Trouble falling Melatonin / Inflammation

asleep circadian / Th transmitters
Dop / Vent mes / Chemical Cellular output

Anxious
Excito GABA Cellular function Fatigue
Chemical Fuel – cortical

Affective Fatigue / sadness SERT / Monoamine
Cellular function Cellular output
Chemical Fuel – cortical

Lability / Irritable TND / CIS
Cellular function Cellular output
Figure 11. Development of mental health problems in the context of mTBI milieu © Joel Brandon
Brock 2013.
We recognize that the same symptoms classified as PPCS can be seen in people without
history of concussion or trauma (184). This is possibly involving the same pathophysiological
characteristics with a different etiology. The methodological quality of neuropsychological
research for concussion, although plentiful over the past decade, has lacked scientific rigor
(185). When looking at the confounding factors that must be considered in the design of
PPCS research, Bigler notes that the major symptoms of PPCS; fatigue, sleep disorder,
headache, dizziness/vertigo, irritability, affective lability, anxiety, apathy and personality
changes, share such great overlap that exist with other psychiatric disorders such as
depression (182).
It appears, as is noted in the research cited above, that PPCS shares a great deal of
similarity with depression, anxiety, attention deficit disorder (ADD) and OCD. The common
thread that holds PPCS, depression, anxiety, OCD and ADD may be a chronic, immune
mediated, inflammatory process also known as immuno-excitotoxicity as well as shared
anatomical circuitry (12).
Research conducted which points out the effect peripheral musculoskeletal injury has on
cognition is similar to that seen with concussion, indicating that injury itself, regardless of
anatomical location can affect objective test scores previously attributed to concussion alone.
Thus a narrow assessment of pre- and post-injury neuropsychological scores should be
avoided (185). This finding may indicate that systemic inflammation occurring outside the
CNS may play a role in the function of cognitive circuitry.
There appear to be significant shortcomings in conceiving PPCS, mTBI and chronic TBI
as a wholly neuropsychological condition requiring a neuropsychological approach to
researching treatment, diagnosis and prognosis. A comprehensive model that addresses multi-

system physiology including but not limited to sensorimotor processing and neuro-immune
function is likely to emerge. The probability of chronic immune inflammatory processes
being involved and the likelihood of compromised neural circuitry that may be discovered
with sensitive analysis of sensorimotor function of neural circuitry shared by cognitive and
behavioral centers; we can design a model for research that incorporates a multisystem
approach to function as opposed to simply ameliorating symptoms. With this in mind the
direction research can take regarding care may be tangible, quantifiable and very different
from rest and cognitive therapy. Research needs to address sensorimotor function of specific
circuits underlying cognitive and behavioral symptoms within PPCS (i.e., vestibular aspects
of posture and ocular function).
Recognizing the pathophysiology as it relates to past medical history, family history,
genetics, multiple system involvement and systemic peripheral contributions to central
nervous system (CNS) function will yield new directions in research, preventive and post-
injury care. Research in several disciplines has indicated that blending the study of the
evolutionarily conserved, shared underlying neural circuitry common to the visual, vestibular,
memory, immune and autonomic regulatory nuclei have been fruitful and are needed if we are
to make progress in chronic brain injury outcomes.
Figure 12. Overview of clinical Socratic thinking in chronic brain injury assessment and care © Joel
Brandon Brock 2013.
There appear to be significant shortcomings in conceiving PPCS, mTBI and chronic TBI
as a wholly neuropsychological condition requiring a neuropsychological approach to
researching treatment, diagnosis and prognosis. A comprehensive model that addresses multi-
system physiology including but not limited to sensorimotor processing and neuro-immune
function is likely to emerge, which addresses compromised cognitive and behavioral neural
circuits that reciprocally affect each other‘s frequency of firing. Generating productive
clinical questions to investigate must be a disciplined thinking process starting at the
molecular level, progressing up through the cellular, receptor, tissue, and sensorimotor, visual

and vestibular systems. Only after this Socratic querying can the collection of quantifiable
evidence begin and have meaning. Further, both laboratory based neurochemical-immune
assessments as well as comprehensive functional neurological examination must be collected
and considered. This will necessarily lead to more precise rehab methods and chemical
management of chronic brain injuries.
CONCLUSION
Many factors in a given patient‘s physiology can influence the outcome of TBI or mTBI,
yielding widely divergent potential outcomes from head trauma, including PPCS. The
clinician‘s ability to understand a given patient depends upon skilled assessment and
appreciation of these variables, their potential interconnections, and their impact at cellular
and systems levels.
An increasing need for strong generalist thinking is therefore required in order to
comprehend and utilize the bounty of recent research, and to avoid the traps of heuristic
decision-making and over-emphasis on specialized niches in both the research and clinical
settings.
Recognizing pathophysiology as it relates to past medical history, family history,
genetics, multiple system involvement and systemic peripheral contributions to central
nervous system (CNS) function will yield new directions in research, preventive and post-
injury clinical care. Research in several disciplines has indicated that blending the study of
the evolutionarily conserved, shared underlying neural circuitry common to the visual,
vestibular, memory, immune and autonomic regulatory nuclei have been fruitful. Their
expansion and integration are needed if we are to make progress in improving chronic brain
injury outcomes.
In both research and clinical settings, careful examination of many wide-ranging patient
measures must be integrated in order to progress, including reflexive eye movements,
hormone panels, sensorimotor changes, immune and inflammatory markers, mental and
emotional states, and other factors required to appreciate each patient‘s uniqueness. History
taking will need to expand to include lifestyle factors previously thought unrelated. The
health status of individuals pre-concussion will be a significant factor in determining PPCS
risk in any individual.
In the research setting, accounting for physiological variables that can impact TBI and
mTBI outcomes is essential in appreciating potential non-homogeneity of patient populations
enrolled in a given study.
In the clinical setting, accounting for the same physiological variables creates the
opportunity to identify key clinical targets that can markedly improve outcomes or, if ignored,
stall progress. Once identified, these clinical targets must be addressed with best-matched
methodologies, not all of which will be pharmacological. Understanding the post-injury, and
ideally the pre-injury status of these patients, utilizing outcome-based multifactorial
neurological assessment and treatment are key in the emerging path for effective concussion
care.

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2010;24(11):1257-71.

Chapter 9
CONNECTIVITY COGNITION AND PSYCHOSIS

IN THE PHYSICAL BRAIN
Avi Peled*, MD
Shaar Menashe Mental Health Center, Hadera and Rappaport Faculty of Medicine,
Technion, Israel Institute of Technology, Haifa, Israel
The brain is composed of multiple levels of elements ranging from single neurons
interconnected by axons dendrites and synapses, up to brain regions and neural network
ensembles connected by multiple modalities, from direct physical pathways to
synchronized functional connectivity. We know that the brain integrates information
going from lower level unimodal processing to multimodal and transmodal higher levels
and that higher levels effect lower levels creating a top-down bottom-up balance in the
hierarchy. This process of local versus global integration is well supported by the small-
world organization recently described for effective optimized neural networks.
Schizophrenia spectrum disorders can be reconceptualized as different combinations of
connectivity and hierarchy imbalances involving disconnectivity, over-connectivity,
bottom-up insufficiency and top-down shifts. The different clinical manifestations depend
on which of these disturbances is predominant at the time of the examination of the
patient. The course of schizophrenia over time typically begins with a psychotic episode,
progresses to post-psychotic residual manifestations, and over longer periods of time
repeated psychotic episodes. Considering this course of the disease over-time, it seems
that the disorder is triggered by a disconnection disturbance which the brain supposedly
tries to correct, probably by over-connecting the system, plunging it to over-connectivity
dynamics with deficient negative symptoms. In an attempt to re-optimize the hierarchy,
the system disconnects again achieving a consecutive psychotic episode, thereafter
becoming even-more over-connected and deficient, thus the disease progresses with the
brain oscillating between connectivity imbalances each time destroying more and more of
the hierarchy of brain organization.
*
Correspondence: Dr. Avi Peled, Shaar Menashe Mental Health Center, Mobile Post Hefer, 38814, Israel. E-mail:
neuroanalysis@gmail.com.

202 Avi Peled
INTRODUCTION
The brain is composed of multiple levels of elements ranging from single neurons
interconnected by axons dendrites and synapses, up to brain regions and neural network
ensembles connected by multiple modalities, from direct physical pathways to synchronized
functional connectivity.
The networks of such interactivity can evolve in many patterns, they can be centralized,
where many units (e.g., neurons or brain regions) of the system are connected to few (or one)
main units (hubs) or they can be distributed with units randomly connected forming no central
organization, thus having no hubs at all. Recently it has been found that the best organization
of well-functioning (optimal) systems is in-between the organizations described above; the
organization is neither too centralized nor randomly dispersed, it is composed of hubs
receiving many connections from many far-away units that are a part of clusters of 'locally'
spread highly connected nearby units (1). This type of organization is most effective for a
well-functioning system. In the case of communication networks, it is most effective for
information transfer earning the title of ―small world network (SWN)‖ describing effective
communication transfer around the globe.
SWN organization entails high clustering and small path length (connections from many
far-away units) comparable to random graphs. Thus in addition to small worldliness
clustering coefficient, path length and hierarchy are also important measures that can be used
to estimate whether a system is optimal and effective. These parameters become critical when
one wants to investigate the efficacy of functioning networks and needs measurable extracted
parameters to decide (or detect) whether a system is functioning optimally.
Figure 1. Schematic structure of a small world network organization.
How is network organization relevant to emergent properties? To answer this question we

shall consider consciousness as an emergent property of the brain. According to Bernard
Baars and Nicole Gage (2), consciousness emerges from global brain organizations, at each
moment in time sets of partial processes integrate to form a global formation of activity.
Across time the participating partial processes may change because some partial processes
might be ―dropped out‖ and new ones engaged in the global formation. Thus, from instant to
instant the global message may change, just as conscious experience is aware of changing

Connectivity cognition and psychosis in the physical brain 203
contents from moment to moment. Stanislav Dehene (3) showed that the small world network
organization is a relevant organization for Baar's formulation. The hubs of long connections
from multiple clusters act as integrators of processes within the clusters, thus partial inter-
cluster activity is integrated more globally at the higher level offered by the hubs. This
structure offers a multiple-level hierarchy where even higher-level integrators that have
nested lower level networks can integrate even more global cognitive computations.
The brain organizes accordingly with hierarchy of lower level activity integrated to form
global organizations (bottom up) which in turn also influence the activity of lower level
processes (top-down). Marcel Mesulam (4) described this as unimodal activity, integrating to
a higher-level multimodal activity and then integrated into an even higher-level transmodal
activity, that of the global all-integrating brain activity. Fuster (5) has also described similar
organization showing its relevancy to cognition and conceptual abstraction.
It now becomes clear how small world optimal brain organization supports consciousness
as an emerging property, and in addition it reveals how such small worldliness explains
integration for perception and cognition with bottom-up and top-down dynamics maintaining
global organizations in balance. How can we now further understand conscious thought
processes using this knowledge?
As early as 1884 Theodor Meynert, a Viennese neuropsychiatrist, stated that thoughts are
represented by activated neuronal ensembles (6). When we have a thought, he said, it is
represented by a group of acting neurons, when we have another thought it is represented by
another group of activated neurons, when we have associations between these two thoughts,
connections form between them. Meynert preceded his time, but today, especially with
artificial intelligence and neural network models, we can understand how neuronal ensembles
actually represent information.
Thus global organizations that support emergence of consciousness can be viewed as
hierarchically emergent neuronal ensembles. At this point one can introduce the concept of
state-space dynamics to offer a good description of the conscious thought process as a process
emerging from physical complex brain systems. In state-space formulation, neuronal
activation at any given instant is a ―state‖ and this state is represented as a point in a ―space.‖
The space represents all the other possible states of the system. As conscious experience
proceeds from one occurrence to the other, and thoughts progress from one concept to the
next, so the point in space ―moves‖ ahead from one point to the next, creating a trajectory.
Thus space-state trajectories can represent the dynamics of consciousness as the dynamics of
a changing physical brain system.
We know that our thoughts and experiences depend on learning and practice. How is
learning and acquisition of experiences accomplished within the physics of the brain? As
already mentioned, as early as 1884 Meynert stated that associating information is related to
the forming of connections in the brain. Donald Hebb in 1948 (7) stated that if two (or more)
neurons fire simultaneously together for certain long periods than the connection between
them is strengthened. The opposite is also relevant, connections weaken if neuronal activity is
not synchronous. More important is the resulting fact that when connections between two (or
more) neurons are strengthened, the chance that they will fire together is increased as one
activates the other (or others).
Today we know that learning is a process that involves formation and strengthening of
connections on a variety of scales from neurotransmitter chemical connections to actual
structural synaptic connections. Once the connection within a neural ensemble is strengthened

204 Avi Peled
that ensemble will tend to activate itself because of mutual activations. As such, the ensemble
is a state of the system and it is represented by a point on the space (of all other states) of the
system, thus the system will tend to assume that state more than other states, where neuronal
connections were not strengthened. In other words, the system will tend to be ―drawn‖ to that
state, or point in space. These dynamics of becoming drawn to a state are called ―attractors‖
because the system as a whole is attracted to the state that activates it. For purposes of
imagination the space of the system can now be viewed as a landscape of basins and peaks
where the peaks represent the states, or activations that the system tends to avoid. In contrast
the basins represent the states that the systems tend to activate and achieve.
Giulio Tononi (8) described the concept of neural complexity to explain an optimal
balance between disconnectivity and over-connectivity achieved by the brain. He used this to
explain the conflicting need of the brain to process information in a segregate, specialized
manner, while at the same time integrating all processes into one coherent whole. The
different sensory motor computations need to be highly specialized and thus segregated so
that they do not interfere with each other's activity. At the same time these specialized
processes must integrate toward a coherent stable whole. Tononi's complexity of connectivity
measure readily lends to the structure and function of small world network organization. The
high clusters organizations can process specialized segregated computations while the hub
structures with long connectivity formation can integrate these processes into organized
wholes. Actually, if small worldliness is disturbed and the number of long connections is
reduced in comparison to clustered connections, a disconnection dynamic activity emerges
within the network, destabilizing it and offering instability where information processes of
different modalities become statistically independent. On the contrary if the opposite occurs,
long-range connections increase in number compared to short clustering connections, and
then over-connectivity dynamics will spread within the system making different processes
overly constrained, less flexible and limited in number.
In terms of state-space dynamics, the disconnection dynamics will result in ―jumps‖
where the trajectory of conscious and thought activation will become more random with a
tendency to jump from one state to another unrelated state. In the case of over-connectivity
dynamics, the system tends to ―coagulate.‖ It will repeatedly occupy the same states, as the
constraints (strong connections) cause the same neuronal ensembles to activate each other
over and over again. In this case the number of states that can be activated is reduced and the
space of the system shrinks making it functionally deficient, inflexible and debilitated, and
thus incapable of adapting and representing environmental occurrences.
THE PHYSICAL BRAIN AND PSYCHOSIS SPECTRUM DISTURBANCES

As mentioned above, Giulio Tononi described the concept of neural complexity as an optimal
balance between disconnectivity and over-connectivity achieved by the brain. His explanation
is relevant to the conflicting need of the brain to process information in a segregate
specialized manner, while at the same time it needs to integrate all processes into one
coherent whole. Tononi's complexity readily lends itself to the structure and function of
small-world-network organization. The high clusters organizations can process specialized
segregated computations while the hub structures with long connectivity formations can

integrate these processes into organized wholes. Accordingly altering the number of long
connections versus short-clustering connections, for example, reducing cluster connectivity or
reducing long connection, disconnects or over-connect respectively, the global connectivity
pattern (see above).
Importantly in the previous section, there is also reference to state-space dynamics. The
disconnection dynamics will result in ―jumps‖ where the trajectory of conscious and thought
activation will become more random with a tendency to jump from one state to another
unrelated state. In the case of over-connectivity dynamics, the system tends to ―coagulate‖ it
will repeatedly occupy the same states, as the constraints (strong connections) cause the same
neuronal ensembles to activate each other over and over again. In this case the number of
states that can be activated is reduced and the space of the system shrinks making it
functionally deficient, inflexible and debilitated, incapable of adapting and representing
environmental occurrences.
This description of jumps (in disconnection) versus reduction and repletion (in over-
connection), metaphorically resembles schizophrenia thought disturbances in a psychotic
episode, versus the negative-signs in residual periods, respectively. Psychotic thought
disorders are characterized by loosening of associations expressed by speech that is
disordered with jumps occurring from one concept to another. The thought process of
negative-signs schizophrenia is characterized by repetitions also called perseverations, and by
poverty of thought and speech with reduced interest and reduced verbal conceptualization
altogether.
These metaphorical resemblances can be successfully modeled using mathematical
models of simplified neural-networks (9). More important, the disconnection dynamics for
modeling the psychotic thought process has been described repeatedly in many imaging
studies of schizophrenia patients suggesting that the idea of disconnection dynamics spread in
the cortex can be a plausible underlying mechanisms of certain schizophrenia manifestations.
As early as 1885, Theodor Meynert (6) hypothesized that psychosis involves ―weakening of
connections.‖ This idea was repeated by Wernike and others, and was modernized by Karl
Friston (10, 11) in his paper on ―Schizophrenia; A disconnection syndrome.‖ Since then a
large body of research using various multiple imaging and signal processing techniques has
shown various aspects of such possible disconnectivity dynamics in patients‘ brains. It must
be emphasized that the ideas in this book relating mental disorders to neuronal-network
disturbances gains the support and validation in the literature from a large body of research
findings. We argue that diagnostic terminology can be replaced with descriptive and non-
brain related nomenclature. This ambitious venture is validated with the vast literature on
'disconnection-dynamics' in psychosis, and the brain-related etiopathological concept of
―disconnection syndrome‖ (12, 13) that readily offers an alternative to the non-brain related
concept of psychosis.
After investigating various disturbances with mathematical models of neural networks for
schizophrenia (9) it seems that four types of disturbances combine to create this
heterogeneous clinical manifestation called ―schizophrenia.‖ The four types of disturbances
can be categorized into two types, one related to 'connectivity,' and the other to 'hierarchy.'
This is obviously an artificial division because disturbance to connectivity inevitably also
disturbs hierarchy, so it is conceivable that all types of disturbances co-occur, but the different
extent to which each is expressed determines the different symptomatic patterns of this
clinically heterogeneous disease.

206 Avi Peled
We have already begun to elaborate on the manifestations of disconnection dynamics,

fragmented small-world organization, state-space dynamics resulting in jumps between states
and fragmentation of associative structure. Logic is based on associations, thus logic is
disturbed and concepts dissociate and re-associate randomly creating new ideas and
convictions. Ideas and convictions that are unrelated to environmental occurrences or internal
consistency are bizarre and other types of delusions are readily formed from illogical
unrelated thinking about the world and the social environment of the patient. If disconnection
in the brain spreads to the extent of disconnecting cortical regions, then cortical regions such
as the auditory cortex with its adjacent speech-processing regions, can disconnect from the
rest of the brain and act independently to generate auditory sensations unrelated to perception,
visual processing and others brain activity. This will be experienced as auditory
hallucinations of speech unrelated to coherent whole-brain activity.
As already mentioned, over-connectivity dynamics restrict the space of state-space
configuration and create impoverished thought and speech as attractor formations form and
cause the system to repeat the same trajectories over and over again resulting in
perseverations that are typical to patients with residual schizophrenia.
As for hierarchy disturbances, two types of dynamics are relevant 1) bottom-up dynamics
and 2) top-down control. Normally these are typically balanced, the bottom-up influences
'traveling' up the hierarchy build the higher-level contextual (schemata) internal repositions.
These higher-level contextual constructs, once formed, act upon lower-level, bottom-up
processes by top-down contextual control.
It is proposed that in schizophrenia-spectrum disorders the delicate top-down, bottom-up
equilibrium and balance is disturbed. Two types of hierarchical imbalances can occur, a
bottom-up insufficiency and a top-down shift. In the first case, that of bottom-up
insufficiency, the building and organization of the hierarchy is impaired, the higher levels are
either undeveloped or destroyed. These higher-level organizations are responsible for higher
level sensation and cognition specifically related to volition and motivation (see (4)). In
effect, negative signs residual schizophrenia patients are markedly impaired in these higher-
level brain functions. These functions presumably involve massive connectivity structures of
higher-level integration, and imaging research in schizophrenia repeatedly shows the
involvement of deficient prefrontal, temporal and hippocampal regions (e.g., hypofronatility)
in residual schizophrenia (14, 15).
Top down shift would impose higher-level contextual ideation over incoming evidence
for such ideation. The brain continually predicts the environment, represents it and generates
internal representations of environmental occurrences. The prediction process travels up the
hierarchy and is maintained by the balance of top-down, bottom-up processes. In a situation
where top-down constraints are stronger than the bottom-up evidence, top-down ideations and
thoughts can bias the bottom up sensory evidence and distort it. Such distortion creates
erroneous thinking about the occurrences in the environment. In addition, such erroneous
thinking is typically stable over-time, and it integrates real-life occurrences into the schemata
of the erroneous ideation causing it to gradually grow. Every new occurrence in the person's
life is integrated to support the false ideation, this kind of activity, concords (at list
metaphorically) with the clinical description of systemized delusions.
To summarize the hypothesis forwarded here, schizophrenia spectrum disorders can be
reconceptualized as different combinations of connectivity and hierarchy imbalances
involving disconnectivity, over-connectivity, bottom-up insufficiency and top-down shifts.

The different clinical manifestations depend on which of these disturbances is predominant at

the time of the examination of the patient.
The course of schizophrenia over time typically begins with a psychotic episode,
progresses to post-psychotic residual manifestations, and over longer periods of time repeated
psychotic episodes, followed by deteriorating more-severe post-psychotic deficiency.
Considering this course of the disease over-time, it seems that the disorder is triggered by a
disconnection disturbance which the brain supposedly tries to correct, probably by over-
connecting the system, plunging it to over-connectivity dynamics with deficient negative
symptoms. In an attempt to re-optimize the hierarchy, the system disconnects again achieving
a consecutive psychotic episode, thereafter becoming even-more over-connected and
deficient, thus the disease progresses with the brain oscillating between connectivity
imbalances each time destroying more and more of the hierarchy of brain organization.
To conclude, the model of disturbed connectivity and hierarchy balance, can explain the
heterogeneous clinical manifestations of schizophrenia spectrum disorders, if similar
connectivity disturbances are afflicted to brain connectivity balance, either by psychoactive
drugs (street drugs) or by some other toxic metabolic effect or alternatively by brain damage
from injury, (e.g., epilepsy or malignancy), then organic psychosis can be conceptualized
similarly as disturbances to brain connectivity.
THERAPY OF THE PHYSICAL BRAIN IN

PSYCHOSIS AND SCHIZOPHRENIA
Generally speaking, there are three major categories of interventions applied today in the field
of treating mental disorders: 1) pharmacotherapy, 2) psychotherapy (i.e., the talking
treatments) and 3) neuromodulations (e.g., electroconvulsive therapy, deep-brain-
stimulations, transcranial magnetic stimulations and others).
The most effective medications in their category are SSRIs (selective serotonin- reuptake
inhibitors). These act by blocking the reuptake of serotonin at the synapses, thus triggering a
cellular biochemical chain-reaction which terminates with synaptogenesis. After 6 weeks
from initiation of treatment neurons grow new dendrites and these are more enriched with
spines than before treatment began.
The most direct external manipulation on the brain is that of direct electrical application
using inserted electrodes. This deep brain stimulation (DBS) is successfully applied to treat
severe Parkinson‘s disease and tremors. Recently it was found to have promising anti-
depressive effect when applied to certain frontal cingulated structures. Additional similar but
less direct interventions involve magnetic (transcranial magnetic stimulation TMS) and direct
scalp electrical stimulations (transcranial direct and alternating current stimulation tDCS and
tACS respectively). These electrical applications are problematic in the sense that they affect
large neuronal groups in the vicinity of the application including mixtures of excitatory and
inhibitory neurons in the surrounding areas and thus are not specific and cannot have focused
control for specific neuronal circuits.
In this regard the most promising direct external manipulation on the brain recently
developed is that of Optogenetics. Optogenetics is a new technology offering control over
neuronal activity by turning on and off distinct neuronal populations using cell-type specific,

208 Avi Peled
optically sensitive, molecular neuronal activity ―switches.‖ These ―switches‖ are microbial,
light-sensitive ion conductance-regulating proteins, e.g., channelrhodopsin-2 (ChR2) and
halorhodopsin (NpHR). They are genetically engineered to become part of the cellular
machinery and introduced individually to target neurons relevant for activating or inhibiting
pre-chosen neuronal circuits. This technology can control specific neurons and thus offers
high-precision intentions not available with other technologies to date.
An example of clever, specifically targeted, direct intervention that involves control over
whole-brain dynamics involves the prefrontal cortex (PFC). As mentioned above, the higher
level global brain organization of which the PFC is most frequently indicated in the
psychopathology of schizophrenia has massive efferent-afferent interconnectivity (Figure 2)
with most of the cortical systems and thus is probably best suited to be involved in
connectivity balance spread in the brain. Due to the massive efferent-afferent
interconnectivity of the prefrontal circuitry it can (at least in part) act as a relay to whole brain
connectivity organization, in other words, input-output activity of the prefrontal pyramidal
neurons can associate, or dissociate signals arriving by efferents from vast cortical regions
with efferent signals from the prefrontal cortex to vast spread-out cortical areas. With this
assumption the input-output transmission relationships of the pyramidal neurons of the
prefrontal become connectivity organizers in vast cortical brain regions if not for the entire
brain. If the input-output transmission is inhibited disconnectivity dynamics will ensue in the
brain and if, inversely, the input-output transmission is enhanced, thus efferents readily excite
afferents overly connecting vast spread-out brain circuits, over-connectivity dynamics
develop.
Wide arbor
cell
Pyramidal
neuron
Dopaminergic pathways
Chandelier
interneuron
within prefrontal
associations
Inhibitory
Dopaminergic cortico-cortical DA
associations
Excitatory
Figure 2. Dopamine circuit of PFC.

Figure 2 shows how the pyramidal neurons that receive and forward signals from the PFC
make connections with inhibitory neurons, the ―Wide-arbor‖ and ―Chandelier‖ cells. These
have inhibitory effects both on the dendrites (Wide-arbor) as well as the axons (Chandelier)
of the pyramidal neurons and are in an ideal position to control input-output relationships of
the pyramidal neurons. Wide-arbor inhibitory activity on dendrites will reduce effects of
incoming afferent signals to the pyramidal neuron, and Chandelier inhibitory activity on the
axons will inhibit pyramidal outputs reducing efferents signals from the pyramidal neurons.
In other words, the control over the input-output threshold of the pyramidal neuronal activity
is directly regulated by the activity of these interneurons. Based on this proposed hypothesis,
optogenetic control over the activity of the Wide-arbor and Chandelier interneurons readily
controls the connectivity-organizing effects of the prefrontal cortex on the brain.
Figure 2 shows that dopaminergic activity in the prefrontal cortex has both excitatory
(directly via excitation of pyramidal dendrite) and inhibitory (via the interneurons) activity
over the pyramidal neuronal network. Even though this puts the dopaminergic activity in a
modulator role for the prefrontal cortex, probably by fine-tuning the activity just mentioned, it
is less relevant as a target of direct optogenetic intervention as the intervention on the
interneurons themselves will probably have corrective affects in patients among whom it
seems that dopaminergic manipulation alone does not really change the course of the disease.
The inter-neurons, with their inhibitory effect, fine-tune the prefrontal system allowing
the activity of maintaining connectivity balance. By intervening in these interneurons with
optogenetics it may be possible to control the input-output relationships of pyramidal
neuronal activity thus directly controlling the connectivity balance in the brain. Let us assume
that in schizophrenia patients with negative signs schizophrenia, over connectivity dominates
brain organization. By activating inhibitory chandelier cells the inhibition of these cells on the
axons of the pyramidal neurons will increase the threshold of their output and thus disconnect
the input signal from output signals. Based on the assumption of relay connectivity with the
rest of the cortex, the disconnection of input-output relationship would cause vast
disconnectivity dynamics spread in the brain. Inhibition of this same inter-neuronal activity
would increase input-output relationships of the pyramidal neurons (by reducing their
thresholds) thus creating input-output connections of efferent-afferent activity ensuing as an
over-connectivity dynamics in the brain.
REFERENCES
[1] Kaiser M, Hilgetag CC. Optimal hierarchical modular topologies for producing limited sustained
activation of neural networks. Front Neuroinform 2010;4:8. doi: 10.3389/fninf.2010.00008.
[2] Baars BJ, Gage NM. Fundamentals of cognitive neuroscience. Oxford: Academic Press, 2013.
[3] Dehaene S., Naccache L. Towards a cognitive neuroscience of consciousness: basic evidence and a
workspace framework. Cognition 2001;79:1-37.
[4] Mesulam, M. From sensation to cognition. Brain 1998;121:1013-52.
[5] Fuster JM. Executive frontal functions. Exp Brain Res 2000;133(1):66-70.
[6] Seitelberger F. Theodor Meynert (1833–1892) pioneer and visionary of brain research. J Hist Neurosci
1997;6(3):264-74.
[7] Hebb DO. The organzation of behaviour. New York: Wiley, 1949.
[8] Tononi, G., Sporns, O., Edelman, G.M. A complexity measure for selective matching of signals by the
brain. Proc Natl Acad Sci USA 1996;93:3422-7.

210 Avi Peled
[9] Geva AB, Peled A. Simulation of cognitive disturbances by a dynamic threshold neural network model.
J Int Neuropsychol Soc 2000;6(5);608-19.
[10] Friston KJ, Frith CD. Schizophrenia: a disconnection syndrome? Clin Neurosci 1995;3(2):89-97.
[11] Friston K, Klass ES. Free-energy and the brain. Sythese 2007;159:417-58.
life, death, and consciousness. Rev Neurosci 1999;20(3–4):151–76.
[13] Melillo R, Leisman G. Autism spectrum disorder as functional disconnection syndrome. Rev Neurosci
2009;20:111–32.
[14] Leisman, G and Melillo, R. The development of the frontal lobes in infancy and childhood: Asymmetry
and the nature of temperament and adjustment. In: Cavanna AE, ed. Frontal lobe: Anatomy, functions
and injuries. Hauppauge, NY: Nova Science, 2012.
[15] Leisman G, Melillo R. The basal ganglia: Motor and cognitive relationships in a clinical
neurobehavioral context. In: Franz E, ed. Basal ganglia. Rijeka, Croatia: InTech, 2012.

Chapter 10
AUDITORY, VISUAL, SPATIAL AESTHETIC

AND ARTISTIC TRAINING FACILITATES
BRAIN PLASTICITY

1
2
3
Institute for Neurology and Neurosurgery, Universidad de Ciencias Médicas
de la Habana, Facultad Manuel Fajardo, Havana, Cuba
Exposure to musical training in childhood has been studied extensively as models of

neuroplasticity. The long-term training and continued practice of complex bi-manual
motor sequences are highly associated with changes in brain structure and cortical motor
maps compared with individuals without such training. We know that the anterior corpus
callosum, with fibers connecting frontal motor regions and pre-frontal areas coordinating
bimanual activity is larger in musicians who started training prior to age seven than in
either controls. Additionally, auditory experiences during early postnatal development
shape the functional neurology of auditory cortical representation resulting in increased
functional areas of the auditory cortex. The developing brain is far more plastic than the
adult brain explaining the results that we see in recovery of function after brain damage
in childhood, neuronal connections are being continuously remodeled by experience,
enrichment, and by performance on specific and complex movements during motor and
cognitive learning. New skill acquisition, present to a much greater degree in childhood is
highly associated with structural changes in the intracortical and subcortical networks in
motor skill training. The relationship between music, visual, and spatial training on brain
organization and plasticity are discussed with applications for solutions to the
rehabilitation of the brain impaired.


212 Gerry Leisman
INTRODUCTION
Semir Zeki (1) has indicated that the laws of the brain govern art, in that the brain sees or
hears art and makes it. Our biology then constrains cultural activity. Today we exhibit great
enthusiasm for neural approaches to just about everything (see Figure 1). The neurosciences
have yet to frame anything like an adequate biological or ―naturalistic‖ account of human
experience — of thought, perception, or consciousness.
Figure 1. Illustration by Leif Parsons.
Figure 2. Illustration by Leif Parsons.
Descartes‘ view of thinking was that its nature was immaterial and not physiologically
based having created the mind-body duality (2). Today we largely hold the view that thinking
and feeling is corporeal and not immaterial. In this thinking we have not gotten any further
than Descartes‘ original conception in that we have no better understanding of how the brain
might produce consciousness lacking at present an even a rudimentary neural theory of
consciousness (3) and it seems to be a position that we are comfortable holding. We are over-
brained (Figure 2) in our explanations. It would perhaps be better to understand art and music
as elements that are external to us that through our interactions with others and our
interactions with them and not our brains that allows us to think, feel, and decide. People and
not their brains allow the enjoyment of art. If we can allow such a notion, then it is the
externality of art and music that can affect plasticity in our nervous systems.
We are not only something inside of us and we need finally to take seriously the
possibility that consciousness is achieved as a result of a dynamic exchange with the world
around us; depending upon a dynamic exchange undoubtedly dependent on the brain and its
interactions with other individuals and the brain‘s environment in organizing patterns of
stimulation that we call arts. In short, the brain is plastic and it is modified by its interaction
with other individuals and its interaction with its environment in the established and

Auditory, visual, spatial aesthetic and artistic training facilitates … 213
organizing patterns of stimuli that ultimately have, with the assistance of the brain and
nervous system, meaningfulness to us and are collectively termed art or music.
PERCEPTUAL ORGANIZATION IN ART AND MUSIC IN

THE CONTEXT OF BRAIN ORGANIZATION
Symmetry is an everyday concept that we use when talking about patterns. For example, the
human body has approximate left-right symmetry. We recognize other types of symmetry in
shapes such as rectangles, squares and circles, and we recognize repetitive types of symmetry
such as those found in wallpaper patterns and music. Informally, we can explain that a pattern
is symmetric if the pattern is equal to itself when it is moved in some way. For example, a
square is equal to itself if it is rotated 90 degrees. A circle is equal to itself if it is rotated any
number of degrees. Both shapes are equal to themselves if they are picked up and turned over
(in the case of a square it must be turned over around one of 4 axes that go through the center,
in the case of the circle we can turn it over around any axis that goes through the center). The
wallpaper is equal to itself if it is shifted by the distance between repetitions of the pattern (in
the direction that the pattern repeats itself).
We can extend this informal intuition about what symmetry is to give a more formal
mathematical definition of symmetry:
Symmetry is a set of transformations applied to a structure, such that the transformations
preserve the properties of the structure.
Music performance requires precise control of timing over extended periods to follow a
hierarchical rhythmic structure. Music performance also requires control of pitch to produce
specific musical intervals (frequency ratios) that are not relevant in speech (even tonal
languages do not rely on specific intervals, but on pitch contours) and music makes unique
demands on the nervous system. The auditory–motor interaction during musical performance
illustrates feedback-feedforward interactions occurring in music performance and is
exemplified in Figure 3. The motor system controls fine movements that are needed for sound
production and are described in more detailed below. Sound processed by auditory circuitry is
then used to adjust motor output. Output signals from the premotor cortices influence
responses within the auditory cortex, even in the absence of or prior to sound. Motor
representations are active even in the absence of movement upon hearing sound. Therefore,
there exists a tight linkage between sensation and music production.
Traditional patterns of education and training have largely been inadequate since they
concentrate almost exclusively on the left hemisphere (e.g., developing powers of linguistic
and numerical reasoning) and neglect the right hemisphere which controls perceptual,
sensory, musical and intuitive abilities and therefore do not address issues and processes of
functional physiological and anatomical asymmetries. All education and training should
develop procedures employing the paradigm of neurological asymmetry.
Training of the whole brain is not only important for rehabilitation but also for education
and the study of music and musicians in hearing and performance in ways that clearly
illustrate that point.
Music production employing motor control systems of the brain and nervous system
requires: timing which relates to the organization of musical rhythm; sequencing which, in

214 Gerry Leisman
turn, relates to playing individual notes on a musical instrument or production of those

sequences by the voice; and by the spatial organization of movement resulting in sensory-
motor integration.
Figure 3. Auditory–Motor Interactions During Musical Performance.
The timing of musical patterns we know to be associated with activity in specific regions
of the brain, albeit influenced both by external stimulation as well as endogenous thought
about the timing of those patterns. Cerebellar, basal ganglia, and pre-motor cortex patients we
know to have impaired ability on perceptual-motor timing tasks, as well as difficulty with
musical prediction, as well as in the control of movement trajectories (4-6). We know that
motor timing is not controlled by a single region of the brain but by regional networks that
control movement (see Figure 4). The high-level control of sequence execution involves the
basal ganglia, pre-motor cortex and supplementary motor areas. The fine-grain correction of
individual movement is a cerebellar function (4-6).
Motor sequencing appears to be a function of the supplementary motor, pre-
supplementary motor, cerebellum, and pre-frontal cortical regions. The cerebellum is largely
responsible for integrating individual movements into unified sequences whereas the pre-

motor cortex is involved in tasks requiring the production of complex sequences that
contribute to motor prediction function (4-6).
The spatial organization component of music production involves parietal,
supplementary, and pre-motor cortical control of movements when the integration of spatial,
sensory and motor information is required. Spatial accuracy in musicians in general and in
cellists in particular do not exhibit typical distance/accuracy trade-off for finger movements
while playing, compared to similar non-musical applications (6).
General Principles of Sensation and Perception
Sensation is a process by which senses acquire visual, auditory, and other sensory stimuli
then transmit that information to the brain (i.e., sensory information is registered in the brain,
but not interpreted). Perception, on the other hand, involves a process by which sensory
information is actively organized and interpreted by the brain.
Visual and auditory perception both share similar organizing principles. In visual
perception, for example, Gestalt principles of perceptual organization are represented in
Figure 4 and include figure-ground organization which depends on what is seen by the
individual as a figure (object) and what is perceived as ground (context). With similarity an
individual perceives similar objects or tones as a unit. Objects or tones perceived as being
closely linked in space and time are termed proximal. Continuity involves the perception of
continuous patterns belonging together and Closure is the perception of perceived figures
with gaps seeming complete or equivalently, the concept of rests in music being heard as part
of the music.
In applying these principles with a cognitive system based on dynamic interactions of the
human with the outside world, cognitive assumptions are made based on facts available that
are based on nervous system principles, but are not the nervous system principles themselves.
This then serves as the basis of prediction, a necessary ingredient in normally functioning
individuals for everything from reading a paragraph to walking down a flight of stairs (4, 7,
8). The effects of prediction as a component of perceptual functioning can be exemplified in
Figure 5.
While brightness is psychophysically related to intensity in visual perception, loudness is
intensity‘s equivalent in auditory perception. Loudness is not the same as intensity in that
frequency and intensity exist in physics as independent functions, whereas in psychophysics,
one can increase the frequency of a tone and it can be perceived as being louder. While
loudness then relates to intensity, the relation is not linear. Loudness can be defined as the
degree of sensation of sound produced in the ear. Loudness obeys an approximate law of
psychology which states that the magnitude of any sensation is proportional to the logarithm
of the physical stimulus which produces it. This is called the Weber-Fechner law. It does not
exactly represent the relationship between loudness and intensity, but is a fair approximation
for pure tones at most frequencies. For complex tones, however, there is no simple
relationship. Thus, according to this law,
1 α log I or
l = K log I

216 Gerry Leisman
As we had noted earlier with the visual equivalents, in auditory perception, pitch would
be equivalent to hue both being related to the frequency domain. Grouping also exists as an
auditory cognitive function as it does with vision in that temporal proximity involves sounds
that occur close in time and they tend to be grouped. We also know that with reference to
similarity, sounds with similar pitch tend to be grouped.
Figure 4. Organizing principles of Visual Perception.
Additional principles of auditory perception in summary include localization (from where

sound arises) and in turn include inter-aural intensity differences in which slight differences
in intensity due to the head‘s sound shadow are effective above approximately 4 kHz and
where inter-aural time differences exist due to the differences time for sound to reach each
ear. These we know to be effective for lower frequencies.
Given that perception then is a cognitive interpretative function of sensation with relation
to both the physics of exogenous signal transmission and endogenous interpretive function
based on nervous system processes, by way of introduction still we require explanation and
understanding of how we rate pleasantness and unpleasantness based on dissonance and how
those functions might relate to brain processes. In doing so we can see the nature of brain
organization, albeit in the context of music reception and production and how those functions
may in turn relate to plasticity and therefore rehabilitation.
In Figure 6 below, we can see that in a PET study of normal individual listening to
varying levels of dissonant auditory stimuli, ratings of very pleasant and unpleasant showed
significant interactions and increased correlation with dissonance level whereas ratings of
sad/happy showed no significant interactions and no correlation with dissonance level.
When we, however, begin to examine the effects of dissonance level and regional
cerebral blood flow more specifically rather than globally, the picture changes considerably
as evidenced in Figure 7.

What do you see?
Now what do you see?
Figure 5. Perceptual prediction from limited data necessary for information automation and perceptual
efficiency.
Figure 6. Music Stimuli and Av. Ratings of Unpleasant/Pleasant and Happy/Sad. (A) Most consonant
(ma. triads, Dissonance 0) and dissonant (flatted 13th triads, Dissonance 5) in PET study. (B) Shows
graphs of average ratings of dissonance 0 through dissonance 5. Ratings of very pleasant
(+5)/unpleasant (–5) with significant interactions and increased correlation with dissonance level.
Ratings of sad (+5)/Happy (–5) showed no significant interactions and no significant correlation with
dissonance level.

218 Gerry Leisman
Figure 7. Regression of regional cerebral blood flow with auditory dissonance level by brain region.
BRAIN ASYMMETRY AS A NECEESARY INGREDIANT

IN MUSIC PRODUCTION
The morphometry of the corpus callosum (see Figure 8) is of particular interest for studies
examining brain asymmetry and interhemispheric exchange for several reasons. First, the
corpus callosum is the main interhemispheric fiber tract and plays an important role in
interhemispheric integration and communication and therefore symmetry. Morphometric
studies that have revealed group differences in the size or shape of the corpus callosum are
generally viewed as based on differences in cerebral asymmetry and interhemispheric
connectivity (9-11). We know also that callosum development is associated with the cycle of
myelination and that its functional development extends into late childhood and early
adolescence (12). In vivo imaging reveals that increases in the mid-sagittal callosal size can
be seen even beyond the first decade with a maximum change in size during the first decade
of human life (see Table 1) (13, 14). Further, for a long while, consensus has existed that the
control of movement and coordination as well as inter-manual transfer of sensorimotor
information improves gradually from ages 4 to 11 years, an age span coinciding with callosal
maturation (15-18).
Early and intensive training in keyboard and string players and the requirement for
increased and faster interhemispheric exchange in order to perform bimanual complex motor
sequences might lead to structural changes in the callosal anatomy.
We know that there exist differences in the brains of musicians and non-musicians
exemplified in Figure 9 (19-21). The examination of the differences in the brains of musicians
and non-musicians provides an ideal model to compare and examine functional and structural

brain plasticity as musicians continuously practice complex motor, auditory, and multimodal
skills. We also know that music training in children results in long-term enhancement of
visual-spatial, verbal, and mathematical performance (4, 22).
(a) (b)
Figure 8. The corpus callosum and its partitions.
It has been found that the brains of adult musician and non-musician (Figure 9) show
differences in the size of the anterior and mid-body of the corpus callosum. In particular, as
exemplified in Figure 9(D), areas of significant difference are noted in voxel size over a
fifteen month period when comparing instrumental against non-instrumental control children.
The changes are mostly noted in the mid-body portion of the corpus callosum of parts that
contain primary sensorimotor and premotor fibers. Figure 9(C) demonstrates the subdivisions
and locations of interhemispheric fibers that connect motor and hand regions located in both
the right and left hemispheres.
Schlaug (24) compared thirty professional musicians and matched non-musician controls
and found that the anterior half of the corpus callosum was significantly larger in musicians
as represented in Table 1 below. He noted that musicians possessed a significantly larger
anterior corpus callosum with early musical training as compared to musicians who started
their training later and both compared to controls.
Previous anatomical studies found a positive correlation between mid-sagittal callosal
size and the number of fibers crossing through the corpus callosum. The anterior part of the
corpus callosum contains mainly fibers from frontal motor-related regions and prefrontal
regions (25), and the anterior corpus callosum matures the latest of all callosal sub-regions.
Therefore, this anatomical difference in the mid-sagittal area of the corpus callosum has to be
seen in the context for a requirement for increased interhemispheric communication
subserving complex bimanual motor sequences in musicians. These reported brain changes
clearly exemplify environmental influences on brain development and should be viewed in
the context of both human development and rehabilitation.

Figure 9. Corpus callosal differences in the brains of adult musicians and non-musicians using the Hofer and Frahm (2006) classification system. (A) Brains of
adult musicians and (B) non-musicians demonstrate differences in the size of the anterior and mid-body of the corpus callosum, (C) demonstrates calossal
subdivisions and locations of interhemispheric fibers that connect motor and hand regions of the right and left hemispheres and (D) represents areas of
significant difference in voxel size over 15 months comparing instrumental and non-instrumental control children that are superimposed on an average image of
all children. The changes found in the mid-body portion of the corpus callosum of parts that contain primary sensorimotor and premotor fibers].

Table 1. Mid-sagittal area measurements of the corpus callosum (CC) in mm2

(mean ± SD) (after Schlaug, (24))
a
Significant differences are those between controls and all musicians, between controls and musicians
with early commencement of musical training, and between the two subgroups of musicians with
or without early commencement of musical training.
The Motor Cortex
As reviewed above, there is much evidence supporting the notion that plastic changes can be
induced in the functional organization of the human sensorimotor cortex following sensory
stimulation or following the acquisition of new motor skills. These functional changes after
skill acquisition may be related to microstructural changes such as increased numbers of
synapses per neuron (26), increased numbers of glial cells per neuron (27), and/or more
capillaries (27) as has been shown in animal experiments.
Many parts of the brain participate in music making (Figure 10). Musical sounds are
processed in the auditory cortex. Pathways then carry music to areas of the brain that perform
and anticipate harmonic and melodic changes, as well as feel, remember and read.
Figure 10. Many parts of the brain participate in music making. Musical sounds are processed in the
auditory cortex (●). Pathways then carry music to areas of the brain that perform (●), anticipate
harmonic and melodic changes (●), feel and remember (●), and read (●).

Figure 11. A) People with no music training learn melody on a keyboard. After hearing the learned piece, they exhibit expected activity in auditory cortex, and
premotor areas. No effect is noted when listening to untrained melody (bar graph). B) Brain activity in musicians while listening to piece they could play (l.
column) with activity playing same piece with no auditory feedback (Mid. column). Significant overlap is noted in auditory and premotor regions in each
condition (r. column). Auditory and motor systems interact during perception and production.

Music production motor control systems require abilities in timing which is related to the
organization of musical rhythm, sequencing, playing individual notes on musical instruments
and the spatial organization of movement that results in sensory-motor integration. Reviewed
in greater detail by Melillo and Leisman (4), we know that cerebellar, basal ganglia, and pre-
motor cortex-involved patients have impaired ability on perceptual-motor timing tasks, as
well as in the computation of movement prediction, in the control of movement trajectories.
We know that motor timing is not controlled by a single region of the brain, but by
regional networks that control movement.
The high-level control of sequence execution at the least involves the basal ganglia and
the pre-motor cortex, whereas fine-grain correction of individual movement is controlled by
the cerebellum.
Motor sequencing, on the other hand, according to Melillo and Leisman (4) implicates
the supplementary and pre-supplementary motor areas, cerebellum, parietal, and pre-frontal
cortical areas. The cerebellum integrates individual movements into unified sequences. The
pre-motor cortex is involved in tasks requiring the production of complex sequences
contributing to motor prediction.
Finally, spatial organization involves the parietal sensorimotor and pre-motor cortices
that control movements when the integration of spatial, sensory and motor information is
required.
Figure 11 indicates that when individuals with no musical training learn a melody on a
keyboard, upon hearing a learned piece they exhibit activity in auditory cortex and premotor
areas. On the other hand, no effect is noted when individuals listen to a melody in which there
has been no training. When examining brain activity in musicians while listening to a piece
that they could play, we can note a significant overlap of activity in auditory and premotor
regions. The auditory and motor systems interact during music perception and production.
Figure 12. The (A) arcuate fasciculus [AF] of healthy 65-year old musician and (B) AF of a 63-year-old
non-musician, matched for handedness, gender, and IQ. The musician has a larger AF on the left as
well as on the right hemisphere than the non-musician. The data supports the notion of plasticity of the
AF in those undergoing instrumental training or therapy using tasks that involve auditory-motor
mapping, a task that musicians do throughout life (see (28)).
We know (28) that musical training is supported by brain plasticity. We can see, for
example, in Figure 12 that training affects the arcuate fasciculus, and auditory-motor tract
which are enhanced by music training.

224 Gerry Leisman
DISCUSSION
Differences in brains of musicians and non-musicians are evident from what we have seen.
The musician–non-musician study is an ideal model to compare and examine functional and
structural brain plasticity as musicians continuously practice complex motor, auditory, and
multimodal skills.
Music training in children results in long-term enhancement of visual–spatial, verbal, and
mathematical performance (22, 29).
Figure 13. Activation to Melody (▄), Sentence Generation (▄), and Common to Both Tasks (▄).
The learning of complex sequences taxes executive processes (e.g., those involved with
error monitoring or motor program structuring). Structural complexity remains the same for
any sequence, be it with music or any other task. Music affords a system to both study and
remediate the acquisition of sequencing behaviors and their impairment. Activations at
varying levels of complexity have demonstrated overlap in the supplementary motor cortex,
among other areas (6). Areas of overlap have also been noted for the cerebellum, basal
ganglia pre-motor cortex, thalamus, ventro-lateral pre-motor cortex, and precuneus, with
increased activations at increased levels of complexity. Increases in musical complexity have
concomitant increases in neural recruitment (6, 22). The available data supports a core circuit
that includes the supplementary motor cortex, cerebellum, and premotor cortex in sequencing.
Brown and colleagues (30) among others (6) have noted that music‘s effect on the brain
is similar to the brain‘s activation by language stimuli. This serves as a rationale in the
employment of music as a therapeutic aid after nervous system trauma and in its
rehabilitation. Exemplified in Figure 13, are areas for generating melodic phrases that appear
in Brodmann area (BA) 45, BA 44, the temporal planum bilaterally, the lateral BA 6, and pre-
supplementary motor area. Areas for generating sentences were of course noted in the
bilateral posterior, superior, and mid temporal cortex (BA 22, 21), BA 39, bilateral, superior,
and frontal (BA 8, 9), the left inferior frontal (BA 44, 45), the anterior cingulate, and the pre-
supplementary motor area. Both tasks showed activations in the same functional brain areas,
including the pre-motor cortex, supplementary motor area, Broca‘s area, anterior insula,
primary and secondary auditory cortices, temporal pole, basal ganglia, ventral thalamus, and
posterior cerebellum. The differences between melodic and sentence generation are seen with
lateralization tendencies, with language tasks favoring the left hemisphere. Data also supports

the notion that component sharing, parallel processing, and adaptive coding explain results
with shared, parallel, and distinctive features of the neural systems supporting both music and
language. Music and language show parallel combinatoric generativity for complex sound
structures (phonology) but distinctly different informational content (semantics).
Figure 14. Effects of music training on cognitive performance post-stroke.
The result of plasticity evidenced in musical training is that a rational basis is provided
for the employment of music in general cognitive growth and in the rehabilitation of cognitive
skills in individuals with brain impairment (see Figure 14).
ACKNOWLEDGMENTS
The paper is based on earlier presentations at the Oxford Roundtable Session on
Childhood Education 11-15 March, 2012 at Harris Manchester College, Oxford University
and at ORT-Braude College of Engineering June 1-2, 2011, Carmiel, Israel. This work is
supported in part by the Ministry of Science, State of Israel, Cyrex Laboratories™, and by the
Children‘s Autism Hope Project.

226 Gerry Leisman
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functional brain organization and cerebral asymmetry. In: Kravchuk T, Groysman A, Soddu C,
Colabella E, Leisman G, eds. Art, science and technology. Milano, Italy: Domus Argenia Publisher,
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Chapter 11
THE PLASTICITY OF NEURAL NETWORK SENSORY-

SUBSTITUTION OBJECT SHAPE RECOGNITION
Ella Striem-Amit1, Ornella Dakwar1, Uri Hertz1,

Peter Meijer2, William Stern3,
Alvaro Pascual-Leone3 and Amir Amedi1,4,*
1
Department of Medical Neurobiology, The Institute for Medical Research Israel-Canada,
Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
2
NXP Semiconductors, High Tech Campus, Eindhoven, The Netherlands
3
Harvard Medical School, Boston, Massachesetts, US
4
The Edmond and Lily Safra Center for Brain Sciences (ELSC),
The Hebrew University of Jerusalem, Jerusalem, Israel
In sensory substitution devices (SSDs), visual information captured by an artificial

receptor is delivered to the brain using non-visual sensory information. Using an
auditory-to-visual SSD called ―The vOICe‖ we previously reported that blind individuals
perform successfully on object recognition tasks and are able to recruit specific ventral
'visual' structures for shape recognition using the device (i.e., through soundscapes).
Comparable recruitment was also observed in sighted individuals learning to use this
device. Here we directly compare a group of seven subjects who learned to perform
object recognition via soundscapes and a group of seven subjects who learned arbitrary
associations between sounds and object identity. We contrast these two groups‘ brain
activity for object recognition using SSD, and for auditory object and scrambled object
soundscapes. We show that the most critical structures specific for shape extraction for
the purpose of object recognition are the left Pre-Central Sulcus (PCS) and the bilateral
Lateral-Occipital Complex (LOC). We also found significant activation in the occipito-
parietal and posterior occipital cortex not previously observed using a smaller sample of
subjects. These results support the notion that interactions between visual structures and a
network of additional areas, specifically in prefrontal cortex (PCS) might underlie the
*
Correspondence: Dr. Amir Amedi, Department of Medical Neurobiology, The Institute for Medical Research
Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91220, Israel. E-mail:
amir.amedi@ekmd.huji.ac.il.

230 Ella Striem-Amit, Ornella Dakwar, Uri Hertz et al.
machinery which is most critical for achieving multisensory or metamodal shape

recognition.
INTRODUCTION
Sensory substitution devices (SSDs) (1-5) are means of providing visual information to the
blind in a non-invasive manner. Sensory substitution can be used even when other promising
methods of visual restoration (i.e., surgical vision restoration, or prosthetic retinas) are
unfeasible. In the case of a visual-to-auditory SSD (1), users wear a video camera linked to a
computer and stereo headphones; the images are converted into ―soundscapes‖ using a
predictable algorithm, allowing them to listen to and then interpret the visual information.
Remarkably, proficient users are able to differentiate the shapes of different objects, identify
the actual objects, and also locate them in space. In a sense, these subjects are ―seeing with
sound.‖ Therefore, in addition to its clinical interest, sensory substitution is a valuable tool in
teasing apart the influence of information modality and information content on neural
processing.
Sensory substitution has already been used with some success to clarify the role of
multisensory brain regions (2-5). For example, a recent study demonstrated that during object
identification, soundscapes activate the lateral-occipital tactile-visual complex (LOtv), an area
which is also activated by visual and tactile object recognition (4). As this area is known to be
a region specialized in object recognition in the visual and tactile, but less so in the auditory
modality (6), these findings support the notion that LOtv may be a metamodal operator (7) for
shape; i.e., that it processes shape regardless of the input modality. In addition to the marked
effect of shape recognition in the LOC, our previous study (4) also showed qualitatively at the
single subject level that other cortical regions are also engaged in sensory-transformed object
recognition such as the pre-central sulcus, inferior frontal sulcus, occipito-parietal sulcus and
the posterior occipital lobe in blind individuals.
Here we directly test the role of these regions in shape recognition (as opposed to
identifying objects based on arbitrary learning) using quantitative measures, in group analysis
and in a contrast further controlling for the exact sensory stimulation. We directly compare a
larger group of seven sighted subjects who learned to perform object recognition by
extracting the object shape from the soundscapes, with a group of seven subjects who learned
to identify the same soundscapes by learning arbitrary associations between sounds and object
identity. Therefore, both groups heard the exact same auditory stimuli but differed in the way
in which object recognition was achieved. Enlarging the group of subjects enabled us to use
random effect ANOVA comparison, whose conclusions can be attributed to the entire
population (8), and to study the network of regions involved in cross-modal object
recognition using visual-to-auditory SSD with more statistical power.
OUR STUDY
We used a visual-to-auditory sensory-substitution device (SSD) called ―The vOICe‖ (1). The
functional basis of this visuo-auditory transformation lies in spectrographic sound synthesis
from any input image, which is then further perceptually enhanced through stereo panning

The plasticity of neural network sensory-substitution object … 231
and other techniques. Time and stereo panning constitute the horizontal axis in the sound
representation of an image, tone frequency makes up the vertical axis, and loudness
corresponds to pixel brightness.
Fourteen healthy subjects participated in the study. All subjects were right-handed as
assessed by the Oldfield questionnaire, had normal hearing and normal vision (corrective
lenses permitted). No subject had any known neurological or psychiatric conditions.
Procedures
Sighted experts training procedures

Seven subjects were trained to interpret the shape information contained in soundscapes at the
Harvard medical school. Subjects underwent training lasting 20 consecutive weekdays using a
multiple choice paradigm, as well as a less structured training paradigm using a video camera
linked to a laptop and stereo headphones, in which subjects were encouraged to actively
explore a library of objects using The vOICe. For further details of the training procedure see
(4). All subjects achieved a minimum level of 50% success on multiple-choice testing for
recognizing novel objects using ―The vOICe‖ during training; since each question had four
possible choices, this represents twice the level of success expected by chance.
Sighted association training procedures

Seven subjects were trained to arbitrarily remember and identify the soundscapes presented
during the fMRI experiment. Each subject had 3-5 training sessions of 2 hours with the 8
required associations. The variable length of training represents the variable time it took the
control subjects to learn the associations. The criterion for success was 100% accurate
recognition on two complete sets of the 8 stimuli (16/16 associations), repeated on two
consecutive days.
General Experiment Design
Each subject was scanned for 4 consecutive runs. During the scans subjects were given
auditory instructions, instructing them to perform 3 tasks. (i) vOICe object recognition using
SSD mapping (vOICeObj), (ii) vOICe scrambled images control (vOICeScr), (iii) auditory
object recognition of ‗natural‘ sounds made by objects (AudObj). During each condition,
subjects heard two sounds of the same type (e.g., vOICe, scramble, animal/object typical
sound) each repeated 3 times. Each sound lasted 2 seconds. Each pair of trials lasted a total of
12 seconds and was terminated with the auditory instruction ―stop.‖ An 8 second rest period
followed, prior to the next trial. Subjects had to recognize each object and covertly name the
object‘s identity. Stimuli were prepared representing eight objects that were recognizable both
by their shape (vision transformed to vOICe) and by the sounds they make. During half of the
runs, subjects were asked to identify the stimuli as ‗man-made’ or ‗animal,’ and to respond
via a two-button response box. This allowed verification that the subjects were correctly
identifying objects during the scanning. To control for hand movements, subjects had to press
the response buttons randomly as well during the vOICeScr condition after each cue for a
stimulus.

3D recording and cortex reconstruction

Separate 3D recordings were used for surface reconstruction. High resolution 3D anatomical
volumes were collected using high-resolution T1-weighted images using a 3D-turbo field
echo (TFE) T1-weighted sequence (equivalent to MP-RAGE). Typical parameters were: Field
of View (FOV) 23cm (RL) x 23cm (VD) x 17cm (AP); Foldover-axis: RL, data matrix:
160x160x144 zero-filled to 256 in all directions (approx 1mm isovoxel native data),
TR/TE=9ms/6ms, flip angle = 8deg. Acquisition was segmented x 3 in order to enhance
gray/white matter contrast. NEX = 2 in separate acquisitions. The 5 parallel imaging head coil
(SENSE head) was used to reduce scan time. Reduction factor = 2.5 (total acquisition time: 5
minutes). The surface reconstruction procedure included the segmentation of the white matter
of the brain of a single subject using a grow-region function. The cortical surface was then
Talairach normalized (9), inflated and the obtained activation maps were superimposed onto
it.
fMRI recording parameters

The BOLD fMRI measurements were performed in a whole-body 3-T, Philips scanner
equipped with 22 mT/m field gradients with a slew rate of 120 T/m/s (Echospeed). The pulse
sequence used was the gradient-echo echo planar imaging EPI sequence. We used 30-33
slices of 3mm thickness, with an interslice gap of 1 mm. Data in-plane matrix size was
128x128, field of view (FOV) 24cm x 24cm, time to repetition (TR) = 3000ms and time to
echo (TE) = 35ms. Each experiment had 180 data points with four repetitions. The first five
images (during the first baseline rest condition) were excluded from the analysis because of
non-steady state magnetization.
Data analysis
Data analysis was performed using the Brain Voyager QX 1.10 software package (Brain
Innovation, Maastricht, Netherlands) using standard preprocessing procedures. Functional
MRI data preprocessing included head motion correction, slice scan time correction and high-
pass filtering (cutoff frequency: 3 cycles/scan) using temporal smoothing in the frequency
domain to remove drifts and to improve the signal to noise ratio. Single subject data were
transformation into Talairach space (9), spatially smoothed with a minimal three dimensional
4 mm half-width Gaussian in order to reduce inter-subject anatomical variability, and then
grouped using a hierarchical random effects analysis (8) and overall analysis of variance
(ANOVA). The minimum significance level was set to p < 0.05 corrected for multiple
comparison by using a cluster-size threshold adjustment, based on Forman et al. Monte Carlo
stimulation approach (10), extended to 3D data sets using the threshold size plug-in Brain
Voyager QX.
Percent signal change analysis

For the region of interest (ROI) signal magnitude analysis (Figure 1B), activation was
sampled from the peaks of activation of the group ANOVA analysis (see Figure 1A): in the
bilateral lateral-occipital complex (LOC), left pre-central sulcus (PCS), bilateral occipito-
parietal sulcus (OccParS) and joining of the right occipito-parietal sulcus and anterior
calcarine sulcus. Activation was then averaged across the four runs (using in each subject
separately the peak voxel in a smoothed volume, after convolution with a Gaussian kernel of
4 mm full width at half maximum). The averaged percent signal change and standard errors
were then calculated for each condition.

FINDINGS
We directly compared a group of seven subjects learning to perform object recognition via
soundscapes with a group of seven subjects learning arbitrary associations between sounds
and object identity. This was done by ANOVA comparisons with a group factor (object via
soundscapes; objects via associations) and conditions (vOICeObj; vOICeScr; AudObj).
Figure 1A presents the direct contrast for areas showing significant differences between
groups for the contrast of the vOICe objects as compared to the auditory controls that did not
contain shape information (vOICeObj > vOICeScr, AudObj). The most significant areas for
this comparison, and thus the most critical structures supporting object shape recognition via
soundscapes, were the left Pre-Central Sulcus (PCS), and the bilateral Lateral-Occipital
Complex (LOC). We also found activation in the occipito-parietal sulcus and the right
posterior medial occipital cortex (Occipito-parietal – anterior calcarine junction, though this
area exhibited a relatively weaker signal and less specificity, see Figure1b). Time courses
from each significant cluster (see Figure 1B) indicated that LOtv in the ventral visual stream
and PCS in the prefrontal cortex showed strong differential activation for vOICe objects
versus the two other object types but only in the group who learned to extract relevant shape
information. The occipito-parietal sulcus showed more selective activation for vOICe objects
in the right hemisphere.
(a)

(b)
Figure 1: The neural network of sensory substitution object shape recognition.

A. Activation for recognizing SSD objects (contrasted with SSD scrambled images and auditory
objects; OBJ > SCR, AO) is compared by a RFX ANOVA analysis between the two groups, which
differ in their ability to extract shape information from the SSD object stimuli. A group of seven
subjects who learned to perform object recognition via shape extraction from soundscapes (OBJ group)
is compared here to a group of seven subjects who learned the same soundscapes identities by arbitrary
associations between sounds and object identity (ASC group). The most significant areas activated for
this contrast (and thus the most critical structures which are specific to object shape recognition via
soundscapes) were the left Pre-Central Sulcus (PCS) and the bilateral Lateral-Occipital cortex (LO).
B. Time courses from each significant ANOVA cluster show that LO and PCS exhibit differential
activation for vOICe objects versus the two other object types but only in the group who learned to
extract relevant shape information.
DISCUSSION
These results suggest that in addition to LOC, an entire cortical network is involved in the
extraction of cross-modal shape information for object recognition, as opposed to identifying
objects based on arbitrary associations of stimulus and identity. These regions include the left
pre-central sulcus, the right occipito-parietal sulcus region and to some extent, the occipito-
parietal sulcus/anterior calcarine region, in addition to the previously reported lateral occipital
complex (4). These results support the assumption that interactions between visual structures
and a specific area in prefrontal cortex (PCS) might define the critical underlying mechanism
for achieving object shape recognition via SSD soundscapes, similar to the mechanism
evidenced for visual object recognition (11). Areas in the lateral prefrontal cortex have been
shown to match object identities across modalities (12, 13), and to have a cross-modal
repetition suppression effect (14) for the combination of visual and haptic stimuli, suggesting
a common neuronal basis for visuo-haptic integration of object identities (using fMRI

adaptation design). Our findings suggest that at least part of this crossmodal platform is
linked to a multisensory comparison of shape, and not to a more abstract association based
solely on arbitrary association or its learning. This finding also supports the expansion of the
metamodal shape network, which is engaged in deciphering shape regardless of input
modality (4, 7), to a specific part of the prefrontal cortex, whereas at least another close-by
area also encodes arbitrary associations between artificially determined (learned) visuo-
auditory ―objects‖ (13).
Interestingly, an additional area which is commonly found in cross-modal binding and
learning with regard to object recognition, the intra-parietal sulcus (13, 14), does not appear,
in this study, to be metamodally activated for processing object shape, and may thus be
involved in binding multisensory object representations via familiarity and learning of the
object identity.
These data contribute to the growing body of evidence that sensory substitution can
cross-modally activate otherwise sensory 'specific' areas (see also (15-21) for studies
supporting this notion with non-SSD approaches). Finally, this study also confirms that
sensory substitution devices are powerful tools for studying key issues in brain research, such
as multisensory interactions, brain plasticity, learning and object recognition.
ACKNOWLEDGMENTS
We thank Zohar Tal for help in commenting and editing the final draft of the paper. This
work was supported in part by an R21-EY0116168 (to APL), the International Human
Frontiers Science Program Organization Career Development Award, The Israel Science
Foundation (grant number 1530/08); a European Union Marie Curie International
Reintegration Grant (MIRG-CT-2007-205357); the Edmond and Lily Safra Center for Brain
Sciences; and the Alon, Sieratzki, and Moscona funds (To AA). We would also like to thank
the Hebrew University Hoffman Leadership and Responsibility Fellowship Program for its
support (to ESA).
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[13] Naumer MJ, Doehrmann O, Muller NG, Muckli L, Kaiser J, Hein G. Cortical plasticity of audio-visual
object representations. Cereb Cortex 2009;19(7):1641-53.
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[15] Beauchamp MS. See me, hear me, touch me: multisensory integration in lateral occipital-temporal
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[16] Amedi A, von Kriegstein K, van Atteveldt NM, Beauchamp MS, Naumer MJ. Functional imaging of
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7881-7.

SECTION TWO: ACKNOWLEDGMENTS

Chapter 12
ABOUT THE EDITORS
Gerry Leisman, MD, PhD, FABFM is an Israeli neuroscientist educated in the

United Kingdom and the United States in medicine, neuroscience, and biomedical
engineering at the University of Manchester, the City University of New York, and Union
University. He holds the position of Director of the National Institute for Brain and
Rehabilitation Sciences-Israel in Nazareth, Israel and Professor of Rehabilitation Sciences in
the Department of Mechanical Engineering at O.R.T.-Braude College of Engineering in
Karmiel, Israel. He is also Professor of Restorative Neurology at the Universidad de Ciencias
Medicas de la Habana, Faculdad Manuel Fajardo, Institute for Neurology and Neurosurgery
in Havana, Cuba. Editor-in-Chief of the journal Functional Neurology, Rehabilitation and
Ergonomics.
He has been active since the early 1970s in the promotion of consciousness as a
scientifically tractable problem, and has been particularly influential in arguing that
consciousness can now be approached using the modern tools of neurobiology and
understood by mechanisms of theoretical physics. He has also been influential in examining
mechanisms of self-organizing systems in the brain and nervous system for cognitive function
exemplified by his work in optimization, memory, kinesiology, consciousness, death, autism
and dyslexia. It is in this context that he was one of the first to identify functional
disconnectivities in the brain and nervous system.
Also, in his long work in rehabilitation sciences, he has been able to apply the tools of
systems sciences in human rehabilitation and technology development to optimize human
performance for those who have sustained traumatic brain injury and in those with
developmental disabilities.
He has served as a consultant to the USA National Sciences Foundation. He was elected
Fellow of the Association for Psychological Science in 1990, a Life Fellow of the American
College of Forensic Examiners in 1994, Senior Member of the Institute for Electrical and
Electronic Engineers Engineering in Medicine and Biology Society in 1988, a Life Fellow of
the Institute for Functional Neurology and Rehabilitation and a recipient of its Lifetime
Achievement Award in 2011. He is the author of over 500 papers, texts, chapters and holder
of patents. He is the co-author of a text with Dr. Robert Melillo on ―Neurobehavioral
disorders of childhood from an evolutionary perspective.‖
E-mail: gerry.leisman@staff.nazareth.ac.il

Joav Merrick, MD, MMedSci, DMSc, born and educated in Denmark is

professor of pediatrics, child health and human development, Division of Pediatrics,
Hadassah Hebrew University Medical Center, Mt Scopus Campus, Jerusalem, Israel and
Kentucky Children‘s Hospital, University of Kentucky, Lexington, Kentucky United States
and professor of public health at the Center for Healthy Development, School of Public
Health, Georgia State University, Atlanta, United States, the medical director of the Health
Services, Division for Intellectual and Developmental Disabilities, Ministry of Social Affairs
and Social Services, Jerusalem, the founder and director of the National Institute of Child
Health and Human Development in Israel. Numerous publications in the field of pediatrics,
child health and human development, rehabilitation, intellectual disability, disability, health,
welfare, abuse, advocacy, quality of life and prevention. Received the Peter Sabroe Child
Award for outstanding work on behalf of Danish Children in 1985 and the International
LEGO-Prize (―The Children‘s Nobel Prize‖) for an extraordinary contribution towards
improvement in child welfare and well-being in 1987. E-mail: jmerrick@zahav.net.il

Chapter 13
ABOUT THE NATIONAL INSTITUTE FOR BRAIN AND

REHABILITATION SCIENCES, NAZARETH, ISRAEL
The National Institute for Brain and Rehabilitation Sciences is a research center based in
Nazareth, Israel associated with that city‘s three hospitals. The Institute‘s purpose is to
investigate solutions for all issues that impede the optimization of human performance. The
ultimate aim is to get every individual from infancy to the fourth age, to contribute to himself,
family and society at the highest level.
Research agenda
As such, the Institute‘s research agenda includes the nature of stress, environmental toxins,
and diet on pregnancy and on the development of the infant and child, neuroeducation,
biomechanics cognitive motor interactions, autism and developmental disabilities, biological
rhythms, ergonomics of classroom and workplace, functional and restorative neurology,
aging, post-stroke and traumatic brain injury, and neurodegenerative conditions all from a
management perspective. The institute is involved not in basic, but rather translational
research, where the end result may be better programing or the development of patents and
new technologies, but clearly the optimization of human potential.
International and national collaborations
The Institute is formally affiliated with laboratories in the USA, the M.I.N.D. Institute at
M.I.T. in Cambridge Massachusetts, The Institute for Neurology and Neurosurgery in Havana
Cuba, as well as the Manuel Fajardo University of the Medical Sciences in Havana, and
cooperative relationships with the School of Medicine of Bar-Ilan University in Safed, Israel
and the National Institute of Child Health and Human Development, Jerusalem, Israel. It is
also formally affiliated with the National Institute for Brain and Rehabilitation Sciences in
Gilbert, Arizona, in the USA.

Contact
Gerry Leisman
Director and Professor of Neuro- and Rehabilitation Sciences
O.R.T.-Braude College of Engineering
Karmiel, Israel
Professor Neurología restaurativa
Universidad de Ciencias Médicas de la Habana, Facultad Manuel Fajardo
Havana, Cuba
51 Snunit
POB 78 Kamiel, Israel
E-mail: g.leisman@alumni.manchester.ac.uk

Chapter 14
ABOUT THE NATIONAL INSTITUTE OF CHILD

HEALTH AND HUMAN DEVELOPMENT IN ISRAEL
The National Institute of Child Health and Human Development (NICHD) in Israel was
established in 1998 as a virtual institute under the auspices of the Medical Director, Ministry
of Social Affairs and Social Services in order to function as the research arm for the Office of
the Medical Director. In 1998 the National Council for Child Health and Pediatrics, Ministry
of Health and in 1999 the Director General and Deputy Director General of the Ministry of
Health endorsed the establishment of the NICHD.
Mission
The mission of a National Institute for Child Health and Human Development in Israel is to
provide an academic focal point for the scholarly interdisciplinary study of child life, health,
public health, welfare, disability, rehabilitation, intellectual disability and related aspects of
human development. This mission includes research, teaching, clinical work, information and
public service activities in the field of child health and human development.
Service and academic activities
Over the years many activities became focused in the south of Israel due to collaboration with
various professionals at the Faculty of Health Sciences (FOHS) at the Ben Gurion University
of the Negev (BGU). Since 2000 an affiliation with the Zusman Child Development Center at
the Pediatric Division of Soroka University Medical Center has resulted in collaboration
around the establishment of the Down Syndrome Clinic at that center. In 2002 a full course
on ―Disability‖ was established at the Recanati School for Allied Professions in the
Community, FOHS, BGU and in 2005 collaboration was started with the Primary Care Unit
of the faculty and disability became part of the master of public health course on ―Children
and society.‖ In the academic year 2005-2006 a one semester course on ―Aging with
disability‖ was started as part of the master of science program in gerontology in our
collaboration with the Center for Multidisciplinary Research in Aging. In 2010 collaborations

with the Division of Pediatrics, Hadassah Hebrew University Medical Center, Jerusalem,
Israel around the National Down Syndrome Center and teaching students and residents about
intellectual and developmental disabilities as part of their training at this campus.
Research activities
The affiliated staff have over the years published work from projects and research activities in
this national and international collaboration. In the year 2000 the International Journal of
Adolescent Medicine and Health and in 2005 the International Journal on Disability and
Human Development of De Gruyter Publishing House (Berlin and New York) were affiliated
with the National Institute of Child Health and Human Development. From 2008 also the
International Journal of Child Health and Human Development (Nova Science, New York),
the International Journal of Child and Adolescent Health (Nova Science) and the Journal of
Pain Management (Nova Science) affiliated and from 2009 the International Public Health
Journal (Nova Science) and Journal of Alternative Medicine Research (Nova Science). All
peer-reviewed international journals.
National collaborations
Nationally the NICHD works in collaboration with the Faculty of Health Sciences, Ben
Gurion University of the Negev; Department of Physical Therapy, Sackler School of
Medicine, Tel Aviv University; Autism Center, Assaf HaRofeh Medical Center; National Rett
and PKU Centers at Chaim Sheba Medical Center, Tel HaShomer; Department of
Physiotherapy, Haifa University; Department of Education, Bar Ilan University, Ramat Gan,
Faculty of Social Sciences and Health Sciences; College of Judea and Samaria in Ariel and in
2011 affiliation with Center for Pediatric Chronic Diseases and National Center for Down
Syndrome, Department of Pediatrics, Hadassah Hebrew University Medical Center, Mount
Scopus Campus, Jerusalem.
International collaborations
Internationally with the Department of Disability and Human Development, College of

Applied Health Sciences, University of Illinois at Chicago; Strong Center for Developmental
Disabilities, Golisano Children's Hospital at Strong, University of Rochester School of
Medicine and Dentistry, New York; Centre on Intellectual Disabilities, University of Albany,
New York; Centre for Chronic Disease Prevention and Control, Health Canada, Ottawa;
Chandler Medical Center and Children‘s Hospital, Kentucky Children‘s Hospital, Section of
Adolescent Medicine, University of Kentucky, Lexington; Chronic Disease Prevention and
Control Research Center, Baylor College of Medicine, Houston, Texas; Division of
Neuroscience, Department of Psychiatry, Columbia University, New York; Institute for the
Study of Disadvantage and Disability, Atlanta; Center for Autism and Related Disorders,
Department Psychiatry, Children‘s Hospital Boston, Boston; Department of Pediatric and
Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine,

About the National Institute of Child Health and Human Development in Israel 245
Kalamazoo, Michigan, United States; Department of Paediatrics, Child Health and

Adolescent Medicine, Children's Hospital at Westmead, Westmead, Australia; International
Centre for the Study of Occupational and Mental Health, Düsseldorf, Germany; Centre for
Advanced Studies in Nursing, Department of General Practice and Primary Care, University
of Aberdeen, Aberdeen, United Kingdom; Quality of Life Research Center, Copenhagen,
Denmark; Nordic School of Public Health, Gottenburg, Sweden, Scandinavian Institute of
Quality of Working Life, Oslo, Norway; The Department of Applied Social Sciences (APSS)
of The Hong Kong Polytechnic University Hong Kong.
Targets
Our focus is on research, international collaborations, clinical work, teaching and policy in
health, disability and human development and to establish the NICHD as a permanent
institute at one of the residential care centers for persons with intellectual disability in Israel
in order to conduct model research and together with the four university schools of public
health/medicine in Israel establish a national master and doctoral program in disability and
human development at the institute to secure the next generation of professionals working in
this often non-prestigious/low-status field of work.
Contact
Joav Merrick, MD, MMedSci, DMSc

Professor of Pediatrics, Child Health and Human Development
Medical Director, Health Services, Division for Intellectual and Developmental Disabilities,
Ministry of Social Affairs and Social Services, POB 1260, IL-91012 Jerusalem, Israel.
E-mail: jmerrick@zahav.net.il

Chapter 15
ABOUT THE BOOK SERIES

“FUNCTIONAL NEUROLOGY”
Functional neurology is a book series with publications from a multidisciplinary group of

researchers, practitioners and clinicians for an international professional forum interested in
the broad spectrum of neurology and human development.
 Vojdani A. Neuroimmunity and the brain-gut connection. New York: Nova Science,
2015.
 Leisman G, Merrick J, eds. Neuroplasticity in learning and rehabilitation. New York:
Nova Science, 2015.
 Leisman G, Merrick J, eds. Considering consciousness clinically. New York: Nova
Science, 2015.
Contacts
Gerry Leisman
Director,
The National Institute for Brain and Rehabilitation Sciences
Nazareth, Israel
Professor, Neuro- and Rehabilitation Sciences
ORT-Braude College of Engineering
Karmiel, Israel
Profesor, Neurología Restaurativa
Universidad de Ciencias Médicas de la Habana, Facultad Manuel Fajardo, Havanna, Cuba
E-mail: g.leisman@alumni.manchester.ac.uk
Professor Joav Merrick, MD, MMedSci, DMSc

Medical Director, Medical Services
Division for Intellectual and Developmental Disabilities
Ministry of Social Affairs and Social Services
POBox 1260, IL-91012 Jerusalem, Israel
E-mail: jmerrick@zahav.net.il

SECTION THREE: INDEX

INDEX
agraphia, 2, 3, 48, 49, 116

A akinesia, 134
albumin, 173
acetylation, 38
alexia, 2, 48, 49
acetylcholine, 104
algorithm, 107, 144, 145, 147, 230
achievement test, 10
alpha wave, 78
acid, 39, 59, 164, 173
alters, 120, 121, 164, 166, 169
acidosis, 169
American Psychiatric Association, 92
acquisition of knowledge, 3
amoeboid, 162
acquisition phase, 139
amplitude, 33, 81, 82, 84, 108
acquisitions, 232
amputation, 111, 118, 119
ACTH, 169, 176, 177, 195
amygdala, 55, 93
action potential, 101, 102, 107, 109, 110, 111, 112
amyotrophic lateral sclerosis (ALS), 50, 62
active transport, 168
anatomy, 8, 10, 34, 40, 58, 61, 62, 82, 218
activity level, 105, 112
anencephaly, 3
adaptation(s), 9, 23, 37, 60, 91, 113, 150, 226, 235,
anger, 187
236
angiogenesis, 43, 60, 61
adaptive organisms, 22
angulation, 107
adenosine, 164, 174
animal behavior, 57
ADHD, 40, 62, 65, 66, 68, 69, 70, 73, 74, 75, 76, 77,
anisotropy, 75, 185
78, 79, 84, 87, 89, 92, 93, 94, 95, 98
ANOVA, 230, 232, 233, 234
adolescent development, 68
anterior cingulate cortex, 94
adolescents, 75, 77, 85, 94, 130
anticonvulsant, 194
adrenal gland(s), 177, 179
antidepressant, 59
adrenal insufficiency, 177, 178, 179, 195
antigen, 160, 164, 173
adrenocorticotropic hormone, 170
anti-inflammatory medications, 161
adulthood, 40, 56, 68, 71, 75, 81, 82, 89, 226
antioxidant, 159, 161
adults, 1, 10, 13, 18, 37, 39, 42, 57, 75, 78, 83, 93,
anxiety, 53, 186, 187, 188
124, 130, 197
apathy, 187, 188
adverse effects, 150, 153
APL, 235
advocacy, 130, 240
apoptosis, 60, 158, 160, 161, 162, 163, 165, 191
affective disorder, 178, 195
apoptotic pathways, 169
age, 11, 19, 37, 39, 42, 43, 51, 56, 57, 58, 60, 68, 69,
apraxia, 91
71, 72, 73, 74, 75, 76, 77, 79, 81, 82, 83, 84, 86,
aptitude, 10, 11
89, 92, 96, 118, 124, 128, 166, 211, 218, 226, 241
arbitrary associations, 229, 230, 233, 234
aggression, 121
arteriography, 116
agility, 74
artery, 39, 107
aging process, 39
artificial intelligence, 203
agonist, 134, 150
ascorbic acid, 169

252 Index
aspartate, 39, 164 blood, 95, 107, 120, 159, 164, 166, 167, 168, 171,
assessment, 38, 72, 91, 92, 122, 125, 126, 156, 176, 172, 173, 174, 175, 176, 177, 180, 182, 186, 192,
177, 186, 188, 189, 190, 198, 236 193, 194, 195, 197, 198
asthma, 104 blood flow, 95, 173, 197
astrocytes, 38, 158, 168, 173, 174, 175, 192, 194 blood pressure, 107, 120, 172
asymmetry, 61, 67, 69, 87, 88, 89, 98, 103, 104, 116, blood-brain barrier (BBB), 164, 166, 167, 168, 169,
117, 118, 213, 218, 226 171, 173, 174, 175, 176, 180, 182, 186, 193, 194,
athletes, 196 195, 197, 198
ATP, 158, 168, 169 body mass index (BMI), 104
atria, 104 bone marrow, 173
atrophy, 71, 88, 171 bowel, 170, 192
auditory cortex, 43, 44, 206, 211, 213, 221, 222, 223, Braille, 42, 60, 119
226 brain abnormalities, 180
auditory modality, 85, 230 brain activity, 18, 24, 76, 107, 108, 121, 123, 124,
auditory stimuli, 216, 230 127, 129, 192, 203, 206, 223, 229
autism, 37, 44, 52, 65, 66, 69, 73, 74, 75, 77, 79, 81, brain asymmetry, 115, 117, 118, 218
85, 86, 87, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, brain chemistry, 58
102, 103, 116, 239, 241 brain damage, 8, 43, 60, 61, 68, 122, 130, 180, 187,
autoimmunity, 164 207, 211
autonomic nervous system, 102, 103 brain dead, 2
axonal pathology, 196 brain functioning, 87, 206
axons, 25, 27, 28, 53, 101, 102, 105, 109, 113, 174, brain growth, 40
201, 202, 209 brain regions, 1, 2, 3, 12, 13, 33, 47, 55, 77, 85, 88,
89, 123, 129, 185, 187, 201, 202, 208, 230
brain stem, 70
B brain structure, 43, 45, 54, 79, 114, 133, 134, 136,
141, 146, 187, 211
Baars, 202, 209
brain tumor, 52
basal forebrain, 115
brain-spinal cord injured, 2
basal ganglia, 46, 53, 86, 92, 97, 114, 120, 133, 134,
brainstem, 40, 44, 68, 92, 103, 115, 181
135, 136, 141, 142, 143, 144, 146, 147, 148, 149,
150, 151, 152, 153, 210, 214, 223, 224
behavior modification, 40 C
behavioral disorders, 178
behavioral problems, 92 calcitonin, 192
behaviors, 2, 23, 36, 45, 53, 80, 86, 115, 224 calcium, 38, 80, 110, 164, 165
beneficial effect, 39 caloric intake, 159
benzodiazepine, 116 cardiovascular function, 103
bilateral, 42, 45, 50, 53, 55, 105, 116, 150, 182, 224, caregivers, 67
226, 229, 232, 233, 234 case study, 150, 192, 198
bilingualism, 11, 18 CDC, 66, 156
binding globulin, 177 cell body, 164
biochemistry, 8, 182 cell death, 39, 113, 165, 178, 181, 192
biological motion, 53 cell division, 38
biological processes, 8 cell membranes, 180
biological rhythms, 241 cell surface, 164
biological sciences, 8 cellular energy, 164, 165, 169
biomarkers, 196 central nervous system (CNS), 37, 39, 56, 57, 71,
biomass, 166 113, 115, 159, 160, 161, 162, 163, 164, 166, 173,
biomechanics, 163, 241 174, 175, 178, 188, 189, 190, 191, 192, 193, 194
bipolar disorder, 84, 89, 98 cerebellum, 39, 50, 72, 77, 79, 86, 87, 92, 97, 114,
birth weight, 72, 92 173, 214, 223, 224
blindness, 60 cerebral asymmetry, 104, 117, 218, 226
cerebral blood flow, 58, 79, 115, 163, 169, 216, 218

Index 253
cerebral cortex, 10, 88, 94, 96, 101, 113, 116, 117, communication, 7, 9, 11, 28, 44, 45, 46, 47, 48, 77,
118, 122, 196 85, 86, 123, 202, 218, 219
cerebral function, 8, 185 community, 123
cerebral hemisphere, 57, 69, 74 comorbidity, 73, 92
cerebral palsy, 72, 87 compaction, 169
cerebrospinal fluid, 171, 193 compartmentalized functioning, 2
cerebrovascular disease, 194 complex behavior, 2
cerebrum, 60, 76 complexity, 23, 24, 25, 28, 31, 36, 37, 42, 57, 58, 59,
chemical, 30, 33, 82, 104, 173, 190, 203 61, 67, 90, 109, 121, 123, 124, 125, 126, 127,
chemokines, 158 128, 129, 130, 204, 209, 224
child development, 2, 18, 56 comprehension, 16, 40, 74
children, 9, 10, 12, 13, 18, 42, 57, 65, 66, 67, 68, 69, compulsive behavior, 53
71, 72, 73, 74, 75, 76, 77, 79, 82, 83, 84, 85, 87, computed tomography (CT), 46
88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 130, 219, concussion, 103, 109, 155, 156, 167, 169, 180, 181,
220, 224, 226 182, 185, 186, 187, 188, 190, 191, 192, 195, 196,
chimpanzee, 32, 66 198, 199
choroid, 171 conditioned response, 58
chromosome, 52 conditioning, 152
chronic recurrent, 197 conductance, 208
CIS, 101, 102, 109, 110, 159 conduction, 49, 91
clinical disorders, 37, 89, 99 connectivity, 3, 13, 15, 16, 18, 19, 42, 43, 45, 50, 51,
clinical interventions, 155 52, 62, 63, 68, 70, 77, 80, 84, 87, 88, 94, 98, 101,
clinical judgment, 74 108, 123, 129, 130, 144, 145, 146, 178, 196, 201,
clinical rehabilitation, 2 202, 204, 205, 206, 207, 208, 209, 218
coaches, 180 connectivity patterns, 13, 18, 19, 94, 123
cocaine, 134, 150 conscious awareness, 26, 31
coding, 58, 86, 225 consciousness, 3, 22, 23, 24, 25, 27, 44, 45, 57, 70,
cognition, 21, 37, 44, 50, 98, 151, 188, 201, 203, 98, 202, 203, 209, 210, 212, 226, 239, 247
206, 209 contralateral hemisphere, 103
cognitive abilities, 66, 69, 84, 88, 178 control group, 76, 124
cognitive activity, 11, 88 corpus callosum, 43, 47, 59, 61, 80, 88, 94, 181, 185,
cognitive deficit(s), 71, 122, 130, 133, 150, 151, 152, 211, 218, 219, 220, 221, 226
175, 196 correlation(s), 13, 50, 62, 63, 71, 72, 76, 84, 108,
cognitive development, 10, 18, 72, 226 117, 123, 125, 127, 185, 216, 217
cognitive dysfunction, 65 correlation coefficient, 127
cognitive function, 1, 2, 3, 10, 12, 18, 46, 71, 84, cortex, 15, 16, 31, 33, 34, 35, 38, 42, 43, 44, 49, 50,
108, 122, 134, 149, 151, 153, 185, 215, 239 53, 55, 59, 60, 61, 62, 66, 68, 78, 79, 84, 96, 98,
cognitive impairment, 46, 87, 91, 124, 178 102, 103, 104, 105, 107, 110, 111, 114, 116, 117,
cognitive level, 146 118, 119, 120, 136, 141, 143, 144, 151, 153, 186,
cognitive performance, 72, 81, 136, 149, 225 205, 208, 209, 214, 221, 223, 224, 227, 232, 234,
cognitive process, 66, 76, 87, 123, 135, 151, 185 235,떐236
cognitive processing, 66, 87, 185 cortical asymmetry, 101, 105, 108
cognitive skills, 225 cortical neurons, 42, 70, 102, 108, 111
cognitive style, 86 cortical systems, 53, 101, 103, 208
cognitive system, 2, 215 corticotropin, 178, 179
cognitive tasks, 11, 48, 82, 87, 88, 134, 151 cortisol, 176, 177, 178, 179, 195
cognitive testing, 71 CPT, 138, 139, 143
cognitive therapy, 189 cranial nerve, 114, 184
coherence, 11, 12, 19, 70, 71, 80, 82, 84, 85, 88, 90, cranium, 68
96, 97, 108, 116, 118, 236 creative potential, 9
coherence measures, 116 creative thinking, 33
commissure, 44, 54 creativity, 9
critical period, 11, 17, 57, 81, 102

254 Index
CSF, 171 dominance, 9, 103, 104, 117, 118, 126, 226

cytokines, 157, 160, 161, 162, 164, 165, 170, 173, dopamine, 39, 88, 95, 98, 117, 133, 134, 136, 141,
174, 180 142, 143, 144, 145, 146, 147, 149, 150, 151, 152,
cytosine, 79 153
cytoskeleton, 24, 25, 163 dopamine agonist, 134, 145, 150, 152, 153
dopaminergic, 99, 142, 146, 147, 149, 150, 152, 209
dorsolateral prefrontal cortex, 46, 151
D DRS, 122
drug treatment, 176
deep brain stimulation, 45, 53, 54, 56, 57, 63, 207
dynamic control, 103
defects, 46, 176
dynamical systems, 123
deficiency(s), 95, 159, 163, 170, 177, 191, 207
dysfunction, 1, 2, 3, 21, 49, 51, 53, 56, 62, 65, 68,
deficit, 2, 47, 49, 50, 73, 75, 76, 77, 84, 85, 86, 89,
71, 72, 73, 74, 75, 78, 85, 86, 87, 91, 92, 96, 101,
90, 91, 92, 93, 94, 95, 96, 97, 102, 103, 176, 184,
102, 103, 108, 112, 134, 149, 153, 164, 165, 169,
187, 188, 192
170, 171, 172, 176, 179, 182, 183, 184, 185, 186,
delusions, 206
192, 193, 198
dementia, 37, 71, 91, 92, 196
dyslexia, 61, 62, 65, 84, 87, 92, 98, 116, 239
demyelination, 175, 176
dendrites, 36, 37, 113, 201, 202, 207, 209
dendritic arborization, 34 E
dendritic spines, 35
depolarization, 80, 110, 169 early postnatal development, 43, 211
depression, 37, 55, 59, 102, 103, 104, 112, 117, 119, economic decisions, 2
151, 178, 179, 181, 186, 187, 188, 193, 195, 198 education, 7, 8, 9, 10, 14, 18, 213
depressive symptoms, 104 educational policy, 7
deprivation, 34, 52, 58, 60, 101, 116, 192 educational system, 8, 9
depth perception, 184, 235 EEG, 11, 12, 13, 18, 19, 81, 82, 84, 88, 94, 95, 96,
desynchronization, 65, 78, 84, 87, 89, 97 104, 108, 110, 116, 117, 118, 123, 129
developing brain, 43, 56, 79, 87, 211 EEG activity, 108
developmental change, 65, 66, 82, 84 elderly population, 72
developmental disorder, 56, 77, 79, 89, 92, 93 electrodes, 54, 55, 82, 83, 108, 207
developmental dyslexia, 91, 98, 226 electroencephalogram, 76
developmental milestones, 65, 90 electroencephalography, 95, 108
developmental process, 81 electromagnetic, 108
diabetes, 159, 176, 192 electromyography, 49
diabetes insipidus, 176 electron(s), 159, 165
Diagnostic and Statistical Manual of Mental EMG, 82, 84, 96
Disorders, 187 emission, 60, 149
diagnostic criteria, 66 emotion, 97, 117, 151
diffusion, 93, 98, 168, 180, 185, 197, 226 emotional processes, 102, 103
disability, 3, 84, 86, 122, 150, 197, 226, 240, 243, emotional responses, 117
245 emotional state, 104, 156, 190
diseased-non-diseased, 2 emotional stimuli, 86
diseases, 62, 165, 191 emotional valence, 103
disequilibrium, 103 encephalopathy, 191, 196
disorder, 40, 49, 51, 53, 66, 73, 74, 76, 79, 84, 89, encoding, 120, 226
90, 91, 92, 93, 94, 95, 99, 102, 103, 134, 187, endocrine, 156, 163, 176, 180, 182
188, 192, 195, 201, 207, 210 endocrine system, 163, 182
dissociation, 40, 196 endonuclease, 163
dissonance, 216, 217, 218 endophenotypes, 95
distribution, 21, 125, 127, 198 endothelial cells, 173, 175
dizziness, 182, 184, 187, 188, 198 endothelium, 162, 175
DNA, 34, 37, 118, 163, 164, 181 energy, 11, 30, 33, 42, 82, 88, 108, 129, 155, 165,
DNA damage, 163 166, 167, 168, 169, 192, 210

Index 255
energy supply, 192 fMRI, 19, 42, 50, 51, 52, 62, 63, 85, 87, 103, 108,
engineering, 3, 18, 239 153, 170, 192, 198, 231, 232, 234, 236
enlargement, 113 follicle, 170
entorhinal cortex, 187 football, 181, 191, 197
entropy, 121, 123, 124, 125, 126, 127, 128, 129, 183 force, 90, 181
environment(s), 2, 10, 22, 23, 33, 34, 35, 36, 39, 56, forebrain, 192
58, 59, 60, 67, 68, 80, 86, 90, 110, 122, 146, 158, formation, 38, 39, 43, 44, 79, 105, 113, 115, 202,
159, 161, 162, 165, 166, 186, 198, 206, 212 203, 204
environmental factors, 79, 90, 95, 112 FOV, 232
environmental influences, 57, 69, 90, 219 fractal dimension, 125
environmental movement, 85 fractures, 176
enzyme(s), 58, 104, 170, 174 fragments, 160, 162
epidemic, 89 free energy, 26
epidemiology, 92, 93 frontal cortex, 15, 16, 42, 51, 52, 77, 94, 104, 117,
epilepsy, 39, 52, 116, 207 150, 153
epithelium, 171 frontal lobe, 46, 51, 62, 66, 68, 69, 71, 129, 149, 150,
equilibrium, 206 184, 185, 187, 193, 210
ERD, 19, 78, 88, 98 FRP, 73
ergonomics, 241 functional activation, 123
ERS, 78 functional analysis, 150, 182
ethanol, 59 functional changes, 22, 89, 221
etiology, 95, 188 functional imaging, 51, 63, 76, 108
euthyroid sick syndrome, 176 functional MRI, 50, 94, 196
event-related desynchronization, 78, 88, 94 function-dysfunction, 2
event-related potential, 152
evoked potential, 116, 120, 165
excitability, 53, 56, 112, 114, 119, 152, 178 G
excitation, 52, 70, 91, 103, 114, 115, 209
GABA, 164, 165
excitotoxicity, 161, 162, 165, 188, 191
gait, 65, 73, 74, 75, 184, 186, 198
execution, 50, 82, 122, 214, 223
gene expression, 56, 69, 70, 79, 80, 95, 112, 119,
executive function(s), 16, 37, 50, 51, 66, 67, 69, 75,
161, 164
76, 94, 124, 125, 184, 186
gene regulation, 79
executive functioning, 50
generativity, 225
executive processes, 51, 224
genes, 66, 67, 68, 79, 80, 89, 90, 111, 112, 180
exercise(s), 35, 36, 37, 38, 39, 59, 66, 89, 159, 177,
genetic background, 38
178, 184, 186, 195
genetic information, 57
exposure, 11, 17, 39, 79, 191, 196, 197
genetic marker, 98
extensor, 71, 84, 107
genetic predisposition, 163
extraction, 229, 234
genetics, 98, 189, 190
extravasation, 173
genome, 63
eye movement, 97, 125, 156, 184, 185, 186, 190, 198
genotype, 60
gerontology, 243
F Gestalt, 7, 81, 215
gestures, 45
family history, 189, 190 gland, 177
family members, 122 glia, 38, 40, 158, 162, 170, 174, 195
fitness, 112 glial cells, 24, 25, 59, 80, 90, 160, 164, 165, 221
flexibility, 23, 57 globus, 53
flexor, 107 glucagon, 170
fluctuations, 94, 163 glucocorticoid(s), 178, 179, 180
fluid, 153, 171, 177, 193, 196 glucocorticoid receptor, 178
fluid intelligence, 153 glucose, 42, 58, 159, 163, 166, 167, 168, 169, 170,
192, 193

256 Index
glucose tolerance, 170 human performance, 2, 21, 239, 241

GLUT, 168 human subjects, 19, 60, 98, 120, 138, 178
GLUT4, 168 human will, 42
glutamate, 158, 164, 165, 168, 174, 192 humanism, 163
glutamine, 168, 192 hydrocephalus, 10, 11, 40, 41
glutathione, 159, 161, 169, 192 hydrocortisone, 177
glycogen, 168, 169, 192 hyperactivity, 89, 90, 91, 92, 93, 94, 95, 102, 103
glycogenesis, 168 hypertension, 37
glycolysis, 169 hypoglycemia, 159, 169, 176, 177
goal-directed behavior, 45, 185 hyponatremia, 176, 177
gray matter, 43, 75, 157, 181 hypotension, 176, 177, 179
growth, 26, 28, 39, 57, 68, 69, 76, 89, 96, 113, 158, hypothalamus, 115, 187
177, 192, 194, 225, 226 hypothyroidism, 176
growth factor, 39, 113, 158, 194 hypoxia, 161, 168, 169, 173, 192
growth hormone, 177
I
H
identity, 229, 230, 231, 233, 234, 235
habituation, 186 idiopathic, 39, 149
hallucinations, 206 image(s), 11, 40, 109, 220, 230, 231, 232, 234, 235
handedness, 117, 223, 226 imagination, 9, 204
Hausdorff dimension, 123 imbalances, 88, 90, 103, 112, 169, 172, 201, 206,
head injury, 51, 163, 164, 165, 178, 180, 181, 196, 207
198 immune activation, 162, 171, 173
head trauma, 22, 52, 187, 190, 196, 197 immune disorders, 104
headache, 187, 188 immune function, 105, 117, 189, 191
health, 90, 92, 163, 165, 190, 240, 243, 245 immune regulation, 157
health status, 190 immune response, 104, 105, 173, 180, 191
heart failure, 37 immune system, 102, 104, 115, 117, 118, 157, 160,
heart rate, 103, 172, 194 163, 173, 191, 197
hemisphere, 9, 44, 46, 69, 71, 74, 80, 88, 90, 101, immunity, 37, 104, 118, 156, 160, 173, 194
102, 103, 104, 105, 115, 116, 117, 226 immunodeficiency, 173, 194
hemispheric asymmetry, 65, 104 immunoreactivity, 194
hemisphericity, 7, 75 immunosuppression, 173
hemodynamic instability, 179 impaired-non-impaired, 2
hemorrhagic stroke, 198 impairments, 51, 71, 85, 185
heterogeneity, 79, 117, 122, 150 impulses, 70
hippocampus, 33, 35, 37, 38, 39, 43, 57, 58, 59, 60, impulsive, 26, 30, 32, 34, 95
81, 178, 195 in vitro, 151
histone deacetylase, 38 in vivo, 53, 75, 99
histones, 79 individual differences, 19, 98
homeostasis, 174 individuals, 2, 11, 18, 22, 39, 42, 43, 45, 46, 50, 53,
homogeneity, 190 55, 71, 74, 75, 76, 78, 84, 85, 86, 87, 88, 94, 102,
hormone(s), 55, 98, 156, 159, 169, 176, 177, 180, 103, 104, 172, 179, 180, 185, 187, 190, 197, 211,
190, 195 212, 215, 223, 225, 229, 230
HPA axis, 177, 178, 179, 186 induction, 160, 174, 194
human body, 213 infancy, 2, 73, 82, 86, 87, 92, 97, 98, 210, 241
human brain, 8, 9, 43, 48, 62, 67, 68, 69, 102, 117, infants, 2, 67, 72, 73, 82, 92
118, 130, 181, 196, 226, 236 infarction, 109
human cerebral cortex, 118 infection, 158, 162, 163, 173, 197
human condition, 40 inflammation, 156, 158, 159, 161, 162, 164, 165,
human development, 22, 96, 219, 240, 243, 245, 247 170, 176, 179, 186, 188, 191, 192, 193, 194
human experience, 212 inflammatory bowel disease, 104

Index 257
inflammatory cells, 171, 191

inflammatory disease, 195
K
inflammatory mediators, 157
ketones, 166
information processing, 150, 151, 152, 153
inheritance, 79, 95
inhibition, 52, 53, 56, 57, 58, 69, 76, 80, 89, 90, 91, L
93, 103, 105, 106, 110, 119, 173, 178, 209
inhibitor, 158, 180 lactate dehydrogenase, 169
initiation, 141, 169, 207 language acquisition, 14
injury(ies), 22, 23, 40, 45, 51, 53, 56, 68, 69, 87, 89, language development, 86, 97
103, 108, 113, 118, 121, 122, 123, 127, 130, 155, language processing, 10, 19
156, 159, 162, 163, 164, 165, 166, 169, 170, 171, language skills, 87
172, 173, 174, 175, 176, 177, 178, 179, 180, 181, languages, 2, 11, 213
185, 186, 187, 188, 189, 190, 191, 193, 194, 195, lateral sclerosis, 50
196, 197, 198, 207, 210 laterality, 69, 87, 91
insomnia, 187 learning, 1, 3, 8, 9, 12, 18, 24, 34, 35, 37, 38, 39, 43,
insulin, 159, 166, 167, 168, 170, 179 50, 55, 56, 59, 61, 62, 70, 84, 85, 86, 91, 92, 93,
insulin resistance, 159 97, 98, 102, 103, 119, 120, 133, 134, 135, 136,
integrated behavior, 2 137, 139, 140, 141, 142, 143, 144, 145, 146, 147,
integration, 2, 11, 13, 18, 23, 28, 40, 44, 51, 53, 67, 148, 149, 150, 151, 153, 164, 178, 187, 203, 211,
69, 77, 80, 85, 86, 90, 94, 107, 114, 115, 120, 224, 226, 229, 230, 233, 235, 247
122, 123, 170, 171, 172, 190, 201, 203, 206, 213, learning difficulties, 92
214, 218, 223, 234, 236 learning disabilities, 62, 93
intelligence, 10, 11, 19, 31, 57, 66, 67, 69, 73, 87, learning efficiency, 61, 98
89, 98, 118 learning process, 9, 135, 144
intercellular adhesion molecule, 171, 193 learning task, 35, 38, 134, 137, 142
interdependence, 46 left hemisphere, 9, 11, 65, 69, 70, 74, 89, 103, 105,
interface, 44, 91, 235 109, 213, 219, 220, 224
interference, 29, 32, 152 left-handers, 116
interferon, 165 legal issues, 196
internal consistency, 206 lesions, 15, 16, 39, 47, 59, 60, 68, 103, 104, 111,
internalization, 165 113, 116, 117, 122, 150, 151, 173, 181, 182, 194,
International Classification of Diseases, 187 196
interneurons, 106, 209 leukocytes, 159
intervention, 7, 22, 40, 45, 66, 90, 92, 122, 125, 126, leukotrienes, 164
198, 208, 209 level of education, 124
intestinal tract, 197 lifestyle changes, 65, 79, 90
intestine, 171 lipases, 164
intracellular calcium, 163, 164, 165 lipid peroxidation, 104
ion channels, 173 localization, 1, 3, 7, 10, 12, 16, 22, 42, 43, 44, 51,
ions, 110, 173 60, 108, 216
ipsilateral, 44, 61, 103, 105, 106, 107 localization of function, 1, 3, 7, 10, 12, 16, 22, 51
IQ scores, 11, 88 loci, 79
irritability, 188 locked-in state, 2
irritable bowel syndrome, 170, 192 long-term memory, 135
ischemia, 39, 59, 60, 165, 168, 171, 195 loss of consciousness, 187
isomers, 163 LTD, 112
lung disease, 104
lupus, 104
J lymphocytes, 173
lymphoid, 104
jejunum, 192
lymphoid organs, 104
joints, 114

258 Index
MHC, 160
M microcirculation, 159
midbrain, 44, 147, 187
macrophages, 157, 173
mind-body, 212
magnetic resonance imaging (MRI), 63, 75, 76, 87,
mission, 8, 243
93, 196, 197, 226, 232, 236
mitochondria, 159, 165, 192
magnetoencephalography, 78, 196
mitochondrial damage, 165
major depression, 53, 63, 193, 197
mitogen, 118
malaise, 187
MMP, 176
malignancy, 207
models, 2, 9, 16, 17, 25, 43, 47, 58, 85, 133, 134,
mammalian brain, 24, 119, 166
136, 141, 142, 143, 144, 146, 147, 148, 149, 153,
manganese, 182
182, 187, 197, 203, 205, 211
manic, 89
modifications, 56, 57, 79, 81, 96, 192
manipulation, 45, 114, 115, 120, 165, 207, 209
modules, 28, 29, 46, 143, 145, 146, 147, 148
mapping, 63, 79, 108, 116, 119, 120, 223, 231
molecular oxygen, 161
marijuana, 52
molecules, 112, 160, 168, 173, 174
matrix metalloproteinase, 175, 195
mood swings, 187
matter, 67, 75, 76, 93, 98, 105, 123, 174, 175, 176,
morbidity, 89
232
morphology, 35, 36, 37, 111, 116, 159, 161, 162,
maze tasks, 151
173, 226
measurement(s), 18, 23, 60, 85, 104, 107, 176, 183,
motivation, 8, 89, 206
198, 221, 232
motor actions, 136
mediation, 51, 61
motor activity, 60, 73, 79, 87, 90
medical, 2, 58, 118, 189, 190, 231, 240
motor behavior, 75
medical history, 189, 190
motor control, 73, 75, 86, 94, 97, 105, 118, 213, 223
medication, 40, 144, 149, 150, 151, 156
motor improvement, 1, 3
medicine, 92, 116, 239, 245
motor neuron disease, 91
medulla, 105
motor neurons, 50, 82
MEG, 13, 78, 94, 123, 124, 125, 128, 196
motor skills, 43, 74, 75, 221, 226
membrane permeability, 165
motor system, 72, 75, 82, 213, 222, 223
memory, 8, 23, 28, 34, 35, 38, 39, 50, 60, 70, 112,
motor task, 42, 50
117, 119, 120, 124, 125, 135, 150, 151, 153, 164,
movement disorders, 92
178, 185, 187, 189, 190, 195, 239
Mozart effect, 8
memory capacity, 153
mRNA, 37, 40
memory formation, 120
mucosa, 171, 193
memory function, 38, 39
multivariate analysis, 130
memory performance, 195
muscles, 50, 73, 80, 82, 84, 96, 106, 114, 119
memory processes, 125
musculoskeletal, 188
mental activity, 187
music, 8, 18, 61, 211, 212, 213, 214, 215, 216, 218,
mental development, 58
219, 221, 222, 223, 224, 225, 226
mental disorder, 66, 92, 205, 207
musicians, 43, 60, 61, 211, 213, 215, 218, 219, 220,
mental health, 156, 188
221, 222, 223, 224, 226
mental illness, 99
mutation(s), 60, 79, 80, 95
mental processes, 9, 58
myelin, 164, 180
mental representation, 62
mental retardation, 87, 95
mesencephalon, 105 N
meta-analysis, 130
metabolic, 91, 191 Na+, 168, 192
metabolic dysfunction, 103 NAD, 169
metabolism, 55, 94, 117, 163, 164, 168, 169, 178, National Institute of Mental Health, 66, 90
182, 192 natural killer cell, 173
methylation, 79 natural selection, 67
methylphenidate, 95, 151 necrosis, 162, 179

Index 259
negative experiences, 21 nigrostriatal, 40

negative mood, 178 nitric oxide synthase, 161, 162, 169
neglect, 26, 45, 46, 47, 61, 62, 91, 184, 213 NMDA receptors, 164, 169
neocortex, 44, 69, 80, 96, 117, 118, 194 nuclei, 86, 94, 115, 170, 171, 182, 189, 190, 194,
nerve, 78, 111, 113, 114, 118, 119, 120, 171, 174, 197
186, 193, 198 nucleus, 53, 54, 55, 112, 115, 117, 119, 120, 150,
nerve growth factor, 113 151, 164, 194
nervous system, 1, 2, 3, 8, 21, 22, 23, 33, 37, 56, 67, nucleus tractus solitarius, 115
68, 69, 87, 89, 111, 113, 173, 191, 212, 213, 215, nutrient(s), 103, 166, 167, 168
216, 224, 239 nystagmus, 85, 96, 97, 182, 184
neural development, 74, 119
neural network(s), 23, 24, 25, 28, 58, 91, 108, 133,
152, 201, 202, 203, 205, 209, 210, 229, 234 O
neural system(s), 75, 225
obsessive-compulsive disorder (OCD), 74, 89, 98,
neurobiology, 8, 98, 118, 153, 197, 239
188
neurodegeneration, 156, 158, 163, 165, 174, 178,
obstacles, 25, 45, 79, 166
191, 196
occipital cortex, 38, 51, 94, 95, 229, 233
neurodegenerative diseases, 160, 165
occipital lobe, 230
neurodegenerative disorders, 181
occlusion, 102
neurodevelopmental disorders, 65, 68, 69, 71, 73, 81,
occupational therapy, 125
95
oculomotor, 85, 182, 184, 185, 186, 198
neurofibrillary tangles, 181
oligodendrocytes, 38, 175, 195
neurofilaments, 164
operating system, 2
neurogenesis, 34, 35, 36, 37, 38, 39, 59, 60
operations, 33, 46
neuroimaging, 11, 52, 79, 122, 130, 180, 192, 196
optimism, 22
neuroinflammation, 156, 161, 162, 163, 171, 192
optimization, 2, 10, 14, 17, 18, 22, 23, 239, 241
neurological basis, 1, 3, 10
organ(s), 67, 68, 115, 203
neurological development, 2, 12
organelle, 163, 165
neurological disease, 53, 155
organism, 22, 23, 39, 51, 56, 80
neurological rehabilitation, 156
oscillation, 82
neurologically intact adult, 2
oscillators, 123
neuronal apoptosis, 161
oscillatory activity, 79, 81, 82, 84
neuronal circuits, 26, 53, 207, 208
osteoarthritis, 104
neuronal density, 39
osteoporosis, 104
neuronal systems, 113
oxidation, 192
neurons, 23, 24, 25, 26, 28, 35, 36, 37, 38, 39, 48,
oxidative damage, 165, 169
56, 58, 59, 68, 69, 70, 78, 80, 82, 84, 87, 90, 91,
oxidative stress, 37, 165
95, 96, 101, 102, 105, 108, 110, 111, 112, 113,
oxygen, 103, 159, 161, 192
114, 115, 118, 135, 143, 144, 145, 146, 148, 151,
152, 157, 158, 159, 160, 162, 164, 165, 166, 167,
168, 174, 175, 191, 192, 195, 201, 202, 203, 207, P
208, 209
neurophysiology, 3, 7, 8, 76, 191 pacemaker, 45
neuropsychology, 58, 61, 62, 117, 199 pain, 45, 106, 107, 172, 179, 186, 192, 193
neurorehabilitation therapies, 125 parasympathetic nervous system, 105
neuroscience, 3, 8, 22, 24, 57, 98, 152, 153, 180, parenchyma, 162
199, 209, 210, 226, 239 paresis, 107
neurotoxicity, 158, 191 parietal cortex, 45, 46, 50, 61, 77, 91
neurotransmission, 81, 82, 99 parietal lobe, 184
neurotransmitter(s), 89, 103, 104, 112, 159, 168, parkinsonism, 150, 153
192, 194, 203 pathogenesis, 170, 196
neurotrophic factors, 37, 40, 164 pathogens, 160, 162, 163
neutrophils, 173, 175

260 Index
pathology, 39, 51, 72, 75, 86, 88, 89, 90, 93, 156, predictability, 125, 181
164, 174, 182, 191, 197 prefrontal cortex, 15, 16, 43, 50, 55, 62, 79, 110,
pathophysiological, 61, 162, 168, 188 136, 146, 149, 150, 151, 152, 153, 186, 208, 209,
pathophysiology, 79, 186, 187, 189, 190, 193, 195, 229, 233, 234
197 pregnancy, 241
pathway(s), 7, 14, 35, 36, 37, 38, 44, 46, 47, 50, 52, preterm infants, 91
59, 62, 75, 80, 84, 86, 87, 103, 97, 104, 110, 114, prevention, 37, 187, 240
115, 143, 155, 164, 168, 169, 174, 197, 201, 202 primary function, 2
pattern recognition, 161 primary visual cortex, 50, 119
peptide(s), 170, 192 priming, 157, 162, 163, 164, 191
peripheral blood, 171 primitive reflex, 2, 59, 65, 66, 68, 69, 71, 72, 79, 80,
permeability, 110, 165, 169, 170, 171, 173, 176, 193, 87, 89, 90, 91, 92
194 principles, 7, 18, 22, 58, 121, 122, 133, 134, 136,
peroxynitrite, 161, 162 142, 215, 216
personality, 153, 187, 188 processing deficits, 85, 151
PET scan, 19, 42, 98 professionals, 243, 245
phagocyte, 161 progenitor cell(s), 36, 39
phagocytosis, 157, 158, 159, 162 prognosis, 165, 186, 187, 188, 189
pharmaceutical, 155 pro-inflammatory, 156, 157, 158, 160, 161, 162, 171,
pharmaceutics, 129 174
pharmacokinetics, 152 prolactin, 118
pharmacotherapy, 55, 207 proliferation, 24, 36, 38, 39, 57, 59, 60, 68, 117
pharynx, 114 prostaglandins, 164
phenomenology, 27 prostheses, 91
phenotype, 37, 162, 163 protection, 39, 40, 171, 174
phonemes, 85 protective role, 194
phonology, 225 protein kinase C, 59
phosphorylation, 155, 164, 169 protein synthesis, 68, 111, 112, 164
physical activity, 37, 59 proteinase, 111
physical exercise, 40 proteins, 112, 163, 164, 165, 171, 181, 193, 208
physical therapy, 184 proteolysis, 164, 195
physics, 13, 24, 130, 203, 215, 216, 239 pruning, 81
physiological constraints, 63 psychiatric disorder(s), 38, 62, 67, 73, 78, 84, 188
physiology, 34, 58, 79, 82, 116, 118, 189, 190 psychiatric illness, 117
pituitary gland, 176, 179 psychiatry, 119
plasticity, 2, 3, 7, 10, 19, 21, 22, 23, 24, 33, 34, 36, psychoactive drug, 124, 207
37, 38, 39, 41, 42, 43, 45, 53, 56, 57, 58, 59, 60, psychological processes, 8
63, 67, 81, 87, 90, 91, 95, 104, 108, 111, 112, psychological stress, 197
113, 114, 116, 117, 118, 119, 120, 121, 122, 128, psychology, 22, 118, 215
130, 156, 163, 164, 165, 178, 186, 195, 211, 212, psychopathology, 208
216, 219, 223, 224, 225, 227, 229, 235, 236 psychophysics, 10, 215
plexus, 171 psychosis, 152, 201, 204, 205, 207
polarization, 101, 102, 109, 111, 160, 163 psychotherapy, 55, 207
policy, 3, 8, 18, 245 public education, 3
polymorphisms, 159 public health, 240, 243, 245
polypeptide, 180 public service, 243
positive correlation, 142, 219 purines, 158
positive feedback, 139 PVS, 10, 40, 41, 43, 44, 46
positron emission tomography (PET), 19, 42, 51, 52,
55, 60, 98, 99, 103, 149, 216, 217, 227
postural control, 75, 85, 103, 117, 183, 198 Q
potassium, 110, 173
quality of life, 122, 178, 240
precursor cells, 174, 175

Index 261
retina, 107
R retrovirus, 37
reversal learning, 133, 134, 135, 136, 140, 141, 142,
reaction time, 42, 76, 82, 126, 185
143, 145, 150, 151
reactions, 71, 170, 171, 173, 192
reversal performance, 133, 134, 139
reactive oxygen, 161, 165
reversal training, 141
reactivity, 85, 86, 93, 96
rheumatic diseases, 191
receptive language, 2, 16, 17
rhythm, 213, 223
receptor(s), 39, 57, 68, 69, 80, 111, 112, 116, 117,
rhythmicity, 78
144, 149, 150, 156, 158, 161, 163, 164, 165, 166,
right hemisphere, 9, 45, 47, 69, 70, 74, 75, 88, 103,
167, 178, 180, 189, 191, 229
104, 105, 117, 213, 223, 233
recognition, 28, 51, 86, 97, 115, 118, 229, 230, 231,
risk, 14, 62, 79, 87, 118, 152, 162, 174, 176, 183,
233, 234, 235, 236
184, 190
reconstruction, 47, 232
risk factors, 87, 118, 162
recovery, 2, 3, 8, 39, 40, 43, 44, 45, 49, 51, 57, 58,
RNA, 34
60, 62, 63, 112, 113, 116, 119, 121, 122, 123,
ROI, 232
127, 129, 130, 156, 163, 174, 177, 180, 182, 185,
187, 195, 197, 198, 211
recovery process, 123 S
redistribution, 123
reference frame, 53 saccades, 185, 186, 198
reflex-based processes, 2 schemata, 206
reflexes, 2, 39, 59, 65, 66, 68, 69, 71, 72, 73, 79, 80, schizophrenia, 51, 62, 81, 84, 89, 141, 151, 153, 192,
87, 89, 90, 91, 92, 115 201, 205, 206, 207, 208, 209
regeneration, 2, 10, 91, 191, 194 schizophrenic patients, 138
regression line, 10 second language, 11, 17, 18, 19
regression model, 45 secrete, 158, 174
rehabilitation, 1, 2, 3, 5, 7, 8, 10, 19, 21, 22, 23, 39, secretion, 104, 173, 175, 178, 195
61, 91, 98, 113, 116, 119, 121, 122, 124, 126, segregation, 13, 18, 94, 123
127, 128, 129, 130, 178, 184, 186, 194, 198, 211, self-awareness, 66
213, 216, 219, 224, 225, 239, 240, 243, 247 self-consciousness, 66
rehabilitation practice, 1, 3 self-image, 53
rehabilitation program, 124, 198 self-organization, 81
reinforcement contingencies, 139 self-regulation, 66
reinforcement learning, 150, 152, 153 self-repair, 113
relative size, 102 semantics, 225
REM, 112 senescence, 91
resolution, 46, 107, 108, 158, 161, 162, 164, 186, sensation(s), 53, 206, 209, 213, 215, 216
232 senses, 215, 226
resources, 192 sensitivity, 96, 165, 177
respiration, 161 sensitization, 191, 194
respiratory disorders, 159 sensor, 123
response, 19, 22, 26, 28, 30, 32, 34, 38, 40, 47, 49, sensory experience, 80, 102
56, 71, 73, 76, 78, 82, 85, 87, 93, 95, 98, 101, sensory system(s), 51, 67, 80
102, 104, 105, 111, 112, 113, 133, 134, 135, 136, sepsis, 170, 179
137, 138, 141, 142, 143, 145, 146, 147, 149, 150, septic shock, 195
151, 152, 157, 160, 162, 163, 171, 172, 173, 174, sequencing, 7, 213, 214, 223, 224
177, 178, 179, 180, 181, 182, 191, 193, 194, 195, serine, 164
231 serotonin, 104, 117, 207
response time, 49 serum, 152, 176, 177
responsiveness, 45, 105, 118, 150, 178 serum albumin, 177
restoration, 44, 49, 53, 91, 129, 186, 198, 230 severe stress, 179
restructuring, 36, 56, 95 shape, 43, 144, 211, 218, 229, 230, 231, 233, 234,
reticular activating system, 108 235, 236

262 Index
short-term memory, 152 123, 124, 125, 129, 130, 157, 158, 159, 162, 163,
showing, 13, 14, 16, 30, 36, 38, 41, 47, 50, 71, 83, 164, 168, 173, 174, 176, 178, 187, 197, 203, 204,
123, 142, 144, 146, 147, 178, 203, 233 205, 206, 215, 232
side effects, 55, 180 statin, 159
SIDS, 163 steroids, 176
signaling pathway, 80 stimulation, 24, 35, 45, 46, 53, 54, 55, 57, 60, 61, 63,
signals, 12, 24, 25, 26, 27, 28, 33, 39, 52, 82, 84, 97, 65, 68, 69, 70, 78, 81, 89, 98, 102, 103, 107, 111,
104, 123, 124, 125, 128, 129, 141, 147, 151, 153, 112, 113, 114, 116, 117, 119, 120, 149, 151, 159,
158, 159, 161, 173, 174, 191, 192, 208, 209, 213, 162, 170, 171, 174, 177, 178, 179, 186, 193, 194,
226 198, 207, 212, 214, 221, 227, 230, 232
signal-to-noise ratio, 144, 151 stimulus, 22, 26, 30, 32, 34, 45, 56, 57, 61, 78, 102,
significance level, 232 105, 110, 111, 112, 113, 114, 133, 134, 135, 136,
signs, 45, 46, 68, 71, 73, 84, 87, 89, 91, 205, 206, 137, 139, 141, 142, 143, 144, 145, 147, 148, 149,
209 215, 231, 234
SII, 78 strabismus, 184
simulation(s), 58, 139, 144, 145, 146, 147 strategy use, 10
Singapore, 130 street drugs, 207
skeletal muscle, 37 strength training, 43
skill acquisition, 43, 119, 211, 221 stress, 37, 55, 56, 99, 165, 175, 176, 177, 178, 195,
SLE, 104 241
sleep disturbance, 179 stress response, 56, 177, 178
small intestine, 170 stressful events, 177
smoothing, 232 stressors, 55, 56
social environment, 206 stretching, 180
social interaction(s), 8, 35, 39, 74, 86 striatum, 50, 79, 117, 134, 135, 141, 144, 146, 149,
social network, 13 151
social skills, 126 stroke, 1, 2, 3, 37, 39, 48, 51, 52, 63, 103, 112, 113,
spatial frequency, 33 116, 117, 119, 124, 186, 194, 195, 198, 225, 241
spatial information, 47 stromal cells, 194
spatial learning, 36, 38, 59 structural changes, 43, 60, 211, 218, 226
spatial memory, 38, 39 structural defects, 75
spatial processing, 84, 86, 235 structure, 9, 26, 33, 48, 59, 67, 81, 98, 111, 123, 125,
species, 23, 25, 26, 27, 28, 66, 67, 69, 161, 165 126, 164, 165, 193, 202, 203, 204, 206, 213
spectral component, 108 subgroups, 97, 221
speech, 42, 85, 116, 125, 150, 205, 206, 213, 226 substitution, 116, 229, 230, 234, 235
speech perception, 86 substrate(s), 104, 112, 113, 153, 168, 184
speech processing, 42 suppression, 37, 78, 234
spinal cord, 2, 37, 70, 105, 114, 119 surface area, 42
spinal cord injury, 37 survival, 35, 36, 38, 68, 80, 164, 175
spindle, 80, 111, 165, 166 survivors, 103, 112, 192
spine, 59, 114, 120 susceptibility, 58, 79, 171, 173, 197
spleen, 104 symmetry, 108, 213, 218
spontaneity, 187 sympathetic nervous system, 105
spontaneous recovery, 2, 10 sympathetic system, 105
sports performers, 2 symptoms, 39, 53, 66, 69, 71, 74, 77, 84, 86, 90, 97,
sprouting, 57, 113 104, 108, 112, 134, 156, 165, 179, 186, 187, 188,
stability, 23, 58, 164, 183, 186 189, 196, 197, 201, 207
stabilization, 81, 149, 183, 184 synapse, 38, 43, 80, 118, 181
standard deviation, 83, 148 synaptic plasticity, 39, 79, 81, 96, 111, 119, 141,
standard error, 232 164, 178
state(s), 2, 3, 10, 11, 21, 22, 25, 28, 35, 40, 46, 50, synaptic strength, 57, 112
60, 61, 62, 71, 78, 81, 82, 87, 88, 94, 96, 101, synaptic transmission, 82, 164
102, 103, 104, 108, 109, 110, 111, 114, 115, 121, synaptic vesicles, 165

Index 263
synaptogenesis, 39, 43, 57, 61, 65, 79, 80, 89, 90 trauma, 1, 3, 22, 41, 51, 56, 112, 156, 158, 162, 171,
synchronization, 18, 48, 69, 70, 72, 78, 81, 82, 84, 175, 176, 179, 180, 181, 182, 184, 187, 188, 193,
87, 90, 94, 98, 108, 123, 124, 129, 198 196, 224
syndrome, 3, 21, 44, 48, 53, 61, 62, 63, 74, 77, 84, traumatic brain injury (TBI), 45, 61, 108, 121, 122,
85, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 99, 101, 124, 126, 127, 128, 129, 130, 155, 156, 163, 167,
102, 103, 116, 156, 163, 171, 180, 181, 185, 186, 170, 171, 173, 177, 178, 179, 180, 191, 192, 193,
187, 191, 196, 198, 199, 205, 210 194, 195, 196, 197, 198, 199, 239, 241
systemic immune response, 173 tremor, 134
triggers, 110, 164
tumor necrosis factor (TNF), 158, 174, 182
T tympanum, 165
T cell(s), 104, 118, 157, 158, 160, 161

tachycardia, 107, 117 U
target, 53, 62, 66, 90, 94, 101, 138, 143, 184, 185,
193, 198, 208, 209 underlying mechanisms, 205
task demands, 51, 149 unwanted thoughts, 115
task difficulty, 151
task performance, 11, 18
techniques, 8, 10, 11, 76, 88, 123, 180, 205, 231 V
technology(s), 23, 24, 116, 207, 208, 226, 239, 241
vagus, 115, 194
temperament, 210
vagus nerve, 194
temperature, 107, 172
vasoactive intestinal peptide, 192
temporal lobe, 16, 46, 52, 150, 187
ventricular fibrillation, 104
temporal lobe epilepsy, 52
verbal fluency, 19, 51, 62, 98
testing, 10, 68, 72, 176, 177, 182, 183, 185, 186, 231
vestibular system, 184, 186, 187, 190
thalamus, 44, 45, 49, 53, 103, 114, 181, 224
vision, 22, 27, 44, 52, 96, 97, 102, 198, 215, 230,
therapeutic interventions, 45
231, 235
therapeutic targets, 194
visual acuity, 184
therapy, 53, 55, 116, 125, 152, 161, 174, 184, 186,
visual area, 42, 44, 236
191, 194, 195, 198, 207, 223
visual field, 46, 184
thymus, 104, 173
visual modality, 85
thyroid stimulating hormone (TSH), 169, 176
visual processing, 3, 206
time series, 50, 125, 129, 183
visual stimuli, 44
tissue, 25, 26, 28, 30, 33, 40, 41, 44, 58, 102, 113,
visual stimulus, 49
118, 156, 157, 158, 160, 161, 162, 166, 168, 173,
visualization, 9, 52
180, 181, 189
TNF-alpha, 158, 193
trajectory, 56, 76, 117, 203, 204, 205 W
transcription, 38, 80, 119, 179, 195
transcription factors, 80, 179 Wernicke‘s areas, 2, 6
transformation(s), 26, 213, 230, 232 white blood cells, 173
translation, 2, 10, 195 word blindness, 49
translocation, 170, 193 working memory, 19, 51, 62, 98, 133, 134, 136, 138,
transmission, 24, 80, 103, 112, 113, 114, 116, 164, 144, 145, 149, 150, 151, 153, 185
208, 216
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Neuroplasticity in learning and rehabilitation

Book · January 2016

Developmental Aspects of Cognitive-Motor Interaction View project

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Neuroimmunity and the Brain-Gut Connection

Considering Consciousness Clinically

Neuroplasticity in Learning and Rehabilitation

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Published by Nova Science Publishers, Inc. † New York

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Chapter 9 Connectivity cognition and psychosis in the physical brain 201

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Gerry Leisman1-3,, MD, PhD

A neuroanatomical conceptualization is a non-starter for rehabilitation practice. It is

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Gerry Leisman1-3,, MD, PhD

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BRAIN ANATOMY IS IRRELEVANT TO EDUCATIONAL PRACTICE

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are characterized by an increased clustering coefficient or an average node-to-node distance

Functional brain networks in children and young-adults show small-world properties. In

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showing elevated subcortical connectivity and decreased paralimbic connectivity in children,

Figure 4. (a) Characterization, Organization & Development of Large-Scale Brain Networks in

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PLASTICITY AND FUNCTIONAL

Gerry Leisman1-3,, MD, PhD

While the clinical and neuropathological evaluation of neurological compromise has

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HOW MIGHT NEURAL FIRINGS LEAD TO INTEGRATION?

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Figure 2. Electrophysiological consequences of consciousness as a function of increasing levels of

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is represented by a mean connection range, where the probability of connection between

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We suggest below a mental phenomenology in which various aspects of ―consciousness‖

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ISBN: (eBook)