Table Of ContentREVIEW OF
SERIES EDITORS
RONALD J. BRADLEY
Department of Pybiatry, School of Medicine
Louisiana State University Medical Center
Shreveport, Louisiana, USA
R. ADRON HARRIS
Department of Pbarmacolagy, University of Colorado
Health SciencesC enter Denvec Colorado, USA
PETER JENNER
Biomedical SciencesD ivision, King2 College, London, UK
EDITORIAL BOARD
PHILIPPEA SCHER KINYAK URIYAMA
ROSSJ . BALDESSARINI BRUCE S. MCEWEN
TAMAS BARTFAI HERBERTY . MELTZER
COLIN BLAKEMORE NOBORU MIZUNO
FLOYD E. BLOOM SALAVADORM ONCADA
DAVID A. BROWN TREVORW . ROBBINS
MATTHEWJ . DURING SOLOMON H. SNYDER
KJELL FUXE STEPHENG . WAXMAN
PAUL GREENGARD CHIEN-PINGW U
SUSAN D. IVERSEN RICHARD J. WYATT
AND
EDITEDB Y
JEROMEE NGELJ, R.
Departments of Neurology and Neurobiology and the Brain Research
Institute, UCLA School of Medicine, Los Angeles, California
PHILIPA . SCHWARTZKROIN
Department of Neurological Surgery
University of Washington, Seattle, Washington
SOLOMONL . MOSHi
Department of Neurology, Neuroscience and Pediatrics
Albert Einstein College of Medicine, Bronx, New York
DANIELH . LOWENSTEIN
Dean of Medical Education
Harvard Medical School, Boston, Massachusetts
ACADEMIC
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Frank Morrell
PREFACE
Frank Morrell was among the most creative and influential academic
neurologists of his generation. He devoted his career to studies of plas-
ticity of the nervous system, with a particular emphasis on epilepsy. As
a clinical neurologist and basic scientist, he pioneered investigations into
fundamental mechanisms of acquired normal behavior and epilepsy-
induced neuronal reorganization responsible for enduring epileptic and
nonepileptic cerebral dysfunction. He was best known for calling atten-
tion to the phenomenon of secondary epileptogenesis (and the associ-
ated hypothesis that some forms of epilepsy are progressive) and for de-
veloping the surgical procedure of multiple subpial transection. Morrell
was an early Honorary Associate of the MIT-based Neuroscience
Research Program, a founding member of the Society for Neuroscience,
a member of the Brain Sciences Committee of the National Academy of
Sciences, and president of the American EEG Society, the Eastern
Association of Electroencephalographers, and the Western Institute of
Epilepsy. As an innovative scientist, a compassionate physician, a provoca-
tive thinker, and an unusually personable human being, Morrell in-
spired countless clinicians and basic researchers. When he died tragically
of a fluminant form of Creutzfeldt-Jakob disease in October 1996, his
friends and colleagues decided to hold a memorial symposium on brain
plasticity and epilepsy and to publish a tribute volume. Clearly, a book
of the highest scientific merit would be the best form of lasting recogni-
tion. The Morrell Symposium on Brain Plasticity and Epilepsy was held
March 26-28, 1999, at the Marine Biological Laboratory, Woods Hole,
Massachusetts, and this book is based on its proceedings.
The chapters in this book are devoted to topics relevant to Frank
Morrell’s contributions to the fields of brain plasticity and epilepsy.
Morrell’s work had unusually broad scope, ranging from fundamental
mechanisms of acquired behavior, through the neuronal substrates of
epileptogenesis and its influence on brain function, to surgical treatment
of epilepsy and its consequences. Therefore, it has been possible to or-
ganize the contents of this book to create a coherent state-of-the-art re-
view of brain plasticity and epilepsy. The chapters cover these topics in
relation to maturation of the nervous system, secondary epileptogenesis,
normal and nonepileptic abnormal behavior, and functional neuro-
xx PREFACE
surgery, specifically multiple subpial transection. Frank Morrell had a
passionate interest in all of these topics and contributed significantly to
our current level of understanding, as represented by this volume. In
recognition of these scientific achievements, and in appreciation of his
role as a teacher, colleague, and friend, we dedicate this book to Frank
Morrell.
Jerome Engel, Jr.
Philip Schwartzkroin
Solomon MoshC
Daniel Lowenstein
ACKNOWLEDGMENTS
We are indebted to Robert Naquet, B. J. Wilder, and Leyla deToledo-
Morrell for helping the editors of this volume to organize the Morrell
Symposium on Brain Plasticity and Epilepsy. We are also grateful to
Parke-Davis, a Division of Warner-Lambert; Hoechst Marion Roussel;
Ortho-McNeil Pharmaceutical; Novartis Pharmaceutical; Elan Pharma;
Cyberonics; Glaxo Wellcome; Wyeth-Ayerst; UCB Pharma; the National
Institute of Neurological Disorders and Stroke; and the Marine Biological
Laboratory, Woods Hole, Massachusetts, for their generous support of
the symposium and this book.
xxi
MECHANISMS OF BRAIN PLASTICITY:F ROM NORMAL BRAIN
FUNCTION TO PATHOLOGY
Philip A. Schwartzkroin
Department of Neurological Surgery, University of Washington, Seattle, Washington
I. Introduction
II. Relationships between Neuropathology and Plasticity
III. Summary
References
1. Introduction
In modern neuroscience, there is a growing recognition of an inti-
mate, but also very complex, relationship between those neural processes
that underlie normal brain function and those mechanisms that give rise
to neuropathologies. In particular, mechanisms that we now call “plas-
tic” appear to play a major role in many neurological disorders in which
neuronal “reorganization” is a major factor. Nowhere is this relationship
more obvious and important than in the development of a chronic
seizure state, that is, in epileptogenesis. This connection is one on which
Frank Morrell focused throughout his pioneering career in basic and
clinical neuroscience (Morrell, 1959-1960, 1989; Morrell et al., 1993).
The goal of this chapter is to highlight a number of neuroplastic processes
that we believe to be critical to normal brain function, and explore their
potential involvement in epileptic processes. In the course of this dis-
cussion, I make the case that there is a strong connection between neu-
ropathologies such as epilepsy and normal brain plasticity, such that the
distinction between underlying mechanisms is almost impossible to dis-
cern.
To start, it is important to have at least a general working definition
of neuroplasticity. In my discussion, I mean by plasticity the ability of the
central nervous system (CNS) to alter its function, usually in response to
a stimulus (internal or external) that requires a modification of the or-
ganism’s behavior.
On the one hand, there may well be neuropathological conditions in
which such plasticity may not play a significant role. For example, in
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2 PHILIP A. SCHWARTZKROIN
neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s
disease, it does not appear that “plasticity” either leads to or results from
the loss of CNS neurons that characterizes these conditions. That is not
to say that plastic processes are not involved or recruited, only that plas-
ticity is not a primary basis (or contributor) to these neuropathologies.
On the other hand, epileptogenesis may be a direct product of plastic
processes such as synaptic potentiation and/or sprouting (see below).
And seizures may lead to significant neuronal loss and glial reactivity,
providing an essential stimulus for changes in neuronal structure and
function, for example, in the reorganization that appears to be “de-
signed” to compensate for the injury.
Plasticity and concomitant changes in brain excitability are not new
concepts in neuroscience. We have long been aware of such phenomena
as:
a. Denervation receptor sensitization (Kuffler, 1943): Denervation su-
persensitivity was described quite early as dramatic changes in the acetyl-
choline (ACh) receptors at the neuromuscular junction of denervated
muscle. Hypersensitivity of the muscle to applied ACh is now known to
be a function of changes in receptor localization, density, and molecular
subunit composition of the receptors (Gu and Hall, 1988). Interestingly,
there was considerable controversy about whether these receptor changes
were due to loss of activity in the muscle itself, absence of released ACh,
or loss of some trophic factor released by the nerve terminal (along with
neurotransmitter) onto the postsynpatic target (L@mo and Rosenthal,
1972). Such questions remain very much a part of the research program
focused on mechanisms of epileptogenesis (Swann, 1995).
b. Changes in neuronal electrical properties following CNS damage (Kuno
and Llinas, 1970). Every electrophysiologist knows that injured neurons
discharge differently from healthy cells. Although it remains unclear
what aspects of injury result in which electrophysiological changes, a
large variety of alterations have been reported, including development of
dendritic spike’initiation zones (Purpura et al., 1966), axonal “backfiring”
(Lisney and Devor, 1987; Gutnick and Prince, 1972), and changes in in-
put resistance (Gao et al., 1999). Since it is now clear that seizures can
(and do) sometimes lead to cell injury, it is relevant to assess whether in-
jury-related changes can alter general excitability. This issue becomes
even more complex when one takes into account the likelihood that
injury-induced changes in glia (astrocytes and/or microglia) may be trans-
mitted to neuronal elements quite directly (Duff, and MacVicar, 1999).
c. Sprouting and development of new circuits (Cotman and Nadler, 1978).
The sprouting phenomenon has been studied within the context of a
NEUROPLASTICITY AND EPILEPTOGENESIS 3
number of neuropathological and learning conditions (Tsukahara, 1985).
Notably, an early focus of this research was on spinal cord injury, where
sprouting was proposed as a basis of spasticity (McCouch et al., 1958;
Goldberger and Murray, 1988). The development of new and/or aber-
rant axonal collaterals and functional synapses has long been associated
with development of hyperexcitable responsiveness, although few stud-
ies have adequately considered the possibility that these new connections
might underlie enhanced inhibition meant to dampen the effects of the
neuropathological condition. Sprouting-like phenomena have also been
considered within the context of normal learning, especially in studies
associated with animal exposure to enriched environments and/or high
levels of activity (Rosenzweig and Bennett, 1996).
More recent studies of plasticity have focused on alterations at the ge-
netic and molecular levels (Wheal et al., 1998). In particular, alterations
in glutamate and y-aminobutyric acid A (GABA-A) receptor subunit
composition have been examined in a variety of behavioral and electro-
physiological protocols. Most prominent among this group of studies are
those focused on changes in synaptic efficacy as a function of activity at
that synapse, that is, long-term potentiation (LTP) (Thomas et al., 1996).
Within the context of epileptic pathologies, it has been somewhat con-
troversial as to whether such “plastic” processes are initiated by some in-
jury/cell death insult or whether they are activity-dependent processes
that can occur in the absence of any overt cell damage. Modern neuro-
biology tells us that cell death (and even neurogenesis) is an integral as-
pect of brain development, maintenance, and function. If that is the case,
then the normal CNS must also be constantly involved in circuitry reor-
ganization and establishment of new synaptic contacts. However, for most
researchers interested in CNS plasticity, it is the activity-dependent set of
processes that have captured the lion’s share of attention. It is here that
the plasticity associated with establishment of “normal” brain circuits,
with “normal” learning processes, is thought to occur. Plasticity surely
can occur in the absence of pathology. The question is whether such nor-
mal plastic mechanisms can, in some cases, give rise to pathologies.
Clearly, Frank Morrell (and many others) believed that he had found a
dramatic example of such injury-independent plasticity in the phenome-
non of “kindling” and/or in the development of secondary epileptic foci.
How is it that plasticity and pathology should be so closely inter-
twined, that pathology can initiate plasticity, and vice versa? I suggest
that this interrelationship is an inevitable consequence of the fact that
they share so many underlying mechanisms. Normal brain plasticity and
neuropathology simply represent different points on the continuum of
4 PHILIP A. SCHWARTZKROIN
cellular mechanisms that have evolved-and have come to a peak of
complexity-in the mammalian CNS. As a corollary to this proposal, I
would also maintain that “normal plasticity” in the mammalian CNS re-
sults from a delicate balancing act, requiring rather precise interplay be-
tween “excitatory” and “inhibitory” mechanisms. Pathologies, for exam-
ple, seizures, occur when these balances fail.
Why design such an apparently unstable system? What is the ratio-
nale for placing the organism at such risk? The answers to these ques-
tions revolve around the means by which a system (the central nervous
system) can be “designed” to optimize plasticity, indeed, in which “plas-
ticity” is its primary mission. The Grand Designer, in his or her great
wisdom, developed a system that could respond readily to different en-
vironmental conditions, that could learn complex tasks in response to
difficult challenges, that could generalize behaviors to new environ-
ments-much as is the case for the immune system (with which the CNS
appears to have much in common). This optimization of plastic neuronal
processes and of circuit reorganizational capabilities, however, comes at
a price, for processes that are designed to support change are intrinsi-
cally unstable. Thus, as the potential for plasticity increases, so also does
the danger of system failure, or at least system “dysregulation.” My view
is that our CNS reflects a “compromise” design, in which some subcom-
ponents of the system are quite stable but relatively “nonplastic” (e.g.,
those systems responsible for basic vegetative functions), while other
components exhibit easily-triggered plastic capabilities. The parts of the
system to which we have been drawn in trying to understand “higher
brain function”-those brain regions that seem so much involved in nor-
mal plasticity-are precisely those that are at greatest risk.
Such a viewpoint is, of course, inherently philosophical (i.e., I cannot
prove any of these proposals) and suffers from a strong teleological mo-
tivation. But there are a number of interesting relationships between
neuropathology (i.e., epilepsy) and plasticity that are, at the very least,
consistent with this thesis.
II. Relationships between Neuropathology and Plasticity
1. Regions specialized for learning/memory (i.e., plasticity) are most prone to
seizures. In thinking about brain regions that are particularly seizure-
prone, we tend to focus on neocortical regions and particularly hip-
pocampus, precisely those parts of the brain that we have also implicated
in complex cognitive functions, e.g., learning and memory. We gener-
