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Neuroanatomy Research at the Leading Edge
TIMOTHY B. WESTLAND
AND
ROBERT N. CALTON
EDITORS
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This publication is designed to provide accurate and authoritative information with regard to the
subject matter covered herein. It is sold with the clear understanding that the Publisher is not
engaged in rendering legal or any other professional services. If legal or any other expert
assistance is required, the services of a competent person should be sought. FROM A
DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE
AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS.
Handbook on white matter : structure, function, and changes / [edited by] Timothy B. Westland and Robert N. Calton.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-61668-975-9 (E-Book)
1. Brain--Histology--Handbooks, manuals, etc. I. Westland, Timothy B. II. Calton, Robert N.
[DNLM: 1. Central Nervous System--physiopathology. 2. Central Nervous System--anatomy & histology. 3. Central
Nervous System--physiology. 4. Nervous System Diseases--physiopathology. WL 300 H2366 2009]
QP376.H275 2009
612.8'2--dc22
2009000172
Preface ix
Research and Review Studies 1
Chapter I Interhemispheric Connectivity: The Evolution
and Nature of the Corpus Callosum 3
Sarah B. Johnson and Manuel F. Casanova
Chapter II White Matter Lesions: From Present to Future 17
R.P.W. Rouhl, R.J. van Oostenbrugge and J. Lodder
Chapter III White Matter Lesions and Aging in HIV Infection: Implications
for Development of Cognitive Decline and Dementia 29
Aaron M. McMurtray, Beau Nakamoto
Kalpana Kallianpur and Erin P. Saito
Chapter IV White Matter Changes in Drug Abuse and in HIV-1 Infection 43
Andreas Büttner, Jeremias Wohlschaeger
Ida C. Llenos and Serge Weis
Chapter V White Matter Changes in Critical Illness and Delirium 71
Max L. Gunther, Carlos Faraco and Alessandro Morandi
Chapter VI White Matter Involvement in Neuromuscular Disorders 89
Petr Vondracek, Marketa Hermanova, Kristina Vodickova,
Lenka Fajkusova, Eva Brichtová and Jarmila Skotakova
Chapter VII White Matter Hyperintensities in Psychiatric Disorders and Their
Association with Suicide Risk 111
Maurizio Pompili, Gianluca Serafini, Silvia Rigucci,
Andrea Romano, Marco Innamorati, Antonio Del Casale,
Daniela Di Cosimo, Roberto Tatarelli and David Lester
Chapter VIII A Quantitative Study of the Pathological Changes in the Cortical
White Matter in Variant Creutzfeldt-Jakob Disease (vCJD) 133
Richard A. Armstrong
vi Contents
White matter is one of the three main solid components of the central nervous system.
White matter tissue of the freshly cut brain appears white to the naked eye because of being
composed largely of lipid. The other two components of the brain are gray matter and
substantia nigra. This new handbook presents the latest research in the field.
Chapter I –The classical neurological notion of a dominant hemisphere responsible for
language abilities and objective processing coupled with a non-dominant hemisphere
prevailing for nonverbal, spatial, and intuitive tasks has been upheld by several studies,
though this dichotomy is not seen with the brains of nonhuman mammals. Still, no matter
how simple the task, no operation involves exclusively one hemisphere without the other; we
are constantly switching between dominant and non-dominant functions, mandating an ample
channel of communication between the two hemispheres. Along with the evolutionarily older
anterior commissure, the corpus callosum has evolved to be one of the two major inter-
hemispheric connectors in mammals.
Chapter II - White matter lesions are caused by cerebral small vessel disease, particularly
by arteriolosclerosis. Arteriolosclerosis consists of a hyaline wall thickening with consequent
narrowing of the arteriolar vessel lumen and tissue ischemia. Arteriolosclerosis relates to
hypertension, and to other cerebral ischemic lesions (lacunar infarcts, symptomatic as well as
asymptomatic). The instigating factors in the pathogenesis of arteriolosclerosis and therefore
of white matter lesions, however, remain elusive. Most accepted of current theories is
disruption of the blood brain barrier caused by endothelial dysfunction. New imaging
modalities, like molecular imaging, and new insights in endothelial biology could therefore
provide further insight into the pathogenesis of arteriolosclerosis. In the present chapter the
authors will discuss these emerging issues, their potential pitfalls, and their possibility to
eventually increase therapeutic options for the vascular pathology which underlies white
matter lesions.
Chapter III - The widespread availability of highly active anti-retroviral therapy has lead
to long-term survival for many individuals living with HIV infection. With advancing age,
many older individuals living with HIV infection are beginning to develop aging-related
changes in the brain structure, including white matter lesions. Given the known effect of
white matter lesions in the general population, these lesions are also likely to have important
effects in aging HIV-seropositive individuals as well. Aging related white matter lesions are
x Timothy B. Westland and Robert N. Calton
central nervous system. In the current chapter the authors review the evidence regarding links
between white matter changes related to critical illness. In particular, they focus on both
acute and distal alterations in white matter that may be caused by a number of factors
including severe infection, glial cell atrophy, declines in axonal fractional anisotropy (FA)
and global hypoperfusion. Evidence from several areas of the neurosciences (animal models,
neuroimaging, case studies, etc.) suggests that delirium may be a hallmark of more permanent
changes that are occurring in the CNS. Taken together, the current evidence suggests that
critical illness may be linked to disruption of white matter tracts in the brain eventually
leading to long-term deficits in cognitive functioning. The chapter concludes by highlighting
several methodological challenges in investigating these hypotheses along with future
directions within the field of delirium and critical illness neuroscience research.
Chapter VI - The frequency of inherited neuromuscular disorders in the human
population is estimated to be approximately 1:3,500 worldwide. In some of these disorders
there is an association of the neuromuscular and central nervous system (CNS) involvement.
The explanation could be in a faulty process of expression of genetic information into the
structure of vital proteins, which play a key role in both muscle and brain functions. In these
multiorgan disorders a muscular dystrophy or peripheral neuropathy can be combined with
the white matter lesion, or other structural abnormalities of the brain, eye, and other organs,
and this combination can result in a spectrum of unusual clinical phenotypes.
The central nervous system involvement can be found especially in congenital muscular
dystrophies (CMD, MDC), myotonic dystrophy types 1 and 2 (DM1, DM2), mitochondrial
encephalomyopathies, and some variants of Charcot-Marie-Tooth disease (CMT).
The authors’ research is focused on these important hereditary neuromuscular disorders
with the white matter involvement in pediatric patients, especially children afflicted with
various forms of congenital muscular dystrophies. They present most interesting and unusual
case reports of our patients to demonstrate difficulties and pitfalls in the diagnostics of these
rare disorders. The white matter lesion is a very important and valuable diagnostic sign, and
also could have a serious impact on the management and prognosis of patients with
neuromuscular disorders.
Chapter VII - Suicide is a major worldwide public health problem. Nearly one million
lives are lost from suicide each year and between 3%-5% of adults make at least one suicide
attempt at some point in their life. Despite intensive efforts, research has failed to find
necessary and sufficient factors that indicate an increased likelihood for suicide, and effective
prevention strategies have remained elusive, suggesting that our understanding of the
interplay of factors that increase the risk of suicide remains incomplete. Furthermore,
although a great deal of research has been published on socio-psychological factors affecting
suicidal behaviour, the results lack sufficient specificity.
In recent years, studies have indicated that up to 43% of the variability in suicidal
behaviour can be explained by genetics. Thus, combining independent clinical and biological
predictors may provide improved predictive models.
A great deal of research analyzing the neurobiological basis of suicide has been
published in the last few decades. For examples, many studies have identified abnormalities
of the serotonergic system in suicidal individuals, particularly in the ventral prefrontal cortex,
as well as several other possible abnormalities, such as reduction in messenger RNA and
xii Timothy B. Westland and Robert N. Calton
of the significant causes contributing to their failure to remyelinate axons in MS. Our data
add to the accumulating scientific knowledge suggesting that early treatment and attempts to
avoid relapses are needed for patients suffering from MS.
Chapter XI - The use of minimal invasive methods and edoscopic procedures for
diagnosis and treatment of certain pathologic entities involving the spina canal expands
permanently. The sacral spinal canal as a place of such interventions is for a long time
known. Thecaloscopy is the endoscopy of lumbar subarachnoid space performed through
different approaches by using flexible endoscopes.
The subject of this study was the measurement of certain anatomic diameters in the sacral
spinal canal by using the lubosacral MRI studies of 25 patients.
Chapter XII – White matter fills nearly half of the brain, but receives disproportionately
less scientific attention when compared to grey matter. For the past century, neuroscientists
have demonstrated little interest in white matter, thought to be simply insulation for the more
important axonal pathways contained within. The importance of white matter in learning
tasks, mastering and executing mental and physical activities, as well as perfecting mental
and social skills has become clearer over the recent decades. Much of this realization has
developed from the study of diseases predominantly affecting white matter, and therefore
disrupting intraneural communication, such as with multiple sclerosis and the
leukodystrophies.
Two diseases that have reached epidemic status—diabetes and hypertension—also
contribute to white matter disease. The mechanisms by which these two common disorders
affect white matter remain under study and may share commonalities but also disparities.
Interestingly, the human condition of white matter abnormalities in patients with diabetes
and/or hypertension can be modeled in rodents, with the hope that this will lead to future
understanding and management.
Chapter XIII - Brain tissue segmentation has important applications in studying the
structure and function of the brain. A number of methods based on structural MRI data have
been proposed for the segmentation problem. In this chapter, the authors present a robust
method for automated brain tissue segmentation based on the multiple-channel fusion in DTI
(diffusion tensor imaging) space. Our method can be employed to define accurate tissue maps
when dealing with fused structural and diffusion MRI data. This enables us to study the gray
matter diffusivity in neurodegenerative and neurological diseases. When fusing structural and
diffusion information, the imperfect alignment of structural MRI data, e.g., SPGR (Spoiled
Gradient Echo) image, with DTI data results in the problem of heterogeneous voxels when
the anatomic information in the structural data is applied to the DTI data. Under the problem
of heterogeneous voxels, the measurements of the GM (Gray Matter) diffusivity based on the
anatomic information in the SPGR image may fail to reveal the real diffusion in the GM.
Specifically, following non-rigid co-registration using the UCLA AIR tools, the GM
boundaries of SPGR image are crossing CSF of ADC image. Consequently, the GM voxels in
the SPGR image correspond to CSF (Cerebrospinal Fluid) voxels in the ADC (Apparent
Diffusion Coefficient) image. Such a problem can occur for a variety of reasons, including
geometric distortion in DTI imaging, partial volume effect, reslicing and interpolation of DTI
data, and errors in co-registration.
Preface xv
which may serve as the flexible optimal neural substrate essential for the generation and
coordination of the bilateral locomotor rhythm in self-induced, goal-directed locomotion.
Short Communication - Among several techniques, single-shot echo-planar imaging has
been a standard technique for diffusion-tensor MR imaging (DTI) of white matter because of
its rapid acquisition time and high signal to noise ratio. However, inherent artifacts and
distortions due to susceptibility often prevent the demonstration of normal structures and
pathological changes in some situations.
Recently some studies have reported that line scan and single-shot fast spin-echo (ssfse)
techniques (non echo-planar imaging techniques) have been used for DTI and their
advantages. The line scan, simple spin-echo based one, can have benefits for brain stem and
spinal cord imaging because of insensitivity of magnetic field inhomogeneity. Ssfse
technique also avoids the artifacts and is useful for the region with geometric distortion (i.e.,
temporal lobe, metals after neurosurgical operation). However, these non echo-planar
techniques have some disadvantages and therefore, are not commonly used in many
institutions.
In this chapter, the authors review and illustrate the merits and limitations of non echo-
planar imaging techniques for the DTI. Moreover, the authors discuss the current role and
feasibility of the DTI for white matter studies in brain and spinal cord, i.e. quantitative
analysis of apparent diffusion coefficient in patients with cervical myelopathy, including
results from our experiments and clinical data.
Commentary - The use of minimal invasive methods and endoscopic procedures for
diagnosis and treatment of certain pathologic entities involving the spinal canal expands
permanently. The sacral spinal canal as a place of such interventions is for a long time
known. Thecaloscopy is the endoscopy of lumbar subarachnoid space performed through
different approaches by using flexible endoscopes.
The subject of this study was the measurement of certain anatomic diameters in the sacral
spinal canal by using the lumbosacral MRI studies of 25 patients with unclear pain
symptoms, in order to estimate, from the pure anatomic point of view, the capability to
perform thecaloscopy in this anatomical region.
Since now anatomic morphometric data of the sacral region were delivered only from the
cadaver specimens’ sectioning performed in anatomic institutes during the 60’s and 70’s
years.
The parameters measured were: 1. the inclination of the lumbosacral angle, 2. the
duralsack’s end, 3. the length of all the sacral spinal processes, 4. The length of the sacral
spinal canal in its centre, and 5. The width of the sacral hiatus.
The results of the measurements were in detail presented and an evaluation of them
concerning the applicability of flexible endoscopes in the sacral spinal canal was performed.
It was proven that the duralsack’s end in 40% of the patients at the middle of the S2
vertebral body lies, an anatomical position, which through the sacral hiatus easy to access is.
The length under the sacral spinal processes is smaller than the length of the sacral spinal
canal in its centre, a fact that makes the manipulation of a flexible endoscope easier, if
someone works straight under the spinal processes and has a smaller distance to run. Through
the sacral hiatus the introduction of the flexible endoscope is by many patients possible
because of its adequate width.
Research and Review Studies
In: Handbook on White Matter ISBN: 978-1-60741-034-8
Editors: T. B. Westland and R. N. Calton © 2009 Nova Science Publishers, Inc.
Chapter I
Interhemispheric Connectivity:
The Evolution and Nature
of the Corpus Callosum
Introduction
Though no one will doubt that animals have evolved into a shocking diversity of shapes
and sizes, it is remarkable that the basic neurological layout of the vast majority of species,
including at least all vertebrates and arthropods, remains preserved, with a pair of organs
arranged about the longitudinal axis of the organism (Houzel and Milleret, 1999).
Accordingly, Houzel and Milleret (1999) go on to suggest that this symmetric layout
represents the manner in which we process and respond to our environment, with “our senses
basically proceed[ing] by a balance between pairs of sensors, as our acts result from a
dynamic equilibrium between pairs of effectors, and our decisions often follow[ing]
judgements from contrasting points of view” (Houzel and Milleret, 1999). Though we
perhaps perceive our surroundings in sensory pairs, it is imperative that the output efforts of
our nervous system be united into a single, coherent, efficient response; as eloquently put by
Charles Sherrington in 1906, “the resultant singleness of action from moment to moment is a
keystone in the construction of the individual whose unity it is the specific office of the
nervous system to perfect” (Sherrington, 1906). Based on this premise of a dichotomous
receptive system requiring coherent processing and a coordinated response, “the brain must
be seen as an ensemble of several multiply interconnected neuronal systems, each with its
own functional specialization, and integration must be seen as the process of interactive
*
Contact Information: Manuel F. Casanova, MD; Department of Psychiatry; University of Louisville; 500 South
Preston Street, Building A, Room 217; Louisville, KY 40202; Email: m0casa02@louisville.edu; Tel:
(502)852-4077 (O)
4 Sarah B. Johnson and Manuel F. Casanova
cooperation between these systems that allows efficient cognition and consistent behavioral
control” (Berlucchi, 1999).
The classical neurological notion of a dominant hemisphere responsible for language
abilities and objective processing coupled with a non-dominant hemisphere prevailing for
nonverbal, spatial, and intuitive tasks has been upheld by several studies (Sperry, 1982),
though this dichotomy is not seen with the brains of nonhuman mammals (Berlucchi, 1999).
Still, no matter how simple the task, no operation involves exclusively one hemisphere
without the other; we are constantly switching between dominant and non-dominant
functions, mandating an ample channel of communication between the two hemispheres
(Houzel and Milleret, 1999). Along with the evolutionarily older anterior commissure, the
corpus callosum has evolved to be one of the two major inter-hemispheric connectors in
mammals (Katz et al., 1983).
The corpus callosum, however, has not always been recognized as the critical cortico-
cortical highway that it is. During the first half of the twentieth century, about the only
importance attributed to this structure was the possibility that it facilitated the
interhemispheric spread of generalizing seizure activity (Berlucchi, 1999); it was therefore
frequently transected surgically as a cure for patients with epilepsy. This view was initially
changed by an experiment by Sperry in 1953 in which the importance of the corpus callosum
in interocular visual transfer was demonstrated by the fact that disrupting the optic chiasm
did not hinder the ease with which visual pattern discriminations learned with one eye are
transferred to the other eye, while disrupting both the optic chiasm and the corpus callosum
certainly did (Sperry, 1961; Berlucchi, 1999). Since then, the importance of the corpus
callosum in interhemispheric cooperation has been studied in increasing detail. Nonetheless,
we still know strikingly little about the exact neuronal mechanisms of interhemispheric
integration, a fact that Houzel and Milleret (1999) attribute to “the abundance of callosal
fibers and to their manifold functions…, exist[ing] for sensory, motor, associative, frontal or
limbic cortices, and… link[ing] heterologous as well as homologous areas” (Houzel and
Milleret, 1999).
Before looking at the trends of corpus callosum evolution relative to brain evolution
overall, it is interesting to consider just how the corpus callosum could have ever come to
exist in the first place. Katz et al. (1983) offer one possible explanation based on ontophyletic
analysis, which involves inferences about callosal evolution based on a comparison of
developmental events in various organisms. Unlike the anterior commissure, which is
believed to have evolved as new axons finding their way through a pre-established “substrate
pathway,” the corpus callosum, which is found only in placental mammals, appears to have
appeared in the mammalian phylogeny with no apparent precursors (Katz et al., 1983). Katz
et al. (1983) theorize the following chain of events in the evolutionary development of the
corpus callosum: (1) the two cerebral hemispheres secondarily fused along the midline rostral
to the lamina terminalis; (2) a small number of critical genomic mutations lead to the
accumulation of a particular population of nonneuronal substrate cells, possibly a transient
class of glia, on either side of this interhemispheric contact; (3) these glia migrated across the
secondary interhemispheric fusion to form an interwoven cellular bridge, or “glial sling,”
between the two hemispheres; and (4) a portion of both new and existing axons eventually
traversed this new passageway to ultimately form the corpus callosum (Katz et al., 1983).
Interhemispheric Connectivity 5