MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES
RESEARCH REVIEWS 6: 1–5 (2000)
OVERVIEW: NORMAL AND ABNORMAL HUMAN
BRAIN DEVELOPMENT
Joseph J. Volpe*
Harvard Medical School and Children’s Hospital, Boston, Massachusetts
T
his issue of MRDD Research Reviews addresses recent
advances in our understanding of normal and abnormal
human brain development. The general emphasis of each
article is one of the major events of human brain development,
beginning with neurulation and proceeding ultimately to my-
elination. The more specific emphases of each article are the
most recent insights into the individual developmental processes,
with a particular focus on advances generated by molecular
biological and genetic techniques. The final two articles address
the impact of advanced magnetic resonance (MR) techniques in
the delineation of the development of brain structure and func-
tion in the living infant.
MAJOR DEVELOPMENTAL EVENTS AND PEAK
TIMES OF OCCURRENCE
The major developmental events and their peak times of
occurrence are shown in Table 1. The periods are those during
which the most rapid progression of the developmental event
occurs. Although there is some overlap among these periods, it
is valid as well as convenient to consider the overall maturational
process in terms of a sequence of individual events.
PRIMARY NEURULATION
Normal Development
Neurulation refers to the inductive events that occur on
the dorsal aspect of the embryo and result in the formation of the
brain and spinal cord. These events can be divided into those
related to the formation of brain and spinal cord exclusive of
those segments caudal to the lumbar region, i.e., primary neuru-
lation, and those related to the later formation of the caudal
segments of the spinal cord, i.e., caudal neural tube formation or
secondary neurulation. Primary neurulation will be emphasized by
Manning et al. in this issue.
Primary neurulation occurs in a peak period of the third
and fourth weeks of gestation. The nervous system begins on the
dorsal aspect of the embryo as a plate of tissue differentiating in
the middle of the ectoderm. The underlying notochord and
chordal mesoderm induce formation of the neural plate, which
is formed at approximately 18 days of gestation. Under the
continuing inductive influence of the chordal mesoderm, the
lateral margins of the neural plate invaginate and close dorsally to
form the neural tube. The neural tube gives rise to the central
nervous system. The anterior end of the neural tube closes at
approximately 24 days, and the posterior end closes at approx-
© 2000 Wiley-Liss, Inc.
imately 26 days. This posterior site of closure is at approximately
the lumbosacral level. Interaction of the neural tube with the
surrounding mesoderm gives rise to the dura and axial skeleton,
i.e., the skull and vertebrae.
Disorders
Disturbances of the inductive events involved in primary
neurulation result in various errors of neural tube closure, which
are accompanied by alterations of axial skeleton as well as of
overlying meningovascular and dermal coverings. The resulting
disorders are considered next in order of decreasing severity
(Table 2).
Craniorachischisis Totalis
In this disorder, there is essentially total failure of neuru-
lation. A neural platelike structure is present throughout, and
there is no overlying axial skeleton or dermal covering. Onset of
this severe disorder is estimated to be no later than 20 –22 days
of gestation. Because most such cases are aborted spontaneously
in early pregnancy and only a few have survived to early fetal
stages, the incidence is unknown.
Anencephaly
The essential defect of anencephaly is failure of anterior
neural tube closure. The most common variety of anencephaly
includes involvement of the forebrain and variable amounts of
upper brainstem. The exposed neural tissue is represented by a
hemorrhagic, fibrotic, degenerated mass of neurons and glia
with little definable structure. The frontal bones above the
supraciliary ridge, the parietal bones, and the squamous part of
the occipital bone are usually absent. This anomaly of skull
imparts a remarkable frog-like appearance to the patient when
viewed face on.
Myeloschisis
The essential defect is failure of posterior neural tube closure.
A neural platelike structure involves large portions of the spinal
cord and presents as a flat, raw, velvety structure with no
overlying vertebrae or dermal covering. Onset is no later than 24
days of gestation. Most of these infants are stillborn, and merge
*Correspondence to: Joseph J. Volpe, Children’s Hospital, 300 Longwood Ave-
nue, Boston, MA 02115.
 Table 1. Major Events in Human Brain Development and
Peak Times of Occurrence
Major Developmental Event
Primary neurulation
Prosencephalic development
Neuronal proliferation
Neuronal migration
Organization
Myelination
with the category of more restricted de-
fects of neural tube closure, i.e., myelo-
meningocele.
Encephalocele
Encephalocele may be envisioned
as a restricted disorder of neurulation, involv-
ing anterior neural tube closure. This con-
cept, however, must be understood with
the awareness that the precise pathogen-
esis of this disorder remains unknown.
The lesion occurs in the occipital region
in 70%– 80% of cases. In the typical oc-
cipital encephalocele, the protruding
brain is usually derived from the occipital
lobe and is often accompanied by dys-
raphic disturbances, involving cerebel-
lum and superior mesencephalon.
Myelomeningocele
The essential defect in myelomen-
ingocele is restricted failure of posterior neural
tube closure. The occurrence of approxi-
mately 80% of all lesions in the lumbar
(thoracolumbar, lumbar, lumbosacral)
area may reflect the fact that this is the last
area of the neural tube to close. The
neural lesion is represented by a neural
plate or abortive neural tube–like struc-
ture in which the ventral half of the cord
is relatively less affected than the dorsal.
The axial skeleton is uniformly deficient,
and an incomplete though variable der-
mal covering is present.
Myelomeningocele and its variants
represent the most important examples of
faulty neurulation, because affected in-
fants usually survive. The major clinical
Table 2. Disorders of
Primary Neurulation—Neural
Tube Defects
Order of decreasing severity:
Craniorachischisis totalis
Anencephaly
Myeloschisis
Encephalocele
Myelomeningocele, Arnold-Chiari
malformation
2 MRDD RESEARCH REVIEWS
Peak Time of Occurrence
3–4 weeks of gestation
2–3 months of gestation
3–4 months of gestation
3–5 months of gestation
5 months of gestation-years postnatal
Birth-years postnatal
features relate primarily to the nature of
the primary lesion, the associated Chiari
type II malformation, and hydrocephalus.
PROSENCEPHALIC
DEVELOPMENT
Normal Development
Prosencephalic development oc-
curs by inductive interactions under the
primary influence of the prechordal me-
soderm. The peak period involved is the
second and third months of gestation,
with the earliest prominent phases in the
fifth and sixth weeks of gestation. The
major inductive relationship of concern
is between the notochord–prechordal
mesoderm and the forebrain. The induc-
tive interaction influences formation of
much of the face as well as the forebrain,
and thus severe disorders of brain devel-
opment at this time usually result in strik-
ing facial anomalies as well.
Development of the prosencepha-
lon is considered best in terms of three
sequential events, i.e., prosencephalic forma-
tion, prosencephalic cleavage, and midline
prosencephalic development. Prosencephalic
formation begins at the rostral end of the
neural tube at the end of the first month
and beginning of the second month,
shortly after the anterior neuropore
closes. Prosencephalic cleavage occurs most
actively in the fifth and sixth weeks of
gestation and includes three basic cleav-
ages of the prosencephalon: 1) horizon-
tally to form the paired optic vesicles,
olfactory bulbs, and tracts; 2) transversely
to separate the telencephalon from dien-
cephalon; and 3) sagittally to form, from
the telencephalon, the paired cerebral
hemispheres, lateral ventricles, and basal
ganglia. The third event, midline prosence-
phalic development, occurs from the latter
half of the second month through the
third month, when three crucial thicken-
ings, or plates of tissue become apparent;
from dorsal to ventral these are the com-
missural, the chiasmatic, and the hypo-
thalamic plates. These structures are im-
portant in the formation, respectively, of
the corpus callosum and septum pelluci-
● NORMAL/ABNORMAL HUMAN BRAIN DEVELOPMENT
Table 3. Disorders of
Prosencephalic Development
Prosencephalic formation
Aprosencephaly
Atelencephaly
Prosencephalic cleavage
Holoprosencephaly
Holotelencephaly
Midline prosencephalic development
Agenesis of corpus callosum
Agenesis of septum pellucidum
(⫾cerebral clefts)
Septooptic dysplasia
Septooptic hypothalamic dysplasia
dum, the optic nerve chiasm, and the
hypothalamic structures. The most
prominent of these developments is for-
mation of the corpus callosum, the earli-
est components of which appear at ap-
proximately 9 weeks, and by 12 weeks an
independent corpus callosum is definable
at the commissural plate. Formation of
the corpus callosum is completed by ap-
proximately 20 weeks of gestation. Major
insights into the molecular genetic deter-
minants of forebrain development have
been gained in recent years and will be
discussed in the article by Muenke and
Cohen, this volume.
Disorders
Disorders of prosencephalic devel-
opment are considered best in terms of
the three major events described earlier,
i.e., prosencephalic formation from the
rostral end of the neural tube, prosence-
phalic cleavage, and midline prosence-
phalic development (Table 3). The spec-
trum of pathology varies from a profound
derangement, i.e., aprosencephaly, to
certain disturbances of midline prosence-
phalic development (e.g., isolated agene-
sis of the corpus callosum) that are some-
times not detected during life.
Aprosencephaly and Atelencephaly
Aprosencephaly and atelencephaly
are the most severe of the disorders of
prosencephalic development. In aprosen-
cephaly, the entire process fails to occur
and the result is an absence of formation
of both telencephalon and diencephalon,
with a prosencephalic remnant located at
the rostral end of a rudimentary brain-
stem. In atelencephaly the anomaly is less
severe in that the diencephalon is rela-
tively preserved. These anomalies are dis-
tinguishable from anencephaly most
readily by the presence of an intact,
though flattened skull and intact scalp.
● VOLPE
Holoprosencephalies
The holoprosencephalic/holote-
lencephalic group of disorders represents
the next most severe derangements of
prosencephalic development and specifi-
cally involve prosencephalic cleavage
(Table 3). In this category of disorders,
the malformation of the forebrain may be
so severe that there is marked disturbance
of formation of both telencephalon and
diencephalon, and the term holoprosen-
cephaly is most appropriate. The essential
abnormality is a failure of the horizontal,
transverse, and sagittal cleavages of the
prosencephalon. In the more common of
the severe cases, in which the telenceph-
alon remains as a single-sphered structure
but the diencephalon is somewhat less
affected, the term holotelencephaly may
be more appropriate.
Disorders of Midline Prosencephalic
Development
The principal disorders of midline
prosencephalic development are consid-
ered best in terms of the normal events
centered around the commissural, chias-
matic, and hypothalamic plates. The spe-
cific disorders observed are shown in Ta-
ble 3.
Agenesis of the corpus callosum, com-
plete or partial, is a striking abnormality.
The superomedial aspects of the lateral
ventricles are deformed by the fibers of
the cerebral hemispheres that were des-
tined to cross in the corpus callosum and
that, with agenesis, instead course longi-
tudinally as the bundles of Probst. With
partial agenesis, the posterior portion is
nearly always affected. The association
with disorders of neuronal migration may
relate to the fact that callosal develop-
ment and neuronal migration occur con-
currently in human brain development.
Absence of the septum pellucidum, like
agenesis of the corpus callosum, is an
important clue to the presence of other,
clinically more serious abnormalities of
prosencephalic development or of con-
comitant developmental events (e.g.,
neuronal migration). One prominent ex-
ample of these disorders is the syndrome
of absence of septum pellucidum with
schizencephalic cerebral clefts (often mis-
takenly termed “porencephaly”).
NEURONAL PROLIFERATION
Normal Development
Major proliferative events occur
initially between 2 and 4 months of ges-
tation, with the peak period quantita-
tively in the third and fourth months. All
neurons and glia are derived from the
ventricular and subventricular zones,
MRDD RESEARCH REVIEWS ● NORMAL/ABNORMAL HUMAN BRAIN DEVELOPMENT
Table 4. Disorders of
Neuronal
Proliferation—Micrencephaly
Diminished number of proliferative units
(?)—“radial microbrain” (genetics
unclear)
Diminished size of proliferative units
(?)—“micrencephaly vera”
Familial
Autosomal recessive
Autosomal dominant
X-linked recessive
Genetics unclear (ocular abnormalities)
Chromosomal translocation
Teratogenic
Irradiation
Metabolic-toxic (fetal alcohol
syndrome, cocaine,
hyperphenylalaninemia, etc.)
Infection (rubella, cytomegalovirus)
Sporadic (nonfamilial, unknown cause)
present in the subependymal location at
every level of the developing nervous
system. This highly critical process clearly
relates to the ultimate integrity of every
system within the neural apparatus. The
fundamental aspects of this process and its
likely sites of regulation are described in
the article by Caviness and coworkers,
this issue.
Disorders
Disorders of neuronal proliferation
would be expected to have a major im-
pact on central nervous system function.
Because of difficulties in quantitating
neuronal populations, however, prolifer-
ative disorders are difficult to define.
Even when the disorder is so extreme
that the brain is grossly undersized, i.e.,
micrencephaly, or is oversized, i.e., ma-
crencephaly, it is extremely difficult to
define the nature and severity of the pro-
liferative derangement by conventional
techniques.
Micrencephaly
Disorders apparently related to im-
paired neuronal proliferation can be di-
vided broadly into the so-called “radial
microbrain” and “micrencephaly vera”
(Table 4).
Radial Microbrain
In radial microbrain, the extremely
small brain has normal gyral formation,
no evidence of a destructive process, and
no disturbance of cortical lamination.
The conclusion that the disturbance in-
volves the early phase of proliferative
events, which generates by symmetrical
divisions of stem cells the total number of
proliferative units, is based on the finding
● VOLPE
of a marked reduction in number of cor-
tical neuronal columns but an apparent
normal complement of the neurons per
column, i.e., normal size of columns.
Micrencephaly Vera
The designation micrencephaly
vera refers to a heterogeneous group of
disorders that appear to have, as the com-
mon denominator, small brain size, the
result of a derangement of proliferation
(Table 4). As discussed previously, in
most cases this conclusion cannot be
made unequivocally because of difficul-
ties in quantitating neuronal populations.
Nevertheless, I refer to cases of micren-
cephaly with no evidence of intrauterine
destructive disease (e.g., cases secondary
to virus, toxoplasmosis, or fetal vascular
insult), no evidence of gross derangement
of other developmental events (e.g., neu-
rulation, prosencephalic cleavage, or mi-
gration of neurons), and no evidence of
severe, early, postnatal destructive dis-
ease. In the cases under discussion, the
brain is generally well formed but is very
small.
The presumed timing of these dis-
orders involves the period of later prolif-
erative events by asymmetrical divisions
of stem cells, i.e., onset at approximately
6 weeks in the human, with rapid pro-
gression until approximately 18 weeks.
The most severely undersized brains
would be expected to have the earliest
onsets and the most marked deficiency of
neurons in each cortical column.
Macrencephaly
The designation macrencephaly
signifies a large brain and is a feature of a
heterogeneous group of disorders that
have not been well defined from the
neuropathological standpoint. Neverthe-
less, it is quite clear that there are several
entities in which the brain is generally
well formed but is unusually large. Ge-
netic varieties, suggestive of a derange-
ment in the developmental program for
neuronal proliferation, have been de-
fined. As with micrencephaly, however,
until central neuronal populations can be
quantified more accurately, the conclu-
sion that we are dealing with proliferative
disorders can be made only tenuously.
NEURONAL MIGRATION
Normal Development
Neuronal migration refers to the
remarkable series of events whereby mil-
lions of nerve cells move from their sites
of origin in the ventricular and subven-
tricular zones to the loci within the cen-
tral nervous system where they will re-
3

Table 5. Disorders of
Neuronal Migration
Order of decreasing severity
Schizencephaly
Lissencephaly—pachygyria
Polymicrogyria
Heterotopias
Focal cerebrocortical dysgeneses
Agenesis of corpus callosum may
accompany these disorders.
side for life. The peak period for this
occurrence is the third to fifth months of
gestation, although neuronal migration
can be detected in certain areas of the
cerebrum as early as the second month
and slightly after the fifth month. Regu-
lation of the timing and direction of these
many simultaneous migrations must be
highly ordered, but only recently has in-
sight been gained into these control
mechanisms. These mechanisms and, in
particular, the insights gained from stud-
ies of human disorders by molecular ge-
netic techniques, are discussed in the ar-
ticle by Walsh, this volume.
Disorders
Disorders of neuronal migration
usually result in overt disturbances of
neurological function. Migrational dis-
turbances often are associated with clin-
ical deficits from the first days of life.
Seizures are most often the dominant
early neurological sign. Nonetheless, the
least severe of these disorders (i.e., cere-
bral neuronal heterotopias) is probably
present to some degree in all of us. The
advent of MRI scanning has increased
markedly the ability to identify these dis-
orders in vivo, has demonstrated the rel-
atively high prevalence of the disorders,
and has shown their broad clinical ex-
pression (see later discussion). The major
disorders are listed in Table 5 in order of
decreasing severity.
Schizencephaly
Schizencephaly is the most severe,
yet restricted, of the cortical malforma-
tions. There is believed to be a complete
agenesis of a portion of the germinative
zones and thereby the cerebral wall, leav-
ing seams or clefts. In the walls of the
clefts, the cortical plate exhibits the hall-
marks of migrational disturbance, e.g.,
thick, microgyric cortex, large neuronal
heterotopias.
The advent of magnetic resonance
imaging (MRI) has expanded greatly un-
derstanding of anatomical and clinical as-
pects of schizencephaly. Indeed, several
4 MRDD RESEARCH REVIEWS
previous notions, based almost exclu-
sively on study of autopsy cases, i.e., that
schizencephaly is rare, bilateral, and asso-
ciated invariably with severe neurological
deficits, have been shown to be incor-
rect. The clefts tend to be in the regions
of the rolandic and sylvian fissures and
involve predominately frontal areas.
Lissencephaly and Pachygyria
In lissencephaly, i.e., “smooth
brain,” the brain has very few or no gyri.
Two anatomical types of lissencephaly
can be distinguished. In Type I lissenceph-
aly, the cerebral wall is similar to that of
an approximately 12-week-old fetus.
The layers consist, from the pial surface,
of an outermost relatively cell-poor mar-
ginal layer, a diffuse cellular layer con-
taining primarily pyramidal and other
neurons characteristic of lower layers of
cortex, a zone of heterotopic neurons in
columns, and an innermost band of white
matter. The pathology indicates that the
diffuse outer cellular layer contains neu-
rons that were destined to comprise the
deep layers of cortex but were never dis-
placed by subsequent migrations, the
neurons of which comprise the hetero-
topic layer. In Type II lissencephaly, the
appearance is quite different. The menin-
ges are thickened and adherent to the
agyric cortical surface. The resulting ra-
diographic appearance of the cortex has
led to the term “cobblestone lissenceph-
aly.” The cortex is represented by clusters
and circular arrays of neurons, with no
recognizable organization or lamination,
separated by glial and vascular septae.
Large heterotopic collections of neurons
are prominent.
In pachygyria, the features are sim-
ilar to those described for lissencephaly
but less marked. The gyri are relatively
few, unusually broad, and associated with
an abnormally thick cortical plate. The
microscopic features are similar to lissen-
cephaly, although the abnormalities are
less marked.
Polymicrogyria
This disorder is characterized by a
great number of very small plications in
the cortical surface, rendering to the ex-
ternal aspect of the cerebrum the appear-
ance of a wrinkled chestnut. The multi-
tude of small gyri are arranged in
complicated festoon-like or glandular
formations, appearing to result from fu-
sion of their molecular layers.
Two basic varieties of polymicrogyria,
layered and unlayered, can be distinguished
from the microscopic appearance. The two
varieties of polymicrogyria appear to have
differing pathogeneses and times of onset.
● NORMAL/ABNORMAL HUMAN BRAIN DEVELOPMENT
The nonlayered variety represents a disor-
der of neuronal migration, and the classic
four-layered variety is a postmigrational
disorder. The first type includes those cases,
such as those with Zellweger syndrome, in
which concomitant migrational defects are
present in cerebrum as well as in brainstem
or cerebellum, or both. In these instances,
the deepest collection of neurons appear to
represent heterotopic neurons, arrested
during migration. The second variety of
polymicrogyria includes those cases with
evidence of laminar neuronal necrosis in
the cortex after the apparent completion of
migration. Such examples of this postmi-
grational polymicrogyria include those
cases associated with carbon monoxide ex-
posure at approximately 20 –24 weeks, as
well as with other less well-defined intra-
uterine insults. In these patients, the
sparsely cellular gliotic third layer represents
an area of laminar cortical necrosis, and the
fourth layer is composed not of heterotopic
neurons but of neurons of the deeper layers
of previously formed cortex.
Neuronal Heterotopias
The least severe of the migrational
disturbances, neuronal heterotopias, are
collections of nerve cells in subcortical
white matter, apparently arrested during
radial migration from the periventricular
germinative zones. Such collections are
constant accompaniments of the more
severe migrational disorders. At the other
end of the spectrum, small collections of
neurons in cerebral white matter are not
unusual incidental findings at autopsy.
Focal Cerebral Cortical Dysgenesis
(Dysplasia).
With the advent of MR scanning
and removal of cortical anomalies for in-
tractable epilepsy, there has been increas-
ing recognition of focal disorders of neu-
ronal migration to cerebral cortex. The
lesions have been described as focal ce-
rebral cortical “dysgeneses” or “dyspla-
sias.”
Agenesis of the Corpus Callosum,
Abnormality of Septum Pellucidum, and
Colpocephaly.
Agenesis of the corpus callosum is a
common accompaniment of the major
disorders of neuronal migration. The rea-
sons for the relationships are at least two-
fold—first, the timing of callosal forma-
tion and of neuronal migration are nearly
coincident, and second, the disturbance
of neocortical development caused by
the migrational failure is followed by a
deficiency in corticocortical fibers des-
tined for the callosum. The first of these
reasons may explain the additional fre-
● VOLPE
quent accompaniment of neuronal mi-
grational disorder, i.e., absence or hyp-
oplasia of the septum pellucidum or
persistently wide cavum of the septum
pellucidum.
ORGANIZATIONAL EVENTS
Normal Development
Organizational events occur in a
peak period from approximately the fifth
month of gestation to several years after
birth. However, it should be recognized
that these complex processes may continue
for many more years in human cerebrum.
The major developmental features include:
1) establishment and differentiation of the
subplate neurons; 2) attainment of proper
alignment, orientation, and layering of cor-
tical neurons; 3) elaboration of dendritic
and axonal ramifications; 4) establishment
of synaptic contacts; 5) cell death and se-
lective elimination of neuronal processes
and synapses; and 6) proliferation and dif-
ferentiation of glia. These events are of
particular importance, because they estab-
lish the elaborate circuitry that distinguishes
the human brain, and they set the stage for
the final developmental event, myelina-
tion. The article by Pomeroy in this vol-
ume on neuronal differentiation addresses
critical aspects of organizational events.
Disorders
The normative data concerning
the features of organizational events de-
fine a critical period in brain develop-
ment that includes the perinatal period.
Unfortunately, we know little about dis-
orders of this phase of neural maturation.
Our ignorance is caused primarily by the
inadequacy of standard neuropathologi-
cal techniques to evaluate the complex
circuitry and synaptic connections of hu-
man brain. Indeed, only a few studies
using appropriate techniques, such as the
Golgi method for staining neuronal pro-
cesses, are available, and often it is not
clear whether the changes observed are
primary or secondary, specific or nonspe-
cific. Newer MR techniques, i.e., quan-
titative volumetric MR, diffusion tensor
MR, and functional MR, may provide
clearer insights into these issues. The ar-
ticle by Inder and Huppi in this volume
on the use of such new MRI techniques
is relevant in this context. In Table 6,
cases are classified according to whether
deficits in organizational events appear to
be the most significant neuropathological le-
MRDD RESEARCH REVIEWS ● NORMAL/ABNORMAL HUMAN BRAIN DEVELOPMENT
Table 6. Disorders of
Organization
Primary disturbance
Mental retardation, with or without
seizures, unknown cause
Down syndrome
Fragile-X syndrome
Angelman syndrome
Infantile autism
Duchenne muscular dystrophy
Associated disturbance
Potential disturbance
Ventilator-dependent premature infant
Other perinatal and postnatal insults
Experiential effects
sion (primary disturbance), an associated le-
sion (associated disturbance), or a likely but
unproven lesion (potential disturbance).
MYELINATION
Normal Development
Myelination is characterized by the
acquisition of the highly specialized my-
elin membrane around axons. The pe-
riod of myelination in the human is very
long, beginning in the second trimester
of pregnancy and continuing into adult
life. Myelination within the central ner-
vous system, particularly the forebrain,
generally progresses most rapidly after
birth. The process of myelination begins
with proliferation of oligodendroglia that
align along axons. The plasma mem-
branes of the oligodendroglia become
elaborated as the myelin membrane of
the central nervous system. The molec-
ular determinants of oligodendroglial de-
velopment and myelination are discussed
in the article by Tennekoon, this vol-
ume.
Myelination in Human Brain Regions
The most informative of the de-
scriptions of the progress of myelination in
the human brain are those by Yakovlev
and Lecours, and by Gilles and cowork-
ers, this volume. Five major general rules
concerning cerebral myelination in the
human can be derived from the available
data: 1) proximal pathways myelinate be-
fore distal pathways, 2) sensory pathways
myelinate before motor pathways, 3)
projection pathways myelinate before as-
sociative pathways, 4) central cerebral
sites myelinate before cerebral poles, and
5) occipital poles myelinate before fron-
● VOLPE
Table 7. Disorders of
Myelination
Primary disturbance
Cerebral white matter hypoplasia
Amino and organic acidopathies
Congenital hypothyroidism
Postnatal undernutrition
Sequela of periventricular leukomalacia
Associated disturbance
Potential disturbance
Other postnatal insults
totemporal poles. Overall, the most rapid
changes in myelination occur within the
first 8 postnatal months.
Disorders
Unequivocal documentation of
developmental disturbances of myelin
formation in the human has been hin-
dered considerably by the inadequacy of
standard neuropathological techniques in
quantifying the degree of myelination in
brain. Moreover, the most commonly
used brain imaging technique in the past,
computed tomography, provided little
information concerning myelination in
the human infant. The advent of MRI
provides considerable capability for the
monitoring of myelination and should
prove invaluable in the future in defining
disturbances of myelination in the hu-
man. Of particular importance will be
quantitative volumetric MR determina-
tions and studies of relative anisotropy by
diffusion tensor MR. These issues are
discussed in the article in this volume by
Inder and Huppi.
Cerebral white matter hypoplasia,
a familial disorder, does appear to qualify
as representative of an inherited disorder
of deficient myelination in the human
cerebrum. Moreover, amino acid and or-
ganic acid disturbances, hypothyroidism,
undernutrition in early infancy, and
periventricular leukomalacia appear to
impair brain development principally at
the level of myelination. These several
disorders are categorized in Table 7 as
primary disturbances of myelination, i.e.,
those in which the most significant neuro-
pathological disturbance involves myelina-
tion. Those disorders in which a de-
rangement of myelination is an associated
defect or a likely but unproven lesion are
categorized as associated or potential distur-
bance, respectively.
5