MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES
RESEARCH REVIEWS 10: 106–111 (2004)
BRAIN DEVELOPMENT IN AUTISM: EARLY
OVERGROWTH FOLLOWED BY PREMATURE
ARREST OF GROWTH
Eric Courchesne*
Center for Autism Research, Children’s Hospital Research Center, La Jolla, California, and Neurosciences Department,
School of Medicine, University of California at San Diego, La Jolla, California
Due to the relatively late age of clinical diagnosis of autism, the early
brain pathology of children with autism has remained largely unstudied.
The increased use of retrospective measures such as head circumference,
along with a surge of MRI studies of toddlers with autism, have opened a
whole new area of research and discovery. Recent studies have now shown
that abnormal brain overgrowth occurs during the first 2 years of life in
children with autism. By 2– 4 years of age, the most deviant overgrowth is
in cerebral, cerebellar, and limbic structures that underlie higher-order cog-
nitive, social, emotional, and language functions. Excessive growth is fol-
lowed by abnormally slow or arrested growth. Deviant brain growth in
autism occurs at the very time when the formation of cerebral circuitry is at
its most exuberant and vulnerable stage, and it may signal disruption of this
process of circuit formation. The resulting aberrant connectivity and dys-
function may lead to the development of autistic behaviors. To discover the
causes, neural substrates, early-warning signs and effective treatments of
autism, future research should focus on elucidating the neurobiological
defects that underlie brain growth abnormalities in autism that appear
during these critical first years of life. © 2004 Wiley-Liss, Inc.
MRDD Research Reviews 2004;10:106 –111.
Key Words: autism; brain growth; development; neuroimaging; head
circumference; MRI; postmortem
T
he first 2 years of life are unique and crucial in human
brain development. Bateson referred to this brief period
as a “window of opportunity.” Dobbing [1981] and
Kinney et al. [1988] observed that it is also a time of particular
vulnerability to abnormal events and conditions. As Hutten-
locher [2002] points out, this early vulnerability arises from the
fact that at birth, neural circuitry in the cerebral cortex is
relatively sparse; and the creation of mature, complex cerebral
circuitry depends heavily on neuronal growth in the first post-
natal months and years. These growth events cause the brain to
triple in size during the first 2 years of life [Blinkov and Glezer,
1968; Courchesne et al., 2000] and are marked by unparalleled
increases in synaptic numbers, dendritic and axonal growth, and
myelination [Huttenlocher, 2002; Kinney et al., 1988; Quartz
and Sejnowski, 1998]. These neuronal and glial growth pro-
cesses form the circuits that underlie growing neurobehavioral
capacity, with early maturing neuronal systems providing sen-
sory, perceptual, and basic memory functions, and later matur-
ing systems providing working memory, social communication,
language and speech, and self-awareness [Herschkowitz, 2000].
© 2004 Wiley-Liss, Inc.
In humans, it is not until after this crucial phase of devel-
opment is largely over that autism is clinically recognized and
diagnosed, typically between 2 and 4 years of age [Baron-Cohen
et al., 1992; De Giacomo and Fombonne, 1998; Lord and Risi,
2000; Rogers and DiLalla, 1990]. However, retrospective stud-
ies, single case reports and parental comments indicate that signs
of abnormal behavior may sometimes appear as early as the first
year of life [Adrien et al., 1993; Dawson et al., 2000; Maestro et
al., 2002; Osterling and Dawson, 1994]. Because its presence
ordinarily goes unrecognized until a later age, brain develop-
ment in autism during the crucial first 2 years of life has, with a
single exception [Hashimoto et al., 1995], remained largely
unstudied.
Hints as to what might be happening during the first 2
years appeared for the first time in recent studies that used either
head circumference [Courchesne et al., 2003] or MRI (Carper
and Courchesne, submitted; Carper and Courchesne; 2000;
Carper et al., 2002; Courchesne et al., 2001; Sparks et al., 2002].
Because head circumference (HC) has been shown in HC-MRI
correlation studies to be a good indicator of brain size in young
autistic and normal children [Bartholomeusz et al., 2002], we
used HC as an indirect index of brain growth during these first
2 years of life [Courchesne et al., 2003]. The neuroanatomical
state of the brain at the end of this critical 2-year period of
development has been documented with MRI in prospective
studies of autism at the age of first clinical concern and referral
(Carper and Courchesne, submitted; Carper and Courchesne,
2000; Carper et al., 2002; Courchesne et al., 2001; Sparks et al.,
2002].
HEAD CIRCUMFERENCE IN EARLY LIFE
Retrospective studies of autism find HC is typically nor-
mal average at birth [Gillberg and de Souza, 2002; Lainhart et
Grant sponsors: This work is supported by grants from NIMH (2-ROI-MH36840) and
NINDS (2-RO1-NS-19855) awarded to Eric Courchesne. Thanks to Karen Pierce
and Philip Schwartzkroin for helpful comments on the article.
*Correspondence to: Eric Courchesne, Center for Autism Research, 8110 La Jolla
Shores Drive, La Jolla, CA 92037. E-mail: ecourchesne@ucsd.edu
Received 23 June 2004; Accepted 25 June 2004
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/mrdd.20020
 volumes exceeding normal average
[Courchesne et al., 2001]. The difference
in brain volume from normal in these
autistic toddlers was 10%. The Sparks et
al. study [2002] also showed brain vol-
ume of autistic 3- and 4-year-olds to be
about 10% larger than normal; addition-
ally, they found cerebrum, cerebellum,
and amygdala volumes to be larger than
normal. In a recent presentation at IM-
FAR, Piven, (2004), reported similar re-
sults from an MRI study in progress. Last,
in a new MRI study of 2- to 5-years-olds
from our laboratory, we found that both
girls and boys with autism had signifi-
cantly enlarged whole-brain volume
(Bloss and Courchesne, submitted). At 2
to 4 years of age, a 10% greater brain
volume translates into roughly a 1.5-cm
greater HC in children with autism as
compared to normal controls [Bar-
tholomeusz et al., 2002].

REGIONAL DIFFERENCES IN
OVERGROWTH IN AUTISM
Given these differences in brain vol-
ume, an important question is whether the
entire brain is uniformly enlarged (at 2– 4
years) or whether the enlargement occurs
differentially in only specific regions. A fur-
Fig. 1. Age-related changes in head circumference during infancy in autism spectrum disorder
shown. At birth and at 1–2-months of age, head circumference in a longitudinal autism spectrum
ther question is whether enlargement re-
disorder group was statistically significantly below the Centers for Disease Control and Prevention flects abnormality in gray matter, white
(CDC) mean for healthy infants, but by 6 –14 months of age, it was more than 1.0 SD (84th matter, or both. A recent study showed
percentile) above the mean for healthy infants. The CDC mean of healthy infants at each age is 0. that in 2- to 3-year-olds, overall brain en-
Error bars are SEM. Reproduced with permission from Courchesne et al. [2003] largement was found to be due to signifi-
cant increases in cerebral white matter (by
18%), cerebral gray matter (by 12%), and
cerebellar white matter (by 39%) (but not
al., 1997; Stevenson et al., 1997] or higher than that at 6 –14 months (Fig. 1). cerebellar gray matter) [Courchesne et al.,
slightly smaller than normal at birth and This observation raises the possibility that 2001]. Within the cerebrum, dorsolateral
1–2 months of age [Courchesne et al., the process of abnormally accelerated and medial frontal regions in 2- to 4-year-
2003] (Fig. 1). Because HC is a good brain growth may conclude during old autistic children were most abnormal,
indicator of brain size at young ages, it the 2nd year of life. A follow-up study whereas occipital lobes were not signifi-
can be concluded that the brains of most in our laboratory which compared autis- cantly different from normal [Carper and
autistic newborns are definitely not larger tic infants to normal healthy infants (n ⫽ Courchesne, submitted; Carper et al.,
than normal. 225) as well as the CDC norms (Pierce, 2002] (Fig. 2). In addition, temporal gray
We recently reported results from a Wideman, Courchesne, in progress) has matter and parietal white matter volumes
longitudinal study of changes in HC dur- replicated and extended this finding of were significantly enlarged. Consistent
ing the first 2 years of life in a sample of abnormally rapid and excessive HC with the differential enlargement of the
autism spectrum disorder (ASD) patients growth during the first 2 years of life in frontal and temporal gray matter, an MRI
(Courchesne et al., 2003). The group autism. sulcal mapping study of autistic preadoles-
included both autistic disorder (the se- cents showed anterior and superior shifting
vere end of the spectrum) and pervasive BRAIN OVERGROWTH IN of several sulci, with the greatest deviations
developmental disorder-not otherwise AUTISM AT 2– 4 YEARS: seen in the superior frontal, inferior frontal,
specified (the mild end) patients. As QUANTITATIVE MRI and superior temporal sulci and the Sylvian
compared to the HC norms from the ANALYSES fissure [Levitt et al., 2003].
Center for Disease Control and Preven- If HC in autistic infants grows be- The neuroanatomy in girls with
tion (CDC), the HC in the ASD groups yond normal HC during the first 2 years autism has been little studied. In a new
was at the 25th percentile at birth and of life, then direct quantitative MRI MRI study, we compared brain volumes
then increased rapidly to the 84th per- measurements at 2– 4 years of age ought in 2- to 5-year-old girls with autism to
centile by 6 –14 months of age (Fig. 1). to show that autistic toddlers have abnor- normal age-matched girls as well as to 2-
This period of abnormally accelerated mally large brain volumes. Three MRI to 5-year-old boys with autism by nor-
HC increase was largely concluded by studies now show this to be the case. In malizing volumes first (Bloss and
the end of the 2nd year of life; by 15–28 the first MRI study of brain size in au- Courchesne, submitted). We found that
months HC was only 2 percentile points tistic toddlers, we found that 90% had for several structures—including whole
MRDD RESEARCH REVIEWS ● BRAIN DEVELOPMENT IN AUTISM ● COURCHESNE 107

Fig. 2. In autistic 2- to 4-year-old children,
frontal lobes have the most abnormal en-
largement of white- and gray-matter vol-
umes. For each white- and gray-matter re-
gion, volumes were converted to z scores for
each 2- to 4-year-old autistic child, based on
the means and standard deviations of nor-
mal children of the same age. The zero on
the y axis indicates the normal mean and
y-axis values indicate z scores above this nor-
mal mean. Among autistic 2- to 4-year-old
children, frontal and parietal white-matter
volumes and frontal and temporal gray-mat-
ter volumes were each significantly larger
(asterisks) than normal. Error bars are stan-
dard error of the mean for autistic children.
Reproduced with permission from Carper et
al. [2002]
brain, cerebrum, frontal cortex, and tem-
poral cortex— enlargement was greater
in girls than boys with autism. Moreover,
every structural volume abnormality
present in boys with autism was also
present in girls with autism. Additionally,
girls with autism showed substantial re-
duction in cerebellar gray matter volumes
as compared to normal girls as well as to
boys with autism. Thus, at least in this
first study of neuroanatomy in young
girls with autism, brain developmental
abnormalities appear to be more severe in
girls than in boys with autism.
THE CEREBELLUM IN AUTISM:
A SITE OF DEVELOPMENTAL
ABNORMALITY
To date, a large number of struc-
tural and functional studies have reported
cerebellar abnormality in autism. Most of
108
this information has come from older
ages: adults, adolescents, and older chil-
dren with autism. One postmortem study
reported malformations of the cerebellar
cortex, Purkinje neuron loss, cerebellar
white defects, and abnormal expression
of nicotinic receptors in the same sample
of autistic cases [Lee et al., 2002]. Other
studies also found reductions in Purkinje
neuron numbers [Bailey et al., 1998;
Bauman and Kemper; 1994; Lee et al.,
2002], and one study found reductions in
Bcl-2 in cerebellar cortex [Fatemi et al.,
2001]. MRS studies have reported re-
ductions in NAA relative to controls
[Chugani et al., 1999; Otsuka et al.,
1999] (a finding consistent with reduc-
tion in neuron numbers, synapses or neu-
ron viability). FMRI studies report re-
duction in activation during attention
tasks in cerebellar regions reported to
have the most Purkinje neuron reduc-
tions, namely posterior neocerebellar
hemispheres [Allen and Courchesne,
2003]. Brain– behavior studies report that
reduction in a measure of vermis anat-
omy is significantly correlated with ab-
normality in orienting attention [Harris
et al., 1999; Townsend et al., 1999] and
exploration [Pierce and Courchesne,
2001]. An association has recently been
found between autism and the EN-2
gene, a cerebellar patterning gene (Gha-
rani et al., 2004). EN-2 mutations are
known to cause reductions in Purkinje
and other cerebellar neurons and folial
malformation in animal studies. The im-
portance of cerebellar abnormality in the
development of autism is also suggested
by a report that among monozygotic
twins, one of whom has autism, discor-
dance for autism is paralleled by discor-
dance in cerebellar— but not cerebral—
anatomical volumes [Kates et al., 2004].
In the largest autism MRI study of
the cerebellar vermis (over 200 autistic and
normal subjects), Hashimoto et al. [1995]
reported underdevelopment of the cerebel-
lar vermis in autistic individuals ranging
from infants to adolescents. In a study of 3-
to 9-year-old children, a reduced size of the
cerebellar vermis lobules VI–VII was found
to be specific to autistic children compared
with normal, fragile X, fragile X with au-
tism, Down syndrome with autism and
Down syndrome children [Kaufmann et
al., 2003]. In another recent study, the pos-
terior vermis was found to be significantly
reduced in size in autistic children [Levitt et
al., 1999]. Interestingly, we previously
found that increased frontal volumes and
decreased cerebellar vermal volumes were
linked in autism [Carper and Courchesne,
2000]. We suggested that frontal over-
growth in early life could be a result of
MRDD RESEARCH REVIEWS ● BRAIN DEVELOPMENT
excessive excitatory output from the cere-
bellum, a consequence of reduced inhibi-
tory Purkinje cell input to deep cerebellar
nuclei.
This remarkably consistent picture of
microscopic, macroscopic, and functional
reductions in the cerebellum stands in sharp
contrast to recent MRI volumetric findings
in very young autistic children. Sparks et al.
[2002] reported a significant increase of 7%
in the volume of the whole cerebellum in
3- and 4-year-old autistic children. In a
study in which we separately measured the
volumes of cerebellar gray and white mat-
ter and the vermis, in 2- and 3-year-old
autistic and normal children [Courchesne
et al., 2001], we found that cerebellar white
matter volume was dramatically (39%)
greater than that in the normal children
[Courchesne et al., 2001]. In contrast, we
also found that cerebellar gray matter vol-
ume was not enlarged, the gray/white ra-
tio was abnormally small, and vermis lob-
ules VI–VII were reduced [Courchesne et
al., 2001]. The fact that cerebellar white
matter is abnormally increased complicates
the effort to measure cerebellar gray matter
volumes. Cerebellar cortex is very thin
(only about 1 mm) and highly convoluted,
and the folia and lobules are highly envagi-
nated with white matter fiber tracts. Cur-
rent widely used MRI volumetric imaging
procedures simply lack the spatial resolu-
tion to accurately and separately resolve the
cerebellar cortex (gray matter) and these
white matter tracts in folia and lobules. So,
if white matter is as much as 39% increased
in autism, then current methodology will
necessarily report whole cerebellar gray
matter volumes that are proportionally in-
flated by these white matter changes.
Why then, do so many studies report
reduction in the size of one or another
region of the vermis in autism [Carper and
Courchesne, 2000; Courchesne et al.,
2001; Hashimoto et al., 1995; Kaufmann et
al., 2003; Levitt et al., 1999]? The answer
might be that, unlike the cerebellar hemi-
spheres, the vermis has very little white
matter volume and so vermis provides a
better index of cerebellar gray matter ab-
normality than do the hemispheres. Be-
cause Purkinje neuron loss is the single
most consistent neural defect known for
autism, and the loss occurs in the hemi-
spheres as well as vermis, future MRI re-
search will have to use new imaging meth-
ods to get an accurate measure in vivo of
cerebellar gray matter. In the meantime,
reports of cerebellar gray volumes based on
commonly used imaging techniques are
unlikely to provide accurate information.
Because the cerebellum plays a role
in perception, attention, memory, lan-
guage, novelty exploration, and emotion
IN AUTISM ● COURCHESNE
[Allen et al., 1997; Allen and Courchesne, Maximum cerebral gray matter volume
1998; Courchesne and Allen, 1997; Levi- in autistic individuals was reached by 2– 4
sohn et al., 2000; Middleton and Strick, years of age, about 4 to 6 years earlier
1994; Pierce and Courchesne, 2001; Pierce than normal. Carper et al., [Carper et al.,
and Courchesne, 2002; Schmahmann, 2002] found that frontal and temporal
1997], it has been theorized that its devel- cortical gray matter increase by 20% and
opmental abnormality likely contributes to 17%, respectively, in normal children be-
dysfunction in these several neurobe- tween 2– 4 and 6 – 8 years of age, but
havioral areas in autism [Allen and change by 1% and –1%, respectively, in
Courchesne, 1998; Courchesne and Allen, autism.
1997; Mostofsky et al., 2000; Pierce and Seven MRI studies have reported
Courchesne, 2001]. Therefore, it is impor- no significant difference from normal in
tant for future studies to replicate and elu- autistic brain volume at ages 5–13 years
cidate the neurobiological reasons and de- [Kates et al., 2004], 7–11 years [Herbert
velopment and functional consequences of et al., 2003], 5–16 years [Courchesne et
the extreme and remarkable increase in al., 2001], 8 – 45 years [Hardan et al.,
cerebellar white matter. 2003], 18 – 40 years [Tsatsanis et al.,
2003], 17– 47 years [Rojas et al., 2002],
LATER CHILDHOOD IN and 13– 46 years [Aylward et al., 2002].
AUTISM: REDUCED AND Aylward et al. [2002] reported brain vol-
ARRESTED BRAIN GROWTH ume in autism to be larger than normal in
In normal brain development, fur- 8- to 12-year-olds but not in adolescents
ther growth, synaptic selection, and neuro- and adults. Dager [2004] reported pre-
nal and circuit elaboration continues liminary findings from a 3-year longitu-
throughout childhood; in the cases of my- dinal study of the 3- to 4-year-olds who
elination and synapse formation and selec- had been in the Sparks et al. [2002] study.
tion, these processes continue well into As described above, those autistic chil-
adult life. For instance, frontal gray matter dren had brain volumes exceeding nor-
volumes increase 20% between early child- mal children by about 10%; however, 3
hood and the end of childhood [Carper et years later, that difference had entirely
al., 2002], maximum volumes not being disappeared. An interesting exception
reached until about 10 to 12 years of age. was the amygdala, which did not show
The size of dendritic arbors in frontal cor- this effect and remained larger than nor-
tex doubles between 2 and about 8 years of mal. This exception raises the possibility
age [Schade and van Groenigen, 1961]. that there may be spatiotemporal heter-
Myelination and axon growth are substan- ogeneity in the growth reduction phase
tial throughout childhood. For example, of autistic brain maldevelopment.
cerebral white matter volumes increase
59% between about 2–3 and 16 years of CONCLUSIONS AND FUTURE
age [Courchesne et al., 2001]. In fact, ce- DIRECTIONS
rebral white matter volume continues to Recent MRI and HC studies lead
increase through middle age [Courchesne to the conclusion that early abnormal
et al., 2000], and the corpus callosum con- growth processes underlie the emergence
tinues to grow throughout childhood and of autistic behavior during the first years
into adulthood [Pujol et al., 1993]. of life. These processes precede the clin-
According to recent MRI studies, ical onset of the disorder and coincide
this slow and methodical maturing of the with the first appearance of more subtle
brain does not happen in autism. Instead, preclinical behavioral abnormalities.
following the relatively brief period of Thus, these studies provide the first evi-
overgrowth, there is a shift to reduced or dence of brain maldevelopment in process
arrested growth. Structures that had been in the first years of life in autism.
far larger than normal in the 2- or 3-year- The abnormal overgrowth is most
old autistic brain stop growing at an ac- marked in neural systems (frontal, tem-
celerated rate [Courchesne et al., 2001]. poral, cerebellar, limbic) that underlie the
Eventually, brain volume in the normal higher-order cognitive, language, emo-
child “catches up” to the autistic brain. In tional and social functions known to be
the first MRI study of age-related impaired in autism. Also, overgrowth oc-
changes from early childhood to adoles- curs at a stage in development when the
cence in autism, we found that cerebral circuits that mediate these functions are
white matter volume increased 59% in being formed; this stage is well known to
normal individuals, but only 11% in chil- be particularly vulnerable to disruption
dren with autism [Courchesne et al., [Dobbing, 1981; Kinney et al., 1988].
2001]. Maximum brain size was reached Further, these neural systems normally
in autism by about 3–5 years of age, need many years to develop fully, but the
about 6 to 10 years earlier than normal. abnormal overgrowth is rather brief and
MRDD RESEARCH REVIEWS ● BRAIN DEVELOPMENT IN AUTISM ● COURCHESNE
is followed by abnormally slow or ar-
rested growth. Thus, it is quite likely
that, despite the initial aberrant over-
growth phase, development in these neu-
ral systems is, in fact, curtailed. Neuronal
underdevelopment and abnormal cir-
cuitry is the likely final outcome in the
autistic brain. This view is consistent
with histological, molecular, MRS and
functional neuroimaging studies, as re-
cently reviewed [Courchesn et al., 2004].
Courchesne and Pierce [in press]
suggest that large pyramidal neurons in
association cortices, especially in frontal
cortex where growth dysregulation in
autism is most extreme, may be most
abnormally underdeveloped and that this
defect may be pivotal. Pyramidal neurons
in frontal cortex play a key role in inte-
grating information from multiple func-
tional domains (e.g., sensory, emotional,
autonomic, social) and in providing es-
sential higher-order, top-down influ-
ences on lower-level systems. Develop-
ment in these large integrating and
projecting neurons is protracted. For ex-
ample, layer III pyramidal neurons in
frontal cortex have dendritic arbors that
are only 3% of mature size at birth, only
50% at 2 years of age, and not fully ma-
ture until the end of childhood [Hutten-
locher, 2002]. Early developmental dis-
ruption or reduced numbers of large
frontal pyramidal neurons will result in
reduced long distance cortico-cortical
connectivity and reduced top-down
control capacity; this disruption, in turn,
might trigger local and short-distance
overconnectivity. In this sense, autism
may be an unusual disconnection disor-
der with sparing (or perhaps even en-
hancement) of lower-level basic process-
ing, but also with an impaired capacity to
fully integrate lower-level detailed infor-
mation into higher-order meaningful
contexts.
The relationship between the post-
natal process of brain overgrowth and
prenatal neural defects detected in the
postmortem brain remain to be deter-
mined. Prenatal neural defects seen in
postmortem studies include cells arrested
in migration to the cerebrum and cere-
bellum, laminar disorganization in frontal
cortex, and dysgenesis of a major input to
the cerebellum—the inferior olive. Per-
haps the postnatal brain overgrowth is a
reaction triggered by adverse events that
cause the prenatal defects. For example,
in an experiment designed to test a spe-
cific hypothesis regarding the etiology of
autism [Fatemi et al., 2002], it was found
that prenatal influenza exposure in mice
resulted in smaller brain sizes at birth but
macrocephaly later in development—a
109
growth pattern evocative of that in au-
tism. This adverse prenatal event caused
reduction in size and increase in density
of pyramidal neurons at birth; both
pathological features persisted into adult-
hood. Many genetic and molecular
causes of brain overgrowth are also
known from the animal literature. For
example, beta-cetenin transgenic mice
have enlarged brains, abnormally ex-
panded cerebral cortex, abnormal hip-
pocampus, neurons arrested in migration,
and laminar disorganization [Chen and
Walsh, 2002, 2003]—again, reminiscent
of features in the autistic brain.
Future research will aim to deter-
mine more precisely the ages of onset,
peak, and cessation of the abnormal brain
overgrowth in autism, as well as the fac-
tors that affect each of these variables.
Individual variability can be expected
and might well be related to important
clinical, behavioral, neurofunctional, and
certainly neuroanatomical outcome mea-
sures. Understanding of such correlations
may provide avenues to developing ear-
lier diagnoses, more accurate prognoses,
and treatments better tailored to the in-
dividual child (and initiated at an earlier
age) than is currently possible. It is likely
that future research will demonstrate that
neuroimaging, conducted in the first two
years of life, will provide valuable diag-
nostic and prognostic information. Stud-
ies of the brain and behavior in the first 2
years of life in autism are essential and
will unlock the door to earlier identifica-
tion, more successful treatment, and un-
derstanding the causes of autism. f
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