It has long been an assumption that serious and chronic
childhood psychiatric disorders reflect, at least in part,
relatively subtle abnormalities of brain development.
Strong indirect support for this has been provided by
the association of childhood psychiatric disorders with
numerous neurological and neurodevelopmental dis-
orders  and from clinical neuropsychological studies
over many decades, indicating abnormal brain function
in child psychiatric populations . Because of the lim-
itations of clinical investigation to validate subtle brain
abnormalities, child psychiatric research has explored
new methods for studying the brain. Brain imaging is an
innovative technology that to date has best furthered the
goal of understanding normal and psychiatrically abnor-
mal brain structure and function. With the advent of
non-invasive brain magnetic resonance imaging (MRI)
Imaging normal and abnormal brain development:
new perspectives for child psychiatry
Judith L. Rapoport, F. Xavier Castellanos, Nitin Gogate, Kristin Janson,
Shawn Kohler, Phillip Nelson
Objective: The availability of non-invasive brain imaging permits the study of normal and
abnormal brain development in childhood and adolescence. This paper summarizes current
knowledge of brain abnormalities of two conditions, attention deficit hyperactivity disorder
(ADHD) and childhood onset schizophrenia (COS), and illustrates how such findings are
bringing clinical and preclinical perspectives closer together.
Method: A selected review is presented of the pattern and temporal characteristics of
anatomic brain magnetic resonance imaging (MRI) studies in ADHD and COS. These
results are discussed in terms of candidate mechanisms suggested by studies in develop-
Results: There are consistent, diagnostically specific patterns of brain abnormality for
ADHD and COS. Attention deficit hyperactivity disorder is characterized by a slightly smaller
(4%) total brain volume (both white and grey matter), less-consistent abnormalities of the
basal ganglia and a striking (15%) decrease in posterior inferior cerebellar vermal volume.
These changes do not progress with age. In contrast, patients with COS have smaller brain
volume due to a 10% decrease in cortical grey volume. Moreover, in COS there is a pro-
gressive loss of regional grey volume particularly in frontal and temporal regions during ado-
Conclusions: In ADHD, the developmental pattern suggests an early non-progressive
‘lesion’ involving neurotrophic factors controlling overall brain growth and selected
dopamine circuits. In contrast, in COS, which shows progressive grey matter loss, various
candidate processes influencing later synaptic and dendritic pruning are suggested by
human post-mortem and developmental animal studies.
Key words: ADHD, brain development, childhood schizophrenia.
Australian and New Zealand Journal of Psychiatry 2001; 35:272–281
Judith L. Rapoport, Chief (Correspondence); F. Xavier Castellanos,
Medical Officer; Nitin Gogate, Clinical Fellow; Kristin Janson, IRTA
Child Psychiatry Branch, National Institute of Mental Health,
Building 10, Room 3N202, 10 Center Drive MSC 1600, Bethesda,
Maryland 20892-1600, USA. Email: firstname.lastname@example.org
Shawn Kohler, Post-Baccalaureate IRTA Fellow; Phillip Nelson, Head
Section on Neurobiology, Laboratory of Developmental Neurobiology
Branch, National Institute of Child Health and Human Development,
Received 17 January 2001; accepted 1 February 2001.
methodology, imaging data can now be acquired for
paediatric populations. Moreover, these data are con-
verging with new information on the organization and
function of circuits in the developing brain, and on the
molecular mediators of these changes. It is hoped that
imaging studies in child psychiatric populations, will not
only define the brain systems underlying illness, but also
suggest candidate molecules for genetic studies. Based
on the nature, location and temporal pattern of these
abnormalities, and preclinical findings, we will be able
to make more specific and testable hypotheses about the
aetiology of these disorders. The quantitative study of
brain development during childhood and adolescence
with MRI began in the late 1980s (e.g. ). Subsequent
cross-sectional [4–7] and mixed longitudinal/cross-
sectional studies (e.g. ) have confirmed that although
total brain volume changes between ages 5 and 18 are
negligible, there are robust and complex changes in white
and grey matter. White matter volume increases linearly
during this age range, reflecting increasing myelination
[4,9], while grey matter volume increases until early
to mid-adolescence before decreasing during late ado-
lescence , presumably from synaptic pruning and
reduction of neuropil. A special feature of these norma-
tive data is that they were acquired in parallel with
prospective clinical studies, so that brain development
for psychiatrically abnormal populations can be com-
pared. Elegant studies of known chromosomal abnor-
malities, such as Down syndrome and Rett’s syndrome,
all testify to abnormal development in these known
retardation syndromes [10,11]. These produce gross dis-
turbances of central nervous system (CNS) development
for which the cause is known and, in principle, relatively
simple screening could be used to detect and prevent
such disorders. More subtle non-dementing disorders,
however, have proven more difficult. There remains con-
siderable controversy, for example, about even the valid-
ity of the diagnosis of attention deficit hyperactivity
disorder (ADHD). Brain morphometric studies may help
validate this diagnosis, and are summarized in detail
here. Since prospective longitudinal rescan data is now
available, we can address not only how the two patient
groups, ADHD and childhood onset schizophrenia
(COS), differed from controls at their initial evaluation
but also examine their differing developmental course.
Anatomic brain magnetic resonance imaging
studies of attention deficit hyperactivity
disorder and childhood onset schizophrenia
Attention deficit hyperactivity disorder
Table 1 summarizes some representative anatomic
brain studies that have been carried out to date in ADHD.
As seen in Table 1, several independent studies have
found a smaller total brain volume. This represents a
global reduction of grey and white equally (not shown
here) [12–16]. There are also subtle and not entirely con-
sistent abnormalities of various basal ganglia structures
(Table 2) [12,13,15,17] and, most striking, a consistent
and significant reduction of the volume of the posterior
inferior cerebellar vermis (Table 2) [16,18,19]. These
findings support other biological models of ADHD
implicating frontal–basal ganglia and dopaminergic
These abnormalities appear to be a fixed, rather than
an ongoing, process. Longitudinal changes during child-
hood and adolescence did not differ between our 73
ADHD subjects, and 75 healthy matched controls studied
prospectively with 2 and 4 year follow-up rescan .
These anatomic abnormalities are not due to stimulant
drug effects since the 17 medication-naïve patients
showed the same brain pattern. Thus, in contrast to COS
(described below), the smaller total brain and cerebellar
vermis in ADHD, seems due to an earlier process (at
least before age 4, the earliest age at which these scans
were obtained). Moreover, since the trajectories of the
total and regional brain development does not differ
between ADHD patients and controls, severe inattention
or impulsivity per se is not likely to cause the late pro-
gressive abnormalities seen for the schizophrenic group.
J.L. RAPOPORT, F.X. CASTELLANOS, N. GOGATE, K. JANSON, S. KOHLER, P. NELSON273
Table 1.Anatomic brain magnetic resonance imaging studies in ADHD
% SmallerEffect size
Aylward et al. 1996 
Filipek et al. 1997 
Bullmore et al. 1999 
Castellanos et al. 1996, 2000 [15,21]
Representative brain volume
Right hemisphere volume
Grey and white matter voxels
Grey and white matter voxels
ADHD, attention deficit hyperactivity disorder.
J.L. RAPOPORT, F.X. CASTELLANOS, N. GOGATE, K. JANSON, S. KOHLER, P. NELSON281
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