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Quantitative Brain Magnetic Resonance Imaging in Girls With Attention-Deficit/Hyperactivity Disorder
F. Xavier Castellanos, MD;
Jay N. Giedd, MD;
Patrick C. Berquin, MD;
James M. Walter, MA;
Wendy Sharp, MSW;
Thanhlan Tran, BS;
A. Catherine Vaituzis;
Jonathan D. Blumenthal, MA;
Jean Nelson, MHS;
Theresa M. Bastain, BA;
Alex Zijdenbos, PhD;
Alan C. Evans, PhD;
Judith L. Rapoport, MD
Arch Gen Psychiatry. 2001;58:289-295.
ABSTRACT
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Background Anatomic studies of boys with attention-deficit/hyperactivity disorder
(ADHD) have detected decreased volumes in total and frontal brain, basal ganglia,
and cerebellar vermis. We tested these findings in a sample of girls with
ADHD.
Methods Anatomic brain magnetic resonance images from 50 girls with ADHD, of
severity comparable with that in previously studied boys, and 50 healthy female
control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with
contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes
of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum,
and cerebellar vermis. Behavioral measures included structured psychiatric
interviews, parent and teacher ratings, and the Wechsler vocabulary and block
design subtests.
Results Total brain volume was smaller in girls with ADHD than in control subjects
(effect size, 0.40; P = .05). As in our previous
study in boys with ADHD, girls with ADHD had significantly smaller volumes
in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size,
0.54; P = .04), even when adjusted for total cerebral
volume and vocabulary score. Patients and controls did not differ in asymmetry
in any region. Morphometric differences correlated significantly with several
ratings of ADHD severity and were not predicted by past or present stimulant
drug exposure.
Conclusions These results confirm previous findings for boys in the posterior-inferior
lobules of the cerebellar vermis. The influence of the cerebellar vermis on
prefrontal and striatal circuitry should be explored.
INTRODUCTION
INVESTIGATIONS of attention-deficit/hyperactivity disorder (ADHD) with
the use of magnetic resonance (MR) imaging implicate dysfunction of prefrontal
cortical-striatal-pallidal circuitry1, 2, 3, 4, 5, 6
and of the cerebellar vermis.7, 8
Although there has been substantial convergence of results,9
some inconsistencies remain. For example, most studies have reported decreased
caudate volume in ADHD, but laterality has varied,2, 3, 10, 11
and one study found larger caudate area in adolescents with ADHD.11
Of the patients described in the anatomic studies cited above, 92% were
male, reflecting in part the male preponderance in the disorder.12
Combining males and females (as has sometimes been done10, 11)
is problematic because there are robust (approximately 10%) male-female differences
in overall brain volume. Most regional brain volumes are also approximately
10% smaller in females, but there are important exceptions, such as the caudate
nucleus, which is proportionately larger in females.13, 14
Differences in caudate nucleus volume or asymmetry have been found by every
group that has examined ADHD samples,2, 3, 10, 11
making this sexual dimorphism particularly interesting in a study of girls
with ADHD.
Studying girls with ADHD raises questions regarding severity and diagnostic
validity,15, 16 which we addressed
by recruiting girls with ADHD in whom severity and phenomenologic characteristics
were comparable with those of our previously studied boys with ADHD.17 We now report, to our knowledge, the first anatomic
brain MR imaging study of female patients with ADHD. Our hypothesis was that
prefrontal-striatal-pallidal and cerebellar abnormalities similar to those
noted in boys with ADHD2, 7 would
be observed in girls.
SUBJECTS AND METHODS
SUBJECTS
Subjects With ADHD
Girls with combined-type ADHD (meeting both hyperactivity-impulsivity
and inattention criteria) (n = 50; mean age, 9.7 years; range, 5.3-16.0 years)
were recruited for National Institute of Mental Health ADHD drug treatment
studies17 within a specialized day program (n
= 36) or specifically for this imaging study (n = 14). Inclusion criteria
were hyperactive, inattentive, and impulsive behaviors that were impairing
in at least 2 settings (home, school, or day program), and a Conners' Teacher
Hyperactivity rating greater than 2 SDs above age mean.18
The DSM-IV19 diagnosis
of ADHD was based on the Diagnostic Interview for Children and Adolescents,20 with a parent and separately with the patient if she
was older than 9 years; Conners Teacher Rating Scale18;
and the Teacher Report Form.21 The Wechsler
Intelligence Scale for Children–Revised (WISC-R)22
was used for 32 patients and the Wechsler Intelligence Scale for Children–Third
Edition (WISC-III)23 for 17 (1 missing). To
allow comparison with our previous studies of boys, WISC-III full-scale, vocabulary,
and block design subscale scores were converted to WISC-R equivalents on the
basis of published data.24, 25, 26, 27
Thirty-five patients (70%) had been previously treated with stimulants,
as determined from parental reports. Measures of stimulant drug exposure were
lifetime exposure (yes or no), current daily dose in methylphenidate hydrochloride
equivalents at the time of scanning (1 mg of amphetamine sulfate = 2 mg of
methylphenidate hydrochloride), and estimated cumulative lifetime methylphenidate
equivalent dose calculated from parental reports.
Exclusion criteria were a full-scale WISC-R IQ less than 80, evidence
of medical or neurologic disorders on examination or by history, Tourette
disorder, or any other Axis I psychiatric disorder requiring treatment with
medication. Thirteen subjects met lifetime criteria for mild anxiety or mood
disorders, and 5 had reading disorder confirmed by discrepancy (z>1.65) between Woodcock-Johnson Psychoeducational Test Battery and
WISC-R standard scores.28, 29 Other
demographic and diagnostic characteristics are included in Table 1.
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Table 1. Characteristics of Girls With ADHD and Control Subjects*
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Normal Control Subjects
Unrelated healthy girls (n = 50; mean age, 10.0 years; range, 4.7-15.9
years) were recruited from the community. Screening included telephone interview,
parent and teacher rating scales, and in-person assessment, which included
physical and neurologic examinations, the 12 handedness items from the Revised
Physical and Neurological Examination for Subtle Signs,31
structured psychiatric interview using the Diagnostic Interview for Children
and Adolescents,20 Child Behavior Checklist,21 the WISC-R (n = 24) or WISC-III (n = 16) vocabulary
and block design tests, and Wide Range Achievement Test, Revised Edition.32 Family psychiatric history for first- and second-degree
relatives was ascertained from 1 or both parents. Individuals with physical,
neurologic, or lifetime history of psychiatric abnormalities, or who had any
first-degree relatives or greater than 20% of second-degree relatives with
major psychiatric disorders, were excluded. Approximately 4 candidates were
screened for every 1 accepted, with the most common exclusions being family
psychiatric history and possible psychiatric diagnosis based on structured
interview or teacher report.
Assent from the child and written consent from the parents were obtained.
The National Institute of Mental Health institutional review board approved
the protocol.
BEHAVIORAL MEASURES
Patients underwent a psychoeducational evaluation (full WISC-R and Woodcock-Johnson
Psychoeducational Test Battery–Revised) by a clinical psychologist (Barbara
Keller, PhD) during medication-free baseline. The hyperactivity factor, extracted
from the Conners' Parent and Teacher Rating Scales,18, 33
was averaged from the 3 weekly placebo ratings, as were physician ratings
on the Children's Global Assessment Scale34
and Clinical Global Impressions scale for severity of illness.35
Baseline ratings were substituted for patients who did not participate in
medication trials (n = 14). Parents also provided ratings on the Child Behavior
Checklist.21
MR IMAGE ACQUISITION
All subjects were studied on the same 1.5-T scanner (Signa; General
Electric Co, Milwaukee, Wis). T1-weighted images with contiguous 1.5-mm slices
in the axial plane and 2.0-mm slices in the coronal plane were obtained by
means of 3-dimensional spoiled gradient recalled echo in the steady state.
Imaging variables were as follows: echo time, 5 milliseconds; repetition time,
24 milliseconds; flip angle, 45°; acquisition matrix, 256 x 192;
number of excitations, 1; and field of view, 24 cm. Vitamin E capsules, wrapped
in gauze and placed in each auditory meatus, were used to standardize head
placement. A third capsule was taped to the lateral aspect of the left inferior
orbital ridge. The capsules are readily identifiable on MR images and were
used to define a reference plane and to verify laterality. The patient's head
was aligned in a padded head holder so that a narrow guide light passed through
each capsule. A sagittal localizing plane was acquired, and from this a multiecho
axial series was obtained. If all 3 capsules were not contained within a single
axial slice, the patient was realigned until this criterion was met. Subjects
were scanned in the evening to facilitate sleep. Younger children brought
blankets and stuffed animals and were read to by their parents. Four healthy
control subjects (aged 5, 7, 8, and 11 years) and 3 subjects with ADHD (aged
5, 6, and 10 years) were unable to complete the scan because of excessive
anxiety or sensitivity to noise. No sedation was used for either group.
IMAGE ANALYSIS
Clinical Interpretation
T2-weighted images were also obtained for evaluation by a clinical neuroradiologist.
A 1.7-cm cystic mass was found in the left cerebellar peduncle–pons
of a 9-year-old girl with ADHD. A presumptive diagnosis of pilocytic astrocytoma
led to her exclusion from this study and neurosurgical referral for eventual
excision. No other gross abnormalities were reported. All raters were blind
to subject characteristics.
Cerebrum and Cerebellar Quantification
An automated technique was used to quantify white and gray matter in
the cerebrum and to quantify the cerebellum by combining an artificial neural
network to classify tissues based on voxel intensity with nonlinear registration
to a template brain for which tissue regions had been manually defined.36, 37 Total cerebral volume was defined as
the algebraic sum of all gray-matter pixels and white-matter pixels, excluding
the cerebellum and brainstem. Intraclass correlation coefficients for subjects
rescanned within several hours were 0.98 for total cerebral volume (TCV) and
0.99 for cerebellum.
Subcortical Gray Matter
The caudate (head and body) was manually outlined from coronal slices
on a computer workstation (Macintosh II FX; Apple Computers Inc, Cupertino,
Calif) with the use of NIH Image (version 1.55).38
Since the sums of areas from the odd- and even-numbered slices correlated
highly with the sum obtained by adding all slices for 118 scans (r>0.97, P<.001; unpublished data), the
same method of outlining every other slice was used.2
Intrarater and interrater intraclass correlation coefficients were 0.87 and
0.88, respectively. Globus pallidus, bounded medially by internal capsule
and laterally by putamen, was also measured on coronal sections but included
every slice on which the structure was found. This measure does not distinguish
internal and external segments. Intrarater (intraclass correlation coefficient,
0.85) and interrater (0.82) reliabilities were acceptable.
Cerebellar Vermis
Volumetric measures of the posterior-inferior vermal lobules (VIII-X)
and of the entire vermis were hand traced in all 3 image planes by means of
morphometric software (Display; McConnell Brain Imaging Centre, McGill University,
Montreal, Quebec)39 as described previously.7, 40 Interrater and intrarater intraclass
correlation coefficients were 0.95 and 0.97, respectively.
STATISTICAL ANALYSIS
Although values of bilateral structures are reported for completeness,
the structures of interest in this replication study were limited to regions
that differed significantly in our studies of boys with ADHD.2, 7
While the same methods and raters were used for subcortical and vermal measures,
the automated algorithms we used previously to quantify TCV and cerebellum41 are no longer in use and do not function on current
computer hardware.
We report unadjusted analyses of variance with diagnosis as the between-group
factor, as well as analyses of covariance adjusted for TCV and Wechsler vocabulary
score and corresponding adjusted effect sizes. As in our study of boys, the
vocabulary subscale score was selected for analyses of covariance because
it is the single best predictor of full-scale IQ.23
We chose to control for group differences in intelligence, since there are
moderate intercorrelations among caseness, TCV, and vocabulary score. Meehl42 challenged the practice of controlling "nuisance variables"
such as social class or IQ that may be inexorably linked to the phenomenon
under study. Differences in IQ may be intrinsic to ADHD,43
but the relationship between IQ and regional brain volume is statistically
equivalent in all brain regions we have examined to date (unpublished data),
and we believe a conservative approach is warranted to focus on the most specific
anatomic correlates of ADHD.
The relations between morphometric measures that differed significantly
between groups and continuous behavioral measures were examined with Pearson
correlations. Possible effects of medication history were assessed by stepwise
multiple regression. All statistical analyses were performed with SAS for
Windows software (SAS Institute Inc, Cary, NC).44
Two-tailed significance levels were used at P .05.
RESULTS
SUBJECTS
Table 1 presents patient
and control characteristics. There were no significant group differences in
age, height, weight, Tanner pubertal stage, handedness, or WISC-R vocabulary
subscale score. Girls with ADHD had significantly lower block design subscale
and estimated full-scale30 scores than control
subjects.
Roughly one third of the sample (n = 15) had never been exposed to psychotropic
medications, including stimulants, before MR imaging. At the time of imaging,
the remaining subjects were taking an average of 17.4 ± 16.7 mg of
methylphenidate equivalents (range, 10-60 mg/d). We estimated that their average
cumulative lifetime exposure was 9.9 ± 11.0 g of methylphenidate equivalents
(range, 0.05-37.0 g). The medications previously used were methylphenidate
hydrochloride (n = 33) and dextroamphetamine sulfate (n = 2).
MORPHOMETRY
As shown in Table 2, TCV
was smaller in girls with ADHD (effect size, d = 0.40, analysis of variance P = .047), although this difference was not significant
after analysis of covariance adjusting for vocabulary subscale score (adjusted
d = 0.32, P = .12). After adjustment for TCV and
vocabulary score, girls with ADHD had significantly smaller volumes in the
posterior-inferior lobules (lobules VIII-X) of the cerebellar vermis (d =
0.54). None of the 5 other regions previously reported in boys with ADHD (right
frontal, right caudate, right globus pallidus, left cerebellum, or total vermis)
remained significant after covariance.
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Table 2. Cerebral Volumes, With Adjustment for Total Cerebral Volume
and Vocabulary, for Girls With ADHD (Present Study) and Summary Unadjusted
and Adjusted Statistics for Previously Studied Boys With ADHD*
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ANATOMIC-BEHAVIOR CORRELATIONS
Within the ADHD group, TCV correlated with estimated full-scale IQ score
(n = 40; r = 0.36, P = .01)
and with Child Behavior Checklist attention problems score (n = 49; r = -0.29, P = .04). Posterior-inferior
vermal volume correlated significantly with Global Assessment Scale score
(n = 49; r = 0.35, P = .01)
and with Child Behavior Checklist anxiety-depression score (n = 48; r = -0.35, P = .01). All
significant correlations were in the predicted direction, ie, smaller volumes
were associated with greater severity.
Within the normal control group, posterior-inferior vermal volume correlated
significantly with estimated full-scale IQ score (n = 41; r = 0.41, P = .008) and with vocabulary subscale
score (n = 41; r = 0.46, P
= .002).
One third of the sample of patients had never been exposed to psychiatric
medications before MR imaging. When TCV and severity of ADHD symptoms were
controlled for, none of the measures of stimulant drug exposure (lifetime
exposure, approximate lifetime cumulative dose, or current dose) were significantly
related to regional brain volumes (P>.20).
COMMENT
In this comprehensive brain morphometric analysis of girls with ADHD,
we found a between-group difference in TCV that did not remain significant
when Wechsler vocabulary score was covaried. For all other analyses, we used
analysis of covariance adjusting for TCV and vocabulary score to focus on
regions that are most selectively affected in girls with ADHD. Analysis of
covariance demonstrated selectively smaller posterior-inferior lobules of
the cerebellar vermis. We did not confirm previously reported smaller volumes
in right frontal lobe, right caudate, right globus pallidus, left cerebellum,
or cerebellar vermis in toto.2, 7
Our finding in the posterior-inferior cerebellar vermis (lobules VIII-X
in the newly standardized cerebellar nomenclature)45
of girls with ADHD replicates our previous report in boys with ADHD.7 In that study, we found that the entire vermis was
also smaller, but this was primarily accounted for by a smaller posterior-inferior
vermis. The finding of a smaller midsagittal area in the posterior-inferior
vermis was replicated in an independent sample of boys with ADHD, which also
confirmed that the posterior-superior lobules (VI-VII) did not differ from
those of control subjects.8
Little is known about the nonvestibular functions of the posterior-inferior
vermis. Forming part of the phylogenetically ancient paleocerebellum, the
vermis has come to mean "midline cerebellum," although, as Schmahmann and
colleagues45 have pointed out, there is no true
vermis in the anterior lobe. The anterior midline cerebellum (lobes I-V) is
often indistinct from overlying hemispheric cortex, and its lateral boundaries
vary depending on the section and definition of lateral boundaries.45 In contrast, the posterior vermis is almost entirely
isolated from the adjacent cerebellar hemispheres.45
The output nuclei for medial cerebellum, including the vermis, are the
paired fastigial nuclei. Vermal or fastigial stimulation evokes short-latency
responses in limbic structures,46 which can
modulate seizure activity in the medial temporal lobe.47
Vermal lesions profoundly ameliorate intense affective states such as rage
or fear in animals,48, 49, 50
and similar robust effects were reported in early studies using long-term
implanted electrodes in vermis in humans with a range of severe behavioral
or psychiatric disorders.51, 52
The posterior vermis includes the central lobules (VI-VII), which are
involved in oculomotor control.53 Lobules I,
IX, and X form the vestibulocerebellum, because of their massive direct and
indirect connections to the vestibular system. Patients with lesions in the
nearby posterior vermal lobe (lobules VI, crus I, crus II, and VIIB) can present
with what has been termed cerebellar cognitive affective
syndrome.54 Impairments in executive
function, difficulties with visuospatial cognition, and memory or language
deficits characterize the syndrome.55 Affective
changes, which can include flattening of affect or disinhibited, impulsive,
immature, or inappropriate behavior, are most common when lesions involve
the vermis. None of our subjects had brain lesions, except for one who had
a cerebellar tumor and was not included in further analyses. However, as previously
found in adults with mood disorders,56 the subgroup
of our patients who had a lifetime history of comorbid unipolar mood and/or
anxiety disorders (n = 13) had the smallest posterior-inferior vermis volumes
(1.93 ± 0.45 mL). This relationship was exemplified by the significant
partial correlation (that remained significant with TCV and vocabulary score
partialed) between posterior-inferior vermal volume and Child Behavior Checklist
anxiety-depression score (n = 48; r = -0.45, P = .002). However, the between-group difference in posterior-inferior
vermis remained significant even when the patients with comorbid mood or anxiety
disorders were removed or when we controlled statistically for lifetime history
of mood and/or anxiety disorders, demonstrating that our finding was not merely
driven by the affectively comorbid group.
Before these results are considered further, the limitations of this
study should be noted. Our subjects were highly screened to match previously
studied boys with combined-type ADHD in impairment and symptomatic severity.17 Accordingly, our results may not be generalizable
to community-based samples of girls with ADHD, who may differ from affected
boys in symptomatic severity and in ADHD typology.16
As is typical in studies of ADHD, our patient group had extensive comorbidity,
particularly for oppositional defiant disorder. However, supplementary analyses
limited to the 26 girls with ADHD who did not have other disruptive behavior
disorders confirmed our findings despite the smaller sample (data not shown).
Before proceeding with this study, we confirmed that our sample of girls
with ADHD was comparable to our previously studied boys on a range of categorical
and dimensional measures,17 including oculomotor
executive function tasks.57 However, we did
not study girls and boys contemporaneously, and the use of historical controls
is potentially problematic. Besides possible subject-based cohort effects,
we encountered a technological cohort effect. The semiautomated quantification
techniques we used in our previous studies2, 41
are now obsolete. Comparisons between our previous study in boys with ADHD
and the current study are least tenable for the frontal lobe measure. Previously,
we quantified the anterior pole by setting the posterior boundary at the anterior-most
point of the corpus callosum.2 Our current measure
is more than twice as large and comprises the entire frontal lobe. Thus, the
question of whether prefrontal brain volumes are decreased in girls with ADHD
remains unresolved until improved quantification algorithms are available
that can then be applied to both sexes.
We continued to use the same manual techniques for subcortical and subcerebellar
structures, but "rater drift" poses a potential problem here as well. Accordingly,
summary data for boys with ADHD are provided for comparison, but conclusions
about sex differences in ADHD, particularly with respect to asymmetry indexes,
must remain tentative until verified in contemporaneously collected and analyzed
longitudinal scans, which are in progress.
In the meantime, we believe that, although we did not replicate the
specific finding of a smaller right caudate in ADHD, our data still support
the hypothesis that the caudate is etiologically implicated in ADHD. Most
anatomic studies have detected volume differences in the left caudate,1, 3, 10 rather than in the right.2, 11 In boys with ADHD we found a difference
in right-left caudate asymmetry.2 By contrast,
girls with ADHD did not differ in asymmetry, but differed significantly in
left caudate volume considered alone or in total caudate volume. Our current
control girls were significantly less lateralized in caudate than our control
boys2 (F1,94 = 6.49; P = .01), consistent with several adult normative samples showing less
lateralization for women.58, 59, 60
The caudate was also proportionately larger in our present sample of control
girls than in our previously studied control boys (t96 = 2.96; P = .004). These normative sex differences
suggest that the caudate nucleus as a whole, rather than just the left caudate,
is preferentially smaller in girls with ADHD. Other data supporting a role
for the caudate nucleus in ADHD have been discussed extensively elsewhere.2, 5, 61, 62, 63, 64, 65, 66, 67
Longitudinal studies are also needed to definitively examine the potentially
confounding role of previous medication exposure. Nevertheless, this is the
first anatomic neuroimaging study in ADHD to include a sizable subgroup of
medication-naive patients (n = 15). Though causality cannot be addressed in
a naturalistic cross-sectional study of referred patients, we did not detect
any evidence that our findings are related to medication history or current
stimulant treatment.
Our finding of 4% decreased TCV in girls with ADHD is consistent with
previous studies, which have used a range of quantitative approaches.1, 2, 3, 68 Using an
automated segmentation algorithm, we found similar volumetric decreases in
both white matter (d = 0.40) and gray matter (d = 0.35) compartments. The
volumes for all 4 major lobes were proportionately decreased in girls with
ADHD (data not presented).
Significant decrease in posterior-inferior vermal volume was also detected
in pediatric subjects with childhood-onset schizophrenia.40
The potential relevance of the posterior-inferior vermis for dopaminergically
related psychiatric disorders such as ADHD and schizophrenia has been highlighted
by the selective finding of dopamine transporter immunoreactivity in ventral
cerebellar vermis, particularly in lobules VIII to X, and to a lesser extent
in lobules I to II, in nonhuman primates.69
Dopamine transporter immunoreactivity was not present in cerebellar hemispheres.
The function and origin of these presumably dopaminergic fibers are not known,
but they may form the afferent portion of a cerebellar circuit that is known
to influence midbrain monoaminergic systems.70, 71
Human functional brain imaging studies have documented the sensitivity of
the cerebellum, and particularly the vermis, to the effects of psychostimulants.72, 73, 74, 75
Schmahmann76 proposed that cerebellar
dysfunction produces not only motor dysmetria but also "dysmetria of thought"
in a range of neuropsychiatric disorders. Our cerebellar finding suggests
that dysmetria of thought should be further explored in ADHD. The selective
and significant decreased volume in girls of one of the candidate brain regions
previously hypothesized to be involved in the pathophysiology of ADHD, ie,
the posterior-inferior lobules of the vermis, extends studies in boys with
ADHD and focuses our attention on this long-neglected region. The cerebellar
abnormality does not appear to reflect stimulant drug exposure or comorbid
conditions. Ongoing studies are extending measurements to other cerebellar
regions and to further explore abnormalities of cerebellar connectivity in
ADHD.
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
Presented at the 1999 Annual Meeting of the Society of Biological Psychiatry,
Washington, DC, May 15, 1999.
We appreciate the dedicated technical support provided by David U. Lee,
PhD, Hong Liu, PhD, Maureen Tobin, BA, and Michelle Williams, BA; psychoeducational
evaluations performed by Barbara Keller, PhD; teacher ratings provided by
Anna L. Davidson, MA, and Susan Job, MA; and helpful comments by Rob Nicolson,
MD, and Carl M. Anderson, PhD.
From the Child Psychiatry Branch, National Institute of Mental Health,
Bethesda, Md (Drs Castellanos, Giedd, and Rapoport, Messrs Walter and Blumenthal,
and Mss Sharp, Tran, Vaituzis, Nelson, and Bastain); Service de Pédiatrie
1, CHU Hôpital Nord, Amiens, France (Dr Berquin); and Montreal Neurological
Institute, McGill University, Montreal, Quebec (Drs Zijdenbos and Evans).
Corresponding author and reprints: F. Xavier Castellanos, MD, Child
Psychiatry Branch, National Institute of Mental Health, Bldg 10, Room 3N-202,
10 Center Dr—MSC 1600, Bethesda, MD 20892-1600.
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