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F. Xavier Castellanos, MD; Patti P. Lee, MD; Wendy Sharp, MSW; Neal O. Jeffries, PhD; Deanna K. Greenstein, PhD; Liv S. Clasen, PhD; Jonathan D. Blumenthal, MA; Regina S. James, MD; Christen L. Ebens, BA; James M. Walter, MA; Alex Zijdenbos, PhD; Alan C. Evans, PhD; Jay N. Giedd, MD; Judith L. Rapoport, MD

JAMA. 2002;288:1740-1748.

Context  Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure.

Objective  To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls.

Design, Setting, and Participants  Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images.

Main Outcome Measures  Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls.

Results  On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F_1,280 = 8.30, P = .004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F_1,280 = 12.29, P = .001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F_2,288 = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P = .002) and cerebellar volumes (-6.2%, F_2,288 = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F_2,288 = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P = .002) and in the cerebellum (P = .003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P = .05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05).

Conclusions  Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.

Author Affiliations: Child Psychiatry Branch, National Institute of Mental Health (Drs Castellanos, Lee, Greenstein, Clasen, James, Giedd, and Rapoport, Mss Sharp and Ebens, and Messrs Blumenthal and Walter), Biostatistics Branch, National Institute of Neurological Disorders and Stroke (Dr Jeffries), National Institutes of Health, Bethesda, Md; and Montreal Neurological Institute, McGill University, Montreal, Quebec (Drs Zijdenbos and Evans). Dr Castellanos is now with the New York University Child Study Center, New York, NY.

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