http://jama.ama-assn.org/issues/current/abs/joc20194.html
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Developmental Trajectories of Brain
Volume Abnormalities in Children and Adolescents With
Attention-Deficit/Hyperactivity Disorder 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 F1,280 = 8.30, P = .004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F1,280 = 12.29, P = .001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F2,288 = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P = .002) and cerebellar volumes (-6.2%, F2,288 = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F2,288 = 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. JAMA. 2002;288:1740-1748
View Full Text Author Contributions: Study concept and design: Castellanos, Evans, Giedd, Rapoport. Acquisition of data: Castellanos, Sharp, Clasen, James, Ebens,Walter, Evans, Giedd. Analysis and interpretation of data: Castellanos, Lee, Jeffries, Greenstein, Blumenthal, Walter, Zijdenbos, Evans, Giedd. Drafting of the manuscript: Castellanos, Lee, Jeffries, James, Giedd, Rapoport. Critical revision of the manuscript for important intellectual content: Castellanos, Lee, Sharp, Jeffries, Greenstein, Clasen, Blumenthal, Ebens,Walter, Zijdenbos, Evans, Giedd. Statistical expertise: Jeffries, Greenstein, Walter, Evans. Administrative, technical, or material support: Castellanos, Lee, Sharp, Greenstein, Clasen, Blumenthal, Ebens, Zijdenbos, Evans, Giedd, Rapoport. Study supervision: Castellanos, Rapoport. Funding/Support: This work was supported in its entirety by the National Institute of Mental Health, Division of Intramural Research Programs. Acknowledgment: We thank John J. Bartko, PhD, for statistical consultation; Barbara Keller, PhD, and Diana Dahlgren, PhD, for psychoeducational assessments; MRI technician Michelle Williams, BA; David U. Lee, PhD, and Hong Liu, PhD, for technical support; Beth Molloy, BA, and Maureen Tobin, BA, for scheduling patients and controls; and Suzanne Bell for administrative support.
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