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George Bush, MD, MMSc; Thomas J. Spencer, MD; Jennifer Holmes, BS; Lisa M. Shin, PhD; Eve M. Valera, PhD; Larry J. Seidman, PhD; Nikos Makris, MD, PhD; Craig Surman, MD; Megan Aleardi, MS; Eric Mick, ScD; Joseph Biederman, MD

Arch Gen Psychiatry. 2008;65(1):102-114.

Context  Previous studies have reported hypofunction, structural abnormalities, and biochemical abnormalities of the dorsal anterior midcingulate cortex (daMCC) in attention-deficit/hyperactivity disorder (ADHD). Stimulant medications are effective treatments for ADHD, but their neural effects have not been fully characterized.

Objective  To determine whether the methylphenidate hydrochloride osmotic-release oral system (OROS) would increase functional magnetic resonance imaging (fMRI) activation, compared with placebo, in the daMCC and other frontoparietal regions subserving attention during the Multi-Source Interference Task (MSIT).

Design  Randomized, placebo-controlled, 6-week, before-after fMRI study.

Setting  Academic medical center ambulatory clinic.

Patients  Twenty-one adults with ADHD randomized to 6 weeks of treatment with methylphenidate OROS (n = 11) or placebo (n = 10).

Interventions  Patients underwent fMRI twice while performing the MSIT (scan 1 at baseline and scan 2 at 6 weeks).

Main Outcome Measures  Group-averaged, random-effects, repeated-measures, general linear model analyses were used to compare daMCC (and whole-brain) fMRI activation during the MSIT. Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented.

Results  Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups. Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylphenidate OROS group than in the placebo group (P < 1 x 10^–4, cluster corrected for multiple comparisons). Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response. Methylphenidate OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks.

Conclusion  Methylphenidate OROS increased daMCC activation during the MSIT and may act, in part, by normalizing daMCC hypofunction in ADHD.

Author Affiliations: Departments of Psychiatry (Drs Bush, Spencer, Shin, Valera, Seidman, Surman, Mick, and Biederman) and Neurology (Dr Makris), Harvard Medical School, Boston, Massachusetts; Psychiatric Neuroscience Division, Department of Psychiatry (Drs Bush, Shin, and Valera and Ms Holmes), Clinical and Research Program in Pediatric Psychopharmacology (Drs Bush, Spencer, Valera, Seidman, Makris, Surman, Aleardi, Mick, and Biederman), and Department of Radiology Services, Center for Morphometric Analysis (Dr Makris), Massachusetts General Hospital, Boston; MIT/HMS/MGH Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging, Massachusetts Institute of Technology, Harvard Medical School, and Massachusetts General Hospital, Charlestown (Drs Bush and Valera); Department of Psychology, Tufts University, Medford, Massachusetts (Dr Shin); and Massachusetts Mental Health Center Public Psychiatry Division and Beth Israel Deaconess Medical Center, Boston (Dr Seidman).

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