The proposal aims to examine functional and structural neuropathology underlying deficits of executive control (indexed by inhibitory control, working memory, and attential set switching, in Attention Deficit Hyperactivity Disorder (ADHD) using whole-brain structural and functional magnetic resonance imaging (fMRI). It is hypothesized that prefontal-striatal-cerebellar circuitry underlying executive control is dysfunctional in ADHD due to abnormal dopaminergic function. We will test two predictions of this hypothesis - (1) fMRI will reveal that the functional activation in prefrontal-striatal-cerebellar regions during inhibitory control (Exp 2), working memory (Exp 3), and attentional set switching (Exp 4) will be abnormal in ADHD children (relative to control children) and will be normalized by the administration of methylphenidate in ADHD children. Sample for Experiments 2-4 will include 48 9-11 year old Combined type ADHD children (24 girls and 24 boys) and 48 age, gender, and IQ-matched healthy children. (2) Functional response to methylphenidate in prefrontal-striatal regions underlying inhibitory control in ADHD will be influenced by dopamine transporter genotype (DAT1) (Exp 1). Sample for Experiment 1 will include 36 Combined-type ADHD children (12 carriers of 480bp-10/10, 480bp-10/9, 440bp-9/9, each). These ADHD subjects were participants in an ongoing pharmacogenetic study at CNMC that found superior clinical efficacy of methylphenidate in carriers of 480bp than 440 bp. We have the unique opportunity to examine the functional brain response to methylphenidate during inhibitory control in those same ADHD children. In all experiments, fMRI will be performed on ADHD children with administration of methylphenidate and placebo; control children (in Experiments 2-4) will be imaged without methylphenidate. Further, high resolution structural imaging will be used to examine whether regions activated during fMRI differ in gray matter volume between ADHD subgroups and controls. Novel features of our proposal include: 1) examination of structural and functional brain differences in the same ADHD and control children and ii) examination of the functional brain response to methylphenidate in ADHD children in whom clinical efficacy of methylphenidate varied by DAT1 genotype. Examination of such genotype-phenotype relationships will elucidate potential etiological factors and neuropathophysiology of ADHD that will be useful in diagnosis, early intervention, and treatment planning.
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