Project 3

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A host of evidence from clinical studies and neuroimaging clearly indicates that elements of cognitive control, such as working memory and response inhibition, are diminished in children and adults with attention deficit/hyperactivity disorder. These functions are subserved in part by the fronto-striatal circuits connecting with dorsolateral prefrontal cortex for working memory, and with ventrolateral prefrontal cortex for response inhibition. Because of the known dopaminergic innervation of these areas, and the therapeutic effects of indirect dopaminergic agonists such as psychostimulants for ADHD, there has been interest in the direct role of dopamine in the modulation of the circuits underlying these abilities. Numerous studies have suggested that DA-modulation can yield behavioral improvements in response inhibition and WM performance in ADHD. Furthermore, neuroimaging work using both EEC and fMRI has suggested that DA modulation can result in normalized activity in children with ADHD. Pharmacologic treatment studies also suggest that other manipulations, such as alpha2 agonist exposure, may improve cognitive control. Our proposed studies aim to clarify the functional anatomy of key circuits subserving cognitive control in children and adolescents with ADHD and to compare and contrast hypothesized mechanisms of cognitive enhancement associated with dopaminergic and noradrenergic treatments in isolation or combination. Subjects recruited will undergo fMRI and EEG at Weeks 0, 4, and 8, allowing measurement of the effects of methylphenidate and guanfacine on behavior and neural activity. The primary aims are to determine how neural activity differs between children with ADHD and normal controls on response inhibition (measured using the stop-signal task) and spatial working memory (measured using a spatial Sternberg task) challenges, and how this response is modulated by pharmacotherapies. The project also aims to determine whether EEG and/or fMRI can predict treatment response to different pharmacotherapy regimens. These aims synergize with the larger Center in providing a neuroscientific basis for understanding the effects of treatments for developmental neuropsychiatric disorders.