This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.A preponderance of evidence has implicated abnormalities in frontal-subcortical circuits as contributing to the pathophysiology of ADHD; however whether these abnormalities are localized to a specific frontal region (i.e., a specific frontal-subcortical circuit), and if so, which region(s), remains unclear. Prevailing hypotheses implicate deficient response inhibition as one of the fundamental features driving the pathophysiology of ADHD. Results from studies of lesions in animals and humans led many investigators to conclude that response inhibition may be localized specifically to ventral prefrontal regions (with a right preponderance) and consequently that ADHD may be the result of developmental abnormalities localized to this region. More recent data from electrophysiology and imaging studies, however, have lent support to a multiple-domain model of response inhibition according to which the specific region of the frontal lobe crucial for response inhibition depends on the nature of the task (skeletomotor, oculomotor, cognitive, socioemotional) being performed. Furthermore, evidence from neurobehavioral and imaging studies in ADHD has indicated that abnormalities within the frontal lobe may not be restricted to ventral prefrontal regions. Accordingly, we propose to investigate the hypothesis that in ADHD there exist abnormalities of several frontal lobe regions, each of which contributes to one of several parallel deficits in response inhibition, involving skeletomotor, oculomotor, cognitive, and socioemotional domains. Alexander's model of frontal-subcortical circuits (recently updated by Middleton and Strick to include skeletomotor, oculomotor, dorsolateral prefrontal, anterior cingulate, and medial/lateral orbitofrontal circuits) will serve as a basis for these experiments. Behavioral paradigms, aMRI and fMRI will be used to determine which frontal circuits are affected in ADHD and in what way abnormalities within specific frontal circuits are associated with the behavioral/cognitive deficits that define ADHD; an important feature of the methodology is the use of behavioral tasks both outside and inside the scanner (i.e. fMRI) that have been carefully designed to probe functioning of specific frontal circuits. The findings will not only contribute to increased understanding of the pathophysiology of ADHD, but also improve clinicians' ability to diagnose ADHD and make decisions regarding targeted interventions (pharmacologic, behavioral, and cognitive) for individuals with the disorder.
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