The clinical diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) affects 5-10% of school-age children, many of whom receive suboptimal or no treatment. At the same time there is increasing concern regarding potential over-diagnosis and unnecessary treatment. This application is to establish an interdisciplinary inter-institutional network focused on testing the specific hypotheses that (1) ADHD results from dysregulation by the cerebellar vermis of brainstem catecholaminergic nuclei, which negatively affect striatal and prefrontal cortical functioning; and (2) that abnormalities in neocerebellar mediated temporal processing result in cascaded deficits in executive function and in excessive behavioral variability.
The specific aims are to (1) form an interdisciplinary inter-institutional network; (2) conduct pilot studies in rats to establish the regional localization of dopamine relative to norepinephrine in cerebellum; determine the effects of stimulants administered locally into cerebellar """"""""hot spots"""""""" on striatal and prefrontal dopamine levels using microdialysis; examine whether low oral doses of stimulants will improve prefrontal behavioral performance; if so, whether those improvements can be blocked by prefrontally administered antagonists; and whether stimulants administered locally into vermis produce enhancements in prefrontal function; and (3) to conduct an FMRI study in adolescents with ADHD and matched controls using a reward anticipation task that activates nucleus accumbens, cerebellar vermis, and prefrontal cortex in adults; and to refine for FMRI a time perception task on which subjects with ADHD perform abnormally. The ultimate aim of this proposal is to test putative links between basic science observations and aspects of the ADHD phenotype so as to initiate the process of evolving diagnostic criteria grounded in etiological and mechanistic constructs. Because of the extensive heterogeneity within current populations defined by syndromal presentations, we anticipate that pursuing a """"""""bottom-up"""""""" (instead of """"""""top-down"""""""") approach is more likely to lead to objective quantitative criteria that could be used to derive neurobiologically meaningful subtypes of ADHD. Eventually, such advances in nosology will lead to improved matches between treatment options and the underlying disorder(s).
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