Diagnostically cross-cutting intermediate phenotypes of impulsivity and compulsivity. (360G-Wellcome-110049_Z_15_Z)

The proposed research will deconstruct impulsivity and compulsivity using cutting-edge neurocognitive tests, structural and functional neuroimaging, pharmacological challenge of the brain dopamine/adenosine systems, and quantification of peripheral dopamine status. In this way I aim to link cognitive and brain systems phenotypes of impulsivity/compulsivity to more mechanistically specific markers of abnormal neurotransmission and to demonstrate how these intermediate phenotypes are expressed dim ensionally in the population, and cut across two major diagnostic categories of psychiatric disorder. The key goals will be to address three core hypotheses: 1. That underlying intermediate phenotypes of impulsivity/compulsivity (measured using neurocognitive tests and psychopathology questionnaires) manifest as extremes of the normal population distribution (in the absence of overt psychiatric disorders) and, similarly, in classical psychiatric disorders of impulsivity and compulsivity (atte ntion-deficit hyperactivity disorder and obsessive-compulsive disorder). 2. That these intermediate phenotypes of impulsivity/compulsivity emerge as a consequence of altered fronto-striatal activity, and are under the modulatory influence of brain dopaminergic and adenosine neurochemical systems. 3. That these intermediate phenotypes of impulsivity/compulsivity, and their tractability to dopaminergic and adenosine drug manipulations, are correlated with peripheral blood-based biomarkers o f dopamine function.