This project is directed towards enhancement of our understanding of OCD pathophysiology and to investigate potential new treatments for this major neuropsychiatric disorder. Our studies focus on regional brain function in OCD, and on investigating possible genetic vulnerabilities to the illness. Prefrontal cortex-basal ganglia circuits are implicated in OCD. We found, using the novel technique of repetitive transcranial magnetic stimulation (rTMS) that focal stimulation of right prefrontal cortex temporarily reduced compulsive urges, suggesting the utility of rTMS as a probe of regional brain activity in OCD. The possibility that repeated rTMS sessions might have therapeutic effects in OCD is currently being explored in a controlled study. A study using a different TMS technique found preliminary evidence of deficits in intracortical inhibitory processes in OCD patients. A pilot study found that that open administration of the GABA-modulatory agent gabapentin, which may enhance intracortical inhibition, improved symptoms in OCD patients poorly responsive to fluoxetine monotherapy. A controlled study of gabapentin augmentation of fluoxetine treatment in OCD is underway. As a test of the hypothesis that injury to the basal ganglia predisposes to OCD, we are performing MRI T2 mapping and volumetric studies of the basal ganglia in OCD patients stratified by age of illness onset. Detection of a neuroimaging signature of such injury would be consistent with hypotheses of autoimmune basal ganglia injury as important in OCD etiology. We are exploring possible genetic etiologies of OCD by focusing on allelic variants which may affect neurotransmission in brain circuits relevant to OCD. A case-control study of a polymorphism in the catechol-O-methyl transferase gene (which produces functional effects on the activity of this enzyme) suggested that this polymorphism may constitute a risk factor for OCD. Preliminary analysis also suggests an association between allelic variation at the serotonin transporter promoter regon polymorphism site and OCD, constituting some of the first evidence that genetic differences in serotonin systems may predispose to OCD.