Neuroimaging and behavioral endophenotypes of response to DBS in OCD

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A core feature of OCD is heightened anxiety resulting in avoidance of situations including rewarding activities. This suggests an abnormal balance between instrumental responses to avoid potentially negative stimuli and those to pursue reward. The most effective behavioral treatment for OCD (exposure and ritual prevention - ERP) teaches patients to extinguish avoidant and compulsive responses to feared situations. However, by definition ERP is unsuccessful for DBS candidates. Clinical experience indicates that patients unable to benefit from ERP before DBS did so afterwards, describing reduced avoidance of OCD triggers and increased pursuit of pleasurable activities. For this reason, measuring both extinction learning and regional brain metabolism in DBS patients is a promising route to improving our understanding of the neural circuitry involved in both ERP and DBS. Project 1 will assess how optimal DBS stimulation at the most clinically effective ventral capsule/ventral striatum (VCA/S) target changes activity within the orbital and medial PFC-BG circuits which have been strongly implicated in reward and avoidance, using FDG PET to measure brain metabolism. The PET experiments will test the hypothesis, informed by preliminary results (P1) and results from rat experiments (P4), that relative OFC and vmPFC activity will shift in favor of vmPFC after chronic DBS. We will interpret these network effects, and refine regions for PET analyses, in the context of the avoidance-reward network derived from information provided by P2, P3, & P4. Subsequent experiments in PI will test the hypothesis that chronic VCA/S DBS is associated with enhanced extinction, which in turn will correlate with improvement in OCD. Moreover, since the components of fronto-striatal circuitry that are implicated in OCD are also involved in both avoidance and reward across species, P1 will adapt and test a new paradigm, originally developed as a primate model (see P3), to assess avoidance- reward competition in OCD patients before and after DBS. Finally, data from P5 & P6 will provide critical information for developing hypotheses about mechanisms underlying changes in PET metabolic measures after DBS. They will also suggesting potential improvements in stimulation devices and paradigms to more effectively modify the circuits involved. RELEVANCE (See instructions): P1 will advance knowledge of brain circuit changes after DBS, and of the roles of extinction learning/recall and avoidance-reward competition as endophenotypes for processes in the development and maintenance of OCD symptoms. Better understanding changes in these circuits and behavioral endophenotypes will aid development of more targeted and effective treatments for OCD and related disorders