Project Summary (Abstract) Overall The overall goal of this Center is to further understand and probe the neural network central to obsessive compulsive disorder (OCD) and the abnormalities within that network that are associated with impaired behavioral flexibility that is reflected in persistent avoidance, a key clinical feature of the disease. The rostral and dorsal anterior cingulate cortex (rACC and dACC), orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), insula and the striatum are associated with abnormalities in OCD and are the cortical nodes in the OCD network (OCDnet). The Center hypothesis is that the behavioral inflexibility reflected in persistent avoidance in OCD is the result of circuit dysfunction between central nodes in the OCD network (OCDnet). Collectively we will use a multimodal, cross-species network approach to achieve 3 overarching aims: 1. Identify cortical regions within the OCDnet that cross-link circuit connections to other nodes; 2. Understand how impairments in behavioral flexibility that results in persistence avoidance are associated with these connections in OCD patients compared to healthy control subjects; and 3. Study the effects of modulation on these circuits and on behavioral inflexibility. Specifically, Aim 1 will use a combination of animal studies (P1, 2), and human studies (P1, 3, Cores B, C) to characterize the OCDnet circuits anatomically, physiologically, and behaviorally; Aim 2 will characterize how impairments in a newly developed probabilistic approach avoidance task PAAT are linked to the abnormalities in the OCDnet (P2-4, Core B-D); and Aim 3 will modulate the OCDnet in OCD patients using both conventional treatments (P4) and direct circuit manipulations (P5) (Cores B-D). Collectively, these studies will further our understanding of circuit interactions of key brain regions implicated in OCD, their involvement in behavioral inflexibility that results in persistent avoidance associated with OCD, and the effects of neuromodulation of those circuits.