ABSTRACT. The goal of Project 3 (P3) is to characterize, in OCD, white matter (WM) bundle and functional neural abnormalities among regions in a putative OCD neural network that are associated with persistent avoidance, a characteristic feature of OCD. Our overarching Center renewal hypothesis, building on our present findings, is that persistent avoidance in OCD is a manifestation of dysfunctional connections among specific hubs, i.e., subregions that integrate and distribute information from multiple regions, in the ventrolateral prefrontal cortex (vlPFC) and rostral anterior cingulate cortex (rACC), and other regions in the OCD network, including the insula, dorsal ACC (dACC), orbitofrontal cortex (OFC) and rostral striatum. These dysfunctional connections lead to impaired behavioral flexibility in response to changing contextual cues, specifically in situations with uncertain aversive outcomes. In P3, we will recruit and examine 50 unmedicated/ serotonin reuptake inhibitor/clomipramine medicated participants with OCD, and 50 healthy participants (18-35 yrs; to minimize effects of long illness history and medication on neural measures). We will use state-of-the-art diffusion imaging (dMRI), using tractography, segmentation and tract profiling - tractometry - to examine WM bundles in the network. We will use functional Magnetic Resonance Imaging (fMRI) to examine activity, functional and effective connectivity (FC, EC) among network regions during a novel probabilistic approach avoidance task (PAAT) that we developed to examine the influence of uncertain rewarding and aversive outcomes on choice behavior, and neural activity, FC and EC during evaluation and anticipation of these outcomes. We will examine relationships among WM, activity, FC and EC abnormalities in the OCD network in OCD participants and the severity of OCD symptom dimensions associated with persistent avoidance, e.g., harm avoidance. Gender will be a covariate in analyses. Aim (A)1 will compare the microstructure of WM bundles that connect vlPFC, rACC, insula, dACC, OFC and rostral striatum in OCD vs. healthy participants, using a novel combination of tractography, segmentation and tractometry. A2 will compare activity within and FC and EC among these OCD network regions in OCD vs. healthy participants during the PAAT, to determine relationships among PAAT performance and fMRI abnormalities in OCD vs. healthy participants. A3 will examine relationships among OCD symptom dimensions that are relevant to persistent avoidance: e.g., harm avoidance, contamination/ washing, responsibility for harm/checking symptoms, and: WM and fMRI abnormalities in A1-2. P3 will benefit from expertise in: NHP neuroanatomy and physiology in P1, 2 (A2); dMRI data analysis in P1, Core B (A1); clinical assessment and treatment of OCD in P4, 5 (A3); the study of individual differences in neuroanatomy in Core C (A2-3); and integration of analyses across projects in Core D. In close collaboration with othe...