PROJECT SUMMARY: Toward Connectomic Deep Brain Stimulation in Obsessive Compulsive Disorder Obsessive-Compulsive-Disorder is a leading cause of disability worldwide with about 10% of patients that are refractory to conventional treatment while suffering from substantial burden of disease. Deep Brain Stimulation (DBS) is a treatment option for these patients, but while some respond excellently to this invasive procedure, not all patients do. One reason could be that we conceptualize DBS to modulate a brain region, rather than a brain network. The goal of this project is to causally link symptom specific improvements in OCD to the stimulation of specific brain networks. By doing so, we will be able to derive symptom-specific network targets for treatment in DBS. In our preliminary research, we identified a specific network target that was associated with optimal response following DBS to four different surgical targets applied world-wide. Our findings were based on the largest multi-center OCD cohort with DBS studied to date (N = 50) and have been confirmed by four additional centers since they were published. While results are promising, three gaps remain before moving toward prospective clinical trials. The aim of this R01 will be to close these gaps. First, we have defined optimal networks by means of structural and functional connectivity but, so far, it remains unclear which of these two modalities (or a combination of both) is best suited to guide DBS. Second, while modulating the network leads to optimal response on a group level, OCD is a heterogeneous disease and symptoms in each patient are different. We will determine which specific symptoms (obsessions, compulsions, depression and anxiety) map to which specific components of the network. This will pave the way to personalize DBS and to define symptom-specific targets tailored to individual patients. Third, while most of our preliminary research is based on normative connectome atlases of the human brain, connectomes of patients with OCD present with individual differences. We will test how much additional variance in clinical outcomes can be explained when using patient-specific instead of normative connectomes. Completion of these aims will validate and refine our OCD response network. If successful, this study will facilitate future trials directly targeting our brain circuit with DBS for OCD.