PROJECT SUMMARY/ABSTRACT According to the WHO, OCD is one of the top ten causes of disability among young adults, and one in ten patients have severe symptoms refractory to cognitive and medical therapies. OCD is thought to be mediated by a cortico-striato-thalamo-cortical (CSTC) circuit anchored in the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). Deep brain stimulation (DBS) is a targeted circuit-based treatment that has been used to treat severe, refractory cases of OCD. However, DBS remains limited in its use because: 1) currently only 50- 60% of patients respond to therapy, 2) DBS programming is a complex, trial-and-error process that can take months to years to optimize, and 3) DBS is associated with adverse effects such as sleep disturbance and mania. We aim to overcomes these limitations by developing methods to target DBS therapy to the neural circuits underlying OCD. Developments in DBS technology now allow for MR imaging to be performed while DBS is On/Off and local field potential recordings can now be acquired from DBS leads, providing a unique opportunity to determine whether DBS therapy is functionally engaging the intended OCD circuitry. Here, we propose to: 1) Develop protocols for generating personalized spatial activation maps using stimulation-based fMRI, and 2) Identify individualized electrophysiological biomarkers of OCD and related psychiatric symptoms responsive to DBS using intracranial recordings. Together, these imaging and electrophysiological methods can be used to verify that DBS is engaging the OCD network. In our pilot studies, we demonstrate the feasibility of generating stimulation maps using fMRI protocols in a single subject, finding activation in the OFC and ACC distant from the empirically determine therapeutic contacts. We also describe the identification of a gamma biomarker of depression within the bed nucleus of the stria terminalis (BNST), serving as a proof-of-concept that it is possible to identify electrophysiological biomarkers of psychiatric symptoms. We currently have FDA investigational device exemption (IDE) approval to implant DBS leads in the OFC and ACC in addition to the standard anterior limb of the internal capsule (ALIC) DBS target for OCD. This proposal seeks to determine whether our initial imaging findings will hold in a larger cohort of subjects and to determine the feasibility of discovering novel OCD biomarkers by performing intracranial recordings across critical nodes of the OCD network. These studies provide a path towards personalized, circuit-based precision medicine to improve DBS for OCD.