Project Summary Obsessive-Compulsive Disorder (OCD) is a debilitating psychiatric illness affecting 1-3% of the world population. Although current therapeutic and pharmacological treatments provide some level of symptom relief, 40-60% of OCD patients do not respond adequately to these approaches. Thus, a better understanding of the OCD neural circuitry is much needed to develop new treatments. Recent studies show that combining non-human primate (NHP) neuroanatomy with human neuroimaging allows for a precise anatomic-functional description of specific brain circuits and pathways. In this application, Dr. Trambaiolli will use NHP neuroanatomy to evaluate specific cortico-striatal connections relevant to avoidance symptoms in OCD. He will map precise connections between these areas using NHP tract-tracing methods and translate these circuits to NHP and human functional magnetic resonance imaging (fMRI) (Aim 1-K99). He will combine the connections mapped in Aim 1 with normative modeling algorithms to identify connections within this circuit that deviate from normality and correlate with OCD symptomatology (Aim 2-R00). This translational circuit will be targeted during a real-time fMRI neurofeedback protocol, in which the participant will be trained to achieve voluntary control over specific functional connections. First, this protocol will be optimized in healthy participants (K99). Later, the effects of neurofeedback control on OCD symptoms will be evaluated in a single-group clinical trial (R00). Dr. Trambaiolli's prior training and publication record indicate his expertise in real-time signal processing, machine learning, and quantitative methods in neuroanatomy. To fully attain his research goals, however, he needs additional training in translational models in psychopathologies (Core A), neuroimaging in clinical settings (Core B), and clinical assessments and interventions (Core C). During the mentored phase, he will receive guidance from a mentoring team led by Dr. Suzanne Haber, a translational neuroanatomist with experience in OCD circuitry (Core A and B), and a Professor of Pharmacology and Physiology at the University of Rochester and a permanent Visiting Professor at McLean Hospital – Harvard Medical School (HMS), Dr. Justin Baker, a clinical neuroscientist experienced in NHP data analysis and biomarker discovery (Cores A and B), and the Scientific Director of the McLean Institute for Technology in Psychiatry (ITP), Dr. Brian Brennan, a clinical scientist with expertise in OCD biomarkers and interventions (Cores B and C), and the Medical Director of the OCD Institute (OCDI) at McLean, and Dr. Darin Dougherty, a clinical scientist experienced in OCD biomarkers and the development of new device- based therapies (Cores B and C), and the Director of the Division of Neurotherapeutics at the Massachusetts General Hospital (MGH). The training and associated research will occur at McLean Hospital and HMS, a unique environment dedicated to providi...