PROJECT SUMMARY/ABSTRACT This proposed study is a step toward the career development goal of becoming an independent researcher who focused on the study of the functional connectivity alterations among opioid users. The opioid overdose results in almost 450,000 deaths during 1999-2018, and 128 people in the United States die every day from the opioid overdose in 2018. Abuse of prescription opioids is likely due to factors that affect the mesolimbic and cortico- striatal system in the brain, including alteration of dopamine release and loss of cognitive control. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum is associated with compulsive reward-seeking behavior despite negative effects (e.g., punishment). At present, it remains unknown whether opioid use is associated with the functional connectivity alterations between the OFC and dorsal striatum in humans. The gold standard to characterize the functional connectivity is to pair brain stimulation with neuroimaging. Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-approved brain stimulation for depression, which is also being pursued as a treatment for opioid use disorder. TMS can be paired with fMRI in concurrent TMS-fMRI experiments to characterize causal manipulations of functional neural circuits. The overarching goal of this application is to use the novel method, concurrent TMS-fMRI, to investigate whether opioid use is associated with the functional connectivity alterations between the mesolimbic and cortico-striatal system in human. I will characterize functional connectivity between the OFC, dorsal striatum, and habenula in both healthy subjects and opioid users (Aim 1). I will then evaluate brain response to the repetitive TMS (rTMS) treatment in opioid users (Aim 2). The results from this proposal will yield a significant step forward in developing the neural- circuit based strategies as treatments for opioid use disorder. The candidate is currently a tenure-track Assistant Professor in the Department of Psychiatry. This application will provide multidisciplinary training for the candidate to learn the needed skills: (1) learn the neurobiological basis of addiction, and learn evidence-based methods of assessment and treatment for individuals with addiction, specifically opioid use disorders (OUD); (2) learn mechanisms and clinical application of rTMS in opioid use, including the experience in designing and conducting randomized controlled trials; and (3) learn clinical outcomes data analysis and interpretation using advanced statistical methods. Completion of the training and research aims will establish a strong foundation from which the candidate will acquire the skills and knowledge to launch an independent scientific career, as well as provide a publicly available brain stimulation solution to opioid users.