SUMMARY With advances in opto-/chemo-genetic stimulation techniques, preclinical studies have demonstrated that activity in frontal-striatal neural circuits has a causal influence on heavy alcohol drinking and relapse-like behavior. Similar findings using modern fMRI imaging techniques in humans have confirmed some of these findings. Clinically, however, we have not yet translated this research into a neural circuit based therapeutic technique for patients with alcohol use disorder (AUD). The long term goal of our multidisciplinary research team is to determine the optimal parameters through which non-invasive transcranial magnetic stimulation (TMS) can be used to improve alcohol drinking outcomes (abstinence, heavy drinking days) among individuals seeking behavioral treatment for AUD. Building on a foundation of several TMS brain target identification studies and a small double-blinded clinical trial in treatment-engaged AUD patients performed by our group in the Charleston Alcohol Research Center (ARC), here we propose a double-blind placebo controlled, randomized study to evaluate the efficacy of theta burst stimulation (TBS) to ventromedial prefrontal cortex (vmPFC) as a treatment to decrease drinking and brain reactivity to alcohol cues among treatment-seeking individuals with AUD. Individuals will be screened initially by the ARC Clinical Intake and Assessment Core, then given an opportunity to enroll in this study, provide informed consent, and be randomized to receive real or sham TBS to the vmPFC 36 sessions (3x/day on each of 3 days/week over 4 weeks, i.e., 12 days). Prior to randomization and again after 4 weeks of TBS treatment, they will receive a well-established and validated alcohol-cue stimulation BOLD fMRI procedure. The scientific premise of this ARC research proposal is that, by modulating the neural circuits that regulate alcohol cue-reactivity, it will be possible to increase alcohol abstinence rates and decrease heavy drinking days over a 4-month period. Accordingly, we will explore the relationship of TBS-induced changes in brain reactivity to alcohol cues as mediators of the TBS treatment response. Also, brain activation to natural reward and threat cues will be studies as a means to probe potential effects of TBS treatment on negative affect/emotionality associated with AUD. With our combined scientific expertise in brain stimulation, neuroimaging, clinical (and preclinical) alcohol-related research in the Charleston ARC, and AUD clinical trial expertise, MUSC is uniquely suited to develop this critical line of research. The outcomes of the proposed Aims will provide an evidence-based foundation for a multisite clinical trial and will hasten progress towards developing a new neural circuit-based treatment for individuals with AUD.