Project Summary Alcohol Use Disorder (AUD) contributes to 88,000 deaths per year in the United States. Although several pharmacological treatments are available, adherence to these treatments is low and approximately 60% of individuals relapse within 6 months. Further, these treatments modulate the brain in a relatively global fashion. Evidence from neuroimaging studies of AUD patients has shown that elevated cortico-striatal activity in response to alcohol cues predicts relapse. Thus, there is an emerging interest in developing novel, neural-circuit specific therapeutic tools to enhance AUD treatment outcomes. Transcranial magnetic stimulation (TMS) is one such non-invasive, neural-circuit specific tool. Through electromagnetic induction, repetitive pulses of TMS can be applied to the cortex to change neural activity within a cortical circuit. Subsequently, TMS for AUD has been developed as a strategy to reduce brain reactivity to alcohol cues within the prefrontal cortex and its downstream targets in the striatum. I recently led an analysis of a randomized, double-blind clinical trial applying 10 days of TMS to the medial prefrontal cortex among AUD patients. Relative to sham, individuals who received real TMS were 3 times more likely to remain sober and experienced a reduction in average brain reactivity to alcohol cues. Despite these positive results, there was considerable variability in that approximately 1/3 of individuals who received real TMS relapsed to alcohol and reductions to striatal reactivity to alcohol cues were not uniform. My NIAAA-sponsored F31 demonstrated that individual patterns of brain response to alcohol cues are highly variable among AUD patients and often occur outside of the prefrontal cortex. Given this spatial variability, delivering TMS to a fixed point on the scalp leads to a situation in which TMS electrical fields do not always overlap with an indvidual’s brain response to alcohol cues. In a proof-of-concept retrospective analysis, I found that patients who had overlap between alcohol cue-reactivity patterns and TMS electrical fields had the best clinical outcomes. This K99/R00 proposal seeks to build upon this analysis by developing prospective functional connectivitiy - guided TMS (fcg-TMS) clinical trials for AUD. First, using an existing dataset, we aim to characterize the spatial topography of TMS cortical targets as defined by peak functional connectivity with the striatum during alcohol cue presentation (Aim 1, K99 phase). Then, we aim to evaluate the efficacy of one session of functional- connectivity guided TMS (fcg-TMS) on reducing striatal response to alcohol cues, a key biomarker of treatment efficacy (Aim 2, K99 Phase). These K99 aims will be complemented by a training plan that includes 4 domains: clinical trial design, fcg-TMS, laboratory leadership, and complex modeling of relapse and brain networks in AUD. Following these foundational trainings and experiments, Aim 3 (R00 phase) of this proposal...