PROJECT SUMMARY There is an urgent need to identify novel treatment targets for cocaine use disorder (CUD), as pharmacological treatments have largely failed. The goal of this award is to evaluate the effects of transcranial magnetic stimulation (TMS) on electroencephalogram (EEG) markers of reward functioning in adults with CUD. This goal will be met by the research strategy and a rigorous training plan for Dr. Webber, who is uniquely positioned to utilize electroencephalogram to assess TMS effects on the brain in CUD. Building on Dr. Webber's expertise in cognitive neuroscience, electrophysiology, and addiction, the current career development plan will provide training in: 1) transcranial magnetic stimulation research and clinical application, 2) advanced time-frequency- based approach to electroencephalogram analysis, and 3) running an independent clinical trial. This training will put Dr. Webber at the forefront of TMS development and mechanism identification for substance use disorders and will position Dr. Webber as an independent investigator in addiction neuroscience. While TMS has shown early success for treating CUD, there are important, yet addressable issues for optimizing TMS treatment. First, the majority of studies have stimulated dorsolateral prefrontal cortex, yet many areas of the prefrontal cortex are hypoactive in chronic cocaine use. Second, it is vital to identify reliable biomarkers to identify targets for treatment and alternative end points in clinical trials. Electrophysiological markers (Reward Positivity and Late Positive Potential) of reward sensitivity and motivated attention toward drug cues, two factors that hinder treatment success and increase risk for relapse, hold promise for TMS manipulation. Third, heterogeneity in TMS effects still need to be explained, which can lead to the improvement of individualized treatment. The current study will compare a novel site, dorsomedial prefrontal cortex, to both sham and traditional dorsolateral prefrontal cortex in a 3-arm, within-subjects, cross-over design to assess the acute effects of TMS administration on the Reward Positivity and Late Positive Potential. This proof-of-concept study will provide critical information on whether TMS administration has the potential to manipulate important reward functioning deficits observed in CUD. This will be accomplished by: 1) Assessing the effects of TMS to the dorsomedial prefrontal cortex and left dorsolateral prefrontal cortex compared to sham on the time-frequency aspects of the Reward Positivity, 2) Assessing the effects of TMS to the dorsomedial prefrontal cortex and left dorsolateral prefrontal cortex compared to sham on the Late Positive Potential, and 3) Identifying individual differences in TMS effects with baseline characteristics (CUD severity, impulsivity, and craving). This work will contribute to increasing knowledge of TMS in CUD and provide a strong foundation for the design and submission of an R01 application in Year 5 of the K01 training, thereby launching Dr. Webber's progression toward an independent research career. Ultimately, this work will lead to the development of optimal brain stimulation procedures to treat CUD and other substance use disorders.

PROJECT NARRATIVE Cocaine use disorder is a chronic, relapsing condition with severe public health impacts and limited effective treatment options. The current proposal aims to assess the acute effects of transcranial magnetic stimulation on electroencephalogram markers that contribute to poor treatment outcomes and has the potential to advance NIDA's objective of developing novel treatments that specifically target underlying neurobiological mechanisms of cocaine use disorder. This study can potentially improve transcranial magnetic stimulation treatment and ultimately lower the health burden of cocaine use disorder on the individual and society.