Alcohol Use Disorder (AUD) is prevalent, devastating, and difficult to treat. The intransigence of AUD is readily apparent in the Trauma Unit of Wake Forest University Baptist Hospital, wherein 23% of trauma related admissions are associated with alcohol - higher than the national average of 16%. Of these trauma related admissions, over 70% are estimated to have AUD and 41% will be likely be admitted to the trauma unit again within 5 years. While Dr. Veach (Co-Investigator) and her team in the Department of Surgery have demonstrated that a brief counseling intervention on the inpatient trauma unit can decrease morbidity and recidivism, the rates of AUD and relapse to drinking among these individuals remains very high. With a growing knowledge of the neural circuits that contribute to relapse in AUD, there is an emerging interest in developing a novel, neural-circuit specific therapeutic tool to enhance AUD treatment outcomes. The long term goal of the multidisciplinary research team (Hanlon \& Veach) is to develop an evidence-based brain stimulation treatment which can ultimately be prescribed to individuals that present to the Trauma Unit with AUD - decreasing their drinking and hospital recidivism.

The competing neurobehavioral decision systems (CNDS) theory posits that in addiction, choice results from a regulatory imbalance between two decision-making systems (impulsive and executive). These behavioral systems are functionally linked to two functional connectivity networks which regulate the incentive salience of the alcohol cue (Salience Network) and cognitive flexibility required for a vulnerable individual to shift attention away from the alcohol cue (Central Executive Network). Modulating these competing neural circuits (e.g. either dampening the incentive salience associated with alcohol cues (Strategy 1) or amplifying cognitive control in the presence of a cue (Strategy 2) may render alcohol users less vulnerable to relapse. Over the past 7 years, Dr. Hanlon's human brain stimulation research group has been focused on focused on Strategy 1 - dampening alcohol craving and brain reactivity to alcohol cues among heavy alcohol drinkers at risk for AUD or relapse to alcohol use. These studies led to a formal double-blind sham-controlled clinical trial of medial prefrontal cortex (mPFC) continuous theta burst stimulation (cTBS) in treatment-seeking alcohol users. Unfortunately, however, this approach is associated with more pain at the stimulation site (forehead) which undermines its promise as a tool to be readily scaled to a larger population, and it is not clear that this improves the attentional bias towards alcohol cues among these individuals.

Hence, the goal of this proposal is to evaluate Strategy 2 of the CNDS theory- increasing activity in executive control circuitry- as an innovative approach to dampening alcohol cue-reactivity (Aim 1) and improving cognitive control in the presence of an alcohol cue (Aim 2). This will be achieved through a double-blind, sham-controlled cohort study in heavy alcohol drinkers with a history of alcohol-related injury. The brain reactivity to alcohol cues (Incentive Salience) and cognitive performance in the presence of an alcoholic beverage cue (Cognitive Control) will be measured immediately before and after participants receive real or sham intermittent theta burst stimulation (iTBS- a potentiating form of transcranial magnetic stimulation (TMS)) to the dorsolateral prefrontal cortex (dlPFC iTBS). iTBS is a high-potency form of brain stimulation wherein two minutes of iTBS (600 pulses) leads to an increase in cortical excitability that lasts for approximately 30 minutes. In 2018 dlPFC iTBS was FDA-cleared as a treatment for major depressive disorder (wherein 30 sessions over 6 weeks lead to a sustained decrease in depressive symptoms for 6 months). In 2019, the first 2 manuscripts were published demonstrating that iTBS decreases cue-reactivity to cocaine. The goals of this pilot study are to quantify the acute effect of a single session of real or sham dlPFC iTBS on brain response to alcohol cues (Aim 1) and cognitive flexibility in the presence of an alcohol cue (Aim 2) among risky drinkers ("target engagement").

Aim 1: Evaluate the effect of dlPFC iTBS on alcohol cue-reactivity. The blood-oxygen level dependent (BOLD) signal associated with exposure to alcohol cues will be measured before and after sham and real iTBS using a validated, patient-tailored alcohol/non-alcoholic beverage cue task. Hypothesis: cue-evoked functional connectivity in the mPFC, anterior cingulate cortex (ACC), amygdala, and ventral striatum will be attenuated after real but not sham iTBS.

Aim 2: Evaluate the effect of dlPFC iTBS on cognitive performance in the presence of an alcohol cue. Following the alcohol cue reactivity task all individuals will perform the well-known alcohol Stroop task (downloaded from the NIH toolbox) on a Tablet PC while a glass of the participant's preferred alcoholic beverage (beer, wine, liquor) is placed within 5 feet of the participant (but out of arms length). This will occur before and after TBS. The participant will not be allowed to consume the drink. Hypothesis: Stroop accuracy and reaction time will be impaired at baseline, but this difference will be attenuated by real (but not sham) iTBS to the dlPFC (three way mixed model ANOVA, correcting for multiple comparisons).