Alcohol Use Disorder (AUD) is prevalent, devastating, and difficult to treat. The majority of therapeutic approaches to date have relied on pharmaceutical modulation or and/or psychotherapy. 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 this multidisciplinary research team is to develop an evidence-based brain stimulation treatment protocol which will improve AUD treatment outcomes. 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 discrete frontal-striatal circuits which regulate limbic and executive control. Modulating these competing neural circuits (e.g. either dampening the limbic/impulsive system or amplifying the executive control system) may render alcohol users less vulnerable to relapse. These two frontal-striatal neural circuits - the limbic loop (ventromedial prefrontal cortex (VMPFC)-ventral striatum), and executive control loop (dorsolateral PFC (DLPFC)-dorsal striatum) can be differentially stimulated by theta burst stimulation (TBS), a patterned form of transcranial magnetic stimulation.

Over the past 7 years, through the scaffolding of a National Institute on Alcohol Abuse and Alcoholism (NIAAA) P50 Center and a strong Brain Stimulation Research program, this multidisciplinary group of clinicians and neuroscientists has demonstrated) it is possible to differentially activate these circuits through TMS/Blood-oxygen-level-dependent (BOLD) imaging TBS to the VMPFC decreases orbitofrontal cortex and ventral striatal/accumbens BOLD signal in heavy alcohol users TBS also decreases alcohol cue reactivity in this population and in AUD patients currently enrolled in intensive outpatient treatment, 10 days of TBS to the VMPFC is feasible, well-tolerated, increases 1 and 2 month retention rates, and attenuates limbic brain reactivity to alcohol cues after 1 month. While these studies provide a strong foundation for pursuing a larger multisite trial of TBS, the CNDS theory and other alcohol TMS studies suggests that the DLPLC may also be a fruitful treatment target. In a sham-controlled pilot study the study team recently compared the efficacy of VMPFC TBS to DLPFC TBS, and, to the study team's surprise demonstrated that a single session of DLPFC TBS had a greater effect on the brain response to alcohol cues than VMPFC TBS. To resolve this gap in understanding, the investigator proposes a randomized, double-blind, sham-controlled clinical trial to evaluate the relative efficacy of these 2 strategies as novel tools to improve AUD treatment outcomes (e.g. percent days abstinent up to 4 months after TMS treatment initiation). These outcomes will be measured with urine ethyl glucuronide (ETG) and blood carbohydrate deficient transferrin (CDT) measurements. The study team will also evaluate the effect of these TBS treatments brain reactivity to alcohol cues. The investigator's long-term vision is that TBS would be used as an adjuvant to behavioral treatment, enabling individuals to maximize the likelihood of behavioral change.

180 treatment-seeking men and women recruited from the community at large, will be randomized to receive 15 visits of TMS (2x/day; 3x/week, 20-30 min intersession interval) of either real or sham TBS to the VMPFC or left DLPFC while they are enrolled in the proposed study. Randomization will occur after the participant has been consented and screened for eligibility and prior to the first treatment visit. Real/Sham TBS will be delivered three times per week for a total of 15 TMS visits. Quantitative ETG will be collected daily. Quantitative CDT will be collected monthly throughout the course of the study. Additional assessments and/or brain reactivity to alcohol cues will be measured at the following timepoints: baseline screening visit, MRI visit #1 (before TMS treatment visit 1), TMS treatment visits 1, 6, 11, and 15, MRI visit #2, and at the 3 monthly Follow Up visits. A saliva sample taken for genetic analysis of a specific Brain-derived neurotrophic factor (BDNF) variant will be obtained on enrollment and used to also analyze across these measures and individual outcomes in response to TMS. Building on recent pilot data, the study team will test the hypotheses that for both Strategy 1 \& 2, real TBS will improve AUD treatment outcomes significantly more than sham. Analysis will be performed using repeated measures analysis of variance (ANOVA) on change scores from baseline for each visit. The main independent variable in the ANOVA will be time (TMS visits 1, 6, 11, and 15), group (VMPFC vs. DLPFC TBS vs. sham) and their interaction.

Aim 1 (Strategy 1): Modulating the limbic system: VMPFC TBS. The study team will evaluate the effect of VMPFC TBS, relative to sham, on number of days abstinent (primary outcome) and heavy drinking days in 30 day intervals for 4 months. Participants will receive stimulation over the left frontal pole electroencephalogram (EEG)10-20 system: Frontal Pole 1 (FP1). This location has been used in previous studies in alcohol users which demonstrate VMPFC target engagement.

Aim 2 (Strategy 2): Modulating the executive system: DLPFC TBS. The study team will evaluate the effect of DLPFC TBS, relative to sham, on the parameters listed. TBS will be delivered over the left DLPFC EEG 10-20 system: Frontal 3 (F3) as this location has also been validated to reliable result in target engagement by this group.

Exploratory Aim- Baseline alcohol cue reactivity as a mediator of TBS clinical response. The study team will test the hypotheses that individuals with a higher ratio of (DLPFC-striatal)/(VMPFC-striatal) response to alcohol cues will be more likely to have a change in drinking after Strategy 2.