Frontal-Striatal Reward Circuit Neuromodulation and Alcohol Self-Administration

This will be a single site randomized, 2-session, within-subject cross-over design pilot study. 20 enrolled (of 30 consented) subjects reporting varying levels of binge and high intensity drinking, defined as at least 2 episodes of drinking 4 (for women) or 5 (for men) drinks on an occasion over the last 5 weeks, (unless determined by PI that drinking history meets study objectives), will be enrolled. Subjects will be randomized to undergo one session of repetitive transcranial magnetic stimulation (rTMS) or sham immediately followed by the investigators rate control intravenous (IV) alcohol self-administration (ASA) paradigm. Subjects will then return 7-14 days later and undergo the same sequence of events with the opposite intervention (i.e. rTMS or sham) from session 1.

This pilot study intends to address the critical unmet need to develop novel treatments for alcohol use disorder (AUD), such as repetitive transcranial magnetic stimulation (rTMS), that directly impact drinking behavior. Binge drinking and high intensity drinking, or consumption meeting at least binge criteria, is a high-risk alcohol self-administration (ASA) pattern associated with the binge-intoxication stage of AUD and the rewarding effects of alcohol. The investigators propose to quantify the impact of medial prefrontal cortex (mPFC) rTMS on ASA using the investigators novel "rate-control" paradigm. The rate control paradigm allows subjects to determine how quickly their breath alcohol concentration (BrAC) will change (increase, decrease, or stay the same) over the next 3-5 minute epoch, at the end of which brief computer-assisted assay of craving for alcohol and subjective response attributed to alcohol's effect on stimulation, sedation, liking and well-being in a manner comparable to the Brief Biphasic Alcohol Effects Scale (BAES). Each assay requires less than 20 seconds to complete and will be administered during the last ~0.5 minutes of alcohol delivery but before selection of the next rate of exposure. The ensemble provides detailed self-administered time course of alcohol exposure and corresponding time-stamped series of quantified perceptions for analysis. This approach has demonstrated sensitivity in associating self-reported high intensity drinking and the time until a binge alcohol exposure of 80 milligrams per decilitre (mg/dL). The investigators premise is that clinically impactful neuromodulation should change ASA. Coupling rTMS to a laboratory-assessed ASA paradigm could document causal changes in drinking behavior attributable to modulation of specific neural circuits. The goal of this project is to generate preliminary data supporting the investigators central hypothesis - rTMS targeting to the mPFC, a primary cortical input to the frontal-striatal reward (FSR) circuit, will decrease the rate of alcohol self-administration.

Subjects will receive one session of low frequency repetitive transcranial magnetic stimulation (rTMS) targeting the medial prefrontal cortex (mPFC), within the following stimulation parameters: Continuous 20-minute train of 1 Hz rTMS, at 110% of motor threshold (MT), for a total of 1200 pulses

The active and sham functions share the same acoustic properties and sham mimics cutaneous stimulation, facilitating double-blinding.

The amount of time subjects take to self-administer enough alcohol to raise their breath alcohol concentration (BrAC) to 80 mg/dL

Drinking patterns as measured by Time Line Follow Back (TLFB) during the 4-week follow-up period. The Timeline Follow-back (TLFB) is modified to assess for one-month recall of alcohol, tobacco, drug, and cannabis use. Using a calendar, subjects provide retrospective estimates of their daily drinking over a specified time period.

Inclusion Criteria: Overtly healthy men and women aged 21 - 35 Able to give informed consent Able to understand/complete questionnaires and procedures in English Willing and able to adhere to the study schedule At least 2 binge drinking events (at least 4 or 5 drinks on a drinking day for women and men respectively over the last 5 weeks, unless determined by study physicians that drinking history meets study objectives Have venous access sufficient to allow blood sampling Exclusion Criteria: Pregnant or breast-feeding Desire to be treated for any substance use disorder or court ordered to not drink alcohol Medical disorders or other conditions, such as lifetime history of a seizure, including history of Electroconvulsive therapy (ECT) but excluding febrile seizures and those induced by substance withdrawal, that may influence study outcome or subject safety First degree relative with idiopathic epilepsy or other seizure disorder Diagnostic and Statistical Manual (DSM) 5 Disorders (non-AUD) or current/history of neurological disease of cerebral origin, or head injury with > 20 min loss of consciousness, if determined by the study physicians to affect subject safety or data integrity Positive urine drug screen for amphetamines/ methamphetamines, barbiturates, benzodiazepines, cocaine, opiates, or phencyclidine if determined by the study physicians to adversely affect subject safety or data integrity Medications (past 30 days) that could influence subject data/subject safety (e.g. antidepressants, antipsychotics, benzodiazepines, etc.) as determined by study physicians Positive BrAC reading at beginning of any study session Actively suicidal (for example, any suicide attempts within the past 3 months or any current suicidal intent, including a plan) or are at serious suicidal risk, by clinical judgment of the study physicians Any condition for which the study physicians determine it is unsafe or not prudent to enroll a subject