The goal of this investigation is to determine if, in heavy alcohol users, a single session of transcranial magnetic brain stimulation (TMS) over a brain region involved in craving (medial prefrontal cortex) and a brain region involved in cogntive control (dorsolateral prefrontal cortex) can lower an individual's craving and brain response to alcohol cues. This study involves a screening visit, followed by three visits which involve brain imaging (using functional MRI) and brain stimulation (using TMS). There is also an additional Magnetic resonance spectroscopy (MRS) exploratory Aim in which we will measure the concentration of glutamate in the prefrontal cortex before and after a session of TMS.

Alcohol Use Disorders (AUDs) are prevalent, devastating, and difficult to treat. High relapse rates are likely due to factors that affect limbic and executive circuits in the brain, including vulnerability to salient cues and loss of cognitive control. Limbic drive and executive control are regulated by two cortical-subcortical neural circuits -the limbic loop that includes projections from the medial prefrontal cortex (mPFC) to the ventral striatum, and the executive control loop that includes projections from the dorsolateral prefrontal cortex (dlPFC) to the dorsal striatum. Optogenetic manipulation in animals has demonstrated a causal relationship between activity in these frontal-striatal circuits and drinking behavior. Consequently, an innovative and potentially fruitful new strategy in the treatment of AUDs in humans would be to selectively attenuate limbic circuitry (to reduce reward salience), and/or amplify executive circuitry, through targeted brain stimulation. Previous studies have demonstrated that a single session of 10 Hz transcranial magnetic stimulation (TMS) over the dlPFC can lead to a decrease in craving for alcohol, nicotine, and cocaine. Our laboratory has demonstrated that a single session of continuous theta burst (cTBS) TMS over the mPFC can also decrease craving, as well as the brain response to drug cues in cocaine users (Hanlon et al, in review) and alcohol users (see Significance). The overarching goal of this proposal is to determine which of these two TMS strategies - amplifying dlPFC activity or inhibiting mPFC activity - is more efficacious in decreasing alcohol craving and the brain response to cues. This will provide an evidence-based foundation for cortical target selection in future TMS clinical trials - an innovative treatment strategy for AUD patients.

As a recent FDA-approved treatment for depression, there is a growing interest in investigating TMS as a treatment for drug and alcohol use disorders. By changing the frequency and pattern of stimulation, it is possible to induce a long-term potentiation (LTP) or long-term depression (LTD) of activity in the cortical area stimulated as well in its monosynaptic targets. To date, nearly all published reports of brain stimulation as a tool for decreasing craving have focused on applying LTP-like stimulation (typically 10 Hz) to the dlPFC, thereby strengthening executive control circuitry. An alternative approach is to apply LTD-like TMS (such as cTBS) to the mPFC, thereby weakening limbic drive circuitry (which is engaged during craving). A sham TMS-controlled crossover study of 12 heavy alcohol users in our lab indicated that a single dose of mPFC cTBS decreases self-reported craving and the BOLD response to alcohol cues in the mPFC and striatum (limbic regions involved in craving). Using MR spectroscopy, we further demonstrated that cTBS-reduced the glutamine concentration in the mPFC, which may be related to the decrease in BOLD signal and functional connectivity with this region. Before moving forward with large and expensive multisite clinical trials, it is important to determine which cortical target (mPFC vs dlPFC) is likely to have a greater effect on the brain response to alcohol cues (Aim 1), and which will have a greater effect on self-reported craving (Aim 2) -a major factor contributing to relapse and sustained heavy drinking among individuals with AUDs. In this three-visit crossover design, a cohort of non-treatment seeking AUD individuals will receive sham, mPFC, or dlPFC TMS at each visit followed by alcohol-cue induced BOLD imaging and MR Spectroscopy. We will determine whether LTD-like mPFC TMS is more effective than LTP-like dlPFC TMS in:

Aim 1: Reducing alcohol cue-elicited brain activity in limbic circuitry. Participants will be exposed to our well-established fMRI alcohol cue paradigm. We will measure the percent BOLD signal change within a network of limbic regions typically activated by alcohol cues (e.g. mPFC, ACC, striatum) (Schacht et al., 2014), as well as functional connectivity between these regions (using psychophysiologic interactions). We will test the hypotheses that 1) both LTD-like stimulation to the mPFC (via cTBS) and LTP-like stimulation to the dlPFC (via 10Hz TMS) will significantly decrease alcohol cue-induced activation of limbic circuitry compared to sham stimulation and 2) this attenuating effect will be more robust when stimulation is targeted at the mPFC directly with cTBS stimulation (rather than indirectly via 10 Hz dlPFC stimulation).

Aim 2: Reducing self-reported alcohol craving. Using intermittent self-reported assessments of the desire to drink alcohol throughout the experimental sessions (before, during, and at several time points after the TMS treatment), we will test the hypothesis that LTD-like stimulation to the mPFC (via cTBS) will decrease self-reported alcohol craving more than will LTP-like stimulation to the dlPFC (via 10Hz TMS).

Finally, to develop a comprehensive and evidence-based foundation for future clinical trials, we will also explore the effects of these innovative brain stimulation treatment strategies on neurochemistry:

Exploratory Aim 3: Regional neurochemistry. Through MR Spectroscopy, we will test the hypothesis that the effects of TMS on the outcomes of Aim 1 & 2 are mediated by changes in mPFC excitatory/inhibitory neurochemical balance (i.e., changes in glutamate, glutamine, GABA concentrations).

Inclusion Criteria: Age 21-40; Current alcohol use greater than 20 standard drinks per week; Current DSM-5 Alcohol Use Disorder diagnosis, including the loss of control item; Currently not engaged in, and do not want treatment for, alcohol related problems; Able to read and understand questionnaires and informed consent; Lives within 50 miles of the study site. Exclusion Criteria: [These are listed in greater detail in the CIA Core] Any current DSM-5 Axis I diagnosis except Alcohol or Nicotine Use Disorder; Current use of any psychoactive substance except nicotine and marijuana or medication as evidenced by self-report or urine drug screen; History of head trauma or epilepsy; Current suicidal or homicidal ideation; Presence of ferrous metal in the body, as evidenced by metal screening and self-report; Severe claustrophobia or extreme obesity that preclude placement in the MRI scanner. For female participants, pregnancy, as evidenced by a urine pregnancy test administered on the day of the scanning session.

Data will be shared with the National Institute of Health Neuroimaging Biorepository at the completion of the study