Charleston ARC Clinical Project 4- Cortical rTMS as a Tool to Change Craving and Brain Reactivity to Alcohol Cues

A. SPECIFIC AIMS 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. The investigators have 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
the investigator's 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.The investigators 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. The investigators 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). The investigators 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), the investigators 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,
the investigators will also explore the effects of these innovative brain stimulation
treatment strategies on neurochemistry:

Exploratory Aim 3: Regional neurochemistry. Through MR Spectroscopy, the investigators 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-V 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-V Axis I diagnosis except Alcohol or Nicotine Use Disorder

- Current use of any psychoactive substance except nicotine and marijuana or medications
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.