Cortical rTMS as a Tool to Change Brain Reactivity to Alcohol Cues

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.