Transcranial Magnetic Stimulation for the Treatment of Veterans With Alcohol Use Disorders

The purpose of this study is to evaluate the efficacy of intermittent theta burst repetitive
transcranial magnetic stimulation (rTMS) as a treatment for Veterans with an alcohol use
disorder (AUD) to decrease the exceedingly high rate of relapse associated with this
condition.

At least 60% of those with AUD will experience a major relapse period within 6 months of
treatment, irrespective of the intervention (psychosocial and/or pharmacological) employed.
Consequently, the high prevalence of AUD and relapse following treatment in Veterans is
associated with substantial resource allocation and costs for the DVA Health Care System.
Current pharmacological and psychosocial interventions demonstrate only a moderate level of
efficacy, which is reflected in the high rate of relapse in AUD.

rTMS is a neurostimulation method that is at the forefront of innovative, non-invasive, and
safe treatments for AUD, and the disorders that commonly co-occur with AUD. To reduce the
high rate of relapse in Veterans with AUD, it is necessary for interventions to more
effectively address the associated neurobiological dysfunction and salient co-occurring
conditions. Accordingly, additional rigorously controlled studies are required to determine
if intermittent theta burst rTMS is an effective treatment for Veterans with AUD.

Participants will be recruited from VA Palo Alto Health Care System (VAPAHCS) residential
substance abuse treatment clinics A double-blind randomized clinical trial with two groups:
Active rTMS Treatment Group (Active rTMS) - will receive five treatments (two treatments per
day) per week for 2 weeks. Sham Control Treatment group (i.e., identical rTMS experimental
procedure, but no active stimulation) will receive the same frequency and duration of rTMS
sessions. The proposed rTMS protocol is consistent with the FDA approved treatment regimen
employed for major depressive disorders at the VAPAHCS MIRECC. Magnetic resonance imaging
(MR) will be completed pre and post rTMS treatment and used to localize the left DLPFC in
each participant to optimize rTMS for this region. Active and Sham rTMS groups will complete
predictive measures [i.e., MR measures of anterior frontal glutamate level, blood flow, and
tissue volume, diffusion tensor imaging, functional connectivity, task-based fMRI] and other
outcome measures (i.e., measures of craving, mood, anxiety, neurocognition) immediately pre-
and post-completion of the 2 weeks of rTMS sessions. Genetic markers (i.e., brain derived
neurotrophic factor plasma levels and polymorphisms) will also be collected. Neuroimaging and
genetic measures are necessary to establish potential biomarkers for prediction of rTMS
treatment response, which is requisite for therapeutic optimization. For the 6 months
following completion of active or sham rTMS treatment, participants will be contacted
monthly, via telephone or in person, to complete a brief standardized measure of alcohol and
substance use, craving, and psychiatric symptomatology to assess for changes in these
variables over the previous 30 days.

This project will deliver completely novel data on the efficacy of intermittent theta burst
rTMS for Veterans with AUD during the first 6 months following treatment. Monitoring over the
entire first 6 months following treatment is crucial, given relapse within the first 6 months
of treatment is robustly related to poor psychosocial functioning over the ensuing 1-3 years.
The ultimate goal of this proposal is provide treatment that more effectively promotes
sustained abstinence in the Veteran with AUD, as extended abstinence is robustly associated
with optimum biomedical, neuropsychological, psychiatric, and psychosocial recovery and
functioning.

Inclusion Criteria:

- The study will be open to male and females, regardless of race and ethnic origin, who
are in active treatment for an alcohol use disorder (AUD).

- Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for
AUD, and alcohol is self-identified as primary substance of misuse.

- Actively in treatment at VA Palo Alto HCS Addiction Treatment Service, and able to
read, verbalize understanding, and voluntarily sign the Informed Consent Form prior to
participation in study procedures.

- Participants will be accepted if taking medications specifically for the treatment of
MDD, cigarette smoking, or for other psychiatric conditions.

- as long as the medications are not documented to lower seizure threshold

- must be stable on any psychotropic medication for at least 1 month prior to
enrollment

- it would be clinically contraindicated to require participants to discontinue
such medications for research.

- Participants will be abstinent from alcohol and non-prescribed substances for at least
7 consecutive days prior to active or sham rTMS and no participant demonstrates active
acute withdrawal symptoms.

Exclusion Criteria:

Psychiatric:

- History of Schizophrenia Spectrum Disorders

- Bipolar Disorders

- A current substance use disorder that exceeds the severity of the AUD

- based on DSM-5 diagnostic criteria

- Current use of an FDA approved medication for treatment of AUD, i.e.:

- disulfiram

- acamprosate

- naltrexone

- Active current suicidal intent or plan

- patients with a previous clinical flag for risk for suicide will be required to
have an established safety plan involving their primary psychiatrist and the
treatment team before entering the clinical trial

- Any form of previous rTMS or electroconvulsive treatment

Biomedical:

- Including but not limited to uncontrolled thyroid disease

- Unstable congestive heart failure

- Angina

- Other severe cardiac illness as defined by treatment regimen changes in the prior 3
months

- Cerebrovascular accident

- Cancer if < 1 year since end of treatment

- Unstable diabetes

- COPD requiring oxygen supplementation

- Alzheimer's disease

- Parkinson's disease

- Any biomedical implants with ferromagnetic content

- Neurostimulation devices

- Cardiac pacemakers or any magnetic resonance contraindications

- Traumatic brain injury with self-reported or observed loss of consciousness > 30
minutes

- Any primary or traumatically induced seizure disorder

General:

- Lack of fluency in English

- Wechsler Adult Reading Test below the 7th percentile, i.e.:

- moderate or greater impairment in estimated general intelligence

- Females who are pregnant or actively attempting pregnancy

- conservative exclusion for magnetic resonance research

- Current use of any medication or substance that is documented to lower seizure
threshold or has been identified as a contraindication for rTMS treatment