The purpose of this study is to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) targeting the insula on alcohol use and neural responses in alcohol-dependent patients.

Objectives: To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) targeting the insula on alcohol use and neural responses in alcohol-dependent patients.

Study population: Treatment seeking alcohol dependent subjects (N=82), aged 18-65 years, who have first completed standard alcohol withdrawal treatment if needed.

Design: This is a double-blind, sham-controlled randomized study, comprising three phases. Participants will be hospitalized during the first two of these, and will be outpatients during the third. During Phase 1 the study (screening; up to 14 days), participants will undergo a set of baseline assessments; this phase will conclude with consent, inclusion and randomization. During Phase 2 (treatment; appr. 3 weeks, with at least the first week being hospitalized), participants will first undergo an MRI scan to collect resting state and structural data, and will then receive one of two treatments: Active (10Hz) rTMS; or sham stimulation, both targeting the insula bilaterally. rTMS sessions will be conducted five times per week, for 3 weeks, for a total of 15 sessions. Stimulation will be with an H-coil designed to reach deeper structures such as the insula. A second MRI scan will be obtained at the end of this phase to assess changes in resting state connectivity, and to evaluate insula activity in tasks known to activate this structure. In addition, a lumbar puncture will be carried out at the end of this phase to assess possible effects on central neurotransmitter and growth factor levels, as indexed in the cerebrospinal fluid. For Phase 3 (follow-up, lasting 12 weeks), patients will be followed as outpatients for 12 weeks, with clinic visits at weeks 1, 2, 4, 8 and 12 post discharge; measures of alcohol use will be collected during this phase.

Outcome measures: The co-primary outcome measures will be heavy alcohol consumption during the follow-up phase, assessed using time-line follow-back methodology; and insula BOLD functional magnetic resonance imaging (fMRI) responses during tasks known to induce insula activation. A number of secondary and exploratory measures will also be assessed, including objective biomarkers of alcohol consumption.

Inclusion Criteria:

1. Age 18 - 65
2. Current Diagnostic and Statistical Manual (DSM-IV-TR) diagnosis of alcohol dependence
3. Alcohol use in the past month
4. Right handed (self-report)
5. If female, negative urine pregnancy test
6. If female, must either agree to practice an effective birth control method; have a partner with a vasectomy; agree to abstinence from intercourse; be surgically sterile or postmenopausal for at least one year

Exclusion Criteria:

1. Currently pregnant or breastfeeding
2. More than mild cognitive impairment, as determined by a score on the Mini Mental State Examination (MMSE) <24.
3. Current DSM-IV diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder
4. Use in the past 4 weeks of any medication or illicit drug listed as being associated with "a strong potential hazard for application of rTMS due to their significant seizure threshold lowering potential" by the international consensus guidelines for delivery of TMS [104], as self-reported, or detected using urine toxicology screening
5. Any history of clinically significant neurological disorders, including organic brain disease, epilepsy, stroke, brain lesions, multiple sclerosis, previous neurosurgery or personal history of head trauma that resulted in loss of consciousness for > 5 minutes and retrograde amnesia for > 30 minutes (self-reported history).
6. Any history of seizures other than febrile childhood seizures (self-reported history)
7. Signs of increased intracranial pressure as determined by the structural MRI-scan
8. Clinically significant hearing impairment or tinnitus
9. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head (pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner, implanted delivery pump, or shrapnel fragments) or fear of enclosed spaces. Eligibility will be determined by the "MRI Safety Screening Questionnaire" (see Appendix 1) and verified, if necessary, by a radiology consultant.
10. Cannot recline comfortably flat on his/her back for up to 2 hours in the MRI scanner.
11. Any psychiatric, medical or social condition whether or not listed above, due to which, in the judgment of the investigators and after any consults if indicated, participation in the study is not in the best interest of the patient.