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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
84
Participants will receive a total of 15 sessions of rTMS targeting the insula bilaterally, Stimulation will be delivered at an intensity of 120% of the motor threshold (MT), with a frequency of 10 Hz, delivered as 50 trains of 30 pulses delivered in each train of 3 seconds duration, with a 20 seconds inter-train interval, for a total of 1500 pulses delivered over app. 20 min. On the very first two sessions stimulations will be given at lower strength for adaptation, starting at 100% for the first and 110% for the second session
Sham stimulation with the same regimen as active treatment
Linkoping University
Linköping, Sweden
RECRUITINGHeavy Drinking
Reduction in heavy alcohol use during the outpatient follow-up phase (%heavy drinking days) measured by standard Time-Line Follow-Back methodology
Time frame: 12 weeks follow-up from treatment completion
Insula activity
Insula activity (%signal change, as measured by fMRI BOLD), during a task known to be associated with insula responses, risky decision making
Time frame: Within 5 days of treatment completion
BOLD responses in a battery of standard fMRI tasks that probe processing of alcohol-associated cues, reward function, and emotional responses.
Time frame: Within 5 days after the last TMS session
Alterations in resting-state connectivity of the insula with other nodes in the putative Salience Network (SN), executive control network (ECN) and the default-mode network (DMN) by rTMS.
Time frame: Within 5 days after the last TMS session
Objective biomarkers of alcohol use
Gamma-glutamyl transferase (GGT); carbohydrate deficient transferrin (CDT); ethyl glucuronide (EtG) in urine and hair.
Time frame: 12 weeks follow-up from treatment completion
Alcohol craving and psychiatric symptoms
Measured by the Penn Alcohol Craving Scale (PACS), mood and anxiety symptoms, as measured using the respective subscales of the Comprehensive Psychiatric Rating Scale (CPRS) and Clinical Global Impression (CGI).
Time frame: 12 weeks follow-up from treatment completion
Smoking
Measured by urine cotinine / creatinine ratios.
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Time frame: 12 weeks follow-up from treatment completion