? DESCRIPTION (provided by applicant): Cortical thickness cocaine dependence is one of the most difficult substance-use disorders to treat and currently has no FDA- approved interventions. While current pharmacological strategies modulate neurochemistry in a spatially- unbiased manner, the development of non-invasive brain stimulation strategies would enable us to directly modulate neural activity in a circuit-specific manner. We recently demonstrated that direct attenuation of the medial prefrontal cortex (a cortical hub of frontal-striatal circuitry tht governs craving) through theta burst stimulation (MPFC cTBS) decreases baseline frontal-striatal activity, neural responses to cocaine uses, and craving in non-treatment seeking cocaine users. The effects of a single session however, erode over the first few hours after treatment. Sustainable effects require multiple days of treatment. GOAL: The primary goal of this proposal is to collect critical feasibility and effect size data which is necessary before moving forward wih multisite clinical trials. The questions that need to be addressed are: 1) Does MPFC cTBS improve retention and abstinence in treatment-engaged patients? and 2) Does it produce an acute and sustainable change in frontal-striatal connectivity among these patients? DESIGN: In this double-blind active sham controlled cohort study, cocaine users enrolled in a 4 week intensive outpatient treatment program will be randomized to receive 3 weeks of real or sham MPFC cTBS. Clinical assessments and neuroimaging data will be acquired four times: before the first cTBS session, after the last cTBS session, at the patient's 1 month follow-up visit, and at the 2 month follow-up visits. Aim 1 - Clinical effects. We will test the hypotheses that real cTBS treatment will enhance retention and decrease cocaine use during the treatment program (part A) and at the follow up visits (part B). Aim 2- Neurobiological effects. We will also test th hypotheses that real cTBS treatment will produce a selective decrease in MPFC-striatal functional connectivity (part A), and that this will be sustained in the individuals that return an have remained abstinent at the follow-up visits (part B). The scientific rationale of this study is an extension of optogenetic studies in animal models of addiction which have demonstrated a causal link between activity in this circuit and drug taking. The experimental design of this study is an extension of the initial clinical trials that led to FDA-approval of repetitive brain stimulaion as a treatment for major depression disorder. Taken together the results of this study may have a high impact and direct relevance to development of brain stimulation as a novel, innovative treatment option for cocaine dependent individuals.

R21DA041610

2016-06-01

2018-05-31