Impact of vMPFC Brain Stimulation on Outcomes in Treatment-Engaged Cocaine Users

 描述(申请人提供)：皮质厚度可卡因依赖是最难治疗的物质使用障碍之一，目前没有FDA批准的干预措施。虽然目前的药物策略以空间上无偏见的方式调节神经化学，但非侵入性脑刺激策略的发展将使我们能够以电路特有的方式直接调节神经活动。我们最近证明，通过theta Burst刺激(MPFC CTB)直接衰减内侧前额叶皮质(额叶-纹状体回路的皮质中枢，支配渴望)会降低基线的额纹状体活动、对可卡因使用的神经反应，以及未寻求治疗的可卡因使用者的渴望。然而，一次疗程的效果在治疗后的最初几个小时内就会消失。可持续的效果需要多天的治疗。目标：这项建议的主要目标是收集关键的可行性和效应大小数据，这在推进多点临床试验之前是必要的。需要解决的问题是：1)MPFC CTB是否改善了接受治疗的患者的保留率和戒断率？2)它是否在这些患者的额叶-纹状体连接性方面产生了急性和可持续的变化？设计：在这项双盲主动假对照队列研究中，登记参加为期4周强化门诊治疗计划的可卡因使用者将随机接受3周的真实或假MPFC CTB。临床评估和神经影像数据将被采集四次：在第一次CTBS会议之前，在最后一次CTBS会议之后，在患者1个月的随访中，以及在2个月的随访中。目标1--临床效果。我们将验证这样的假设，即在治疗计划(A部分)和随访(B部分)期间，真正的CTBS治疗将增强保留和减少可卡因的使用。目的2-神经生物学效应。我们还将检验这样的假设，即真正的CTBS治疗将导致MPFC-纹状体功能连接的选择性降低(A部分)，并且这种假设将在在后续访问中保持戒断的患者中持续存在(B部分)。这项研究的科学基础是 对成瘾动物模型的光遗传学研究的扩展，证明了该回路的活动与吸毒之间的因果联系。本研究的实验设计 是最初临床试验的延伸，这些试验导致FDA批准重复脑刺激作为治疗严重抑郁症的方法。综上所述，这项研究的结果可能对脑刺激作为一种新颖的、创新的可卡因依赖者治疗方案的发展具有很高的影响和直接的相关性。

 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.