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

 描述（由申请人提供）：皮质厚度可卡因依赖是最难治疗的物质使用障碍之一，目前尚无FDA批准的干预措施。虽然目前的药理学策略以空间无偏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异性方式直接调节神经活动。我们最近证明，直接衰减内侧前额叶皮层（皮层枢纽的额叶-纹状体电路的tht管辖的渴望）通过theta爆发刺激（MPFC cTBS）减少基线额叶-纹状体活动，神经反应可卡因的使用，并渴望在非治疗寻求可卡因用户。然而，单次治疗的效果会在治疗后的最初几个小时内逐渐消失。可持续的效果需要多天的治疗。目标：该提案的主要目标是收集关键的可行性和效应量数据，这在进行多中心临床试验之前是必要的。需要解决的问题是：1）MPFC cTBS是否改善治疗参与患者的保留和禁欲？以及2）它是否在这些患者中产生了额叶-纹状体连接的急性和可持续的变化？产品设计：在该双盲活性假对照队列研究中，参加4周强化门诊治疗计划的可卡因使用者将随机接受3周的真实的或假MPFC cTBS。将采集四次临床评估和神经影像学数据：首次cTBS治疗前、末次cTBS治疗后、患者1个月随访访视时和2个月随访访视时。目标1 -临床效果。我们将检验以下假设：在治疗计划（A部分）和随访访视（B部分）期间，真实的cTBS治疗将增强保留并减少可卡因使用。目标2-神经生物学效应。我们还将检验以下假设：真实的cTBS治疗将产生MPFC-纹状体功能连接的选择性降低（A部分），并且这将在随访访视时返回并保持禁欲的个体中持续（B部分）。这项研究的科学原理是 这是在成瘾动物模型中进行的光遗传学研究的延伸，该研究已经证明了该回路中的活动与吸毒之间的因果关系。本研究的实验设计 是最初临床试验的延伸，该临床试验导致FDA批准重复脑刺激作为治疗重度抑郁症的方法。总之，这项研究的结果可能对脑刺激作为可卡因依赖者的一种新型创新治疗选择的发展产生很大的影响和直接相关性。

 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.