mPFC Theta Burst Stimulation as a Treatment Tool for Alcohol Use Disorder: Effects on Drinking and Incentive Salience

摘要 随着光/化学遗传刺激技术的进步，临床前研究已经证明了这种活性 额叶-纹状体神经回路对酗酒和复发行为有因果影响。 在人类身上使用现代功能磁共振成像技术的类似发现已经证实了其中的一些发现。 然而，在临床上，我们还没有将这项研究转化为基于神经回路的治疗技术 酒精使用障碍(AUD)患者。我们多学科研究团队的长期目标是 确定无创经颅磁刺激(TMS)的最佳参数 用于改善饮酒结果(禁酒、酗酒天数) AUD的行为治疗。建立在几个TMS脑目标识别研究和一个 我们小组在查尔斯顿对接受治疗的AUD患者进行的小型双盲临床试验 酒精研究中心(ARC)，在这里，我们提出了一项双盲安慰剂对照随机研究 电刺激前额叶腹内侧区的疗效评价 在寻求治疗的AUD患者中，减少饮酒和大脑对酒精提示的反应性。 ARC临床招生和评估核心最初将对个人进行筛查，然后给予机会 登记参加这项研究，提供知情同意，并随机向vmPFC接收真实或虚假的TBS 36次会议(每天3次，每周3次，为期4周，即12天)。在随机化之前和之后 在4周的TBS治疗中，他们将接受良好的酒精提示刺激BOLD fMRI 程序。这项ARC研究提案的科学前提是，通过调节神经回路 调节酒精提示反应性，就有可能提高戒酒率，降低酒重 饮酒天数超过4个月。因此，我们将探索TBS引起的变化与 大脑对酒精暗示的反应性作为TBS治疗反应的中介。此外，大脑的激活恢复到自然状态 奖励和威胁线索将作为探索TBS治疗对阴性的潜在影响的一种手段进行研究 与澳元相关的情感/情绪性。结合我们在脑刺激方面的科学专业知识， 查尔斯顿ARC和AUD临床试验中的神经成像、临床(和临床前)酒精相关研究 凭借专业知识，MUSC是唯一适合发展这一关键研究领域的机构。拟议目标的结果 将为多点临床试验提供循证基础，并将加快开发进程 一种新的基于神经回路的治疗AUD的方法。

SUMMARY With advances in opto-/chemo-genetic stimulation techniques, preclinical studies have demonstrated that activity in frontal-striatal neural circuits has a causal influence on heavy alcohol drinking and relapse-like behavior. Similar findings using modern fMRI imaging techniques in humans have confirmed some of these findings. Clinically, however, we have not yet translated this research into a neural circuit based therapeutic technique for patients with alcohol use disorder (AUD). The long term goal of our multidisciplinary research team is to determine the optimal parameters through which non-invasive transcranial magnetic stimulation (TMS) can be used to improve alcohol drinking outcomes (abstinence, heavy drinking days) among individuals seeking behavioral treatment for AUD. Building on a foundation of several TMS brain target identification studies and a small double-blinded clinical trial in treatment-engaged AUD patients performed by our group in the Charleston Alcohol Research Center (ARC), here we propose a double-blind placebo controlled, randomized study to evaluate the efficacy of theta burst stimulation (TBS) to ventromedial prefrontal cortex (vmPFC) as a treatment to decrease drinking and brain reactivity to alcohol cues among treatment-seeking individuals with AUD. Individuals will be screened initially by the ARC Clinical Intake and Assessment Core, then given an opportunity to enroll in this study, provide informed consent, and be randomized to receive real or sham TBS to the vmPFC 36 sessions (3x/day on each of 3 days/week over 4 weeks, i.e., 12 days). Prior to randomization and again after 4 weeks of TBS treatment, they will receive a well-established and validated alcohol-cue stimulation BOLD fMRI procedure. The scientific premise of this ARC research proposal is that, by modulating the neural circuits that regulate alcohol cue-reactivity, it will be possible to increase alcohol abstinence rates and decrease heavy drinking days over a 4-month period. Accordingly, we will explore the relationship of TBS-induced changes in brain reactivity to alcohol cues as mediators of the TBS treatment response. Also, brain activation to natural reward and threat cues will be studies as a means to probe potential effects of TBS treatment on negative affect/emotionality associated with AUD. With our combined scientific expertise in brain stimulation, neuroimaging, clinical (and preclinical) alcohol-related research in the Charleston ARC, and AUD clinical trial expertise, MUSC is uniquely suited to develop this critical line of research. The outcomes of the proposed Aims will provide an evidence-based foundation for a multisite clinical trial and will hasten progress towards developing a new neural circuit-based treatment for individuals with AUD.