Deep Brain Stimulation (DBS) For Severe Treatment Refractory Methamphetamine Use Disorder

摘要： 物质使用障碍很普遍，会导致严重的发病率，是可预防的常见原因 死亡。与酒精和阿片类药物相反，目前还没有FDA批准的药物疗法来治疗 甲基苯丙胺使用障碍(MUD)，尽管在之前的药物试验中做出了广泛的努力。心理社会 干预措施被用来治疗泥浆，但许多人仍然顽固，突显了继续需要 新的治疗方法开发。近几十年来，我们对成瘾的神经基础的理解有所增长， 强调有可能选择性地瞄准与成瘾相关的大脑区域，如伏隔核 (NAC)。脑深部刺激通常用于治疗运动障碍和强迫症。 此外，它还可能导致神经功能紊乱，并允许对皮质下结构(如NAC)进行慢性刺激。不断增长的动物身体 模型和人类临床数据表明，刺激NAC可能对治疗成瘾有益。这里 我们提出了一项两阶段研究，以测试双侧NAC治疗MUD的DBS。在UG3阶段， 我们将招募一小部分患有难治性泥浆的受试者(n=5)，并将雇用一名受试者-和 评分者盲目交叉设计，受试者作为自己的对照。受试者将接受住院戒毒治疗， 然后是DBS手术，然后是1个月的居住物质使用障碍治疗，以及12周的 心理社会干预，以及18个月的监测DBS规划(受试者随机分为6- 几个月-假治疗然后12个月-积极刺激与积极然后假治疗)。我们的临床结果是 甲基苯丙胺的使用，通过时间线跟踪测量，并通过尿液药物筛查确认，以及自我 据报道，他对冰毒有渴望。我们也会仔细评估研究程序的安全性和可行性。 为了研究基于回路的目标参与，我们将测试在渴望线索和休息时活动的变化 具有纵向功能磁共振成像(FMRI)和局部场电位记录(DBS编程前、6、12和 术后18个月)。美敦力Percept植入式脉冲发生器允许从 植入DBS引线，在渴望事件期间提供来自NAC自身的局部场电位记录 在日常生活中有经验，并在临床上有渴望线索的陈述。如果我们预案的安全性、可行性和 达到临床和目标参与终点后，我们将进入UH3阶段。在这一阶段，我们将 进行随机、受试者和评价者盲、假对照的DBS甲基苯丙胺使用试验 精神障碍20例。我们的设计将受到UG3调查结果的影响(例如，确定星展银行的预期时间进程 回应)，并将寻求测试NAC DBS添加到标准的心理社会干预是否提供临床 在减少甲基苯丙胺使用和渴求方面的改进，超越了虚假干预。我们会 进一步探索与DBS治疗反应相关的潜在机制，通过研究电路- 根据NAC的fMRI信号和电生理记录。通过我们的实验设计，我们努力 在维护安全和获取有关人类粪便的最大信息之间取得最佳平衡。

Abstract: Substance use disorders are prevalent, cause significant morbidity, and are a common cause of preventable death. In contrast to alcohol and opioids, there are currently no FDA approved pharmacotherapies for methamphetamine use disorder (MUD), despite extensive efforts at prior medication trials. Psychosocial interventions are used to treat MUD, but many individuals remain refractory, highlighting the continued need for novel treatment development. Our understanding of the neural basis of addiction has grown in recent decades, underscoring the potential to selectively target addiction-related brain areas such as the nucleus accumbens (NAc). Deep brain stimulation is commonly used to treat movement disorders, as well as obsessive compulsive disorder, and allows chronic stimulation of subcortical brain structures, such as NAc. A growing body of animal model and human clinical data suggests NAc stimulation may be beneficial in the treatment of addiction. Here we propose a two-phase study, to test DBS of bilateral NAc for the treatment of MUD. Under the UG3 phase, we will enroll a small number of subjects (n=5) with treatment-refractory MUD and will employ a subject- and rater-blinded cross-over design using subjects as their own control. Subjects will receive inpatient detoxification, followed by DBS surgery, then 1 month of residential substance use disorder treatment, and 12 weeks of psychosocial interventions, along with 18 months of monitored DBS programming (subjects randomized to 6- months-sham then 12-months-active stimulation vs. active-then-sham treatment). Our clinical outcomes are methamphetamine use as measured by timeline followback and confirmed by urine drug screens, and self- reported methamphetamine craving. We will also carefully assess safety and feasibility of the study procedures. To investigate circuit-based target engagement, we will test for changes in activity during cue-craving and at rest with longitudinal functional MRI (fMRI) and local field potential recording (pre-DBS programming, 6-, 12-, and 18-months post-surgery). The Medtronic Percept implantable pulse generator allows recording from the implanted DBS leads, providing local field potential recording from the NAc itself during craving events experienced in daily life and with cue-craving presentation in the clinic. If our pre-hoc safety, feasibility and clinical and target engagement endpoints are achieved, we will proceed to the UH3 phase. In this phase, we will conduct a randomized, subject- and rater-blinded, sham-controlled trial of DBS for methamphetamine use disorder (n=20). Our design will be informed by UG3 findings (e.g., to determine expected time course for DBS response) and will seek to test whether NAc DBS added to standard psychosocial interventions provides clinical improvement in reducing methamphetamine use and craving above and beyond sham intervention. We will further explore the underlying mechanisms associated with DBS treatment response by investigating circuit- based fMRI signal and electrophysiological recordings of NAc. Through our experimental design, we have strived for the optimal balance between maintaining safety while deriving maximal information about human MUD.