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

深部脑刺激 (DBS) 治疗难治性甲基苯丙胺使用障碍

基本信息

批准号：
10630368
负责人：
AVIVA ABOSCH
金额：
$ 64.5万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630368
关键词：
Abstinence Admission activity Affect Aftercare Alcohols American Anhedonia Animal Model Animals Anterior Area Back Behavioral Paradigm Bilateral Bioethics Consultants Biological Biological Markers Biometry Blinded Brain Case Study Cessation of life Chronic Clinic Clinical Clinical Data Clinical Trials Controlled Study Cross-Over Studies Crossover Design Cues Deep Brain Stimulation Drug Metabolic Detoxication Drug Screening Drug usage Electrophysiology (science)Enrollment Equilibrium Event Experimental Designs FDA approved Feasibility Studies Functional Magnetic Resonance Imaging Functional disorder Glutamates Human Implant Impulsivity Incidental Findings Individual Inpatients Intervention Knowledge Life Measurement Measures Medial Methamphetamine Methamphetamine use disorder Monitor Morbidity - disease rate Movement Disorders Neurology Neurons Neurosciences Neurosurgeon Nucleus Accumbens Obsessive-Compulsive Disorder Operative Surgical Procedures Opioid Outcome Patient Self-Report Persons Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Physiologic pulse Placebos Play Prefrontal Cortex Procedures Psychiatrist Publishing Randomized Recording of previous events Refractory Reporting Rest Rewards Risk Taking Role Safety Signal Transduction Stimulant Stimulus Stream Structure Substance Use Disorder Synapses Technology Testing Time Treatment outcome United States Substance Abuse and Mental Health Services Administration Urine Ventral Tegmental Area addiction arm clinical outcome assessment cognitive process craving design evidence base experience improved methamphetamine use mortality neural neural circuit novel novel strategies phase 2 study preventable death prospective psychosocial psychostimulant recruit relapse patients response safety and feasibility safety assessment sham-controlled study success therapy development timeline treatment response visual stimulus

项目摘要

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.

抽象的：物质使用障碍很普遍，导致显着的发病率，并且是可预防的常见原因死亡。与酒精和阿片类药物相比，目前尚无 FDA 批准的药物疗法甲基苯丙胺使用障碍（MUD），尽管在之前的药物试验中进行了广泛的努力。社会心理干预措施用于治疗 MUD，但许多人仍然难治，这突出表明仍然需要新的治疗方法的开发。近几十年来，我们对成瘾神经基础的理解不断加深，强调选择性地针对与成瘾相关的大脑区域（例如伏隔核）的潜力（NAc）。深部脑刺激通常用于治疗运动障碍以及强迫症紊乱，并允许慢性刺激皮层下大脑结构，例如 NAc。不断成长的动物身体模型和人体临床数据表明 NAc 刺激可能有益于治疗成瘾。这里我们提出了一项两阶段研究，以测试双侧 NAc 的 DBS 治疗 MUD 的效果。在UG3阶段下，我们将招募少数患有难治性 MUD 的受试者（n = 5），并雇用一名受试者使用受试者作为自己的对照的评估者盲交叉设计。受试者将接受住院戒毒，随后进行 DBS 手术，然后进行 1 个月的居家药物滥用治疗，以及 12 周的药物滥用治疗。心理社会干预，以及 18 个月的 DBS 规划监测（受试者随机分配到 6- 几个月的假治疗，然后 12 个月的主动刺激与主动然后假治疗的治疗）。我们的临床结果是甲基苯丙胺的使用通过时间线追踪进行测量并通过尿液药物筛查和自我检测来确认据报告对甲基苯丙胺的渴望。我们还将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度，我们将测试在渴望提示和休息期间的活动变化具有纵向功能 MRI (fMRI) 和局部场电位记录（DBS 前编程、6、12 和术后 18 个月）。 Medtronic Percept 植入式脉冲发生器允许从植入 DBS 导线，在渴望事件期间提供 NAc 本身的局部场电位记录在日常生活中经验丰富，在诊所中表现出对提示的渴望。如果我们事前的安全性、可行性和达到临床和目标参与终点后，我们将进入 UH3 阶段。在这个阶段，我们将进行一项 DBS 治疗甲基苯丙胺使用的随机、受试者和评估者盲法、假对照试验紊乱（n=20）。我们的设计将根据 UG3 的发现（例如，确定 DBS 的预期时间进程）反应），并将寻求测试将 NAc DBS 添加到标准社会心理干预措施中是否可以提供临床效果在减少甲基苯丙胺的使用和渴望方面取得了超越假干预的改善。我们将通过调查环路，进一步探讨与 DBS 治疗反应相关的潜在机制基于 NAc 的功能磁共振成像信号和电生理记录。通过我们的实验设计，我们努力在保持安全性和获取有关人类 MUD 的最大信息之间取得最佳平衡。