Limbic Pallidum DBS for the treatment of severe alcohol use disorder

边缘苍白球 DBS 用于治疗严重酒精使用障碍

• 批准号: 10539383
• 负责人: Jorge Alvaro Gonzalez-Martinez
• 金额: $ 70.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539383
• 关键词: Abstinence; Acute; Adaptive Behaviors; Address; Alcohol consumption; Alcohols; Animal Model; Behavior Therapy; Behavioral; Bilateral; Blood Tests; Brain; Case Study; Clinical; Cognitive; Compulsive Behavior; Cues; DSM-V; Deep Brain Stimulation; Dependence; Development; Devices; Double-Blind Method; Economic Burden; Electrodes; Electroencephalography; Enrollment; Essential Tremor; FDA approved; Functional disorder; Genetic; Gilles de la Tourette syndrome; Globus Pallidus; Hemorrhage; Human; Implant; Implanted Electrodes; Impulsivity; Individual; Infection; Institutional Review Boards; Investigation; Knowledge; Lesion; Literature; Liver diseases; Measures; Morbidity - disease rate; Motivation; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Outcome; Parkinson Disease; Participant; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Phase III Clinical Trials; Pilot Projects; Plant Roots; Positron-Emission Tomography; Process; Protocols documentation; Quality of life; Questionnaires; Randomized; Refractory; Relapse; Rewards; Role; Safety; Schedule; Signal Transduction; Stimulus; Substance Use Disorder; Testing; Thalamic structure; Time; TimeLine; Transplantation; Universities; Ventral Striatum; active method; adverse event monitoring; adverse outcome; alcohol craving; alcohol seeking behavior; alcohol use disorder; base; cognitive process; compliance behavior; craving; cue reactivity; design; disability; discounting; efficacious treatment; efficacy testing; fluorodeoxyglucose; hedonic; improved; innovation; meetings; mortality; neural circuit; neuroadaptation; neurophysiology; neuroregulation; novel; open label; opioid use disorder; patient population; phosphatidylethanol; pilot trial; pre-clinical; preclinical study; prevent; primary outcome; public health priorities; randomized trial; recruit; reduced alcohol use; research clinical testing; reward circuitry; reward processing; safety and feasibility; safety outcomes; safety testing; secondary outcome; standard of care; substance use treatment; success; treatment response

ABSTRACT Alcohol use disorder (AUD) is a major cause of morbidity, with an economic burden estimated at ~$250 billion/year. Current pharmacologic and behavioral treatments of AUD have limited efficacy, and despite increased knowledge of the neurobiology of AUD, the relapse rate has not improved over the past 50 years (~55% within 6 months). Thus, identifying novel and more efficacious treatments to prevent relapse is an urgent public health priority. This need is especially acute for patients with alcohol-associated liver disease (ALD), for whom continued alcohol use is associated with high mortality and withholding of transplantation. In this proposal, we aim to test a novel treatment approach for severe and refractory AUD: neuromodulation of the reward circuit with Deep Brain Stimulation (DBS) of the limbic pallidum (LP). We hypothesize that LP DBS prevents relapse to alcohol use by reducing craving and modulating behavioral and cognitive processes associated with vulnerability to relapse like cue reactivity, reward processing, and impulsivity. We will test our hypothesis by conducting an initial pilot study to test safety, tolerability, and feasibility of LP DBS in 3 patients with severe AUD and concomitant advanced compensated (asymptomatic) ALD (UG3 phase). Upon meeting the UG3 phase milestones, we will conduct a double-blind, randomized, sham-controlled trial to further test safety, tolerability, and feasibility, and to assess preliminary efficacy of LP DBS for the treatment of severe AUD (UH3 phase). For the UH3 phase, we will enroll 20 patients with severe AUD and concomitant advanced compensated ALD. In both the UG3 and UH3 phases, we will assess alcohol use and craving pre- and post- DBS at multiple time points. We will also assess target engagement and the effects of LP DBS on alcohol- induced changes in the reward circuitry using PET scans and neurophysiology. This proposal could pave the way for a new treatment approach (i.e., DBS) and a new target (i.e., LP) to treat patients with severe AUD and other substance use disorders.

抽象的 酒精使用障碍 (AUD) 是发病的主要原因，经济负担估计约为 250 美元 十亿/年。目前 AUD 的药物和行为治疗效果有限，尽管 AUD神经生物学知识增加，近50年复发率未见改善 （6 个月内约 55%）。因此，寻找新的、更有效的治疗方法来预防复发是一个重要的任务。 紧急公共卫生优先事项。对于患有酒精相关性肝病的患者来说，这种需求尤其迫切 （ALD），对于他们来说，持续饮酒与高死亡率和拒绝移植有关。在 在这个提案中，我们的目的是测试一种治疗严重和难治性 AUD 的新方法：神经调节 苍白球边缘 (LP) 的深部脑刺激 (DBS) 奖励回路。我们假设 LP DBS 通过减少渴望并调节行为和认知过程来防止酗酒复发 与复发的脆弱性有关，如提示反应性、奖励处理和冲动。我们将测试我们的 通过进行初步试点研究来测试 3 名患者 LP DBS 的安全性、耐受性和可行性 患有严重的 AUD 和伴随的高级代偿性（无症状）ALD（UG3 期）。见面时 UG3阶段里程碑，我们将进行双盲、随机、假对照试验来进一步测试 安全性、耐受性和可行性，并评估 LP DBS 治疗严重疾病的初步疗效 澳元（UH3 阶段）。对于 UH3 阶段，我们将招募 20 名患有严重 AUD 并伴有晚期疾病的患者 补偿性 ALD。在 UG3 和 UH3 阶段，我们将评估饮酒前后的酒精使用情况和渴望程度。 DBS 在多个时间点。我们还将评估目标参与度以及 LP DBS 对酒精的影响 使用 PET 扫描和神经生理学诱导奖励回路的变化。该提案可以为 寻找新的治疗方法（即 DBS）和新的靶点（即 LP）来治疗严重 AUD 和 其他物质使用障碍。