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

基本信息

批准号：
10706607
负责人：
Brian A Coffman
金额：
$ 72.98万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10706607
关键词：
Acceleration Acute Adaptive Behaviors Address Alcohol consumption Alcoholic Liver Diseases Alcohols Animal Model Back Behavior Therapy Behavioral Bilateral Blood Tests Brain Case Study Clinical Cognitive Compensation 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 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 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 Transplantation Universities Ventral Striatum active method adverse event monitoring adverse outcome alcohol craving alcohol seeking behavior alcohol use disorder cognitive process compliance behavior craving cue reactivity design disability discounting efficacious treatment efficacy testing hedonic improved innovation meetings mortality neural circuit neuroadaptation neurophysiology neuroregulation novel novel therapeutic intervention open label opioid use disorder patient population phosphatidylethanol pilot trial pre-clinical preclinical study primary outcome prolonged abstinence public health priorities randomized trial recruit reduced alcohol use relapse prevention research clinical testing reward circuitry reward processing safety and feasibility safety outcomes safety testing secondary outcome standard of care substance use treatment success timeline treatment response

项目摘要

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。