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：
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
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/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

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）是发病率的主要原因，经济负担估计约为250美元十亿/年。 AUD的当前药理和行为治疗的功效有限，尽管在过去的50年中，对AUD神经生物学的了解增加了，复发率没有提高（6个月内约55％）。因此，确定新颖和更有效的治疗方法以防止复发是一种紧急公共卫生优先事项。对于酒精相关肝病患者而言，这种需求尤其急切（ALD），持续的饮酒与高死亡率和移植的扣留有关。在该提议，我们旨在测试一种新颖的治疗方法，以实现严重和难治性的AUD：边缘颗粒（LP）的深脑刺激（DB）的奖励电路。我们假设LP DBS 通过减少渴望和调节行为和认知过程来防止饮酒复发与提示反应性，奖励处理和冲动等复发的脆弱性有关。我们将测试我们的假设3例患者的LP DBS的安全性，耐受性和可行性来测试安全性，具有严重的AUD和伴随的晚期补偿（无症状）ALD（UG3期）。开会 UG3相里的里程碑，我们将进行双盲，随机，假对照试验以进一步测试安全性，耐受性和可行性，并评估LP DBS的初步功效 AUD（UH3阶段）。对于UH3阶段，我们将招募20例严重AUD和随之而来的晚期患者补偿Ald。在UG3和UH3阶段中，我们将评估饮酒并渴望前后 DB在多个时间点。我们还将评估目标参与度以及LP DB对酒精的影响 - 使用PET扫描和神经生理学诱导奖励电路的变化。该提议可以铺平采用新的治疗方法（即DBS）和新目标（即LP）的方法来治疗严重AUD和其他物质使用障碍。