Limbic Pallidum DBS for the treatment of severe alcohol use disorder

摘要 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 亿元/年。目前AUD的药物和行为治疗效果有限，尽管 随着对AUD神经生物学知识的增加，复发率在过去50年中没有改善 （6个月内约55%）。因此，确定新的和更有效的治疗，以防止复发是一个重要的问题。 紧急公共卫生优先事项。对于酒精相关性肝病患者来说，这种需求尤其迫切 (ALD)对他们来说，持续饮酒与高死亡率和拒绝移植有关。在 这项建议，我们的目的是测试一种新的治疗方法，严重和难治性AUD：神经调节 奖励电路与脑深部电刺激（DBS）的边缘苍白球（LP）。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酒精使用的复发 与易复发性相关，如线索反应、奖励处理和冲动。我们将测试我们的 通过在3例患者中进行初步研究以测试LP DBS的安全性、耐受性和可行性， 伴有重度AUD和伴随的晚期代偿性（无症状）ALD（UG3期）。一见面 UG3阶段的里程碑，我们将进行一项双盲、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治疗重度患者的初步疗效 AUD（UH3阶段）。对于UH3期，我们将入组20例重度AUD患者，并伴随晚期 补偿ALD。在UG3和UH3阶段，我们将评估饮酒前后的酒精使用和渴望。 在多个时间点进行DBS。我们还将评估目标参与和LP DBS对酒精的影响- 通过PET扫描和神经生理学来诱导奖赏回路的变化。这一提议可以为 一种新的治疗方法（即，DBS）和新目标（即，LP）治疗重度AUD患者， 其他物质使用障碍。

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.