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，估计经济负担约为250美元 十亿/年。目前对AUD的药物和行为治疗效果有限，尽管 对澳门氏症神经生物学知识的增加，复发率在过去50年里没有改善 (6个月内~55%)。因此，寻找新的和更有效的治疗方法来防止复发是一种 紧急公共卫生优先事项。对于与酒精相关的肝病患者来说，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……里面 这项建议，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 边缘苍白球深部脑刺激(DBS)的奖赏回路。我们假设LP DBS 通过减少渴求和调节行为和认知过程来防止再次饮酒 与易复发有关，如线索反应性、奖赏处理和冲动。我们将测试我们的 通过在3名患者中进行初步初步研究来测试LP DBS的安全性、耐受性和可行性 伴有严重的AUD和伴随的晚期代偿性(无症状)ALD(UG3期)。一见钟情 在UG3阶段的里程碑中，我们将进行双盲、随机、假对照试验以进一步检验 安全性、耐受性和可行性，并评估LP DBS治疗重型肝炎的初步疗效 AUD(UH3期)。对于UH3期，我们将招募20名患有严重AUD和伴发晚期的患者 补偿ALD。在UG3和UH3两个阶段，我们将评估酒精使用和渴望前后 多个时间点的DBS。我们还将评估目标参与度和LP DBS对酒精的影响- 通过正电子发射计算机断层扫描和神经生理学，诱发奖赏回路的变化。这项提议可能会为 寻找新的治疗方法(即DBS)和新的靶点(即LP)来治疗严重的AUD和 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.