Limbic Pallidum DBS for the treatment of severe alcohol use disorder

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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.