In vivo human addiction biomarkers: towards closed loop deep brain stimulation

酒精和阿片类药物使用障碍等成瘾障碍是主要的公共卫生问题，具有显著的发病率、死亡率和经济负担。许多人仍然对治疗难以治疗。成瘾障碍的特征是大脑网络异常。这项研究建议使用神经外科手术，脑深部刺激，旨在提供刺激来改变大脑网络，对运动障碍和强迫症具有长期公认的安全性和治疗效果。在这里，我们提出了一项针对伏隔核和腹侧内囊的治疗难治性酒精和阿片类药物使用障碍的脑深部刺激研究。刺激这些脑区对吸毒成瘾有潜在的效果。这项建议侧重于直接从大脑深层结构记录成瘾的理论机制，以及以个性化的方式修改核心成瘾过程的能力。我们评估了刺激线索的神经生理学，以及线索和压力诱导的复发背后的负面情绪。我们在戒酒过程中跟踪这些过程，并将它们与其他核心成瘾认知过程联系起来，包括冲动控制和行为灵活性。我们询问与上瘾相关的关键神经化学物质如何影响这些过程。关键的是，我们随后询问刺激治疗可能如何影响神经生理学、网络和行为，目的是识别刺激反应的特定生物标记物。这导致我们在治疗复发缓解性疾病时开发出用于行为调节的闭环响应性神经刺激和实时反馈。在一项先导性随机对照试验中，我们进一步评估了脑深部刺激治疗成瘾的潜在疗效。总之，这些研究为活着的人脑中成瘾的核心理论机制提供了新的直接的机械见解，并立即产生了治疗效果，导致了精确反应神经调节的新出现的潜力。

Disorders of addiction like alcohol and opioid use disorder are major public health issues with marked morbidity, mortality and financial burden. Many remain refractory to treatment. Addiction disorders are characterized by abnormal brain networks. This study proposes to use neurosurgical procedure, deep brain stimulation, designed to deliver stimulation to change brain networks, with longstanding established safety and therapeutic efficacy for movement disorders and obsessive-compulsive disorder. Here we propose a deep brain stimulation study in treatment refractory alcohol and opioid use disorder, targeting the nucleus accumbens and ventral internal capsule. Stimulation of these brain regions is potentially effective in drug addictions. This proposal focuses on theoretical mechanisms underlying addictions recording directly from deep brain structures and the ability to modify core addiction processes in a personalised manner. We assess the neurophysiology of incentive cues and negative emotionality underlying cue- and stress-induced relapse. We track these process over the course of abstinence and link them with other core addiction cognitive processes including impulse control and behavioural flexibility. We ask how these processes are influenced by key neurochemicals relevant to addictions. Critically, we then ask how stimulation treatment might influence neurophysiology, networks and behaviour with the goal to identify stimulation-responsive specific biomarkers. This leads us towards the development of closed-loop responsive neurostimulation and real-time feedback for behavioural regulation in the treatment of a relapsing remitting illness. We further assess the potential therapeutic efficacy of deep brain stimulation for addiction in a pilot randomized controlled trial. Together these studies provide novel direct mechanistic insights of core theoretical mechanisms of addictions in the living human brain with immediate therapeutic impact leading to the emerging potential for precise responsive neuromodulation.