Avoidance learning and pain circuit dysfunction in alcohol use disorders

项目摘要/摘要 酒精使用障碍(AUD)是一种慢性衰弱疾病，占所有物质的一半以上 在美国的虐待治疗案件。尽管接受了治疗，但大多数AUD患者仍会复发。它越来越多地 认识到回避学习的缺陷与激发习惯性酗酒密切相关 使用。具体地说，由于酒精的抗焦虑和止痛特性，许多人会饮酒以避免痛苦 身体和情感状态。矛盾的是，长期饮酒与疼痛反应增强有关 认知控制能力下降。这些变化强化了强迫饮酒作为一种不适应的回避。 战略，并进一步妥协其有害后果的学习。然而，神经、生理和 心理过程与回避学习障碍的维持和复发相关 人们对澳元仍知之甚少。这项K99/R00提案解决了研究中的这一关键差距。 为此，我们建议在治疗中收集功能磁共振成像(FMRI)数据- 在以痛苦和回报为特征的概率学习任务中寻找AUD患者。我们的首要目标是 描述在回避过程中支持疼痛反应和认知控制的大脑回路功能障碍 与社交饮酒者相比，AUD患者的学习能力。在第二个目标中，我们将评估神经是如何 标记物以及临床、生理和行为指标可用于(1)诊断区分 临床特征；以及(2)建立维持习惯性饮酒的关键病理生理途径的模型。在……里面 第三个目标是，我们将确定在12个月的随访中最能预测复发的风险因素，因此 为改善治疗结果提供临床意义。 候选人的长期目标是在神经科学研究领域开始独立的职业生涯。 酗酒。这项拟议的研究将通过作为候选人的发射台来支持这一目标 过渡到一个独立的调查员。候选人接受过广泛的认知神经科学培训， 他投身于成瘾神经科学领域。通过进行这项研究，候选人将拓宽他的 对AUD的临床和神经生物学研究进行培训，并获得机器学习方面的专业知识 和贝叶斯建模。候选人已经确定了他的培训需求，并组建了一个专家团队 这份K99/R00建议书的导师。培训计划包括结构化指导、监督研究、 正式的课程作业，在科学会议上的演讲，以及专业发展。不同寻常的 耶鲁大学的研究环境和智力资源将使应聘者获得充足的 指导，学习新技术，获得独立，同时追求他所热爱的研究。

PROJECT SUMMARY / ABSTRACT Alcohol use disorder (AUD) is a chronic debilitating condition that accounts for over half of all substance abuse treatment cases in the United States. Most AUD patients relapse despite treatment. It is increasingly recognized that deficits in avoidance learning are critically involved in motivating habitual and heavy alcohol use. Specifically, due to alcohol’s anxiolytic and analgesic properties, many engage in drinking to avoid painful physical and affective states. Paradoxically, chronic alcohol use is associated with increased pain reactivity and decreased cognitive control. These changes reinforce compulsive drinking as a maladaptive avoidance strategy and further compromise learning of its harmful consequences. Yet, the neural, physiological, and psychological processes inter-relating avoidance learning dysfunction with the maintenance and relapse of AUD remain poorly understood. This K99/R00 proposal addresses this critical gap in research. To this end, we propose to collect functional magnetic resonance imaging (fMRI) data in treatment- seeking AUD patients during a probabilistic learning task which features pain and reward. Our first aim is to characterize dysfunctions of the brain circuits supporting pain reactivity and cognitive control during avoidance learning in AUD patients, as compared to social drinkers. In the second aim, we will evaluate how the neural markers, along with clinical, physiological and behavioral metrics, may be used to (1) diagnostically distinguish clinical characteristics; and (2) model the key pathophysiological pathways that sustain habitual alcohol use. In the third aim, we will identify the risk factors that best predict relapse during the 12-month follow-up, thus offering clinical implications for improving treatment outcomes. The long-term goal of the candidate is to start an independent career in neuroscience research of alcohol addiction. This proposed study will support this goal by serving as a launchpad for the candidate to transition to an independent investigator. The candidate has trained extensively in cognitive neuroscience and devoted himself to the field of addiction neuroscience. By conducting this study, the candidate will broaden his training in the clinical and neurobiological investigation of AUD as well as gain expertise in machine learning and Bayesian modeling. The candidate has identified his training needs and assembled a team of expert mentors for this K99/R00 proposal. The training plan includes structured mentoring, supervised research, formal coursework, presentations at scientific meetings, and professional development. The exceptional research environment and intellectual resources at Yale University will allow the candidate to receive ample guidance, learn novel techniques, and gain independence, while pursuing the research he is passionate about.