Multi-method signature of risk for compulsive substance use: Human translation of the incentive-sensitization model

项目摘要/摘要 这一K01奖项的目的是通过为候选人(洛拉·科普博士)提供 她需要在行为成瘾研究的关键组成部分、神经成像和 统计数据。为了追求这一目标，科普博士将与她精心挑选的指导团队在 将在三个关键培训领域提供指导：1)激励- 成瘾敏化理论与巴甫洛夫条件化方法：2)神经影像研究 开发和实施；3)先进的多元统计。培训将由课程组成， 导师会议、研讨会、科学会议、体验学习和其他活动，如 职业发展规划。科普博士的短期职业目标是研究冲动的选择和暗示 从激励敏感化的角度看成瘾倾向的基于反应性的个体差异(见 具体目标)，同时接受本提案中概述的培训。她的长期职业目标是 在成瘾神经成像领域的终身学术地位，指导重要和临床 关于成瘾倾向的个体差异的有意义的翻译研究。 本申请中提出的研究不仅将促进这一培训，而且还将增进对 成年期青少年中的强迫性物质使用和物质使用障碍倾向。这个 密歇根大学开发的激励-敏感化框架区分了 “手势跟踪”和“目标跟踪”响应。它是一种被广泛研究和支持的动物模型 这项拟议的研究建立在将这一框架转化为人类的有希望的尝试的基础上。这 这项工作将通过测量1)符号来描绘人类激励性显著归因的多方法特征。 使用巴甫洛夫条件方法范式的跟踪和目标跟踪，2)神经生物回路 使用功能磁共振成像参与冲动选择和线索反应，3)特质结构 与物质使用相关，以及4)物质使用结果。该项目将对92名患有低血压的参与者进行研究 到中度酒精和/或大麻使用水平，在基线评估时年龄为16-18岁。 参与者将接受超过2.5年的详细药物使用和行为评估的跟踪调查。这部作品 主要研究目标如下：1)描述激励显著的神经特征 归因，以及2)确定物质使用结果的纵向多方法预测因素。长的- 这项工作的术语目标是利用对激励突显的大脑机制的详细理解来 构建客观的生物标记物来指导物质使用障碍的诊断和治疗，最终 限制过渡到强制使用，减少复发，并改善人类健康的目标。

PROJECT SUMMARY/ABSTRACT The purpose of this K01 award is to advance the career of the candidate (Dr. Lora Cope) by providing the specialized training she needs in key components of behavioral addiction research, neuroimaging, and statistics. In pursuit of this goal, Dr. Cope will work closely with her carefully selected mentorship team at the University of Michigan, who will provide mentorship in three critical training domains: 1) incentive- sensitization theory of addiction and Pavlovian conditioned approach, 2) neuroimaging study development and implementation, and 3) advanced multivariate statistics. Training will consist of courses, mentor meetings, workshops, scientific meetings, experiential learning, and other activities as described in the Plan for Career Development. Dr. Cope's short-term career goal is to study impulsive choice- and cue reactivity-based individual differences for addiction liability from an incentive-sensitization perspective (see Specific Aims) while receiving the training outlined in this proposal. Her long-term career goal is to hold a tenure-track academic position in the field of addiction neuroimaging, conducting important and clinically meaningful translational research on individual differences for addiction liability. The research proposed in this application will not only facilitate this training, but also advance understanding of compulsive substance use and substance use disorder liability in adolescents transitioning to adulthood. The incentive-sensitization framework developed at the University of Michigan draws a critical distinction between “sign tracking” and “goal tracking” responses. It is an extensively studied and supported animal model of addiction, and the proposed research builds on promising attempts to translate this framework to humans. This work will delineate the multi-method signature of incentive salience attribution in humans by measuring 1) sign- tracking and goal-tracking using a Pavlovian conditioned approach paradigm, 2) neurobiological circuitry involved in impulsive choice and cue reactivity using functional magnetic resonance imaging, 3) trait constructs correlated with substance use, and 4) substance use outcomes. The project will study 92 participants with low to moderate levels of alcohol and/or marijuana use, aged 16–18 at the time of baseline assessment. Participants will be followed over 2.5 years for detailed substance use and behavioral assessment. This work will address the following research aims: 1) Delineate the neural signature of incentive salience attribution, and 2) Identify longitudinal multi-method predictors of substance use outcomes. The long- term objective of this work is to use detailed understanding of the brain mechanisms of incentive salience to construct objective biomarkers to guide diagnosis and treatment of substance use disorders, with the ultimate goals of limiting transition to compulsive use, reducing relapse, and improving human health.