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

项目概要/摘要 该K 01奖项的目的是通过提供以下信息来促进候选人（Lora科普博士）的职业生涯 她需要在行为成瘾研究的关键组成部分，神经成像， 统计为了实现这一目标，科普博士将与她精心挑选的导师团队密切合作， 密歇根大学，谁将在三个关键的培训领域提供指导：1）激励- 成瘾敏感化理论和巴甫洛夫条件反射方法; 2）神经影像学研究 开发和实施，和3）先进的多元统计。培训将包括课程， 导师会议、研讨会、科学会议、体验式学习以及 职业发展计划。科普博士的短期职业目标是研究冲动选择和暗示 从激励敏感的角度来看，成瘾倾向的基于反应的个体差异（见 具体目标），同时接受本建议书中概述的培训。她的长期职业目标是 在成瘾神经影像学领域的终身学术地位，进行重要的和临床 成瘾倾向的个体差异的有意义的转化研究。 本申请中提出的研究不仅有助于这种培训，而且还可以促进对 青少年向成年过渡时的强迫性物质使用和物质使用障碍倾向。的 密歇根大学开发的一个激励敏感化框架， “符号跟踪”和“目标跟踪”响应。这是一个广泛研究和支持的动物模型， 成瘾，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之上。这 工作将描绘激励显着性归因于人类的多方法签名，通过测量1）符号- 跟踪和目标跟踪使用巴甫洛夫条件方法范例，2）神经生物学回路 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。该项目将研究92名参与者， 中度酒精和/或大麻使用水平，基线评估时年龄为16-18岁。 参与者将被跟踪超过2.5年，以进行详细的物质使用和行为评估。这项工作 本文的研究目标如下：1）描述激励显著性的神经信号 归因，以及2）确定物质使用结果的纵向多方法预测因子。很长的- 这项工作的长期目标是利用对激励显著性大脑机制的详细了解， 构建客观的生物标志物，以指导物质使用障碍的诊断和治疗， 目标是限制过渡到强迫使用，减少复发，改善人类健康。

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.