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

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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.