An Experimental Medicine Approach for the Mechanistic Understanding of Cocaine Use Disorder: Reinforcer Pathology - PROJECT SUMMARY Developing a new generation of interventions for cocaine use disorder (CUD) constitutes an important scientific gap and, if addressed, will open innovation opportunities. To address this gap, we employ the Experimental Medicine approach to mechanistically examine Reinforcer Pathology, an emerging novel framework for addiction, that may provide a principled foundation for intervention development. Reinforcer Pathology specifies that reinforcers are integrated over a temporal window, and the length of that window determines the relative value of different reinforcers. When the temporal window is short, reinforcers such as cocaine, which are brief, intense, and reliable, will have greater value. Conversely, as the temporal window lengthens, other more temporally extended reinforcers begin to have greater influence and cocaine valuation will decrease. The concept of Reinforcer Pathology identifies the temporal window, measured with delay discounting (i.e., the decline in the value of a reinforcer as a function of its delay), as a therapeutic target for CUD, and it permits target engagement via innovative interventions (e.g., episodic future thinking; EFT) to provide novel insights into cocaine valuation. This project uses multiple analytical levels (e.g., the behavioral laboratory, neuroimaging, and computational modeling) to quantify, predict, and modulate cocaine valuation among individuals with CUD. In Aim 1, we will examine manipulations that increase and decrease the temporal window in parallel to mechanistically test the Reinforcer Pathology framework. In Aim 1a, we will examine the effects of successive exposure to an intervention that increases the temporal window (EFT) on concomitant changes in cocaine valuation (demand and craving). In Aim 1b, we will examine the effects of a manipulation that decreases the temporal window (stress probes) after exposure to EFT on concomitant changes in cocaine valuation. Throughout Aim 1, neural activity associated with changes in the temporal window will also be examined. In Aim 2, we will use multi-voxel analyses of fMRI data to explore two independent sub-aims related to Reinforcer Pathology in CUD. First, in Aim 2a, we will build multivariate group regression models of fMRI delay discounting data in a subset of participants with CUD to predict discounting in an independent subset of participants. Second, in Aim 2b, we will use real-time fMRI neurofeedback to enhance participants’ ability to control their temporal window, and hence their ability to modulate delay discounting and cocaine valuation. In Aim 3, we will model the temporal window by computationally quantifying results from Aims 1 and 2 (Aim 3a), and connecting subjective value to brain regions of interest using computational neuroscience (Aim 3b). Together, the findings from this rigorous and innovative research project will improve our understanding of CUD and highlight potential novel and efficacious intervention strategies.
