PROJECT SUMMARY Developing a new generation of interventions for alcohol use disorder (AUD) constitutes an important scientific gap and, if addressed, will open innovation opportunities. To address this gap, we propose to examine an emerging novel framework for addiction, reinforcer pathology. 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 alcohol, 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 alcohol 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 AUD, and it permits target engagement via innovative interventions (e.g., episodic future thinking; EFT) to provide novel insights into alcohol valuation. This project uses multiple analytical levels (e.g., the behavioral laboratory, an outpatient field study, neuroimaging, and computational modeling) to quantify, predict, and modulate alcohol valuation among individuals with AUD. In Aim 1, we will examine manipulations that increase and decrease the temporal window to mechanistically test the reinforcer pathology framework. In Aim 1a, we will examine the effects of an intervention that increases the temporal window (EFT) on concomitant changes in alcohol valuation (self-administration, craving, and behavioral economic alcohol demand). In addition, participants in Aim 1a will participate in a proof-of-concept field study, where remote implementation of EFT will be used to impact alcohol drinking (measured by remote monitoring of breath alcohol) in the natural environment. In Aim1b, we will examine the effects of a manipulation that decreases the temporal window (simulation of economic scarcity) on concomitant changes in alcohol 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 AUD. First, in Aim 2a, we will build multivariate group regression models of fMRI delay discounting data in a subset of participants with AUD 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 alcohol valuation. In Aim 3, we will model the temporal window to extend the existing literature 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 AUD and highlight potential novel and efficacious intervention strategies.

PROJECT NARRATIVE The proposed project mechanistically tests a new conceptual framework for understanding alcohol use disorder, reinforcer pathology, which identifies novel determinants of alcohol valuation at multiple levels of analysis (behavioral, neural, clinical, and computational). Existing treatments for alcohol use disorder are less than optimally robust and are further limited by an incomplete understanding of the mechanisms of alcohol use disorder - a gap that this project aims to address. Results from these studies will positively impact public health because reinforcer pathology suggests innovative interventions that will decrease alcohol consumption and valuation.