Negative reinforcement in early abstinence from an alcohol use disorder - PROJECT ABSTRACT Alcohol use disorder (AUD) rates have doubled in the past five years. Despite having effective treatments, over 50% of patients relapse within the first year. Theories suggest that a primary reason for high relapse rates is the development of anxiety during abstinence that causes continued alcohol use. That is, individuals with AUD use alcohol for its negative reinforcing property, which removes anxiety that occurs during alcohol abstinence. Chronic alcohol use impacts negative reinforcement neural circuits, which contain the bed nucleus of the stria terminalis (BNST) at its core. The BNST is a region that contributes to negative affect, mediates stress-induced reinstatement (relapse), and was recently implicated in negative reinforcement. The BNST has extensive inputs from regions implicated in reward and emotion processing—specifically, the amygdala, ventral and dorsal striatum, and dorsal anterior cingulate cortex (dACC). In alcohol research, the primary emphasis has been on positive reinforcers (i.e., alcohol), providing us with extensive knowledge about the effects of positive reinforcement on behavior and brain function in AUD. In contrast, the alcohol field has a limited understanding of the effects of negative reinforcement on behavior and brain function. Considering that conceptual models of AUD cite negative reinforcement as a driver of relapse, this represents a major gap in knowledge. Human studies can leverage findings from animal models to provide a better understanding of negative reinforcement in AUD. Specifically, cross-species translation will be foundational for determining underlying behavioral and brain mechanisms of AUD and relapse. To address cross-species translation and underlying mechanisms of negative reinforcement, we formed a collaboration with a preclinical researcher to translate a well-validated animal paradigm of negative reinforcement into humans. The proposed project will investigate negative reinforcement behaviors and connectivity in a negative reinforcement neural network in adults with AUD who are in early abstinence (EA). Specific Aim 1 will characterize negative reinforcement learning and bias in EA adults compared to controls (CON). Specific Aim 2 will determine connectivity strength of a BNST negative reinforcement neural network using intrinsic (‘resting state’) functional connectivity and diffusion tensor imaging (DTI). Both aims will test for group differences (EA, CON) and exploratory analyses will determine whether negative reinforcement network connectivity is associated with negative reinforcement behaviors in the task. The hypotheses are that EA participants will (1) learn negative reinforcement faster and have a bias for negative reinforcement and (2) display stronger negative reinforcement network connectivity than controls. The results of this study will fill a critical gap in knowledge to better understand the behavioral and neural mechanisms that underly AUD and relapse, representing a critical target to guide future prevention and treatment of AUDs.
