Investigating individual differences in alcohol abstinence associated anxiety and depression across the BNST network.

Alcohol use disorders (AUDs) are disabling and prevalent conditions that affect almost one-third of Americans. While initial treatments exist, relapse is common, making long-term recovery difficult. Given the high rates of relapse, interventions that seek to prevent relapse have high potential impact. Animal models have shown that the bed nucleus of the stria terminalis (BNST) is heavily implicated in alcohol dependence, alcohol withdrawal, and withdrawal-induced alcohol seeking. Neuroadaptive changes in response to chronic alcohol exposure modify BNST function through multiple processes. During abstinence, these changes in the BNST are associated with heightened negative affect and potentially relapse through negative reinforcement. While animal models of addiction are heavily studied under the assumption of their utility in translation to humans, a major unmet need in the field is to translate these animal models to humans. A major barrier to this work has been technological limitations in neuroimaging of the BNST because of its small size. We have recently overcome this challenge. We have characterized the BNST neural circuitry in humans and developed novel methods to test BNST function. Our team also conducted an NIAAA funded R21 pilot study of BNST function and connectivity during abstinence in humans with an AUD. We confirmed alterations in a BNST network in early abstinence. However, one of the most striking findings was that there is substantial heterogeneity in anxiety and depression symptoms; critically, variation in symptoms was correlated with BNST function and connectivity. Data from a large residential treatment sample further points to several subgroups, or phenotypes, of how negative affect changes across the first 30 days of abstinence. Together, these findings highlight that early abstinence is not homogenous and that important individual differences exist. The goal of this project is use precision neuroscience methods to establish BNST circuits associated with negative affect during early abstinence and to forward-translate findings from rodent model lab studies. The Vanderbilt Alcohol Research & Education Center will provide the infrastructure needed to perform forward-translational and reverse-translational studies. The current study will investigate three specific aims: (1) Identify and characterize negative affect phenotypes during early abstinence; (2) Test the hypothesis that alterations in BNST network function and connectivity are associated with individual differences in negative affect; (3) Forward Translation: Test novel anatomical pathways identified by Projects 2-4. The successful completion of this study, in close collaboration with the Research Core and other Research Components, will fill a critical knowledge gap in identifying the neurobiological basis of individual differences in negative affect during abstinence and will cross-validate the pathways identified in Projects 2-4. The results will provide foundational information to inform future studies investigating mechanisms of negative affect in abstinence and can guide the development of personalized treatments for AUD.