Alcohol misuse is a leading cause of human misery, morbidity, and mortality. Existing treatments are far from curative. While the roots of alcohol misuse are complex and multifactorial, Anxiety plays a key role. Models of addiction suggest that many drinkers misuse alcohol to relieve excess anxiety (‘self-medicate’). Anxiety-related states, traits, and disorders increase the odds of alcohol use and problems, and these associations are magnified among individuals who habitually use alcohol for relief. Recent research motivates the hypothesis that anxiety- fueled alcohol misuse reflects hyper-reactivity to Uncertain Threat, the prototypical trigger of anxiety. Yet several key gaps in our understanding remain: (G1) There have been no systematic, well-powered efforts to test the relevance of Uncertain Threat circuitry to dimensional variation in alcohol misuse, impeding the development of more effective or tolerable therapeutics. Prior imaging studies have largely focused on cortical regions. The relevance of subcortical regions implicated in animal models of addiction and anxiety remains unclear. (G2) Computational psychiatry recognizes 2 distinct kinds of uncertainty: Risk and Ambiguity. Which of these is more relevant to alcohol misuse remains unexplored, thwarting the development of precision treatments. (G3) Preclinical work has identified a distributed brain circuit that is sensitive to Uncertain Threat, but it remains unknown which components of this circuit are most relevant to anxiety-fueled craving and consumption in the real world. To address these questions, we will recruit a racially diverse community sample of 240 AUD+ adults, over-sampling those who use alcohol for anxiety relief. Parametric threat-anticipation paradigms will allow us to probe circuits sensitive to categorical and dimensional variation in threat uncertainty. Smartphone phenotyping will assess real-world threat exposure, threat uncertainty, anxiety, craving, and alcohol use. These data will enable us to address 3 aims. (A1) Identify the brain regions and facets of threat uncertainty most relevant to clinical variation in alcohol use, symptoms, and problems. (A2) Use smartphone technology to pinpoint modifiable factors—including alterations in perceived threat and anxiety—that trigger craving and consumption. (A3) Fusing the fMRI and smartphone data-streams will allow us to fractionate the Uncertain Threat circuit and pinpoint the components most relevant to anxiety-fueled alcohol misuse in the real world—an aim that cannot be addressed using either tool in isolation. This integrative approach promises to bridge levels of analysis and has never been applied to alcohol misuse. Summary: AUD is notoriously heterogeneous, with >2,000 unique clinical profiles. Our focus on a theoretically coherent set of dimensional measures in a diverse, clinically relevant sample promises to overcome this barrier and provide fresh insights into the underlying neurobiology. Building on well-established negative reinforcement models and a fruitful line of psychophysiological research, this study will provide a potentially transformative opportunity to identify new treatment targets; guide the development of new translational models; and inform the development of new digital interventions.

PUBLIC HEALTH SIGNIFICANCE Alcohol misuse imposes a staggering burden on public health and the global economy. While the root causes of alcohol misuse are complex and heterogeneous, there is ample evidence that many individuals use alcohol to dampen excess anxiety (‘self-medicate’). This study will harness an innovative combination of computational, brain imaging, and smartphone technologies to understand the chain of neurobiological and psychological factors that govern anxiety-fueled alcohol misuse, paving the way for developing more precise and effective treatment strategies for this debilitating illness.