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.
