Brain correlates and functional connectivity linking stress, autonomic dysregulation, and alcohol motivation

High stress is a key risk factor for alcohol use disorder (AUD) and often accompanied by physiological dysregulation including autonomic nervous system (ANS) disruptions. However, neural mechanisms underlying drinking behaviors associated with stress and ANS disruptions remain unclear. The current study aims to understand neural correlates of stress, ANS disruptions, and subsequent alcohol intake in social drinkers with risky drinking. Using functional magnetic resonance imaging (fMRI), we investigated brain and heart rate (HR) autonomic responses during brief exposure to stress, alcohol, and neutral cues utilizing a well-validated, individualized imagery paradigm in 48 social drinkers of which 26 reported high-risk drinking (HD) while 22 reported low-risk drinking (LD) patterns. Results indicated that HD individuals showed stress and ANS disruptions with increased basal HR, stress-induced craving, and decreased brain response to stress exposure in frontal-striatal regions including the ventromedial prefrontal cortex (VmPFC), anterior cingulate cortex, striatum, insula, and temporal gyrus. Furthermore, whole-brain correlation analysis indicated that greater basal HR was associated with hypoactive VmPFC, but hyperactive medulla oblongata (MOb) responses during stress, with an inverse association between activity in the VmPFC and Mob (whole-brain corrected (WBC), p < 0.05). Functional connectivity with the MOb as a seed to the whole brain indicated that HD versus LD had decreased functional connectivity between the VmPFC and MOb during stress (WBC, p < 0.05). In addition, those with more compromised functional connectivity between the VmPFC and MOb during stress consumed greater amount of alcohol beverage during an experimental alcohol taste test conducted on a separate day, as well as in their self-reported weekly alcohol intake. Together, these results indicate that stress-related, dysfunctional VmPFC control over brain regions of autonomic arousal contributes to greater alcohol motivation and may be a significant risk factor for hazardous alcohol use in non-dependent social drinkers. Findings also suggest that restoring VmPFC integrity in modulating autonomic arousal during stress may be critical for preventing the development of AUD.