Altered Neural Processing of Threat in Alcohol-Dependent Men

Background: Stress-response biological systems are altered in alcohol-dependent individuals and are reported to predict future relapse. This study was designed to assess neural disruptions in alcohol-dependent participants when exposed to a conditioned stimulus (CS) warning of the impending onset of a universal, nonpersonalized stressor. Methods: Fifteen alcohol-dependent men abstinent for 3 to 5 weeks and 15 age- and race-similar healthy controls were studied. Anticipatory anxiety was induced by a CS paired with an uncertain, physically painful unconditioned stressor. Neural response was assessed using functional magnetic resonance imaging. Results: Both groups experienced significant, similar levels of anticipatory anxiety in response to the high-threat relative to the low-threat CS. Whereas control participants markedly increased the blood oxygen level-dependent (BOLD) amplitude in cortical-limbic-striatal regions during the high-threat, relative to low-threat, stimulus, alcohol-dependent participants decreased BOLD amplitude in the pregenual anterior cingulate cortex (pgACC), medial prefrontal cortex (mPFC), medial orbitofrontal cortex, posterior cingulate cortex (PCC), bilateral parietal/occipital cortex, and right hippocampus. Alcohol-dependent participants significantly deactivated pgACC/mPFC and PCC clusters, relative to controls, during the high- versus low-threat stimulus. This difference was due to a decrease in %BOLD amplitude during the high-threat stimulus in the alcohol-dependent, but not the control, participants. Conclusions: Alcohol-dependent men show cortical-limbic-striatal deactivation during anticipatory anxiety, particularly in regions associated with emotional regulation. These findings suggest a lack of engagement of affective regulatory mechanisms during high-stress situations in alcohol-dependent men.