Altered Neural Processing of Threat in Alcohol-Dependent Men

Disrupted functioning of biological stress-response systems is thought to underlie stress-induced drinking. Peripherally, both basal reactivity (Sinha et al., 2011) and provoked pituitary–adrenal reactivity to pharmacologic and behavioral stressors (Adinoff et al., 2005b,c) are altered in alcohol-dependent individuals. Centrally, multiple neurotransmitters and neuropeptides are mutually involved in stress reactivity and drinking behaviors, including serotonin, norepinephrine, opioids, corticotropin-releasing factor, neuropeptide Y, and GABA (Brady and Sinha, 2005). Persistent and excessive alcohol use, repeated withdrawal episodes, and recurrent environmental stressors (Heilig et al., 2010), overlaid upon genetic predisposing factors and early life trauma (Schepis et al., 2011), all appear relevant to the induction of stress sensitivity and resultant alcohol intake. Clinically, disruptions in peripheral stress-response systems have been associated with poorer treatment retention (Daughters et al., 2009) and increased relapse rates (Adinoff et al., 2005a; Sinha et al., 2011). The experience and response to stress requires an organism to simultaneously assess, regulate, predict, and respond to anxiety- and/or fear-inducing stimuli. The dorsal–caudal regions of the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) appear integral to the appraisal and expression of emotions generated during stress, whereas the ventral–rostral regions regulate these emotions (Etkin et al., 2011). The expression of fear, including conditioned fear, induces amygdalar activation (Sehlmeyer et al., 2009), and both the amygdala and striatum track fearpredictive stimuli (Schiller et al., 2008). Both hippocampal reactivity and amygdalar reactivity are highly correlated with the hypothalamic–pituitary–adrenal (HPA) stress response (Pruessner et al., 2010). Connectivity within the default mode network (DMN), which surveys and assesses internal and external environments (Gusnard et al., 2001), shows decreased coupling in post-traumatic stress disorder (PTSD), a disorder notable for abnormal stress responses (Sripada et al., 2012). Disruptions in these various brain regions have been identified in alcohol-dependent individuals, although whether these alterations are related to stress-response disruptions is uncertain. To further clarify and isolate the neurobiological alterations triggering stress-related drinking, the central processes occurring during stress require real-time assessment. A number of paradigms have been developed to evoke stress while simultaneously monitoring the central nervous system activity in humans. These paradigms include computerized mental arithmetic tasks coupled with negative social comments (Pruessner et al., 2010), verbal serial subtraction with increasing time speed demands (Wang et al., 2005), negative pictures from the International Affective Pictures System (Sarinopoulos et al., 2010), and script-guided imagery (Sinha and Li, 2007). These paradigms utilize a block design, in which stressors are administered for several minutes and compared to a nonstressed condition administered for the same amount of time. Despite the relevance of stress to alcohol use, only Seo and colleagues (2013) have assessed stress reactivity using functional magnetic resonance imaging (fMRI) in alcohol-dependent patients. In that study, stress-induced script-guided imagery paradigm evoked a hyperactive response during neutral-relaxing trials in the patients relative to healthy controls. In order to further clarify the central processes involved in stress reactivity in alcohol dependence, we assessed the blood oxygen level-dependent (BOLD) response with fMRI during anticipatory anxiety in a group of abstinent, alcohol-dependent men and age- and race-matched healthy controls. In an attempt to remove, at least in part, the personalized interpretation and demands of a particular stressor, anxiety was induced by a conditioned stimulus (CS) paired with a painful unconditioned stimulus (US). This approach, adapted from Ploghaus and colleagues (1999), has the advantage of (i) eliciting anxiety in association with an otherwise neutral stimulus, thus disassociating the stimulus from any intrinsic, personalized interpretation; (ii) eliciting anxiety in response to the threat of a universal noxious stimulus (pain); (iii) using a US that can be adjusted for individual differences in pain response; (iv) using a mixed event-related/block design, providing the relatively rapid alteration of a high-anxiety and a low-anxiety CS; and (v) providing real-time, participant anxiety ratings during the presentation of each CS. We have previously reported that this paradigm induces marked striatal–limbic–cortical activation in healthy controls during the high-threat CS relative to a low-threat CS (Yang et al., 2012). In addition, the amplitude of BOLD signal change generally paralleled the subjective rating of anticipatory anxiety (Yang et al., 2012). To avoid the fluctuation in stress-response systems during early withdrawal (Adinoff et al., 1991), alcohol-dependent subjects were studied during 3 to 5 weeks of abstinence.