Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity

Abstract

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P_(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P_(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P_(Bonferroni) = .009), depressive symptoms (r = .37, P_(Bonferroni) = .015), trait anxiety (r = .41, P_(Bonferroni) = .006), and perceived stress (r = .45, P_(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.

Keywords: addiction; alcohol use disorder; amygdala; anxiety; depressive symptoms; fear conditioning.

Figure 1

Digital photographs of two different rooms were used as the conditioning context (CX+; office) and extinction context (CX-; conference room), respectively. Both rooms contained a lamp with a black lamp shade that turned blue or yellow, constituting the conditioned stimuli (CS). During fear conditioning, one of the colors (blue) was followed by a 0.5-second electrical stimulation (CS+) in 75% of the trials, while the other (yellow, not shown) was never followed by a shock (CS-). During extinction, the CS+ was presented in the CX- and never followed by a shock. On day 2, participants were presented with the CS+ and CS- in the CX+ (fear renewal phase) and in the CX- (extinction recall phase). No shocks were delivered.

Figure 2

Skin conductance responses during fear conditioning and extinction. SCR= skin conductance response; HC= healthy controls; ALC= alcohol-dependent individuals; CS+ = conditioned stimulus predicting shock; CS- = conditioned stimulus predicting no shock; ***P < .001

Figure 3

Region of interest findings of significant functional activation group differences. Results are derived from 2-sample t-tests SVC with cluster-P < .05 FWE‐corrected for a priori ROIs comparing alcohol-dependent and healthy individuals, controlling for age, gender, and early life stress: a) Fear Conditioning (contrast CS+ versus CS-, trials 2–20): parameter estimates of reduced right amygdala-ROI BOLD responses in ALC compared to HC, Cohen’s d = .89, P_(FWE) = .037; b) Fear Renewal (contrast CS+ versus CS-, all trials 1–15): reduced left amygdala-ROI BOLD responses in ALC compared to HC, Cohen’s d = .68, P_(FWE) =.039. Neuroimaging findings are rendered onto the CH2better template in MRIcron (a) displayed at MNI y= 0.335322 and b) displayed at MNI y= 0.365229). ALC= alcohol-dependent individuals; BOLD= Blood Oxygenation Level-Dependent; CS+ = conditioned stimulus predicting shock; CS- = conditioned stimulus predicting no shock; HC= healthy controls; MNI= Montreal Neurologic Institute; ROI= region of interest; SVC= small volume correction; * P_(FWE) < .05

Figure 4

Clinical associations found in ALC between extracted parameter estimates of right amygdala-ROI BOLD responses (identified as a significant group activation difference in fear conditioning, contrast CS+ versus CS-, trials 2–20) and a) Alcohol Dependence Severity (assessed by ADS), b) Depressive Symptoms (assessed by MADRS), c) Trait Anxiety (assessed by STAI), and d) Perceived Stress (assessed by PSS). Neuroimaging finding of reduced functional right amygdala-ROI activations is rendered onto the CH2better template in MRIcron. ALC= alcohol-dependent individuals; ADS= Alcohol Dependence Scale; BOLD= Blood Oxygenation Level-Dependent; CS+ = conditioned stimulus predicting shock; CS- = conditioned stimulus predicting no shock; MADRS= Montgomery-Asberg Depression; PSS= Perceived Stress Scale; ROI= region of interest; STAI= Spielberger State-Trait Anxiety Inventory -Y2; SVC= small volume correction