Neural responses to stress and alcohol cues in individuals with pain with and without alcohol use disorder

Abstract

Pain and alcohol use disorder (AUD) frequently co-occur, but the underlying neurobiology is not well-understood. Although many studies have reported disruptions in stress and reward cue-elicited neural reactivity and heightened alcohol craving in individuals with AUD, little is known about these constructs among patients who experience pain. Here, individuals with pain (Pain+, n = 31) and without pain (Pain-, n = 37) completed a well-validated functional magnetic resonance imaging (fMRI) paradigm involving stress (S), alcohol (A) and neutral (N) cue exposure with repeated alcohol craving assessments. Using whole-brain, voxel-based analyses (p < 0.001, whole-brain cluster correction at α < .05), the Pain+ versus Pain- group evidenced greater dorsal anterior cingulate cortex and left amygdala hyperactivation during N, but hypoactivation during the S-N contrast. Additionally, Pain+ exhibited blunted right anterior insular cortex (AIC) during S-N and blunted anteromedial thalamus and left AIC with hyperactive orbitofrontal cortex (OFC) during A-N. Exploratory analyses further revealed that individuals with pain and AUD (n = 17) relative to pain alone (n = 14) showed hyperactive bilateral AIC and hypoactive right dorsal caudate during A-N. Alcohol cue-induced craving, significantly higher in Pain+ (p = 0.03), correlated with blunted right AIC and OFC responses during A-N. In sum, these results provide first evidence of heightened alcohol cue-elicited craving and disrupted stress- and alcohol cue-reactivity within corticostriatal-limbic regions implicated in negative affect and preoccupation/anticipation stages of AUD in those with pain and with comorbid pain and AUD. Future investigations of pain-AUD interaction are needed that include systematic pain assessment and longitudinal designs with larger sample sizes.

Keywords: AUD; alcohol craving; fMRI; insula; pain; stress and alcohol cue reactivity.

FIGURE 1

Functional magnetic resonance imaging (fMRI) cue provocation task involves sustained exposures to stress, alcohol cue and neutral pictures in a block design. Each block consists of three baseline grey‐fixation runs of 1 min length for comparison with the subsequent six consecutive runs of 1 min in length. Each run includes 11 trials, where each trial consists of 5‐s of visual image presentation with a 1‐s interstimulus interval for each of the alcohol, stress or neutral conditions. Each alcohol cue, stress and neutral condition was counterbalanced across participants and presented in randomized order to prevent order effects in the responses. Subjective alcohol craving (ratings ranges from 1 to 9) was assessed after each baseline and provocation run in each condition block. There was a 5‐min post‐provocation recovery period after each condition (not included in the analyses), during which participants were asked to relax without viewing any cues. During that time, they viewed a black background with a white crosshair on the screen.

FIGURE 2

Group differences (pain/no pain) in subjective alcohol craving responses during functional magnetic resonance imaging (fMRI). Mean alcohol craving ratings in response to neutral‐relaxing (N), stress cue (S) and alcohol cue (A) imagery relative to baseline runs (imagery minus baseline for each task run, then averaged per condition block). Alcohol craving was significantly higher in response to stress and alcohol cue compared to neutral imagery (a > N: p < 0.001; S > N: p < 0.001, a > S: p < 0.001). Individuals with pain relative to those without pain reported greater alcohol craving during alcohol condition (p = 0.03), but not during stress (p = 0.06) or neutral condition (p = 0.59). All data are displayed as mean ± S.E.M. *p < 0.05, **p < 0.001, n.s., not significantly different.

FIGURE 3

Whole‐brain voxelwise post hoc linear mixed‐effects (LME) analyses controlling for age and sex show disruptions in corticostriatal‐limbic activation patterns in response to stress (S) and alcohol cue (A) relative to neutral (N). Horizontal brain slices show the difference in activation during S‐N and A‐N between the pain and no pain groups, with activations in red indicating pain > no pain and activations in blue indicating pain < no pain. All differences were significant after whole‐brain familywise error [FWE] correction at p < 0.001 and cluster correction at α < 0.05. The bar plots show the average change in region‐of‐interest (ROI) beta weights for the pain and no pain groups. Abbreviations: AIC, anterior insular cortex; AM thalamus, anteromedial thalamus; dACC, dorsal anterior cingulate cortex; L, left; OFC, orbitofrontal cortex.

FIGURE 4

Whole‐brain voxel‐wise post‐hoc LME analyses controlling for age and sex show disruptions in cortico‐striatal‐limbic activation patterns in response to alcohol cue (A) relative to neutral (N). (A) Horizontal brain slice shows the difference in activation during A‐N between the alcohol use disorder (AUD) patients with pain and social drinkers (SD) with pain, with activations in red indicating AUD>SD and activations in blue indicating AUD<SD. All differences were significant after whole‐brain family‐wise error [FWE] correction at p<.001 and cluster correction at α<.05. No significant group differences were found during S‐N contrast and N condition. (B) The bar plots show the average change in region‐of‐interest (ROI) beta weights for the AUD and SD groups. Abbreviations. AIC = anterior insula, L = left.

FIGURE 5

Whole‐brain correlation analysis (p < 0.005, uncorrected) between neural response to alcohol cue (A) relative to neutral (N) and average alcohol craving rating during alcohol runs relative to baseline runs in pain individuals. Right anterior insular cortex (AIC; x = 42, y = 2, z = −6, k = 20, z = 3.4) and orbitofrontal cortex (OFC; x = 10, y = 18, z = −24, k = 45, z = 3.6) hypoactivity (shown here in blue) was significantly associated with higher alcohol craving. AUD, alcohol use disorder; SD, social drinker.