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Original Investigation |

Disrupted Ventromedial Prefrontal Function, Alcohol Craving, and Subsequent Relapse Risk

Dongju Seo, PhD1; Cheryl M. Lacadie, BA2; Keri Tuit, PsyD1; Kwang-Ik Hong, MS1; R. Todd Constable, PhD2; Rajita Sinha, PhD1
[+] Author Affiliations
1Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
2Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut
JAMA Psychiatry. 2013;70(7):727-739. doi:10.1001/jamapsychiatry.2013.762.
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Importance  Alcohol dependence is a chronic relapsing illness; stress, alcohol-related cues, and neutral-relaxing states significantly influence craving and relapse risk. However, neural mechanisms underlying the association between these states and alcohol craving and relapse risk remain unclear.

Objectives  To identify neural correlates associated with alcohol craving and relapse outcomes in 45 treatment-engaged, 4- to 8-week abstinent alcohol-dependent (AD) patients, and to compare brain responses of 30 demographically matched AD patients and 30 healthy control subjects during stress, alcohol, and neutral-relaxing cues.

Design  Functional magnetic resonance imaging study while participants were engaging in brief individualized script-driven imagery trials of stress, alcohol cues, and neutral-relaxing scenarios, and a prospective clinical outcome design to assess alcohol relapse 90 days postdischarge from inpatient treatment in the AD group.

Settings  Inpatient treatment setting in a community mental health center and hospital-based research unit.

Patients  Forty-five recovering AD patients in inpatient treatment for examining relapse, and 30 healthy control subjects demographically matched to 30 AD patients (subgroup of the relapse sample) for group comparisons.

Intervention  Twelve-step recovery–based addiction treatment for the patient group.

Main Outcomes and Measures  Brain response, alcohol craving, and relapse outcome measures (time to relapse and relapse severity).

Results  Increased ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) activation during neutral-relaxing trials was correlated with high alcohol cue–induced and stress-induced craving in early recovering AD patients (x = 6, y = 43, z = −6; P < .01, whole-brain corrected). This vmPFC/ACC hyperactivity significantly predicted subsequent alcohol relapse, with a hazards ratio greater than 8 for increased relapse risk. Additionally, vmPFC/ACC hyperactivation during neutral trials and reduced activity during stress trials were each predictive of greater days of alcohol used after relapse (P < .01, whole-brain corrected). In contrast, matched control subjects showed the reverse pattern of vmPFC/ACC responses to stress, alcohol cues, and relaxed trials (F = 6.42; P < .01, whole-brain corrected).

Conclusions and Relevance  Findings indicate that disrupted vmPFC/ACC function plays a role in jeopardizing recovery from alcoholism and may serve as a neural marker to identify those at risk for alcohol relapse.

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Figures

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Figure 1.
Study Design

A, For relapse sample, all 45 alcohol-dependent (AD) patients resided in an inpatient treatment research facility for 6 weeks with functional magnetic resonance image (fMRI) testing in week 5, and patients were assessed with follow-up interviews at 14, 30, and 90 days following inpatient treatment discharge. For group comparisons, neural responses of 30 healthy control (HC) subjects were compared with 30 demographically matched AD patients from the relapse sample. B, Relapse sample including 45 AD patients. Mean behavioral ratings (and standard errors) in response to stress (S), alcohol cue (AC), and neutral-relaxing (N) imagery relative to baseline (imagery minus baseline [I − B] rating) for anxiety (S > N: t = 8.0, P < .001; AC > N: t = 4.9, P < .001; and S > AC: t = 3.1, P < .01) and alcohol craving (S > N: t = 4.7, P < .001; AC > N: t = 7.1, P < .001; and AC > S: t = 2.4, P < .05) before and after each trial using 10-point Likert scale verbal ratings. Averaged heart rate increases from baseline during stress (t = 5.7, P < .001) and alcohol cue (t = 4.1, P < .001) relative to neutral-relaxing trials. The dependent measures (I − B) were averaged across 2 trials of the same type (alcohol cue, stress, and neutral).

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Figure 2.
Neural Correlates of Alcohol Craving in the Relapse Sample (N = 45)

During neutral-relaxing trials, ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex (ACC) hyperactivity was significantly associated with alcohol craving during alcohol cue (A) and stress (B) conditions (P < .01, whole-brain corrected). In addition, hyperactivity in the ventral striatum and precuneus during the neutral condition was correlated only with stress-induced alcohol craving. There were no outliers in the associations between alcohol craving and brain activity in these regions during neutral-relaxing trials. There were no brain responses during stress and alcohol cue trials that significantly correlated with alcohol craving that survived whole-brain correction for multiple comparisons at P < .01. Yellow/red voxels = positive correlation. I − B indicates imagery minus baseline rating.

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Figure 3.
Estimated Survival Functions and Receiver Operating Characteristic (ROC) Curves for Craving-Related Neural Responses Predicting Subsequent Time to Alcohol Relapse

Estimated survival functions for time to first alcohol relapse (with the number of years of alcohol use and stress-induced alcohol craving held constant) is predicted by mean β value and +1 and +2 standard deviation (SD) above the mean and −1 and −2 SD below the mean in the ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex (ACC) (A), ventral striatum (B), and precuneus (C) during neutral-relaxing trials. The survival analysis is based on a 90-day period, but these figures of estimated survival functions show the x-axis up to day 60 because patients with altered brain activity 2 SD above the mean had relapsed by day 60. D, ROC curves for the vmPFC/ACC (area under the curve = 0.82; χ2 = 4.94; P < .05; 95% CI, 0.67-0.97), ventral striatum (area under the curve = 0.77; χ2 = 1.96; P = .16; 95% CI, 0.61-0.93), and precuneus (area under the curve = 0.79; χ2 = 4.16; P < .05; 95% CI, 0.66-0.93).

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Figure 4.
Neural Responses and Association With the Number of Days Alcohol Was Used After Relapse During Follow-up in 45 Alcohol-Dependent Patients

Whole-brain voxel-based correlation analysis (P < .01, whole-brain corrected) indicated reduced activation during the stress condition in the ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex (ACC) (r = −0.56, R2 = 0.31) and right insula (r = −0.59, R2 = 0.34) (A), as well as hyperactivation in the vmPFC/ACC (r = 0.47, R2 = 0.23) and ventral striatum (r = 0.45, R2 = 0.20) (B) during neutral-relaxed trials were each predictive of the number of days alcohol was used during the 90-day follow-up period. Brain response to alcohol cue trials was not predictive of the days alcohol was used during follow-up. Blue/purple voxels indicate negative association and yellow/red voxels indicate positive correlation. Coordinates are given in Montreal Neurological Institute space. There were no outliers in the relation between brain activity and the number of days alcohol was used during follow-up in the stress condition. In the neutral condition, there was 1 outlier (greater than 1 using Cook distance) in the relation between brain activity and the number of days alcohol was used. The correlation still remained significant even after removing this value. To reduce the influence of this value, the results here are presented after Winsorization and in Table 2 for the neutral condition. L indicates left; R, right.

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Figure 5.
Group Comparisons of the Means and Standard Errors of the Mean for Group Differences

Group comparisons of the means and standard errors of the mean for group differences (30 alcohol-dependent [AD] and 30 healthy control participants) in subjective anxiety (A), alcohol craving (B), heart rate response (C), and basal heart rate (D) during stress, alcohol cue, and neutral imagery trials. Baseline (B) ratings of anxiety and alcohol craving were not different between groups and in each condition. However, to account for any variation in B levels, all data analyses used change from baseline (imagery minus baseline [I − B]) values. A, Alcohol-dependent patients showed greater anxiety ratings during alcohol exposure (t = 2.8, P < .01), but not in the stress and neutral conditions relative to healthy control subjects. B, In addition, AD patients showed significantly higher levels of craving in both alcohol cue (t = 4.42, P < .001) and stress (t = 2.7, P < .01) exposures compared with healthy control subjects. C, For heart rate response, there is no group difference between AD and healthy control participants in each condition. D, However, in basal heart rate, there was a significant group main effect (F1,56 = 5.92, P = .02), such that AD patients displayed significantly greater basal heart rate than healthy control subjects (t = 2.43, P < .05).

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Figure 6.
Whole-Brain Voxel-Based Functional Magnetic Resonance Images Showing Group × Condition Interaction for 30 Alcohol-Dependent (AD) and 30 Healthy Control Subjects

A, Brain activity from group × condition interaction is displayed on the left, and mean β values in the ventromedial prefrontal cortex (vmPFC)/anterior cingulate cortex (ACC) in each condition per group are displayed in the bar graph (P < .01, whole-brain corrected). B, Group difference in the vmPFC/ACC during stress, alcohol cue, and neutral-relaxing conditions (P < .05, whole-brain corrected). Alcohol-dependent patients showed decreased activity in the vmPFC/ACC during the stress and alcohol cue conditions, but increased activity in the neutral-relaxing condition relative to healthy control subjects. Activity in the vmPFC/ACC during the neutral-relaxing condition was part of a significant cluster that included the ventral striatum, but the ventral striatum was not included in the significant vmPFC cluster for the stress or the alcohol cue conditions in AD patients relative to control subjects. Additional data from whole-brain contrasts between groups are shown in eTable 4 in Supplement. Coordinates are given in Montreal Neurological Institute space. L indicates left; R, right.

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