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

Alcohol dependence is a chronic, relapsing illness, which contributes to significant global disease burden.1 The risk for relapse further perpetuates this disease burden and is increased in stress-related and alcohol-related contexts that promote anxiety and alcohol craving.2-6 Neuroendocrine studies have demonstrated that upregulated hypothalamic-pituitary-adrenal axis response during a neutral-relaxing condition and blunted cortisol responses to stress significantly contribute to chronic alcoholism and relapse.6-8 Evidence from electrophysiological studies also indicates disrupted electroencephalographic responses at rest during early recovery from alcoholism. For example, excessive alcohol use leads to neuroadaptations akin to a kindling-like process,9 resulting in a hyper-excitable neuronal state, particularly in frontal regions.10,11 Furthermore, alcohol-related neuroadaptations increase stress sensitivity2,12 and stress-related anxiety response.13 These studies suggest the importance of examining neural mechanisms of stress and nonemotional, neutral-relaxing states in assessing their contribution to alcohol relapse risk. Although recent advances in neuroimaging techniques have provided insights into neuronal abnormalities in brain structure and function associated with chronic alcoholism, research on functional mechanisms associated with alcohol relapse has been rare and primarily focused on alcohol cue–related neural processes in the mesocortical-limbic pathways,14 with little attention to neural mechanisms involved in stress and neutral-relaxing states and their associations with alcohol craving and relapse. Because chronic alcohol-related neuroadaptations target prefrontal networks that include the corticostriatal motivation pathways,15 such neuroadaptations could promote increased craving and relapse risk.2,6,12,16 Alcohol-related dysfunction in frontal networks might particularly affect higher order executive function including response inhibition and decision-making functions.17-19 Furthermore, chronic alcohol-related hyperactivity of the mesolimbic dopamine-related impulsive pathways may further compromise the prefrontal self-control regions involved in the regulation of cravings and the will to resist relapse.17,19,20 However, the specific role of the prefrontal regions and their interconnected networks in alcohol craving and relapse risk in the context of stress and neutral-relaxing states is not known. Integrating the previously mentioned theoretical and empirical perspectives, the current study aimed to identify neural correlates of alcohol craving and future relapse risk in the context of stress, alcohol cue, and neutral-relaxing situations in recovering alcohol-dependent (AD) patients using a combined functional magnetic resonance imaging (fMRI) and prospective clinical design study. We examined all 3 conditions known to influence alcoholism in previous studies to investigate patterns of differential neural responses during these conditions. The neutral-relaxing condition was included as an active comparison state because it does not increase alcohol craving,6 but it provides a context to assess changes in a resting-relaxed state while controlling for the non-specific effects of the experimental manipulation. In previous work, we identified disrupted neuroendocrine responses in the relaxed states in AD patients with a strong association with alcohol relapse.6 A second aim was to identify whether the same neural responses that are predictive of alcohol relapse show differences in brain responses when comparing recovering AD patients and demographically matched healthy control (HC) subjects. For the relapse aim, 45 inpatient treatment–engaged, 4- to 8-week–abstinent, recovering AD individuals participated in an fMRI session. Participants were discharged from inpatient treatment following the fMRI session and prospectively followed up with repeated face-to-face assessments at days 14, 30, and 90 to assess relapse risk (Figure 1A). Relapse risk was assessed with the frequently used clinical outcome measures of time to first drink (relapse), time to heavy drinking relapse (5 or more drinks/occasion in men; 4 or more drinks/occasion in women), and alcohol relapse severity as measured by frequency of drinking days after first relapse. For group comparisons, we compared brain responses of age-matched, sex-matched, and intelligence-matched, right-handed, abstinent AD patients (a subgroup of the relapse sample) vs healthy, socially drinking individuals (30 in each group; eTable 1, http:www.jamapsych.com). 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 ... A block design approach that used a well-validated, individually calibrated, script-driven guided-imagery procedure (see Sinha article21 for review) was implemented to experimentally induce challenging stress and alcohol cue states and an active neutral-relaxing control state via exposure to 6 brief trials of 2 stress, 2 alcohol cue, and 2 neutral-relaxing scenarios (different scripts presented in randomized order). The same fMRI procedures were used with both the AD patients and HC subjects in the study.