Alcohol availability during withdrawal gates the impact of alcohol vapor exposure on responses to alcohol cues

Background: Chronic intermittent ethanol (CIE) vapor inhalation is a widely used model of alcohol dependence, but the impact of CIE on cue-elicited alcohol seeking is not well understood. Here, we assessed the effects of CIE on alcohol-seeking elicited by previously learned cues, and on acquisition of new cue-alcohol associations. Methods: In Experiment 1, male and female Long Evans rats were first trained in a discriminative stimulus (DS) task, in which one auditory cue (the DS) predicts the availability of 15% ethanol and a control cue (the NS) predicts nothing. Rats then underwent CIE or served as controls. Subsets of each group received access to oral ethanol twice a week during acute withdrawal. After CIE, rats were presented with the DS and NS cues under extinction and retraining conditions to determine whether they would alter their responses to these cues. In Experiment 2, rats underwent CIE prior to training in the DS task. We also assessed alcohol consumption, aversion resistant drinking, somatic withdrawal symptoms, and behavior in an open field. Results: We found that CIE enhanced behavioral responses to previously learned alcohol cues, but only in rats that received access to alcohol during acute withdrawal. CIE disrupted cue responses in rats that did not. When CIE occurred before cue learning, male rats were slower to develop cue responses and less likely to enter the alcohol port, even though they had received alcohol during acute withdrawal. We also found that CIE increased alcohol consumption and aversion-resistant drinking in male but not female rats. Conclusions: These results suggest that CIE alone does not potentiate the motivational value of alcohol cues, but that an increase in cue responses requires the potentiation of the value of alcohol during acute withdrawal. Further, under some conditions CIE may disrupt responses to previously learned and subsequently acquired alcohol cues.

Mindfulness Promotes Control of Brain Network Dynamics for Self-Regulation and Discontinues the Past from the Present

Mindfulness is characterized by attentiveness to the present experience with nonjudgmental awareness and acceptance. Practicing mindfulness alters brain function to support the executive regulation of thoughts, feelings, and behavior. While early stages of practice are thought to require greater "neural effort" for later efficiency, current evidence relies on circular definitions of effort based on functional activity magnitude. Here we used network control theory as a model of how external control inputs, which operationalize effort, can distribute changes in neural activity across the macro-scale structural brain network. Further, we inferred the intrinsic timescale of activity to operationalize present-centered activity as shorter momentary timescales that discontinue the past and update the present. To explain effects of mindful regulation on alcohol consumption, we applied these methods to a randomized controlled intervention study with resting-state and task fMRI data. The task primed participants to either mindfully respond or naturally react to alcohol cues. Mobile text interventions and measurements of alcohol consumption were administered using ecological momentary assessments during the subsequent 4 weeks. We hypothesized that neural states of mindfulness require greater effort to enact and sustain. This effort may support deautomatized habitual natural reactions, discontinued processing, and updated present-centered neural dynamics. We found that mindful regulation of alcohol cues, compared to the natural reactions of the benchmark group, involved more effortful control of neural dynamics across cognitive control and attention networks. This effort persisted in the natural reactions of the mindful group compared to the benchmark group. Using resting-state fMRI, we found that more effortful neural states tended to occur over shorter timescales than less effortful states. Our findings provide an explanation for how neural dynamics with altered effort and stability, such as mindful states, tend to center the present experience.

A Randomized Controlled Trial of Attentional Control Training for Treating Alcohol Use Disorder

Background: There is consistent evidence that community and clinical samples of individuals with an alcohol use disorder (AUD) have attentional biases toward alcohol cues. The alcohol attentional control training program (AACTP) has shown promise for retraining these biases and decreasing alcohol consumption in community samples of excessive drinkers. However, there is a lack of evidence regarding the effectiveness of ACTP in clinical AUD samples. The main aim of the present study is to investigate whether primary pharmacological and psychological, evidence-based alcohol treatment can be enhanced by the addition of a gamified AACTP smartphone application for patients with an AUD.Design and Methods: The study will be implemented as a randomized controlled trial. A total of 317 consecutively enrolled patients with AUD will be recruited from alcohol outpatient clinics in Denmark. Patients will be randomized to one of three groups upon initiation of primary alcohol treatment: Group A: a gamified AACTP smartphone application + treatment as usual (TAU); Group B: a gamified AACTP sham-control application + TAU; or Group C: only TAU. Treatment outcomes will be assessed at baseline, post-treatment, and at 3- and 6-month follow-ups. Repeated measures MANOVA will be used to compare the trajectories of the groups over time on alcohol attentional bias, alcohol craving, and drinking reductions. It is hypothesized that Group A will achieve better treatment outcomes than either Group B or Group C.Perspectives: Because attentional bias for alcohol cues is proportional to the amount of alcohol consumed, and these biases are not addressed within current evidence-based treatment programs, this study is expected to provide new evidence regarding the effectiveness of the gamified AACTP in a clinical population. Furthermore, due to promising results found using AACTP in community samples of excessive drinkers, there is a high probability that the AACTP treatment in this study will also be effective, thereby allowing AACTP to be readily implemented in clinical settings. Finally, we expect that this study will increase the effectiveness of evidence-based AUD treatment and introduce a new, low-cost gamified treatment targeting patients with an AUD. Overall, this study is likely to have an impact at the scientific, clinical, and societal levels.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT05102942?term=NCT05102942&draw=2&rank=1, identifier: NCT05102942.

Cardiac signals and the interference of reward on attention and inhibitory control

Interoceptive responses can act as potent cues to cognition and behavior; discrete cardiac signals can shape emotional and motivational adaptation towards reward-related cues, but also affect response inhibition. Novel addiction perspectives posit an interoceptive basis for the interplay between reward processing and inhibitory control, but there is a lack of behavioral evidence for this relationship. In this registered report we extend on previous findings to examine how reward cues interact with cardiac-facilitated attention and motor inhibition. Across two sessions, a sample of 35 social drinkers will complete a visual search task (VST) and two instances of a stop signal task (SST). In each task, alcohol or neutral cues will be presented as targets or distractors respectively. In the VST, target stimuli will be presented synchronized with participants’ cardiac phase (systole vs. diastole), examining how cardiac signals support alcohol attentional biases. In a modified SST, Go cues will appear synchronized with cardiac phase while alcohol or neutral cues appear as distractors, examining how cardiac signals increase reward interference in inhibitory control. Finally, in another instance of the SST, Stop signals will appear synchronized with cardiac phase, examining whether interoceptive signals can improve inhibitory control in the presence of reward cues. We hypothesize, at systole, higher attentional biases and interference in inhibitory control for alcohol cues, and that Stop signals can facilitate response inhibition. These results can provide evidence for the role of cardiac signaling in alcohol attentional biases and inhibitory control, extending our understanding of the interoceptive components of addiction.

Ibudilast, a neuroimmune modulator, reduces heavy drinking and alcohol cue-elicited neural activation: a randomized trial

Ibudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast’s effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = −0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.

Pushing or Pulling Your “Poison”: Clinical Correlates of Alcohol Approach and Avoidance Bias Among Inpatients Undergoing Alcohol Withdrawal Treatment

Introduction: Alcohol approach bias, the tendency to automatically move toward alcohol cues, has been observed in people who drink heavily. However, surprisingly, some alcohol-dependent patients demonstrate an alcohol avoidance bias. This inconsistency could be explained by the clinical or demographic profile of the population studied, yet this has not been examined in approach bias modification (ABM) trials to date. We aimed to determine the proportion of patients with an approach or avoidance bias, assess whether they differ on demographic and drinking measures, and to examine the clinical correlates of approach bias.Method: These research questions were addressed using baseline data from 268 alcohol-dependent patients undergoing inpatient withdrawal treatment who then went on to participate in a trial of ABM.Results: At trial entry (day 3 or 4 of inpatient withdrawal), 155 (57.8%) had an alcohol approach bias and 113 (42.2%) had an avoidance bias. These two groups did not differ on any demographic or relevant drinking measures. Approach bias was significantly and moderately associated with total standard drinks consumed in the past 30 days (r = 0.277, p = 0.001) but no other indices of alcohol consumption or problem severity.Conclusion: Whilst the majority of alcohol-dependent patients showed an alcohol approach bias, those with an avoidance bias did not differ in demographic or clinical characteristics, and the strength of approach bias related only to recent consumption. Further research is needed to develop more accurate and personally tailored measures of approach bias, as these findings likely reflect the poor reliability of standard approach bias measures.

Alcohol cues elicit different abnormalities in brain networks of abstinent men and women with alcohol use disorders

We employed fMRI in 84 men and women with and without a history of alcohol use disorders (ALC and NC, respectively), to explore how gender interacts with alcoholism as reflected in brain activity elicited by alcohol cues. Brain activation was measured in a working memory task (delayed matching-to-sample) with emotional faces as the sample and match cues. During the delay period, intervening distractors were either reward-salient cues (alcoholic beverages) or neutral cues (nonalcoholic beverages or scrambled pictures). ALC women (ALCw) had higher accuracy than ALC men (ALCm). Analyses of scans during the viewing of distractor images revealed significant group-by-gender interactions. Compared to NC men, ALCm evidenced lower activation contrast between reward-salient cues and neutral cues in default mode network regions (including superior prefrontal and precuneus areas), while ALCw had more activation than NC women. Similar interactions were observed for task-regions (including superior parietal, lateral occipital, and prefrontal areas). Region of interest analyses showed that the ALC group had significantly higher levels of activation throughout reward-related circuitry during alcohol distractor interference than during scrambled picture interference. These results suggest that abstinent ALCm and ALCw differ in processing reward-salient cues, which can impact treatment and recovery.