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Background: Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes., Methods: We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access i.v. alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 nonsmoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG)., Results: We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared with nonsmokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group., Conclusions: Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses., (Published by Oxford University Press on behalf of CINP 2024.)

Objectives: Alcohol use disorder (AUD) is a global health problem with significant negative consequences, including preventable deaths. Although olfactory dysfunction is associated with chronic alcohol drinking, the relationship among specific types of olfactory deficits, depressive symptoms, and problematic drinking remains to be explored. Here, we examined the prevalence of olfactory distortion (parosmia) and hallucination (phantosmia) and assessed their associations with problematic drinking and depressive symptoms., Methods: In April-June 2022, 250 participants across the spectrum of AUD were recruited for assessment in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol study. Surveys covered self-reported olfactory function, depressive symptoms, and problematic drinking, with key measures assessed, including the Alcohol Use Disorders Identification Test and the Patient Health Questionnaire. Predictors in the analysis included parosmia and phantosmia, with covariates comprising age, sex, socioeconomic status, race, ethnicity, COVID-19 infection status, and smoking status., Results: Among 250 individuals, 5.2% experienced parosmia and 4.4% reported phantosmia. Parosmia was associated with higher Alcohol Use Disorders Identification Test scores (β = 7.14; 95% confidence interval = 3.31, 10.96; P < 0.001), whereas phantosmia was linked to higher Patient Health Questionnaire scores (β = 3.32; 95% confidence interval = 0.22, 6.42; P = 0.03). These associations persisted in both the full sample and the subset of participants without COVID-19., Conclusions: Our study highlights strong existing links among olfactory deficits, problem drinking, and depressive symptoms, underscoring the need to assess smell impairments in clinical settings. Future research should explore these connections further to develop new treatments for individuals with AUD and depression., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Alcohol use disorder (AUD) is commonly associated with distressing psychological symptoms. Pathologic changes associated with AUD have been described in both the gut microbiome and brain, but the mechanisms underlying gut-brain signaling in individuals with AUD are unknown. This study examined associations among the gut microbiome, brain morphometry, and clinical symptoms in treatment-seeking individuals with AUD., Methods: We performed a secondary analysis of data collected during inpatient treatment for AUD in subjects who provided gut microbiome samples and had structural brain magnetic resonance imaging (MRI; n = 16). Shotgun metagenomics sequencing was performed, and the morphometry of brain regions of interest was calculated. Clinical symptom severity was quantified using validated instruments. Gut-brain modules (GBMs) used to infer neuroactive signaling potential from the gut microbiome were generated in addition to microbiome features (e.g., alpha diversity and bacterial taxa abundance). Bivariate correlations were performed between MRI and clinical features, microbiome and clinical features, and MRI and microbiome features., Results: Amygdala volume was significantly associated with alpha diversity and the abundance of several bacteria including taxa classified to Blautia, Ruminococcus, Bacteroides, and Phocaeicola. There were moderate associations between amygdala volume and GBMs, including butyrate synthesis I, glutamate synthesis I, and GABA synthesis I & II, but these relationships were not significant after false discovery rate (FDR) correction. Other bacterial taxa with shared associations to MRI features and clinical symptoms included Escherichia coli and Prevotella copri., Conclusions: We identified gut microbiome features associated with MRI morphometry and AUD-associated symptom severity. Given the small sample size and bivariate associations performed, these results require confirmation in larger samples and controls to provide meaningful clinical inferences. Nevertheless, these results will inform targeted future research on the role of the gut microbiome in gut-brain communication and how signaling may be altered in patients with AUD., (© 2024 The Author(s). Alcohol, Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Electroencephalographic (EEG) deficits in slow wave activity or Delta power (0.5-4 Hz) indicate disturbed sleep homeostasis and are hallmarks of depression. Sleep homeostasis is linked to restorative sleep and potential antidepressant response via non-rapid eye movement (NREM) slow wave sleep (SWS) during which neurons undergo essential repair and rejuvenation. Decreased Low Delta power (0.5-2 Hz) was previously reported in individuals with depression. This study investigated power levels in the Low Delta (0.5-<2 Hz), High Delta (2-4 Hz), and Total Delta (0.5-4 Hz) bands and their association with age, sex, and disrupted sleep in treatment-resistant depression (TRD). Mann-Whitney U tests were used to compare the nightly progressions of Total Delta, Low Delta, and High Delta in 100 individuals with TRD and 24 healthy volunteers (HVs). Polysomnographic parameters were also examined, including Total Sleep Time (TST), Sleep Efficiency (SE), and Wake after Sleep Onset (WASO). Individuals with TRD had lower Delta power during the first NREM episode (NREM1) than HVs. The deficiency was observed in the Low Delta band versus High Delta. Females with TRD had higher Delta power than males during the first NREM1 episode, with the most noticeable sex difference observed in Low Delta. In individuals with TRD, Low Delta power correlated with WASO and SE, and High Delta correlated with WASO. Low Delta power deficits in NREM1 were observed in older males with TRD, but not females. These results provide compelling evidence for a link between age, sex, Low Delta power, sleep homeostasis, and non-restorative sleep in TRD., Competing Interests: Declaration of competing interest Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise., (Published by Elsevier Ltd.)

Substance use disorder (SUD) is a chronic relapsing disorder with long-lasting changes in brain intrinsic networks. While most research to date has focused on static functional connectivity, less is known about the effect of chronic drug use on dynamics of brain networks. Here we investigated brain state dynamics in individuals with opioid use (OUD) and alcohol use disorder (AUD) and assessed how concomitant nicotine use, which is frequent among individuals with OUD and AUD, affects brain dynamics. Resting-state functional magnetic resonance imaging data of 27 OUD, 107 AUD, and 137 healthy participants were included in the analyses. To identify recurrent brain states and their dynamics, we applied a data-driven clustering approach that determines brain states at a single time frame. We found that OUD and AUD non-smokers displayed similar changes in brain state dynamics including decreased fractional occupancy or dwell time in default mode network (DMN)-dominated brain states and increased appearance rate in visual network (VIS)-dominated brain states, which were also reflected in transition probabilities of related brain states. Interestingly, co-use of nicotine affected brain states in an opposite manner by lowering VIS-dominated and enhancing DMN-dominated brain states in both OUD and AUD participants. Our finding revealed a similar pattern of brain state dynamics in OUD and AUD participants that differed from controls, with an opposite effect for nicotine use suggesting distinct effects of various drugs on brain state dynamics. Different strategies for treating SUD may need to be implemented based on patterns of co-morbid drug use., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The neurobiology of typical moral cognition involves the interaction of frontal, limbic, and temporoparietal networks. There is still much to be understood mechanistically about how moral processing is disrupted; such understanding is key to combating antisociality. Neuroscientific models suggest a key role for attention mechanisms in atypical moral processing. We hypothesized that attention-bias toward alcohol cues in alcohol use disorder (AUD) leads to a failure to properly engage with morally relevant stimuli, reducing moral processing. We recruited patients with AUD ( n  = 30) and controls ( n  = 30). During functional magnetic resonance imaging, participants viewed pairs of images consisting of a moral or neutral cue and an alcohol or neutral distractor. When viewing moral cues paired with alcohol distractors, individuals with AUD had lower medial prefrontal cortex engagement; this pattern was also seen for left amygdala in younger iAUDs. Across groups, individuals had less engagement of middle/superior temporal gyri. These findings provide initial support for AUD-related attention bias interference in sociomoral processing. If supported in future longitudinal and causal study designs, this finding carries potential societal and clinical benefits by suggesting a novel, leverageable mechanism and in providing a cognitive explanation that may help combat persistent stigma.

Objective: To identify latent classes of positive coping behaviors during the COVID-19 pandemic and examine associations with alcohol-related and mental health outcomes across participants with and without a history of alcohol use disorder (AUD)., Methods: Baseline data from 463 participants who were enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol (C19-PIA) Study were analyzed. Latent class analysis (LCA) was applied to five positive coping behaviors during COVID-19: taking media breaks, taking care of their body, engaging in healthy behaviors, making time to relax, and connecting with others. Latent class differences and the moderating role of history of AUD on six alcohol-related and mental health outcomes were examined using multiple regression models., Results: LCA revealed two latent classes: 83.4% High Positive Coping and 16.6% Low Positive Coping. Low Positive Coping was associated with higher levels of perceived stress, anxiety symptoms, and loneliness. A history of AUD was consistently associated with higher levels of alcohol-related and mental health outcomes. Significant interactions between Coping Latent Classes and history of AUD indicated that the associations of Low Positive Coping with problematic alcohol use, depressive symptoms, and drinking to cope motives were either stronger or only significant among individuals with a history of AUD., Conclusions: Individuals with a history of AUD may be particularly vulnerable to depressive symptoms and alcohol-related outcomes, especially when they do not utilize positive coping strategies. The promotion of positive coping strategies is a promising avenue to address alcohol-related and mental health problems during a public health crisis and warrants future research., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Early life stress (ELS) significantly increases susceptibility to alcohol use disorder (AUD) by affecting the interplay between the executive and the salience networks (SNs). The link between AUD and higher body-mass index (BMI) is known, but we lack understanding of how BMI impacts the relationship between ELS and brain connectivity in individuals with AUD. To bridge this gap, we investigated the main and interaction effects of ELS and BMI on brain connectivity in individuals with AUD compared to non-AUD participants (n = 77 sex-matched individuals per group). All participants underwent resting-state functional magnetic resonance imaging, revealing intriguing positive functional connectivity between SN seeds and brain regions involved in somatosensory processing, motor coordination and executive control. Examining the relationship of brain connectivity with ELS and BMI, we observed positive associations with the correlations of SN seeds, right anterior insula (RAIns) and supramarginal gyrus (SMG) with clusters in motor [occipital cortex, supplementary motor cortex]; anterior cingulate cortex (ACC) with clusters in frontal, or executive, control regions (middle frontal gyrus; MFG, precentral gyrus) that reportedly are involved in processing of emotionally salient stimuli (all |β | > 0.001, |p | < 0.05). Interestingly, a negative association of the interaction effect of ELS events and BMI measures with the functional connectivity of SN seeds ACC with decision-making (MFG, precentral gyrus), RAIns and RSMG with visuo-motor control regions (occipital cortex and supplementary motor cortex) (all |β | = -0.001, |p | < 0.05). These findings emphasize the moderating effect of BMI on ELS-associated SN seed brain connectivity in AUD. Understanding the neural mechanisms linking BMI, ELS and AUD can guide targeted interventions for this population., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance., Methods: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method., Results: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments., Discussion: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples., Competing Interests: RS has served on the scientific advisory board of Embera Neuro-therapeutics. DS has received research grants and/or consultancy honoraria from Lundbeck and Sun. MY has received funding from several law firms in relation to expert witness reports. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cao, McCabe, Callas, Cupertino, Ottino-González, Murphy, Pancholi, Schwab, Catherine, Hutchison, Cousijn, Dagher, Foxe, Goudriaan, Hester, Li, Thompson, Morales, London, Lorenzetti, Luijten, Martin-Santos, Momenan, Paulus, Schmaal, Sinha, Solowij, Stein, Stein, Uhlmann, van Holst, Veltman, Wiers, Yücel, Zhang, Conrod, Mackey, Garavan and the ENIGMA Addiction Working Group.)

Real-time fMRI neurofeedback (rt-fMRI-NF) is a technique in which information about an individual's neural state is given back to them, typically to enable and reinforce neuromodulation. Its clinical potential has been demonstrated in several applications, but lack of evidence on optimal parameters limits clinical utility of the technique. This study aimed to identify optimal parameters for rt-fMRI-NF-aided craving regulation training in alcohol use disorder (AUD). Adults with AUD (n = 30) participated in a single-session study of four runs of rt-fMRI-NF where they downregulated "craving-related" brain activity. They received one of three types of neurofeedback: multi-region of interest (ROI), support vector machine with continuous feedback (cSVM), and support vector machine with intermittent feedback (iSVM). Performance was assessed on the success rate, change in neural downregulation, and change in self-reported craving for alcohol. Participants had more successful trials in run 4 versus 1, as well as improved downregulation of the insula, anterior cingulate, and dorsolateral prefrontal cortex (dlPFC). Greater downregulation of the latter two regions predicted greater reduction in craving. iSVM performed significantly worse than the other two methods. Downregulation of the striatum and dlPFC, enabled by ROI but not cSVM neurofeedback, was correlated with a greater reduction in craving. rt-fMRI-NF training for downregulation of alcohol craving in individuals with AUD shows potential for clinical use, though this pilot study should be followed with a larger randomized-control trial before clinical meaningfulness can be established. Preliminary results suggest an advantage of multi-ROI over SVM and intermittent feedback approaches., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The early abstinence period is a crucial phase in alcohol use disorder (AUD) in which patients have to find a new equilibrium and may start recovery, or conversely, relapse. However, the changes in brain functions during this key period are still largely unknown. We set out to study longitudinal changes in large-scale brain networks during the early abstinence period using resting-state scans. We scanned AUD patients twice in a well-controlled inpatient setting, with the first scan taking place shortly after admission and the second scan 4 weeks (±9 days) later near the end of the treatment period. We studied 37 AUD patients (22 males) and 27 healthy controls (16 males). We focused on three networks that are affected in AUD and underly core symptom dimensions in this disorder: the frontoparietal networks (left and right FPN) and default mode network (DMN). Both the whole brain and within network connectivity of these networks were studied using dual regression. Finally, we explored correlations between these brain networks and various neuropsychological and behavioral measures. In contrast to the controls ( Z  = -1.081, p  = 0.280), the AUD patients showed a decrease in within left FPN connectivity ( Z  = -2.029, p  = 0.042). However, these results did not survive a strict Bonferroni correction. The decrease in left FPN connectivity during the early abstinence period in AUD may reflect an initially upregulated FPN, which recovers to a lower resting-state connectivity level during subsequent weeks of abstinence. The AUD patients showed a trend for a positive association between the change in left FPN connectivity and trait anxiety (r s  = 0.303, p  = 0.068), and a trend for a negative association between the change in left FPN connectivity and delay discounting (r s  = -0.283, p  = 0.089) (uncorrected for multiple comparisons). This suggests that the FPN might be involved in top-down control of impulsivity and anxiety, which are important risk factors for relapse. Although there were no statistically significant results (after multiple comparison correction), our preliminary findings encourage further research into the dynamic neuroadaptations during the clinically crucial early abstinence period and could inform future study designs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Oort, Diazgranados, George, Horneffer, Schwandt, Goldman and Momenan.)