Exome-wide association analysis identifies novel risk loci for alcohol-associated hepatitis.

BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder (AUD). Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variation that contribute to the development of AH. APPROACH AND RESULTS: Exome-sequencing of patients with AH (N=784) and heavy drinking controls (N=951) identified exome-wide significant association for AH at PNPLA3, as previously observed for AC in GWAS, although with a much lower effect-size. SNPs of large effect-size at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant. ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation. TOX4 was previously implicated in diabetes and immune system function. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B. Polygenic signals for AH were observed in both common and rare variant analysis and identified genes with roles associated with inflammation. CONCLUSIONS: This study has identified two new genes of high effect size with a previously unknown contribution to ALD, and highlights both the overlap in etiology between liver diseases, and the unique origins of AH.

Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder.

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.

Drinking motives link positive and negative life events to problematic alcohol use during the COVID-19 pandemic: a longitudinal study.

PURPOSE: Stressful life events are associated with problematic drinking, and alcohol misuse has been exacerbated during the coronavirus disease 2019 (COVID-19) pandemic. While coping motives may account for this association, positive life events (PLEs) and enhancement motives are understudied. To address these gaps, we examined the associations of history of alcohol use disorder (AUD), negative life events (NLEs), and PLEs with problematic alcohol use and tested coping and enhancement motives as mediators. METHODS: The sample included baseline and follow-up data from 241 participants enrolled in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study. Endorsements of past year PLEs and NLEs and their associations with problematic alcohol use were examined. Among the 202 current drinkers, path analyses tested mediational pathways via coping and enhancement motives. RESULTS: The top two PLEs were change in work conditions (21.6%) and taking a vacation (20.3%). The top two NLEs were change in social activities (36.5%) and major change in recreation (26.6%). Individuals with a history of AUD and those who experienced more NLEs reported higher coping and enhancement motives, which were associated with higher problematic alcohol use. Individuals who experienced more PLEs reported lower coping motives, which was associated with lower problematic alcohol use. CONCLUSIONS: Besides coping motives, enhancement motives were also associated with pandemic problematic alcohol use. Alcohol interventions targeting reward- and relief-driven drinking patterns may be beneficial to individuals with a history of AUD and those who experienced more NLEs. More research is needed to study PLEs which may help inform the development of strength-based alcohol interventions.

Chemosensory Alterations and Impact on Quality of Life in Persistent Alcohol Drinkers.

BACKGROUND: Heavy alcohol consumption-associated chemosensory dysfunction is understudied, and early detection can help predict disease-associated comorbidities, especially those related to four quality of life (QOL) domains (physical, psychological, social and environment). We examined self-reports of chemosensory ability of individuals with different alcohol drinking behaviors and their association with changes in QOL domains. METHODS: Participants (n = 466) were recruited between June 2020 and September 2021 into the NIAAA COVID-19 Pandemic Impact on Alcohol study. Group-based trajectory modeling was used to categorize participants without any known COVID-19 infection into three groups (non-drinkers, moderate drinkers and heavy drinkers) based on their Alcohol Use Disorders Identification Test consumption scores at four different time points (at enrollment, week 4, week 8 and week 12). Linear mixed models were used to examine chemosensory differences between these groups. The associations between chemosensory abilities and QOL were determined in each group. RESULTS: We observed significant impairment in self-reported smell ability of heavy drinking individuals compared to non-drinkers. In contrast, taste ability showed marginal impairment between these groups. There were no significant differences in smell and taste abilities between the moderate and non-drinking groups. Heavy drinkers' impairment in smell and taste abilities was significantly associated with deterioration in their physical, psychological, social and environmental QOL. CONCLUSION: Persistent heavy drinking was associated with lower chemosensory ability. Heavy drinkers' reduced smell and taste function and association with poorer QOL indicate that early assessment of chemosensory changes may be crucial in identifying poorer well-being outcomes in heavy drinkers at risk for alcohol use disorder.

Accelerated Aging of the Amygdala in Alcohol Use Disorders: Relevance to the Dark Side of Addiction.

Here we assessed changes in subcortical volumes in alcohol use disorder (AUD). A simple morphometry-based classifier (MC) was developed to identify subcortical volumes that distinguished 32 healthy controls (HCs) from 33 AUD patients, who were scanned twice, during early and later withdrawal, to assess the effect of abstinence on MC-features (Discovery cohort). We validated the novel classifier in an independent Validation cohort (19 AUD patients and 20 HCs). MC-accuracy reached 80% (Discovery) and 72% (Validation). MC features included the hippocampus, amygdala, cerebellum, putamen, corpus callosum, and brain stem, which were smaller and showed stronger age-related decreases in AUD than HCs, and the ventricles and cerebrospinal fluid, which were larger in AUD and older participants. The volume of the amygdala showed a positive association with anxiety and negative urgency in AUD. Repeated imaging during the third week of detoxification revealed slightly larger subcortical volumes in AUD patients, consistent with partial recovery during abstinence. The steeper age-associated volumetric reductions in stress- and reward-related subcortical regions in AUD are consistent with accelerated aging, whereas the amygdalar associations with negative urgency and anxiety in AUD patients support its involvement in the "dark side of addiction".

Elevated transferrin saturation in individuals with alcohol use disorder: Association with HFE polymorphism and alcohol withdrawal severity.

Iron loading has been consistently reported in those with alcohol use disorder (AUD), but its effect on the clinical course of the disease is not yet fully understood. Here, we conducted a cohort study to examine whether peripheral iron measures, genetic variation in HFE rs1799945 and their interaction differed between 594 inpatient participants with alcohol use disorder (AUD) undergoing detoxification and 472 healthy controls (HC). We also assessed whether HFE rs1799945 was associated with elevated peripheral iron and can serve as a predictor of withdrawal severity. AUD patients showed significantly higher serum transferrin saturation than HC. Within the AUD group, transferrin saturation significantly predicted withdrawal symptoms (CIWA-Ar) and cumulative dose of benzodiazepine treatment during the first week of detoxification, which is an indicator of withdrawal severity. HFE rs1799945 minor allele carriers showed elevated transferrin saturation compared to non-carriers, both in AUD and healthy controls. Exploratory analyses indicated that, within the AUD cohort, HFE rs1799945 predicted CIWA withdrawal scores, and this relationship was significantly mediated by transferrin saturation. We provide evidence that serum transferrin saturation predicts alcohol withdrawal severity in AUD. Moreover, our findings replicated previous studies on elevated serum transferrin saturation in AUD and an involvement of HFE rs1799945 in serum transferrin saturation levels in both AUD and healthy controls. Future studies may use transferrin saturation measures as predictors for treatment or potentially treat iron overload to ameliorate withdrawal symptoms.

TSPO polymorphism in individuals with alcohol use disorder: Association with cholesterol levels and withdrawal severity.

The translocator protein (TSPO) transports cholesterol into mitochondria and is involved in steroidogenesis. The TSPO polymorphism rs6971 influences binding of cholesterol and other TSPO ligands including positron-emission tomography (PET) imaging radiotracers. Although it is recognized that alcohol increases plasma high-density lipoproteins (HDLs), its effects on total cholesterol and triglycerides along with its relationship to TSPO genotype have not been assessed. Here, we evaluated whether plasma cholesterol and triglycerides are disrupted in alcohol use disorder (AUD) and their association with rs6971 in 932 AUD participants (DSM IV or 5) and 546 controls. AUD participants compared with controls had significantly higher plasma levels of total cholesterol, HDL, and triglycerides, but not of low-density lipoprotein (LDL). In the AUD group only, TSPO rs6971 had a significant effect on plasma levels of cholesterol, LDL, and triglycerides (AA (n = 62) > AG (n = 319) > GG (n = 551)), but not on HDL levels. Additionally, we showed a significant effect of TSPO rs6971 on withdrawal scores (Clinical Institute Withdrawal Assessment for Alcohol [CIWA]), with higher scores in AA (n = 50) compared with AG (n = 238) and GG (n = 428). CIWA scores in AUD participants correlated negatively with LDL and positively with HDL, but not with total cholesterol or triglycerides. These findings corroborate elevated plasma cholesterol and HDL levels in AUD and document significant increases in triglycerides. We also reveal for the first time an association in AUD participants between TSPO rs6971 genotype and plasma cholesterol, LDL, and triglyceride levels (not for HDL) and with withdrawal severity. Mediation analyses revealed that LDL (but not HDL) influenced the association between TSPO and alcohol withdrawal severity.

A Distinct Neurophenotype of Fearful Face Processing in Alcohol Use Disorder With and Without Comorbid Anxiety.

BACKGROUND: Individuals with alcohol use disorder (AUD) can present with comorbid anxiety symptoms and often have deficits in emotional processing. Previous research suggests brain response is altered during facial affect recognition tasks, especially in limbic areas, due to either AUD or anxiety symptomology; however, the impact of both AUD and clinically significant anxiety symptoms during these tasks has not yet been examined. METHODS: In this study, we investigated neural activation differences during an emotional face-matching task. Participants (N = 232) underwent fMRI scanning, as part of a larger study. Three groups were investigated: individuals with diagnosed AUD and elevated anxiety traits (AUD + ANX, n = 90), individuals with diagnosed AUD but non-clinically significant levels of anxiety (AUD-ANX, n = 39), and healthy controls (HC, n = 103). RESULTS: Our results illustrate distinct neurophenotypes of AUD, where individuals with comorbid anxiety symptomology have blunted emotional face processing while those with singular AUD are hyperresponsive. CONCLUSIONS: This suggests AUD with anxiety symptomology may have a unique neurobiological underpinning, and treatment and intervention should be tailored to individual constellations of symptoms.

Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2.

BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

Insula Sensitivity to Unfairness in Alcohol Use Disorder.

AIMS: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. METHODS: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. RESULTS: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. CONCLUSION: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. SHORT SUMMARY: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.

International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder.

OBJECTIVES: Bipolar disorder is associated with a high risk of suicide attempts and suicide death. The main objective of the present study was to identify and quantify the demographic and clinical correlates of attempted and completed suicide in people with bipolar disorder. METHODS: Within the framework of the International Society for Bipolar Disorders Task Force on Suicide, a systematic review of articles published since 1980, characterized by the key terms bipolar disorder and 'suicide attempts' or 'suicide', was conducted, and data extracted for analysis from all eligible articles. Demographic and clinical variables for which ≥ 3 studies with usable data were available were meta-analyzed using fixed or random-effects models for association with suicide attempts and suicide deaths. There was considerable heterogeneity in the methods employed by the included studies. RESULTS: Variables significantly associated with suicide attempts were: female gender, younger age at illness onset, depressive polarity of first illness episode, depressive polarity of current or most recent episode, comorbid anxiety disorder, any comorbid substance use disorder, alcohol use disorder, any illicit substance use, comorbid cluster B/borderline personality disorder, and first-degree family history of suicide. Suicide deaths were significantly associated with male gender and first-degree family history of suicide. CONCLUSIONS: This paper reports on the presence and magnitude of the correlates of suicide attempts and suicide deaths in bipolar disorder. These findings do not address causation, and the heterogeneity of data sources should limit the direct clinical ranking of correlates. Our results nonetheless support the notion of incorporating diagnosis-specific data in the development of models of understanding suicide in bipolar disorder.

Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder.

OBJECTIVES: Bipolar disorder is associated with elevated risk of suicide attempts and deaths. Key aims of the International Society for Bipolar Disorders Task Force on Suicide included examining the extant literature on epidemiology, neurobiology and pharmacotherapy related to suicide attempts and deaths in bipolar disorder. METHODS: Systematic review of studies from 1 January 1980 to 30 May 2014 examining suicide attempts or deaths in bipolar disorder, with a specific focus on the incidence and characterization of suicide attempts and deaths, genetic and non-genetic biological studies and pharmacotherapy studies specific to bipolar disorder. We conducted pooled, weighted analyses of suicide rates. RESULTS: The pooled suicide rate in bipolar disorder is 164 per 100,000 person-years (95% confidence interval = [5, 324]). Sex-specific data on suicide rates identified a 1.7:1 ratio in men compared to women. People with bipolar disorder account for 3.4-14% of all suicide deaths, with self-poisoning and hanging being the most common methods. Epidemiological studies report that 23-26% of people with bipolar disorder attempt suicide, with higher rates in clinical samples. There are numerous genetic associations with suicide attempts and deaths in bipolar disorder, but few replication studies. Data on treatment with lithium or anticonvulsants are strongly suggestive for prevention of suicide attempts and deaths, but additional data are required before relative anti-suicide effects can be confirmed. There were limited data on potential anti-suicide effects of treatment with antipsychotics or antidepressants. CONCLUSION: This analysis identified a lower estimated suicide rate in bipolar disorder than what was previously published. Understanding the overall risk of suicide deaths and attempts, and the most common methods, are important building blocks to greater awareness and improved interventions for suicide prevention in bipolar disorder. Replication of genetic findings and stronger prospective data on treatment options are required before more decisive conclusions can be made regarding the neurobiology and specific treatment of suicide risk in bipolar disorder.

A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: Part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder.

OBJECTIVES: Many factors influence the likelihood of suicide attempts or deaths in persons with bipolar disorder. One key aim of the International Society for Bipolar Disorders Task Force on Suicide was to summarize the available literature on the presence and magnitude of effect of these factors. METHODS: A systematic review of studies published from 1 January 1980 to 30 May 2014 identified using keywords 'bipolar disorder' and 'suicide attempts or suicide'. This specific paper examined all reports on factors putatively associated with suicide attempts or suicide deaths in bipolar disorder samples. Factors were subcategorized into: (1) sociodemographics, (2) clinical characteristics of bipolar disorder, (3) comorbidities, and (4) other clinical variables. RESULTS: We identified 141 studies that examined how 20 specific factors influenced the likelihood of suicide attempts or deaths. While the level of evidence and degree of confluence varied across factors, there was at least one study that found an effect for each of the following factors: sex, age, race, marital status, religious affiliation, age of illness onset, duration of illness, bipolar disorder subtype, polarity of first episode, polarity of current/recent episode, predominant polarity, mood episode characteristics, psychosis, psychiatric comorbidity, personality characteristics, sexual dysfunction, first-degree family history of suicide or mood disorders, past suicide attempts, early life trauma, and psychosocial precipitants. CONCLUSION: There is a wealth of data on factors that influence the likelihood of suicide attempts and suicide deaths in people with bipolar disorder. Given the heterogeneity of study samples and designs, further research is needed to replicate and determine the magnitude of effect of most of these factors. This approach can ultimately lead to enhanced risk stratification for patients with bipolar disorder.

Neural correlates of rapid antidepressant response to ketamine in bipolar disorder.

OBJECTIVES: Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. METHODS: Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures. RESULTS: The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. CONCLUSIONS: Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.

Stress and alcohol-related coping mechanisms linking lifetime suicide ideation and attempt to multidimensional quality of life.

BACKGROUND: Suicide ideation and attempt are linked to adverse mental health outcomes, but few studies have examined their associations with quality of life (QoL). This study examined the impact of lifetime history of suicidal ideation and attempt on four QoL domains via perceived stress and problematic drinking. METHODS: Participants were drawn from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol (N = 1055), including those with no history of suicidality (78.6 %), suicidal ideation only (15.3 %), and a history of suicide attempt (6.2 %). Structural equation modeling (SEM) was utilized to test perceived stress and drinking as mediational pathways to multidimensional QoL. RESULTS: Individuals with a history of suicide ideation and/or attempt reported higher perceived stress in the past month, more problematic drinking in the past year, and lower QoL domains in the past two weeks. SEM showed significant mediation effects through dimensions of perceived stress (helplessness, lack of self-efficacy) and alcohol problems. When these mediators were considered simultaneously, the mediation effects through alcohol problems were attenuated, while several direct effects of suicidality on physical, psychological, and social QoL were weakened but remained significant. LIMITATIONS: Cross-sectional data with retrospective report of suicidality history. CONCLUSIONS: A lifetime history of suicidality was associated with lower multidimensional QoL. These associations were partially explained by stress and alcohol-related coping mechanisms such as feeling helpless or inadequate when encountering stressors and problematic drinking. Perceived stress and drinking to cope may be important intervention targets to improve QoL among those with a history of suicidality.

Associations of history of alcohol use disorder with loneliness, social support, and mental health during the COVID-19 pandemic.

This study examined the effects of alcohol use disorder (AUD) and treatment history on changes in loneliness, social support, and mental health symptoms from before to during the pandemic, and tested loneliness and social support as mediators of the AUD-mental health associations. Participants (n = 427) enrolled in the NIAAA COVID-19 Pandemic Impact on Alcohol Study were categorized into three groups: healthy control (62.3%), nontreatment AUD (14.1%), and treatment AUD (23.7%). Multilevel generalized linear models were conducted to examine changes in loneliness, social support, and mental health symptoms by group. Path analyses tested the mediating roles of loneliness and social support. Loneliness increased during the pandemic, especially in the nontreatment AUD group. Social support decreased in the healthy control and AUD treatment group. Anxiety and depressive symptoms increased in the nontreatment AUD group. Individuals with a history of AUD regardless of treatment history reported greater loneliness, which was linked to higher anxiety and depressive symptoms. Loneliness, but not social support, mediated the AUD-mental health associations. Psychosocial interventions aimed at increasing positive social engagement among individuals with AUD may help alleviate feelings of loneliness and mitigate mental health symptoms. Study findings can also help improve preparedness for future public health crises.

Early life stress and body-mass-index modulate brain connectivity in alcohol use disorder.

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 |ß | > 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 |ß | = -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.

Disrupted brain state dynamics in opioid and alcohol use disorder: attenuation by nicotine use.

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.

Hepatology consultation is associated with decreased early return to alcohol use after discharge from an inpatient alcohol use disorder treatment program.

BACKGROUND: Alcohol cessation is the only intervention that both prevents and halts the progressions of alcohol-associated liver disease. The aim of this study was to assess the relationship between a return to alcohol use and consultation with hepatology in treatment-seeking patients with alcohol use disorder (AUD). METHODS: Two hundred forty-two patients with AUD were enrolled in an inpatient treatment program, with hepatology consultation provided for 143 (59%) patients at the request of the primary team. Patients not seen by hepatology served as controls. The primary outcome was any alcohol use after discharge assessed using AUDIT-C at 26 weeks after discharge. RESULTS: For the primary endpoint, AUDIT at week 26, 61% of the hepatology group and 28% of the controls completed the questionnaire (p=0.07). For the secondary endpoint at week 52, these numbers were 22% and 11% (p = 0.6). At week 26, 39 (45%) patients in the hepatology group versus 31 (70%) controls (p = 0.006) returned to alcohol use. Patients evaluated by hepatology had decreased rates of hazardous alcohol use compared to controls, with 36 (41%) versus 29 (66%) (p = 0.008) of the patients, respectively, reporting hazardous use. There were no significant differences in baseline characteristics between groups and no difference in rates of prescribing AUD therapy. There was no difference in outcomes at 52 weeks. CONCLUSIONS: Patients evaluated by hepatology had significantly lower rates of return to alcohol use and lower rates of hazardous drinking at 26 weeks but not at 52 weeks. These findings suggest that hepatology evaluation during inpatient treatment of AUD may lead to decreased rates of early return to alcohol use.

Parosmia Is Positively Associated With Problematic Drinking, as Is Phantosmia With Depressive Symptoms.

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 (ß = 7.14; 95% confidence interval = 3.31, 10.96; P < 0.001), whereas phantosmia was linked to higher Patient Health Questionnaire scores (ß = 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.