Sleep Delta power, age, and sex effects in treatment-resistant depression.

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.

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.

Exercising healthy behaviors: A latent class analysis of positive coping during the COVID-19 pandemic and associations with alcohol-related and mental health outcomes.

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.

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.

Preliminary evidence for changes in frontoparietal network connectivity in the early abstinence period in alcohol use disorder: a longitudinal resting-state functional magnetic resonance imaging study.

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 (rs = 0.303, p = 0.068), and a trend for a negative association between the change in left FPN connectivity and delay discounting (rs = -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.

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 executive and salience networks (SN). 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 effects of ELS on brain connectivity in AUD participants, taking into account differences in BMI. The cohort included 401 individuals with AUD, with approximately 60% having a BMI ≥ 25. Within the overall cohort, 123 participants underwent resting-state functional magnetic resonance imaging, revealing intriguing anticorrelations between SN seeds and brain regions involved in somatosensory processing, motor coordination, and executive control as an effect of ELS. Examining the relationship between ELS-driven brain connectivity and BMI, we observed negative correlations in connectivity among low BMI (≤ 24.9) vs. high BMI (≥ 25) individuals. For example, the left supramarginal gyrus (SMG) seed exhibited decreased connectivity with emotion regulation and decision-making regions, including the right occipital cortex, posterior cingulate cortex, and precuneus clusters (all |ß| < -0.03, |p| < 0.05). Additionally, the right SMG seed showed reduced connectivity with impulse control and executive function regions, such as the left postcentral/middle frontal gyrus cluster (ß = 0.04, p = 0.02). These findings highlight the role of ELS-induced alterations in SN seed connectivity, influenced by BMI, in the neurobiology of AUD. Understanding the neural mechanisms linking obesity, AUD, and ELS can guide targeted interventions for this population.

Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis.

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.

Selecting an optimal real-time fMRI neurofeedback method for alcohol craving control training.

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.

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.

Corticotropin-Releasing Factor receptor 1 (CRF1) antagonism in patients with alcohol use disorder and high anxiety levels: effect on neural response during Trier Social Stress Test video feedback.

In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.

Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Influence of age and sex on alcohol pharmacokinetics and subjective pharmacodynamic responses following intravenous alcohol exposure in humans.

There are substantial inter-individual variations in alcohol metabolism and response that are likely due to sex and age; however, these are not well understood. We investigated age and sex influences on alcohol elimination rate (AER) and subjective responses following intravenous (IV) administration in non-dependent drinkers. Participants underwent a 2-session study where they received IV alcohol (target breath alcohol level: 0.05 g%) and placebo in counter-balanced order. AER was higher in males than in females across age groups. These differences were partly explained by sex differences in lean body mass and liver volume. Alcohol significantly increased peak feelings of high, intoxication, drug-effects, liking-effects, and wanting-more, with no major sex differences. There were no age-related differences in feelings of high and intoxication; however, the older group reported significantly lower peak liking-effects and stimulation responses than the younger group. These findings highlight the significant impact of sex and age as sources of variability in the clinical pharmacology of alcohol.

A person-centered approach to capture health disparities and multidimensional impact of COVID-related stressors.

The COVID-19 pandemic has influenced people's lives in diverse ways. The authors utilized latent class analysis (LCA), a person-centered approach, to examine distinct patterns of COVID-related stressors and their associations with alcohol-related, mental health, and quality of life outcomes. Participants were 463 adults who completed the baseline assessment of the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study from June 2020 to January 2022. Using cross-sectional data, three analytic methods (continuous sum score, categorical grouping, and LCA) were applied to model 17 COVID-related stressors. Regression analyses indicated higher COVID-related stress and endorsement of four or more COVID-related stressors were generally associated with worse health-related outcomes. LCA revealed four classes: Class 1: Minimal COVID-Related Impact (51.6%); Class 2: Work Interruptions (24.8%); Class 3: Family/Friends Affected by COVID (14.5%); and Class 4: Serious Financial Stress (9.1%). Racial/ethnic minorities were more likely to be in Class 3, whereas individuals with more years of education and higher income were less likely to be in Class 4. Individuals with a history of alcohol use disorder were more likely to be in Classes 2 and 4. Compared with Class 1, Class 4 reported highest levels of perceived stress, problematic alcohol use, anxiety symptoms, depressive symptoms, alcohol craving, loneliness, drinking to cope, and lowest levels of physical, psychological, social, and environment quality of life. COVID-related stressors disproportionately affected minority and vulnerable groups. Individuals who experienced multiple financial stressors had the greatest risk for negative health-related outcomes and may benefit from holistic interventions and community outreach. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Recalibrating single-study effect sizes using hierarchical Bayesian models.

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.

Alcohol use disorder-associated structural and functional characteristics of the insula.

Based on our current understanding of insular regions, effects of chronic alcohol use on the insula may affect the integration of sensory-motor, socio-emotional, and cognitive function. There is no comprehensive understanding about these differences in individuals with alcohol use disorder that accounts for both structural and functional differences related to chronic alcohol use. The purpose of this study was to investigate these variations in both the anterior and posterior insula in persons with alcohol use disorder. We investigated insula gray matter volume, morphometry, white matter structural connectivity, and resting state functional connectivity in 75 participants with alcohol use disorder (females = 27) and 75 age-matched healthy control participants (females = 39). Results indicated structural differences mostly in the anterior regions, while functional connectivity differences were observed in both the anterior and posterior insula in those with alcohol use disorder. Differing connectivity was observed with frontal, parietal, occipital, cingulate, cerebellar, and temporal brain regions. While these results align with prior studies showing differences primarily in anterior insular regions, they also contribute to the existing literature suggesting differences in anterior insular connectivity with brain regions shown to be engaged during higher cognitive and emotional tasks.

Severity of alcohol use disorder influences sex differences in sleep, mood, and brain functional connectivity impairments.

Growing evidence suggests greater vulnerability of women than men to the adverse effects of alcohol on mood and sleep. However, the underlying neurobiological mechanisms are still poorly understood. Here, we examined sex difference in resting state functional connectivity in alcohol use disorder using a whole-brain data driven approach and tested for relationships with mood and self-reported sleep. To examine whether sex effects vary by severity of alcohol use disorder, we studied two cohorts: non-treatment seeking n = 141 participants with alcohol use disorder (low severity; 58 females) from the Human Connectome project and recently detoxified n = 102 treatment seeking participants with alcohol use disorder (high severity; 34 females) at the National Institute on Alcohol Abuse and Alcoholism. For both cohorts, participants with alcohol use disorder had greater sleep and mood problems than healthy control, whereas sex by alcohol use effect varied by severity. Non-treatment seeking females with alcohol use disorder showed significant greater impairments in sleep but not mood compared to non-treatment seeking males with alcohol use disorder, whereas treatment-seeking females with alcohol use disorder reported greater negative mood but not sleep than treatment-seeking males with alcohol use disorder. Greater sleep problems in non-treatment seeking females with alcohol use disorder were associated with lower cerebello-parahippocampal functional connectivity, while greater mood problems in treatment-seeking females with alcohol use disorder were associated with lower fronto-occipital functional connectivity during rest. The current study suggests that changes in resting state functional connectivity may account for sleep and mood impairments in females with alcohol use disorder. The effect of severity on sex differences might reflect neuroadaptive processes with progression of alcohol use disorder and needs to be tested with longitudinal data in the future.

Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use.

Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system is involved in mechanisms underlying alcohol seeking and consumption. Accordingly, the GLP-1 receptor (GLP-1R) has begun to be studied as a potential pharmacotherapeutic target for alcohol use disorder (AUD). The aim of this study was to investigate the association between genetic variation at the GLP-1R and brain functional connectivity, according to the severity of alcohol use. Participants were 181 individuals categorized as high-risk (n = 96) and low-risk (n = 85) alcohol use, according to their AUD identification test (AUDIT) score. Two uncommon single nucleotide polymorphisms (SNPs), rs6923761 and rs1042044, were selected a priori for this study because they encode amino-acid substitutions with putative functional consequences on GLP-1R activity. Genotype groups were based on the presence of the variant allele for each of the two GLP-1R SNPs of interest [rs6923761: AA + AG (n = 65), GG (n = 116); rs1042044: AA + AC (n = 114), CC (n = 67)]. Resting-state functional MRI data were acquired for 10 min and independent component (IC) analysis was conducted. Multivariate analyses of covariance (MANCOVA) examined the interaction between GLP-1R genotype group and AUDIT group on within- and between-network connectivity. For rs6923761, three ICs showed significant genotype × AUDIT interaction effects on within-network connectivity: two were mapped onto the anterior salience network and one was mapped onto the visuospatial network. For rs1042044, four ICs showed significant interaction effects on within-network connectivity: three were mapped onto the dorsal default mode network and one was mapped onto the basal ganglia network. For both SNPs, post-hoc analyses showed that in the group carrying the variant allele, high versus low AUDIT was associated with stronger within-network connectivity. No significant effects on between-network connectivity were found. In conclusion, genetic variation at the GLP-1R was differentially associated with brain functional connectivity in individuals with low versus high severity of alcohol use. Significant findings in the salience and default mode networks are particularly relevant, given their role in the neurobiology of AUD and addictive behaviors.

Compounding Vulnerability in the Neurocircuitry of Addiction: Longitudinal Functional Connectivity Changes in Alcohol Use Disorder.

AIMS: The addiction neurocircuitry model describes the role of several brain circuits (drug reward, negative emotionality and craving/executive control) in alcohol use and subsequent development of alcohol use disorder (AUD). Human studies examining longitudinal change using resting-state functional magnetic resonance imaging (rs-fMRI) are needed to understand how functional changes to these circuits are caused by or contribute to continued AUD. METHODS: In order to characterize how intrinsic functional connectivity changes with sustained AUD, we analyzed rs-fMRI data from individuals with (n = 18; treatment seeking and non-treatment seeking) and without (n = 21) AUD collected on multiple visits as part of various research studies at the NIAAA intramural program from 2012 to 2020. RESULTS: Results of the seed correlation analysis showed that individuals with AUD had an increase in functional connectivity over time between emotionality and craving neurocircuits, and a decrease between executive control and reward networks. Post hoc investigations of AUD severity and alcohol consumption between scans revealed an additive effect of these AUD features in many of the circuits, such that more alcohol consumption or more severe AUD was associated with more pronounced changes to synchronicity. CONCLUSIONS: These findings suggest an increased concordance of networks underlying emotionality and compulsions toward drinking while also a reduction in control network connectivity, consistent with the addiction neurocircuitry model. Further, they suggest a compounding effect of continued heavy drinking on these vulnerabilities in neurocircuitry. More longitudinal research is necessary to understand the trajectories of individuals with AUD not adequately represented in this study, as well as whether this can inform effective harm reduction strategies.