Objectives Childhood trauma (CT) increases risk for alcohol use disorder (AUD) and is linked to alterations in several brain regions. However, it remains unclear whether CT is associated with network-level resting-state functional connectivity (rs-FC) alterations in adults with AUD, and whether trauma subtypes show dissociable neural signatures. We examined associations between cumulative and subtype-specific CT exposure and amygdala- and insula-seeded rs-FC in adults with AUD versus healthy controls (HC). Methods The sample included 214 adults (120 with AUD; 94 HC) who underwent resting-state fMRI and comprehensive clinical assessment. CT exposure was retrospectively assessed using the Childhood Trauma Questionnaire (CTQ). Whole-brain seed-to-voxel rs-FC analyses were conducted using bilateral amygdala and insula seeds to probe connectivity with large-scale brain networks. Linear mixed-effects models tested interactions between diagnostic group (AUD vs. HC) and CT exposure (total CTQ score and exploratory subtype scores). Results Greater cumulative CT exposure was associated with weaker amygdala- and insula-centered rs-FC in AUD relative to HC. The most consistent effects involved reduced connectivity between these seeds—core nodes of the fronto-limbic and salience networks—and regions within the default mode network (DMN) and ventral visual stream. Exploratory CT subtype analyses (emotional abuse, emotional neglect, physical neglect) revealed largely overlapping rs-FC patterns. Conclusions CT is associated with a distinct pattern of network-level hypoconnectivity in adults with AUD, affecting circuits relevant to emotion regulation, memory, and socio-affective visual processing. The convergence of subtype-specific findings likely reflects high polytraumatization and widespread AUD-related network disruption and should be further investigated in future studies.

BACKGROUND. In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver disease (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express allograft inflammatory factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation. METHODS. Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not, based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single-nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles. RESULTS. AIF1 transcript levels were genotype dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in about 70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than 3-fold increase in hepatic immune cells, including infiltrating AIF1+ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared with C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence. CONCLUSION. These findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD. TRIAL REGISTRATION. ClinicalTrials.gov NCT02231840. FUNDING. Research support was provided from the National Institute on Alcohol Abuse and Alcoholism of the NIH under grants 1ZIAAA000440-02 and R24AA025017.

Copy number variants (CNVs) can alter disease susceptibility by gene deletion, duplication, and other mechanisms, and have been implicated in neuropsychiatric diseases. However, their rarity or de novo nature impedes linkage analysis. Therefore, we identified recurrent CNVs (rCNVs) in Native Americans with low genetic admixture and high prevalence of alcohol use disorder (AUD) and other psychiatric disorders. Large (> 200 kb) rCNVs were abundant in Plains Indians (PI) and Southwest American Indians (SWI), almost all carrying at least one rCNV, with some CNVs found in both geographically and linguistically distinct tribes. In patients carrying rCNVs, gene deletions led to haploinsufficiency, and duplications led to increased gene dosage. Haplotype analysis revealed a common chromosome 6p21.33 recurrent CNV (rCNV) that persisted in Native Americans for at least 750 generations, leading to haploinsufficiency of at least two genes. Gene-based CNV burden and CNV count did not predict AUD or other psychiatric disorders. However, an rCNV, found in PI and duplicating three genes within the 22q11.2 velocardiofacial syndrome region, showed nominally elevated odds ratios in generalized linear mixed models accounting for kinship as a random effect and age and sex as fixed covariates. For AUD, the odds ratio was 3.19 (95

Background: Premenstrual disorders (PMDs) are characterized by affective and physical symptoms before menses, likely due to abnormal sensitivity to normal hormone fluctuations. While sizable heritability has been indicated in twin studies, there are no genome-wide association studies (GWASs) to inform the genetic architecture of PMDs. Methods: We conducted a GWAS of 17,511 women with premenstrual symptoms (PSs) and 54,786 control women of European ancestry from 2 Nordic population-based cohorts. PSs were assessed using questionnaires or identified as a clinical diagnosis of PMD in the nationwide health care registers. A GWAS was performed in each study before meta-analysis, followed by analyses of single nucleotide polymorphism (SNP)–based heritability (h2SNP) and genetic correlations to psychosocial and gynecological phenotypes. Results: In the meta-analysis, 1 locus at 12p13.3 (rs758170, CACNA1C, p = 1.53 × 10−8, odds ratio [OR] = 0.93, 95% CI [0.90 to 0.95]) was associated with PSs; while the effect sizes were comparable between cohorts (LifeGene OR = 0.95 vs. MoBa [The Norwegian Mother, Father and Child Cohort Study] OR = 0.92, p for heterogeneity = .59), the association was not significant in LifeGene (p = .242). Moreover, we identified 6 loci with borderline significance, 3 of which were nominally significant in both cohorts (rs76665457, rs147346386, and rs4773561). The SNP-based heritability was estimated as 0.072 (SE = 0.01, p = 2.46 × 10−12). The strongest correlation was with major depression (rg = 0.62, 95% CI = [0.49 to 0.74], p = 3.04 × 10−22). Conclusions: This study provides initial genetic insights into the biology of PSs by identifying an SNP associated with PSs and genetic correlations with a range of psychosocial and gynecological traits. If confirmed in larger independent populations, these findings may advance our understanding of the underlying mechanisms of PMDs.

Slow-wave activity (SWA), a key indicator of sleep homeostasis, is often diminished in individuals with treatment-resistant depression (TRD). Ketamine, a rapid-acting antidepressant, increases SWA during the first period of non-rapid eye movement (NREM1) sleep. However, research into how ketamine affects sleep and its connection to treatment outcomes in TRD has been limited by small sample sizes and a lack of comparison with healthy volunteers (HVs). This placebo-controlled study compared the effects of ketamine on NREM1 SWA in a large sample of unmedicated TRD patients (n = 91; 51 F/40 M) and HVs (n = 42; 23 F/19 M). Linear mixed-effects models and regression analyses, with post-hoc testing (paired ttests and Wilcoxon matched-pairs signed rank tests), were used to assess condition-related effects across baseline, ketamine, and placebo in TRD and HV participants. Age-related moderation of ketamine-associated NREM1 SWA changes and condition-related changes in sleep variables were also examined. At baseline, TRD patients had lower NREM1 SWA than HVs. Ketamine, but not placebo, increased NREM1 SWA in TRD patients, particularly in responders. In contrast, ketamine had no effect on NREM1 SWA in HVs. Following ketamine, TRD patients also showed significant increases in total sleep time and sleep efficiency and a reduction in sleep latency. In TRD patients, the ketamine-related increase in NREM1 SWA diminished with increasing age. Together, the results indicate that ketamine’s antidepressant effects appear closely associated with its ability to modulate early SWA. These effects may also be linked to ketamine’s ability to improve sleep architecture in TRD. Clinical Trials Identifier: www.clinicaltrials.gov , NCT00088699, NCT01204918.

Background: Racial/ethnic disparities in health-related outcomes may have been exacerbated during the COVID19 pandemic. Individuals from racial/ethnic minority groups or with a history of alcohol use disorder (AUD) may have greater medical mistrust. We examined racial/ethnic and AUD-related differences in group-based medical mistrust during the pandemic and tested whether medical mistrust dimensions were associated with mental health symptoms. Methods: Two hundred and fifty participants from the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol Study completed an online survey between April and July of 2022. Exploratory factor analysis and path analysis were conducted. Results: Group-based medical mistrust scores were elevated among participants who identified as Non-Hispanic Black and those with a history of AUD. Two medical mistrust dimensions were found: (1) Suspicion and Lack of Provider Support, and (2) Group Disparities in Health Care. Compared to Non-Hispanic White participants, Non- Hispanic Black participants reported higher scores on the Suspicion and Lack of Provider Support dimension of medical mistrust, which was associated with higher mental health symptoms. This medical mistrust dimension was also a significant mediator of the observed group differences in mental health symptoms. Limitations: Cross-sectional data, aggregation of racial/ethnic groups with small sample sizes, and nonrepresentative sample. Conclusions: Non-Hispanic Black individuals and individuals with AUD may be more vulnerable to mental health symptoms due to higher suspicion toward medical professionals and healthcare systems and perceived lack of support from healthcare providers. Increased awareness among healthcare providers may help address medical mistrust, encourage help-seeking behaviors, and alleviate mental health symptoms.

Despite extensive research on DNA methylation (DNAm) signatures associated with alcohol use disorder (AUD), findings are often inconsistent and not replicated. We conducted a large-scale meta-analysis of epigenome-wide association studies (EWAS) to identify reliable, reproducible epigenetic markers of AUD. Seven cohorts, comprising 3,775 individuals (1,325 with AUD), contributed to this meta-analysis within the framework of the Psychiatric Genomics Consortium Substance Use Disorders Epigenetics Working Group. Downstream analyses included the identification of differentially methylated regions, overrepresentation analyses, and the construction of a methylation risk score (MRS). We identified 118 significant CpG sites associated with AUD, with the strongest association found at cg24889777 ( p =5.12×10 -17 ) in the long non-coding RNA LOC100505942. CpG sites were enriched for pathways related to GTPase signaling and transmembrane transporter activity, as well as EWAS signals of alcohol consumption. The MRS explained 10.44% of variance in heavy drinking in an independent cohort (N=2,534, AUC=0.657). This large-scale meta-analysis offers key insights into the epigenetic mechanisms of AUD and lays the groundwork for future research on methylation risk scores for the diagnosis, prognosis, and treatment in AUD.

BACKGROUND:Sleep disruptions are a core feature of both major depressive disorder and treatment-resistant depression (TRD), which is defined by persistent symptoms despite multiple treatment efforts. In addition, disruptions in wakeful gamma power and sleep-related delta power have been observed in individuals with TRD. This study explored the association between gamma oscillations (30-100 Hz) occurring during wakefulness and delta power (0.5-4 Hz) in non-rapid eye movement (NREM) sleep-both of which have separately been implicated in plasticity-in healthy volunteers (HVs) and individuals with TRD. Specifically, the study explored whether a relationship exists between daytime wake gamma power and sleep NREM delta power in HVs and those with TRD. METHODS:Brain activity was measured via electroencephalography (night-time) and magnetoencephalography (daytime resting state) in 23 HVs (9M/14F; 20-56 yrs) and 40 medication-free TRD participants (20 M/20F; 18-63 yrs). RESULTS:In HVs, NREM episode (NREM1) sleep delta power correlated with daytime wake gamma power (r = 0.417; p = 0.04). This correlation was absent in TRD participants (r = 0.108; p = 0.50). LIMITATIONS:The sample size of the HVs (n = 23) was smaller than the TRD participants (n = 40), and the measurement order for wake gamma power and sleep delta power varied. CONCLUSIONS:These findings identify a possible link between daytime wake gamma power and NREM1 sleep delta power in HVs, supporting an association between gamma and delta power in sleep homeostasis. The lack of such a relationship in medication-free individuals with TRD suggests disrupted synaptic homeostasis that may contribute to impaired synaptic plasticity in TRD. Clinical Trials Identifiers: NCT00088699 and NCT01204918.

BACKGROUND:Impulsivity underlies both alcohol misuse and suicidal behavior, but limited research has examined whether impulsivity dimensions vary by problematic drinking and history of suicidality. The objective of this study was to examine differences in trait and task-based impulsivity dimensions based on clinical assessment of alcohol use disorder (AUD), suicidal ideation (SI), and suicidal attempt (SA). METHODS:1250 participants from the National Institute on Alcohol Abuse and Alcoholism Natural History Protocol were categorized into 5 groups: neither suicidality nor AUD ("neither"; 49.1 %), suicidality without AUD ("SI-SA Only"; 3.0 %), AUD without suicidality ("AUD Only"; 30.5 %), AUD with SI ("AUD-SI"; 12.1 %), and AUD with SA ("AUD-SA"; 5.2 %). We measured impulsivity using the UPPS-P Impulsive Behavior Scale, the Barratt Impulsiveness Scale (BIS), and the delay discounting task. Linear regression models were conducted. RESULTS:Compared with the Neither group, negative urgency, lack of premeditation, lack of perseverance, positive urgency, and all BIS subscales (attentional, motor, and non-planning) were consistently higher among individuals with AUD only (Hedges's g ranged 0.56-1.13), and the scores were even higher among those who also endorsed history of SI (Hedges's g ranged 0.90-1.83) or SA (Hedges's g ranged 1.14-2.16). These findings were robust against adjustment for covariates. Mean score on the delay discounting task was highest in the AUD-SA group, but group differences were not statistically significant after adjusting for covariates. CONCLUSION:Individuals with both current AUD and suicide attempt history scored the highest across multiple dimensions of trait impulsivity. Findings underscore the importance of suicide assessment and prevention in the context of AUD treatment.