Alcohol Use Disorder Individuals Research Articles

Etiological contributions of adolescent binge alcohol on onset of Alzheimer’s disease‐associated basal forebrain neuropathology in 5xFAD mice and post‐mortem human AUD brain

AbstractBackgroundHeavy alcohol use is an etiological factor for development of dementia and may contribute to onset of Alzheimer’s disease (AD). Both alcohol use disorder (AUD) and AD share common underlying neuropathology, including basal forebrain cholinergic neuron degeneration and proinflammatory neuroimmune activation, and evidence suggest these systems are particularly sensitive to adolescent alcohol exposure. Using the 5xFAD mouse model of AD, we tested the hypothesis that adolescent intermittent ethanol (AIE), which models human adolescent binge drinking, would accelerate onset of AD‐associated pathology in the adult basal forebrain.MethodIn Experiment 1, non‐transgenic and 5xFAD male and female mice received AIE treatment (5.0 g/kg, i.g. 2‐days on/2‐days off; postnatal day [P]30 – P55) and basal forebrain tissue collected for immunohistochemistry and gene expression analysis on P100. In Experiment 2, 5xFAD female mice received AIE treatment as described above followed by glycyrrhizic acid (GA; 150 mg/L), a high mobility group box 1 (HMGB1) inhibitor, in drinking water from P56 – P100. At study conclusion, basal forebrain tissue was collected for immunohistochemistry and gene expression analysis on P100. In Experiment 3, AD‐associated neuropathology was assessed in the post‐mortem human basal forebrain of individuals with AUD relative to age‐matched moderate drinking CONs.ResultIn Experiment 1, AIE accelerated loss of basal forebrain cholinergic neurons and heterogeneous nuclear ribonucleoprotein (hnRNP) expression in 5xFAD females, but not males, relative to age‐matched 5xFAD CONs. This was accompanied by a female‐specific accelerated accumulation of plaque markers (e.g., Aβ1‐42, Thioflavin‐S, HMGB1) as well as microglial activation and proinflammatory neuroimmune signaling genes (e.g., HMGB1, RAGE) in the adult basal forebrain. In Experiment 2, post‐AIE treatment with the HMGB1 inhibitor GA reversed AIE‐induced accelerated loss of cholinergic neurons, accumulation of plaque markers, and upregulation of microglial activation markers and proinflammatory signaling molecules. In Experiment 3, AUD individuals exhibited decreased cholinergic and hnRNP markers and increased Aβ1‐42 immunoreactivity as well as cholinergic neuron co‐expression with Aβ1‐42 that negatively correlated with an adolescent age of drinking onset.ConclusionThese data reveal that adolescent binge ethanol exposure may be an etiological factor contributing to onset of AD‐associated neuropathology in the adult basal forebrain through HMGB1‐neuroimmune signaling.

A whole exome sequencing study to identify rare variants in multiplex families with alcohol use disorder.

Alcohol use disorder (AUD) runs in families and is accompanied by genetic variation. Some families exhibit an extreme susceptibility in which multiple cases are found and often with an early onset of the disorder. Large scale genome-wide association studies have identified several genes with impressive statistical probabilities. Most of these genes are common variants. Our goal was to perform exome sequencing in families characterized by multiple cases (multiplex families) to determine if rare variants might be segregating with disease status. A case-control approach was used to leverage the power of a large control sample of unrelated individuals (N = 8,983) with exome sequencing [Institute for Genomic Medicine (IGM)], for comparison with probands with AUD (N = 53) from families selected for AUD multiplex status. The probands were sequenced at IGM using similar protocols to those used for the archival controls. Specifically, the presence of a same-sex pair of adult siblings with AUD was the minimal criteria for inclusion. Using a gene-based collapsing analysis strategy, a search for qualifying variants within the sequence data was undertaken to identify ultra-rare non-synonymous variants. We searched 18,666 protein coding genes to identify an excess of rare deleterious genetic variation using whole exome sequence data in the 53 AUD individuals from a total of 282 family members. To complete a case/control analysis of unrelated individuals, probands were compared to unrelated controls. Case enrichment for 16 genes with significance at 10-4 and one at 10-5 are plausible candidates for follow-up studies. Six genes were ultra rare [minor allele frequency (MAF) of 0.0005]: CDSN, CHRNA9, IFT43, TLR6, SELENBP1, and GMPPB. Eight genes with MAF of 0.001: ZNF514, OXGR1, DIEXF, TMX4, MTBP, PON2, CRHBP, and ANKRD46 were identified along with three protein-truncating variants associated with loss-of-function: AGTRAP, ANKRD46, and PPA1. Using an ancestry filtered control group (N = 2,814), nine genes were found; three were also significant in the comparison to the larger control group including CHRNA9 previously implicated in alcohol and nicotine dependence. This study implicates ultra-rare loss-of-function genes in AUD cases. Among the genes identified include those previously reported for nicotine and alcohol dependence (CHRNA9 and CRHBP).

Alcohol use disorders in patients with bipolar disorder: a systematic review and meta-analysis

Alcohol consumption has a key role in more than 200 diseases and health injuries, being an important factor for social and public health costs. Studies with clinical populations show an association between alcohol use disorders (AUD) and bipolar disorder. In this meta-analysis we included studies, reports, or summaries identified in Google Scholar, Lilacs, Medline, and MedCaribe that reported original data published up to 31 January 2023. We included cross-sectional and longitudinal observational studies that investigated the prevalence of AUD in patients with bipolar disorder. We calculated the prevalence rates and conducted a meta-analysis using a random effects model. The meta-analysis included 20 unique studies conducted in 12 countries, with a total sample of 32,886 individuals with bipolar disorder, comprising 17,923 women and 13,963 men, all aged 18 years or older. The prevalence of AUD in individuals with bipolar disorder was found to be 29.12%, while the prevalence of Alcohol Dependence (AD) was 15.87% and the prevalence of Alcohol Abuse (AA) was 18.74%. The high prevalence of AUD individuals with bipolar disorder is important because it highlights the need for targeted interventions to prevent and address comorbid conditions, which may improve treatment outcomes, reduce harm, and promote public health.

Striatal ups or downs? Neural correlates of monetary reward anticipation, cue reactivity and their interaction in alcohol use disorder and gambling disorder.

Dysfunction of the striatum, a brain region part of the mesolimbic reward system, is a key characteristic of addictive disorders, but neuroimaging studies have reported conflicting findings. An integrative model of addiction points to the presence or absence of addiction-related cues as an explanation for hyper- or hypoactivation, respectively, of the striatum. To test this model directly, we investigated striatal activation during monetary reward anticipation in the presence versus absence of addiction-related cues using functional MRI. Across two studies, we compared 46 alcohol use disorder (AUD) patients with 30 matched healthy controls; and 24 gambling disorder (GD) patients with 22 matched healthy controls. During monetary reward anticipation, hypoactivation of the reward system was seen in AUD individuals compared to HCs. Additionally, a behavioral interaction was seen where gambling cues made participants, across groups, respond faster for bigger, but slower for smaller rewards. However, no striatal differences were seen in response to addiction-related cues between AUD or GD patients and their matched controls. Finally, despite substantial individual differences in neural activity to cue-reactivity and reward anticipation, these measures did not correlate, suggesting that they contribute independently to addiction aetiology. Our findings replicate previous findings of blunted striatal activity during monetary reward anticipation in alcohol use disorder but do not support the idea that addiction-related cues explain striatal dysfunction as suggested by the model.

Rosiglitazone improves alveolar macrophage mitochondrial derangements induced by chronic alcohol consumption and infection with Klebsiella pneumoniae.

Abstract Objective: People with alcohol use disorders (AUDs) are 2–4 times more likely to develop lung infections, sepsis, and acute respiratory distress syndrome. Chronic alcohol misuse blunts alveolar macrophage (AM) immunity, in part, due to decreased peroxisome proliferator-activated receptor (PPAR)γ which increases cellular oxidative stress. Mitochondrial (MT) oxidative stress may impair AM phagocytosis; thus, we posited that chronic alcohol plus acute Klebsiella pneumoniae(Kp) dysregulates MT and treatment with rosiglitazone (RSG), a PPARγ ligand, reverses these effects to improve AM phagocytosis of Kp. Methods: AMs were isolated from 8–10-month-old male C57BL/6J mice fed ± ethanol (EtOH, 20% wt/vol in drinking water) for 12 wks ± intratracheal 2 × 10 4CFU of Kpin saline vehicle for the last 24 h of water or EtOH ± RSG (10 mg/kg/d in methylcellulose vehicle) via oral gavage 4 h prior to sacrifice (n=5/group). MT O 2•−and H 2O 2were assessed by fluorescence microscopy. mRNA and protein levels of PPARγ and MT dynamics mediators, transcription factor A mitochondrial (TFAM), dynamin-related protein 1 (DRP1), and mitofusin-2 (MFN2) were measured by qRT-PCR and cytoimmunostaining. Kpclearance by AMs was determined by plating lysed AMs on MacConkey agar. Results: EtOH feeding to mice increased MT oxidative stress; decreased PPARγ, TFAM, and MFN2 levels; and increased DRP1 levels in AMs. Kpexacerbated EtOH’s MT derangements by ~51–63% and impaired Kpclearance in AMs by 57.3 ± 11.2%. RSG treatment in vivoreversed EtOH- and Kp-induced MT derangements in AMs and restored AM clearance of Kp. Conclusion: RSG may provide a novel therapeutic strategy for mitigating AM MT derangements and immune dysfunction in AUD individuals infected with Kp. NIAAA R01-AA026086

Investigating the relationship between early life adversity, inflammation and alcohol use.

Early life adversity (ELA) has long-lasting and potentially harmful effects on adult mental and physical health, including a higher likelihood of developing psychiatric conditions such as depression, anxiety and alcohol use disorder (AUD). It has been suggested that inflammation may play a role in linking ELA to the development of AUD. Here, we evaluated a number of predictive factors of high sensitivity C-reactive protein (hsCRP), a key inflammatory marker, and the potential mediating role of hsCRP in the relationship between ELA and alcohol misuse in adulthood. Data was collected from participants who participated in NIAAA screening protocols between January 2013 and December 2019. In this secondary analysis, we first tested, via multiple linear regression, potential predictors of hsCRP levels among adults with AUD (N= 781) and non-AUD (N= 440) individuals. We subsequently conducted mediation analyses to evaluate the potential role of hsCRP in the relationship between early life stress and alcohol use. Regression analysis showed that stress in early life, but not childhood trauma, significantly predicted increased hsCRP levels in adulthood (p< 0.05). Additionally, a greater amount of alcohol drinking, but not a diagnosis of AUD, significantly predicted increased hsCRP levels (p< 0.05). Furthermore, hsCRP mediated the relationship between early life stress and alcohol consumption. Early life stress and heavier alcohol drinking both predicted increased hsCRP levels; however, an AUD diagnosis did not. Elevated inflammation, due to and/or predicted by greater early life stress, may contribute to the development of unhealthy alcohol use in adulthood.

The therapeutic potential of glucagon-like peptide-1 for persons with addictions based on findings from preclinical and clinical studies.

Although the multifaceted mechanisms underlying alcohol use disorder (AUD) have been partially defined, the neurobiological complexity of this disorder is yet to be unraveled. One of the systems that have gained attention in recent times is the gut-brain axis. Although numerous peptides participate in this axis, glucagon-like peptide-1 (GLP-1) plays a central role. GLP-1 is a crucial anorexigenic peptide, with potent abilities to reduce food intake and body weight. The physiological complexity of GLP-1 entails glucose homeostasis, gastrointestinal motility, and the release of insulin and glucagon. As reviewed in this study, acute or repeated treatment with GLP-1 receptor (GLP-1R) agonists decreases alcohol consumption in rodents. Moreover, the abilities of alcohol to promote hyperlocomotion, dopamine release in the nucleus accumbens, and reward in the conditioned place preference paradigm are all suppressed by GLP-1R ligands. Moreover, activation of GLP-1R suppresses the motivation to consume alcohol, alcohol-seeking behaviors, and relapse drinking in male rodents. Similarly, abstinence symptoms experienced during alcohol withdrawal are attenuated by activation of the GLP-1 pathway. On a similar note, the activation of GLP-1 receptors within areas of the brain that are processing reward modulates these alcohol-related responses. Another area that is crucial for this ability is the nucleus of the solitary tract, which is where GLP-1 is produced and from which GLP-1-containing neurons project to areas of reward. These findings may have clinical relevance as AUD is associated with polymorphisms in GLP-1-related genes. Although a GLP-1R agonist does not alter alcohol intake in AUD patients, it reduces this consumption in a sub-population of obese AUD individuals. Given the uncertainty of this outcome, additional clinical studies of obese AUD patients should explore the effects of the GLP-1R agonists on alcohol intake and body weight. Furthermore, GLP-1 receptors modulate the behavioral and neurochemical responses to addictive drugs. Taken together, these preclinical and clinical findings imply that the GLP-1 pathway plays a role in the complex mechanisms regulating alcohol and drug consumption patterns, unveiling a novel aspect of addiction medicine.

Striatal ups or downs? Neural correlates of monetary reward anticipation, cue reactivity and their interaction in gambling disorder and alcohol use disorder

AbstractStriatal dysfunction is a key characteristic of addictive disorders, but neuroimaging studies have reported conflicting findings. An integrative model of addiction points to the presence or absence of addiction-related cues as an explanation for striatal hypo- or hyperactivations, respectively, but has never been directly tested. Here, we developed a novel paradigm to investigate striatal activation during monetary reward anticipation in the presence versus absence of addiction-related pictures using functional MRI. Across two studies, we compared 24 gambling disorder (GD) patients with 22 matched healthy controls and 46 alcohol use disorder (AUD) patients with 30 matched healthy controls. A behavioral interaction was seen where gambling cues made participants respond faster for bigger, but slower for smaller rewards. During monetary reward anticipation, hypoactivation of the reward system was seen in AUD individuals compared to HCs. However, no striatal differences were seen between the participants with GD or AUD and their matched controls. In sum, these findings suggest that striatal dysfunction is a key but heterogeneous mechanism within both AUD and GD and indicate an important but complex role for addiction-related cues in explaining striatal dysfunction in addiction.Disclosure of InterestNone Declared

Decoding fMRI alcohol cue reactivity and its association with drinking behaviour

BackgroundCue reactivity, the enhanced sensitivity to conditioned cues, is associated with habitual and compulsive alcohol consumption. However, most previous studies in alcohol use disorder (AUD) compared brain activity between alcohol...

Pharmacological reversal of post-transcriptional alterations implicated in alcohol-induced alveolar macrophage dysfunction.

Alcohol use disorders (AUD) cause alveolar macrophage (AM) immune dysfunction and increase risk of lung infections. Excessive alcohol use causes AM oxidative stress, which impairs AM phagocytosis and pathogen clearance from the alveolar space. Alcohol induces expression of NADPH oxidases (Noxes), primary sources of oxidative stress in AM. In contrast, alcohol decreases AM peroxisome proliferator-activated receptor gamma (PPARγ), a critical regulator of AM immune function. To explore the underlying molecular mechanisms for these effects of alcohol, we hypothesized that ethanol promotes CCAAT/enhancer-binding protein beta (C/EBPβ)-mediated suppression of Nox-related microRNAs (miRs), in turn enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. We also hypothesized that PPARγ activation with pioglitazone (PIO) would reverse alcohol-induced C/EBPβ expression and attenuate AM oxidative stress and phagocytic dysfunction. Cells from the mouse AM cell line (MH-S) were exposed to ethanol invitro or primary AM were isolated from mice fed ethanol invivo. Ethanol enhanced C/EBPβ expression, decreased Nox 1-related miR-1264 and Nox 2-related miR-107 levels, and increased Nox1, Nox2, and Nox 4 expression in MH-S cells invitro and mouse AM invivo. These alcohol-induced AM derangements were abrogated by loss of C/EBPβ, overexpression of miRs-1264 or -107, or PIO treatment. These findings identify C/EBPβ and Nox-related miRs as novel therapeutic targets for PPARγ ligands, which could provide a translatable strategy to mitigate susceptibility to lung infections in people with a history of AUD. These studies further clarify the molecular underpinnings for a previous clinical trial using short-term PIO treatment to improve AM immunity in AUD individuals.

Molecular Imaging Studies of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a serious public health problem in many countries, bringing a gamut of health risks and impairments to individuals and a great burden to society. Despite the prevalence of a disease model of AUD, the current pharmacopeia does not present reliable treatments for AUD; approved treatments are confined to a narrow spectrum of medications engaging inhibitory γ-aminobutyric acid (GABA) neurotransmission and possibly excitatory N-methyl-D-aspartate (NMDA) receptors, and opioid receptor antagonists. Molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can open a window into the living brain and has provided diverse insights into the pathology of AUD. In this narrative review, we summarize the state of molecular imaging findings on the pharmacological action of ethanol and the neuropathological changes associated with AUD. Laboratory and preclinical imaging results highlight the interactions between ethanol and GABA A-type receptors (GABAAR), but the interpretation of such results is complicated by subtype specificity. An abundance of studies with the glucose metabolism tracer fluorodeoxyglucose (FDG) concur in showing cerebral hypometabolism after ethanol challenge, but there is relatively little data on long-term changes in AUD. Alcohol toxicity evokes neuroinflammation, which can be tracked using PET with ligands for the microglial marker translocator protein (TSPO). Several PET studies show reversible increases in TSPO binding in AUD individuals, and preclinical results suggest that opioid-antagonists can rescue from these inflammatory responses. There are numerous PET/SPECT studies showing changes in dopaminergic markers, generally consistent with an impairment in dopamine synthesis and release among AUD patients, as seen in a number of other addictions; this may reflect the composite of an underlying deficiency in reward mechanisms that predisposes to AUD, in conjunction with acquired alterations in dopamine signaling. There is little evidence for altered serotonin markers in AUD, but studies with opioid receptor ligands suggest a specific up-regulation of the μ-opioid receptorsubtype. Considerable heterogeneity in drinking patterns, gender differences, and the variable contributions of genetics and pre-existing vulnerability traits present great challenges for charting the landscape of molecular imaging in AUD.

Functional roles, regulatory mechanisms and theranostics applications of ncRNAs in alcohol use disorder.

Alcohol use disorder (AUD) is one of the most prevalent neuropsychological disorders worldwide, and its pathogenesis is convoluted and poorly understood. There is considerable evidence demonstrating significant associations between multiple heritable factors and the onset and progression of AUD. In recent years, a substantial body of research conducted by emerging biotechnologies has increasingly highlighted the crucial roles of noncoding RNAs (ncRNAs) in the pathophysiology of mental diseases. As in-depth understanding of ncRNAs and their mechanisms of action, they have emerged as prospective diagnostic indicators and preclinical therapeutic targets for a variety of psychiatric illness, including AUD. Of note, dysregulated expression of ncRNAs such as circRNAs, lncRNAs and miRNAs was routinely found in AUD individuals, and besides, exogenous regulation of partial ncRNAs has also been shown to be effective in ameliorating alcohol preference and excessive alcohol consumption. However, the exact molecular mechanism still remains elusive. Herein, we systematically summarized current knowledge regarding alterations in the expression of certain ncRNAs as well as their-mediated regulatory mechanisms in individuals with AUD. And finally, we detailedly reviewed the potential theranostics applications of gene therapy agents targeting ncRNAs in AUD mice. Overall, a deeper comprehension of functional roles and biological mechanisms of ncRNAs may make significant contributions to the accurate diagnosis and effective treatment of AUD.

Association between iron accumulation in the dorsal striatum and compulsive drinking in alcohol use disorder

RationaleBrain iron accumulation has been observed in neuropsychiatric disorders and shown to be related to neurodegeneration.ObjectivesIn this study, we used quantitative susceptibility mapping (QSM), an emerging MRI technique developed for quantifying tissue magnetic susceptibility, to examine brain iron accumulation in individuals with alcohol use disorder (AUD) and its relation to compulsive drinking.MethodsBased on our previous projects, QSM was performed as a secondary analysis with gradient echo sequence images, in 186 individuals with AUD and 274 healthy participants. Whole-brain susceptibility values were calculated with morphology-enabled dipole inversion and referenced to the cerebrospinal fluid. Then, the susceptibility maps were compared between AUD individuals and healthy participants. The relationship between drinking patterns and susceptibility was explored.ResultsWhole-brain analyses showed that the susceptibility in the dorsal striatum (putamen and caudate) among AUD individuals was higher than healthy participants and was positively related to the Obsessive Compulsive Drinking Scale (OCDS) scores and the amount of drinking in the past three months.ConclusionsIncreased susceptibility suggests higher iron accumulation in the dorsal striatum in AUD. This surrogate for the brain iron level was linearly associated with the compulsive drinking pattern and the recent amount of drinking, which provides us a new clinical perspective in relation to brain iron accumulation, and also might indicate an association of AUD with neuroinflammation as a consequence of brain iron accumulation. The iron accumulation in the striatum is further relevant for functional imaging studies in AUD by potentially producing signal dropout and artefacts in fMRI images.

HPA-Axis Activity and Nutritional Status Correlation in Individuals with Alcohol Use Disorder

Impaired activity of the hypothalamic-pituitary-adrenal axis (HPA-axis) is evident in alcohol use disorder (AUD), and may be implicated in various nutritional and metabolic alterations often seen in individuals with this disorder. The present study examined a possible correlation between HPA-axis activity and nutritional status components in individuals with AUD. Fourteen AUD and fourteen non-AUD males participated; anthropometric and body composition measurements were made, and fasting blood samples were analysed for plasma adrenal corticotropic hormone (ACTH), catecholamines, cortisol and beta-endorphin. Nutrient intake was estimated via a three-day diet record. Waist circumference and waist-to-hip ratio were increased in the AUD group. Thiamine and folic intake were lower in AUD group, although only folic acid intake was insufficient in both AUD and non-AUD groups. Increased epinephrine and norepinephrine were also observed in AUD group compared to non-AUD group. No clear correlation between HPA-axis activity and nutritional status components was found. This study showed that nutrient intake, body composition, and HPA-axis activity were different among AUD and non-AUD individuals. More research on the correlation between nutritional status and HPA-axis activity in AUD individuals should be conducted.

Insufficient Physical Activity Is a Global Marker of Severity in Alcohol Use Disorder: Results from a Cross-Sectional Study in 382 Treatment-Seeking Patients.

Improving physical activity (PA) in patients with alcohol use disorder (AUD) has recently emerged as an important component of the global treatment strategy to improve drinking outcomes and quality of life. However, this new approach should focus on AUD patients with insufficient baseline PA and requires this subgroup to be better characterized. In a population of 382 treatment-seeking AUD patients, PA was assessed using the International Physical Activity Questionnaire, and participants were divided into two groups: insufficient PA group and sufficient PA group. The severity of the AUD was assessed using the DSM-5 criteria, the Alcohol Use Disorder Identification Test, and the Severity of Alcohol Dependence Questionnaire. In logistic regression models, individuals with insufficient PA were more likely than other AUD individuals to present a higher Body Mass Index (p < 0.001), a higher number of AUD DSM-5 criteria (p < 0.05), more frequent opioid use (p < 0.05), higher scores at the Fagerström Test for Nicotine Dependence (p < 0.001), State-Trait Anxiety Inventory (p < 0.001), impulsivity scale (p < 0.05), Pittsburgh Sleep Quality Inventory (p < 0.05), and lower WHO Quality of Life (p < 0.001) scores. In AUD, an insufficient baseline PA is associated with several markers of severity, and physical exercise interventions should be part of a multimodal treatment program integrating the global impairments of patients.

Lack of amygdala habituation to negative emotional faces in alcohol use disorder and the relation to adverse childhood experiences.

Aberrant limbic circuit reactivity to negative stimuli might be related to alterations in emotion processing and regulation in alcohol use disorder (AUD). The current study tested for the first time in AUD the hypothesis of aberrant amygdala habituation to repeated aversive stimuli-a robust and reliable neuroimaging marker for emotion processing. We explored the link between deficits in habituation to adverse childhood experience (ACE), a common risk factor for impaired emotion regulation and AUD. AUD individuals (N= 36) and healthy controls (HC; N= 26) participated in an observational case-control functional magnetic resonance imaging (fMRI) study. An established habituation index was used to investigate processing of aversive emotional faces of the amygdala. AUD individuals showed an overall deficit in amygdala habituation (right: t = 4.26, pFWE =0.004; left: t = 4.79, pFWE ≤0.001). Amygdala habituation was significantly related to increased exposure to ACE in HC (t = 3.88, pFWE =0.012), whereas this association was not observed in AUD individuals (T = 1.80, pFWE =0.662). Further, a significant association between higher alcohol consumption and reduced amygdala habituation (right: R2 = -0.356, F= 8.736, p= 0.004; left: R2 = -0.309, F= 6.332, p= 0.015) was observed. We found novel evidence for neural alterations in emotion processing in AUD individuals, indexed by deficient amygdala habituation to negative emotional content. We replicated a prior report on a link between ACE and amygdala habituation, a well-established environmental risk factor for mental disorders and emotion dysregulation, in our control sample. Additionally, deficient amygdala habituation related to the amount of alcohol consumption in the overall sample might indicate a short-term substance effect.

Brain glutamate and sleep efficiency associations following a ketogenic diet intervention in individuals with Alcohol Use Disorder

We previously showed that ketogenic diet (KD) was effective in curbing alcohol withdrawal and craving in individuals with alcohol use disorder (AUD). We hypothesized that the clinical benefits were due to improvements in sleep. To test this, we performed a secondary analysis on the KD trial data to (1) examine the effects of KD on total sleep time (TST) and sleep quality and (2) investigate the association between KD-induced alterations in cingulate glutamate concentration and changes in TST and sleep quality. AUD individuals undergoing alcohol detoxification were randomized to receive KD (n=19) or standard American diet (SA; n=14) for three weeks. TST was measured weekly by self-report, GENEActive sleep accelerometer, and X4 Sleep Profiler ambulatory device. Sleep quality was assessed using subjectively ratings of sleep depth and restedness and Sleep Profiler (Sleep Efficiency [%]). Weekly 1H magnetic resonance spectroscopy scans measured cingulate glutamate levels. TST was lower in KD than SA and increased with effect of time. Sleep depth, restedness, and Sleep Efficiency improved with time, but exhibited no effect of diet. In KD and SA combined, week 1 cingulate glutamate levels correlated positively with Sleep Efficiency, but not with TST. Although cingulate glutamate levels correlated positively with Sleep Efficiency in week 1, KD-induced glutamate elevation did not produce significant sleep improvements. Rather, KD was associated with lower TST than SA. Given the well-established associations between sleep and alcohol relapse, longer follow up assessment of KD's impact on sleep in AUD is warranted.

Poor subjective sleep predicts compromised quality of life but not cognitive impairment in abstinent individuals with Alcohol Use Disorder.

How disrupted sleep contributes to cognitive dysfunction over the dynamic course of Alcohol Use Disorder (AUD) is an emerging topic of investigation. Here, the Pittsburgh Sleep Quality Index (PSQI) was used to evaluate subjective sleep in 90 individuals with AUD sober for an average of 3 months and in 50 healthy controls. Relative to controls, AUD individuals had higher global PSQI scores (worse sleep), higher scores on the Beck Depression Inventory (BDI-II), worse Quality of Life (QoL) indicators, and poorer performance on cognitive composite tests (executive functioning, attention and working memory, visual and verbal learning or memory). Among AUD individuals, a higher PSQI score correlated with a higher BDI-II score and worse QoL, but not with cognitive scales. Also noted in the AUD group were higher global PSQI scores in individuals also diagnosed with major depressive disorder (MDD) or generalized anxiety disorder (GAD). The four variables explained 29.8% of the variance in AUD PSQI scores. In women with AUD, the four factors explained 39.3% of the variance in PSQI scores (MDD was salient); in AUD men, the four measures explained 19.9% of the variance (QoL predominated). Together, these results suggest that poor PSQI-defined sleep does not predict cognitive performance in abstinent AUD individuals and further, that differential factors associate with poor sleep in men and women with AUD.

Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

Differentiating Individuals with and without Alcohol Use Disorder Using Resting-State fMRI Functional Connectivity of Reward Network, Neuropsychological Performance, and Impulsivity Measures.

Individuals with alcohol use disorder (AUD) may manifest an array of neural and behavioral abnormalities, including altered brain networks, impaired neurocognitive functioning, and heightened impulsivity. Using multidomain measures, the current study aimed to identify specific features that can differentiate individuals with AUD from healthy controls (CTL), utilizing a random forests (RF) classification model. Features included fMRI-based resting-state functional connectivity (rsFC) across the reward network, neuropsychological task performance, and behavioral impulsivity scores, collected from thirty abstinent adult males with prior history of AUD and thirty CTL individuals without a history of AUD. It was found that the RF model achieved a classification accuracy of 86.67% (AUC = 93%) and identified key features of FC and impulsivity that significantly contributed to classifying AUD from CTL individuals. Impulsivity scores were the topmost predictors, followed by twelve rsFC features involving seventeen key reward regions in the brain, such as the ventral tegmental area, nucleus accumbens, anterior insula, anterior cingulate cortex, and other cortical and subcortical structures. Individuals with AUD manifested significant differences in impulsivity and alterations in functional connectivity relative to controls. Specifically, AUD showed heightened impulsivity and hypoconnectivity in nine connections across 13 regions and hyperconnectivity in three connections involving six regions. Relative to controls, visuo-spatial short-term working memory was also found to be impaired in AUD. In conclusion, specific multidomain features of brain connectivity, impulsivity, and neuropsychological performance can be used in a machine learning framework to effectively classify AUD individuals from healthy controls.