Cell-type brain-region specific changes in prefrontal cortex of a mouse model of alcohol dependence.

The prefrontal cortex is a crucial regulator of alcohol drinking, and dependence, and other behavioral phenotypes associated with AUD. Comprehensive identification of cell-type specific transcriptomic changes in alcohol dependence will improve our understanding of mechanisms underlying the excessive alcohol use associated with alcohol dependence and will refine targets for therapeutic development. We performed single nucleus RNA sequencing (snRNA-seq) and Visium spatial gene expression profiling on the medial prefrontal cortex (mPFC) obtained from C57BL/6 J mice exposed to the two-bottle choice-chronic intermittent ethanol (CIE) vapor exposure (2BC-CIE, defined as dependent group) paradigm which models phenotypes of alcohol dependence including escalation of alcohol drinking. Gene co-expression network analysis and differential expression analysis identified highly dysregulated co-expression networks in multiple cell types. Dysregulated modules and their hub genes suggest novel understudied targets for studying molecular mechanisms contributing to the alcohol dependence state. A subtype of inhibitory neurons was the most alcohol-sensitive cell type and contained a downregulated gene co-expression module; the hub gene for this module is Cpa6, a gene previously identified by GWAS to be associated with excessive alcohol consumption. We identified an astrocytic Gpc5 module significantly upregulated in the alcohol-dependent group. To our knowledge, there are no studies linking Cpa6 and Gpc5 to the alcohol-dependent phenotype. We also identified neuroinflammation related gene expression changes in multiple cell types, specifically enriched in microglia, further implicating neuroinflammation in the escalation of alcohol drinking. Here, we present a comprehensive atlas of cell-type specific alcohol dependence mediated gene expression changes in the mPFC and identify novel cell type-specific targets implicated in alcohol dependence.

Clustering care pathways of people with alcohol dependence using a data linkage of routine data in Bremen, Germany.

BACKGROUND: Although many individuals with alcohol dependence (AD) are recognized in the German healthcare system, only a few utilize addiction-specific treatment services. Those who enter treatment are not well characterized regarding their prospective pathways through the highly fragmented German healthcare system. This paper aims to (1) identify typical care pathways of patients with AD and their adherence to treatment guidelines and (2) explore the characteristics of these patients using routine data from different healthcare sectors. METHODS: We linked routinely collected register data of individuals with a documented alcohol-related diagnosis in the federal state of Bremen, Germany, in 2016/2017 and their addiction-specific health care: two statutory health insurance funds (outpatient pharmacotherapy for relapse prevention and inpatient episodes due to AD with and without qualified withdrawal treatment (QWT)), the German Pension Insurance (rehabilitation treatment) and a group of communal hospitals (outpatient addiction care). Individual care pathways of five different daily states of utilized addiction-specific treatment following an index inpatient admission due to AD were analyzed using state sequence analysis and cluster analysis. The follow-up time was 307 days (10 months). Individuals of the clustered pathways were compared concerning current treatment recommendations (1: QWT followed by postacute treatment; 2: time between QWT and rehabilitation). Patients' characteristics not considered during the cluster analysis (sex, age, nationality, comorbidity, and outpatient addiction care) were then compared using a multinomial logistic regression. RESULTS: The analysis of 518 individual sequences resulted in the identification of four pathway clusters differing in their utilization of acute and postacute treatment. Most did not utilize subsequent addiction-specific treatment after their index inpatient episode (n = 276) or had several inpatient episodes or QWT without postacute treatment (n = 205). Two small clusters contained pathways either starting rehabilitation (n = 26) or pharmacotherapy after the index episode (n = 11). Overall, only 9.3% utilized postacute treatment as recommended. CONCLUSIONS: A concern besides the generally low utilization of addiction-specific treatment is the implementation of postacute treatments for individuals after QWT.

Changes of neurofilament light chain in patients with alcohol dependence following withdrawal and the genetic effect from ALDH2 Polymorphism.

Neurofilament light chain (NFL), as a measure of neuroaxonal injury, has recently gained attention in alcohol dependence (AD). Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme which metabolizes the alcohol breakdown product acetaldehyde. An ALDH2 single nucleotide polymorphism (rs671) is associated with less ALDH2 enzyme activity and increased neurotoxicity. We examined the blood NFL levels in 147 patients with AD and 114 healthy controls using enzyme-linked immunosorbent assay and genotyped rs671. We also followed NFL level, alcohol craving and psychological symptoms in patients with AD after 1 and 2 weeks of detoxification. We found the baseline NFL level was significantly higher in patients with AD than in controls (mean ± SD: 264.2 ± 261.8 vs. 72.1 ± 35.6 pg/mL, p < 0.001). The receiver operating characteristic curve revealed that NFL concentration could discriminate patients with AD from controls (area under the curve: 0.85; p < 0.001). The NFL levels were significantly reduced following 1 and 2 weeks of detoxification, with the extent of reduction correlated with the improvement of craving, depression, and anxiety (p < 0.001). Carriers with the rs671 GA genotype, which is associated with less ALDH2 activity, had higher NLF levels either at baseline or after detoxification compared with GG carriers. In conclusion, plasma NFL level was increased in patients with AD and reduced after early abstinence. Reduction in NFL level corroborated well with the improvement of clinical symptoms. The ALDH2 rs671 polymorphism may play a role in modulating the extent of neuroaxonal injury and its recovery.

Interactions between overweight/obesity and alcohol dependence impact human brain white matter microstructure: evidence from DTI.

There is inconsistent evidence for an association of obesity with white matter microstructural alterations. Such inconsistent findings may be related to the cumulative effects of obesity and alcohol dependence. This study aimed to investigate the possible interactions between alcohol dependence and overweight/obesity on white matter microstructure in the human brain. A total of 60 inpatients with alcohol dependence during early abstinence (44 normal weight and 16 overweight/obese) and 65 controls (42 normal weight and 23 overweight/obese) were included. The diffusion tensor imaging (DTI) measures [fractional anisotropy (FA) and radial diffusivity (RD)] of the white matter microstructure were compared between groups. We observed significant interactive effects between alcohol dependence and overweight/obesity on DTI measures in several tracts. The DTI measures were not significantly different between the overweight/obese and normal-weight groups (although widespread trends of increased FA and decreased RD were observed) among controls. However, among the alcohol-dependent patients, the overweight/obese group had widespread reductions in FA and widespread increases in RD, most of which significantly differed from the normal-weight group; among those with overweight/obesity, the alcohol-dependent group had widespread reductions in FA and widespread increases in RD, most of which were significantly different from the control group. This study found significant interactive effects between overweight/obesity and alcohol dependence on white matter microstructure, indicating that these two controllable factors may synergistically impact white matter microstructure and disrupt structural connectivity in the human brain.

Characteristics of amplitude of low-frequency fluctuations in the resting-state functional magnetic resonance imaging of alcohol-dependent patients with depression.

The high comorbidity of alcohol use disorder and depressive disorder is associated with poor patient prognosis. The mechanisms underlying this comorbidity, however, are largely unknown. By applying the amplitude of low-frequency fluctuations parameter in resting-state functional magnetic resonance imaging, this study investigated changes in the brain functioning of alcohol-dependent patients with and without depression. Alcohol-dependent patients (n = 48) and healthy controls (n = 31) were recruited. The alcohol-dependent patients were divided into those with and without depression, according to Patients Health Questionnaire-9 scores. Amplitude of low-frequency fluctuations in resting-state brain images were compared among the alcohol-dependent patients with depression, alcohol-dependent patients without depression, and healthy controls groups. We further examined associations between amplitude of low-frequency fluctuations alterations, alcohol-dependence severity, and depressive levels (assessed with scales). Compared with the healthy controls group, both alcohol groups showed amplitude of low-frequency fluctuations enhancement in the right cerebellum and amplitude of low-frequency fluctuations abatement in the posterior central gyrus. The alcohol-dependent patients with depression group had higher amplitude of low-frequency fluctuations in the right cerebellum than the alcohol-dependent patients without depression group. Additionally, we observed a positive correlation between amplitude of low-frequency fluctuations value and Patients Health Questionnaire-9 score in the right superior temporal gyrus in the alcohol-dependent patients with depression group. Alcohol-dependent subjects showed abnormally increased spontaneous neural activity in the right cerebellum, which was more significant in alcohol-dependent patients with depression. These findings may support a targeted intervention in this brain location for alcohol and depressive disorder comorbidity.

A qualitative study about explanatory models of alcohol use disorder among patients and relatives in a Ugandan mental hospital.

BACKGROUND: Alcohol use disorder (AUD) is a major clinical problem in Uganda. Explanatory models (EMs) of illness are important as they have consequences for treatment. Clinicians´ knowledge about patients´ EMs can improve understanding of the latter´s perspectives and adapting treatments. There is a lack of African studies about EMs of AUD. The aim of this study was to explore EMs for AUD among hospitalized patients and their relatives at the alcohol and drug unit (ADU) at Butabika hospital in Uganda. METHODS: An adapted version of the Explanatory Model Interview Catalogue (EMIC) was used for interviews with ten patients and five relatives to investigate how both hospitalized patients with AUD and their relatives understand the disease. Data were analysed for themes with a qualitative content analysis and support of the software program, OpenCode 4.03. RESULTS: Five major themes were identified from the patient interviews: "Context promotes AUD"; "Alcohol is part of culture"; "Spiritual causes of AUD in the community"; "Help through Western medicine and religious sources is preferred" and "Social problems and stigmatization". Six major themes identified from the interviews with relatives were: "Numerous causes of drinking alcohol"; "Devastating consequences of drinking alcohol"; "Exploiting persons with AUD"; "Others' suffering"; "Relatives struggling for help" and "Suggested solutions". CONCLUSIONS: Patients' EMs of AUD included social and spiritual explanations. Alcohol is seen as an important part of the Ugandan culture among both patients and their relatives. The results indicate it is important in clinical contexts to investigate the EMs of the patients and relatives to individually tailor treatment interventions.

Prevalence, sociodemographic, and clinical correlates of underweight in a sample of Chinese male alcohol-dependent patients.

BACKGROUND: Underweight is a significant symptom in alcohol-dependent patients, yet few studies have examined underweight in Chinese male patients. The current study aimed to identify the prevalence, sociodemographic, and clinical correlates of underweight in Chinese male patients with alcohol dependency. METHODS: In this cross-sectional study, 405 male inpatients with alcohol dependence and 383 healthy male controls were recruited. Participants' demographic and clinical data, including anthropometric data, were collected. We first conducted univariate analysis to identify seven variables with significant differences between groups: smoking behavior, hospitalization, alcohol consumption, cerebral infarction, hypertension, Hamilton Depression Scale (HAMD) score, and Scale for Assessment of Negative Symptom (SANS) score. Then, binary logistic regression was used to assess their relationship with underweight, with a significance level of .05. RESULTS: The prevalence of underweight was significantly higher in the study population than in the control group (2.99% vs. 2.87%; P < .001). Patients with underweight had significantly higher rates of smoking behavior and cerebral infarction, as well as higher scores of SANS and HAMD than non-underweight patients. The non-underweight patients had higher daily alcohol consumption and times of hospitalization. Furthermore, logistic regression analysis showed that smoking behavior [odds ratio (OR) = 2.84, 95% confidence interval (CI) = 1.03-7.80, P = .043)], cerebral infarction (OR = 5.20, 95% CI = 1.13-23.85, P = .036), SANS score (OR = 1.22, 95% CI = 1.16-1.28, P < .001), and HAMD score (OR = 1.06, 95% CI = 1.02-1.11, P = .005) were associated with underweight. CONCLUSIONS: More than 20% of male alcohol-dependent patients in a Chinese sample were underweight. Some demographic and clinical variables independent correlates for underweight in alcohol-dependent patients. We need to focus on alcohol-dependent patients with smoking, cerebral infarction, depression, and more prominent negative symptoms.

Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

BACKGROUND: The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. METHODS: This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. RESULTS: We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. CONCLUSIONS: The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

Implementing Approach-Bias Modification as Add-On to Varieties of Clinical Treatment for Alcohol Use Disorders: Results of a Multicenter RCT.

INTRODUCTION: Abstinence rates after inpatient treatment for alcohol use disorder (AUD) are modest (1-year rate around 50%). One promising approach is to re-train the automatically activated action tendency to approach alcohol-related stimuli (alcohol-approach bias) in AUD patients, as add-on to regular treatment. As efficacy has been demonstrated in well-controlled randomized controlled trials, the important next step is to add alcohol-approach-bias modification (alcohol-ApBM) to varieties of existing treatments for AUD. Therefore, this prospective, multicenter implementation-RCT examined whether adding alcohol-ApBM to regular treatments (various abstinence-oriented treatments including both individual and group-based interventions) would significantly increase abstinence rates compared to receiving regular treatment only, in a variety of naturalistic settings with different therapeutic approaches. METHODS: A total of 1,586 AUD inpatients from 9 German rehabilitation clinics were randomly assigned to receive either ApBM in addition to regular treatment or not. Training satisfaction of patients and therapists was measured after training. Success rates were determined at 3, 6, and 12 months post-treatment. RESULTS: Return rates of the post-treatment assessments varied greatly between clinics, often being low (18-76%). Nevertheless, ApBM significantly increased success rates after 3 months. After 6 and 12 months, the differences were not significant. ApBM was evaluated mostly positively by patients and therapists. DISCUSSION/CONCLUSION: ApBM was an effective add-on to regular treatment of AUD at 3 months follow-up, across a variety of AUD treatment settings. However, low return rates for the clinical outcomes reduced the effect size of ApBM considerably. The application of ApBM proved feasible in varying clinical settings, offering the opportunity to modify automatic processes and to promote abstinence.

DNA Sequence Variations Affecting Serotonin Transporter Transcriptional Regulation and Activity: Do They Impact Alcohol Addiction?

Genetic features of alcohol dependence have been extensively investigated in recent years. A large body of studies has underlined the important role of genetic variants not only in metabolic pathways but also in the neurobiology of alcohol dependence, mediated by the neuronal circuits regulating reward and craving. Serotonin transporter (5-HTT), encoded by the SLC6A4 gene (Solute carrier family 6-neurotransmitter transporter-member 4), is targeted by antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) and plays a pivotal role in serotoninergic transmission; it has been associated with psychiatric diseases and alcohol dependence. Transcriptional regulation and expression of 5-HTT depend not only on epigenetic modifications, among which DNA methylation (CpG and non-CpG) is primarily involved, but also on sequence variations occurring in intron/exon regions and in untranslated regions in 5' and 3', being the first sequences important for the splicing machinery and the last for the binding of transcription factors and micro RNAs. This work intends to shed light on the role of sequence variations known to affect the expression or function of 5-HTT in alcohol-dependent individuals. We found a statistically significant difference in the allelic (p = 0.0083) and genotypic (p = 0.0151) frequencies of the tri-allelic polymorphism, with higher function alleles and genotypes more represented in the control population. Furthermore, we identified three haplotypes more frequent in subjects with AUD (p < 0.0001) and one more frequent in the control population (p < 0.0001). The results obtained for the tri-allelic polymorphism in alcohol dependence confirm what is already present in part of the literature. The role of haplotypes requires further studies to be clarified.

Cognitive Alterations Associated with Remission and Alcohol Dependence Severity in Ethnically Diverse Patients of Siberia.

Background: Impaired cognition in individuals with alcohol dependence may be associated with increased relapse risk. It has been recorded in more than half of patients during six months after treatment. In certain ethnic groups, for example, Tuvinians, the indigenous people of Siberia, relapses occur in extremely short periods of one to three months after treatment. An approach currently used to alcohol dependence treatment may be less effective for these patients. Objective: The study aimed to investigate cognitive sequelae in indigenous Tuvinian patients with alcohol dependence. Methods: The sample included 166 patients, 74 of indigenous ethnicity (Tuvinians) and 92 non-indigenous white patients. Data on inhibitory control, cognitive flexibility, attention, and working memory were collected from all the patients and processed using cluster analysis. The clustering data were then complemented by indicators of disorder dynamics, impulsivity, and emotion regulation. Results: The clustering procedure revealed groups with severe cognitive sequelae. More than four-fold attention decrease was found in 43.5% of non-indigenous patients, and more impaired cognitive flexibility was revealed among 60.8% of indigenous patients. Groups with severe cognitive sequelae had higher impulsivity, maladaptive emotion regulation, more hospitalizations, faster disease progression, and shorter remissions. The latter was significantly reduced to 90 days on average in the severe group of indigenous patients versus 135 days of remission in the non-indigenous severe group. Conclusion: Results obtained may advance tailored intervention in alcohol-dependent patients of the indigenous Tuvinian ethnicity. While little is still known about the alcohol dependence course and consequences in the indigenous Tuvinians of Siberia, this study contributes to the global mental health data on alcohol abuse and dependence in indigenous communities.

Evaluation of the Relationship Between Dopamine Receptor D2 Gene TaqIA1 Polymorphism and Alcohol Dependence Risk.

Several studies are published, that investigated dopamine receptor 2 (DRD2) gene TaqIA polymorphism as a risk factor for alcohol dependence (AD) with positive and negative associations. To derive a more precise estimation of the relationship, a meta-analysis of case-control studies that examined the association between DRD2 gene Taq1A polymorphism and alcohol dependence was performed. Eligible articles were identified through a search of databases including PubMed, Science Direct, Springer link, and Google Scholar. The association between the DRD2 TaqIA polymorphism and AD susceptibility was conducted using odds ratios (ORs) and 95% confidence intervals (95% CIs) as association measures. A total of 69 studies with 9125 cases and 9123 healthy controls were included in the current meta-analysis. Results of the present analysis showed significant association between DRD2 TaqIA polymorphism and AD risk using five genetic modes (allele contrast model-OR 1.22, 95% CI 1.13-1.32, p < 0.0001; homozygote model-OR 1.35, 95%CI 1.18-1.55; p ≤ 0.0001; dominant model-OR 1.29; 95% CI 1.20-1.39; p < 0.0001; recessive model-OR 1.21; 95% CI 1.08-1.36; p = 0.0006). There was no significant association found in subgroup analysis, TaqIA polymorphism was not significantly associated with AD risk in the Asian population under all genetic models, but in the Caucasian population, TaqIA polymorphism was significantly associated with AD risk. Overall, results support the hypothesis that DRD2 Taq1A polymorphism plays a role in alcohol dependence.

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.

A research on the expression of Nucb2/ cAMP / PKA in the hippocampus of alcohol-dependent rats.

To probe into the expression of Nucb2/cAMP/PKA signaling in the hippocampus of alcohol-dependent rats. Male SD rats were first divided into control (n = 8) and model groups (n = 8) at random. Subsequently, alcohol dependence model was prepared by double bottles of intermittent drinking 20% alcohol. Apart from that, the changes of body weight, alcohol intake and alcohol preference were recorded during the modeling period; the behavioral changes of rats were recorded by elevated plus maze and water maze; Followed by model establishment, qRT-PCR was being applied to detect mRNA levels and protein expression levels of nucleobindin-2 (Nucb2), adenylate cyclase (AC), cAMP-dependent protein kinase A (PKA) and cAMP-responsive element binding protein (CREB) etc. There was no remarkable distinction between the weight of rats in both control and model groups throughout the experiment (P＞0.05); after the alcohol consumption of rats in the drinking group exceeded 28d, the alcohol intake finally reached the plateau (16.65 ± 1.31) g/(kg.24 h). What's more, the alcohol preference (61.77 ± 2.81) % reached the stable baseline, which means that the rat alcohol dependence model was established; in comparison with those of the control group (P < 0.01), the number of open arm entries and the retention time of open arm in the model group were remarkably decreased in the elevated plus maze assay; in the water maze assay, the memory ability of the model group was reduced in comparison with the control group (P < 0.05); In comparison with the control group, the relative expression levels of Nucb2, AC, PKA and CREB were noticeably decreased in the model group. Nucb2 is not only bound up with alcohol dependence,but also may conduct a pivotal role in alcohol dependence by regulating the cAMP/PKA signaling pathway.

Hazard of substance abuse onset among adults diagnosed with epilepsy or migraine.

OBJECTIVE: We investigated adult-onset epilepsy as a risk factor for the development of substance use disorder (SUD) by comparing the rate of SUD diagnosis among adults diagnosed with epilepsy with presumably healthy controls with lower extremity fractures (LEF). For additional comparison, we investigated the risk for adults with migraine only. Epilepsy and migraine are both episodic neurological disorders and migraine is frequently comorbid with epilepsy. METHODS: We conducted a time-to-event analysis using a subset of surveillance data of hospital admissions, emergency department visits, and outpatient visits in South Carolina, USA from January 1, 2000, through December 31, 2011. Individuals aged 18 years or older were identified using the International Classification of Disease, 9thRevision Clinical Modification (ICD-9) with a diagnosis of epilepsy (n = 78,547; 52.7% female, mean age 51.3 years), migraine (n = 121,155; 81.5% female, mean age 40.0 years), or LEF (n = 73,911; 55.4% female, mean age 48.7 years). Individuals with SUD diagnosis following epilepsy, migraine, or LEF were identified with ICD-9 codes. We used Cox proportional hazards regression to model the time to SUD diagnosis comparing adults diagnosed with epilepsy, migraine, and LEF, adjusting for insurance payer, age, sex, race/ethnicity, and prior mental health comorbidities. RESULTS: Compared to LEF controls, adults with epilepsy were diagnosed with SUD at 2.5 times the rate [HR 2.48 (2.37, 2.60)] and adults with migraine only were diagnosed with SUD at 1.12 times the rate [HR 1.12 (1.06, 1.18)]. We found an interaction between disease diagnosis and insurance payer, with hazard ratios comparing epilepsy to LEF of 4.59, 3.48, 1.97, and 1.44 within the commercial payer, uninsured, Medicaid, and Medicare strata, respectively. SIGNIFICANCE: Compared to presumably healthy controls, adults with epilepsy had a substantially higher hazard of SUD, while adults with migraine only showed a small, but significant, increased hazard of SUD.

Grouping motivational interviewing is only effective for younger patients with alcohol dependence in the rehabilitation stage.

Alcohol dependence (AD) is a risk factor for death and disability. Relapse prevention for AD has been exclusively dominated by psychotherapy intervention for many years. Our study aimed to investigate the efficacy of group motivational interviewing (MI) on the psychological craving for alcohol and depressive symptoms in AD patients in the rehabilitation phase, as well as the impact of age. The participants included 108 individuals with AD in the rehabilitation phase. All participants were assigned to the MI intervention group or the control group and were treated for 6 weeks. The severity of psychological craving for alcohol was assessed by the Penn Alcohol Craving Scale (PACS), and psychological status was evaluated by the Hamilton Depression Rating Scale (HAMD). We found that group MI significantly reduced the psychological craving for alcohol in patients with AD in the rehabilitation phase (p < 0.05). In addition, when patients were divided into two groups according to their ages, we found that group MI interventions tended to be effective only in younger patients with AD, but not in older patients. Our findings provide further evidence that the efficacy of group MI interventions was influenced by the age of patients with AD in the rehabilitation stage.

Relationship between serum vitamin D and thyroid hormone profiles in male patients with alcohol dependence.

BACKGROUND: Alcohol dependence (AD) results in several medical problems including vitamin D deficiency and thyroid dysfunction. However, the relationship between these two complications remains unclear. The aim of the present study was to explore the relationship between serum vitamin D and thyroid hormone profiles in male patients with AD. METHODS: A total of 117 male patients with AD were enrolled. Vitamin D deficiency was defined as serum concentrations of the main circulating vitamin D, 25-hydroxy vitamin D [25(OH)D], below 50 nmol/L. The AD patients were divided into two groups accordingly: 46 patients with normal vitamin D levels (normal group) and 71 patients with vitamin D deficiency (deficiency group). The levels of thyroid hormone profiles including total triiodothyronine 3 (TT3), total thyroxine 4 (TT4), thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) between the two groups were compared. Correlation between the serum levels of 25(OH)D and thyroid hormone profiles was evaluated using simple correlation (Pearson's correlation) and multivariable analysis using linear regression models. RESULTS: The prevalence of vitamin D deficiency in male patients with AD is 60.7% (71/117; 95% confidence interval: 51.6-69.1%). Moreover, the serum levels of TT3 (t = -2.682, p = 0.009), TT4 (t = -2.033, p = 0.044), fT3 (t = -2.986, p = 0.003), and fT4 (t = -2.558, p = 0.012) in deficiency group were significantly higher than those in normal group. Post hoc power analyses showed that the power for fT3 was sufficient (power > 0.80). Furthermore, univariate analysis showed that the serum vitamin D levels were negatively correlated with the TT3 (r = -0.189, p = 0.044), fT3 (r = -0.350, p < 0.001), and fT4 (r = -0.198, p = 0.033) levels, while multivariate analysis indicated that only fT3 was independently related to the serum levels of vitamin D in male patients with AD. CONCLUSIONS: These results suggested that the serum vitamin D levels may be associated with fT3 in male patients with AD.

Effects of virtual reality-based cue exposure therapy on craving and physiological responses in alcohol-dependent patients-a randomised controlled trial.

BACKGROUND: Cue exposure therapy is used to treat alcohol dependence. However, its effectiveness is controversial due to the limitations of the clinical treatment setting. Virtual reality technology may improve the therapeutic effect. The aim of this study is to explore whether virtual reality-based cue exposure therapy can reduce the psychological craving and physiological responses of patients with alcohol dependence. METHODS: Forty-four male alcohol-dependent patients were recruited and divided into the study group (n = 23) and the control group (n = 21) according to a random number table. The control group received only conventional clinical treatment for alcohol dependence. The study group received conventional clinical treatment with the addition of VR cue exposure (treatment). The primary outcome was to assess psychological craving and physiological responses to cues of patients before and after treatment. RESULTS: After virtual reality-based cue exposure therapy, the changes in VAS and heart rate before and after cue exposure in the study group were significantly lower than those in the control group (P < 0.05), while the changes in skin conductance and respiration between the study group and the control group were not significantly different (P > 0.05). The changes in VAS and heart rate before and after cue exposure in the study group were significantly lower than those before treatment (P < 0.05), while the changes in skin conductance and respiration were not significantly different from those before treatment (P > 0.05). The changes in VAS, heart rate, skin conductance and respiration before and after cue exposure in the control group were not significantly different from those before treatment (P > 0.05). CONCLUSION: Virtual reality-based cue exposure therapy can reduce the psychological craving and part of the physiological responses of alcohol-dependent patients during cue exposure in the short term and may be helpful in the treatment of alcohol dependence. TRIAL REGISTRATION: The study protocol was registered at the China Clinical Trial Registry on 26/02/2021 ( www.chictr.org.cn ; ChiCTR ID: ChiCTR2100043680).

Hypothalamic-pituitary-adrenal and autonomic response to psychological stress in abstinent alcohol use disorder individuals with and without depressive symptomatology.

BACKGROUND: Stress and depression have each been associated with relapse risk. In clinical practice, chronic alcohol use is often accompanied by poor emotional and self-regulatory processes. Tonic and phasic changes in stress responsivity impact an individual's relapse risk to alcohol. A further complicating factor is the pervasive coexistence of depressive symptoms in those with Alcohol Use Disorder (AUD), where the contribution of depressive symptomatology to these processes is not well understood. Individuals with AUD (AD) (21 with and 12 without sub-clinical depressive symptoms) and 37 social drinking controls (16 with and 21 without sub-clinical depressive symptoms) as part of a more extensive study (Fox et al., 2019). All participants were exposed to two 5-min personalized guided imagery conditions (stress and neutral) in a randomized and counterbalanced order across consecutive days. Alcohol craving, negative mood, Stroop performance, and plasma measures (cortisol, adrenocorticotrophic hormone, and salivary alpha-amylase) were collected before and after imagery exposure. RESULTS: Elevations in autonomic response (heart rate) to imagery (stress and neutral) were observed as a function of drinking (in both depressed and non-depressed individuals with alcohol use disorder compared with depressed and non-depressed social drinkers). Conversely, suppressed cortisol following stress was observed as a function of depressive symptomatology across both drinking groups. Individuals with comorbid AD and depressive symptoms demonstrated attenuated Adrenocorticotropic Hormone and poor Stroop performance compared with the other groups, indicating an interactive effect between drinking and depression on pituitary and inhibitory systems. CONCLUSION: Sub-clinical depressive pathophysiology may be distinct from drinking severity and may alter relapse-related stress adaptations during protracted abstinence from alcohol.

Psychometric properties of the German Penn Alcohol Craving Scale.

Craving for alcohol is an important diagnostic criterion in alcohol use disorder (AUD) and an established predictor of future relapse. The 5-item Penn Alcohol Craving Scale (PACS) is one of the most widely used questionnaires to quantify craving and has been translated into different languages. It is assumed that the PACS constitutes one factor, although theoretical considerations suggest an additional second factor. We conducted stability and factor analyses (principal component and confirmatory factor analyses) of the German PACS (PACS-G) in samples of patients with AUD from the following three German study sites: Erlangen, N = 188 (mean age: 47.1 years, 43.5% female); Mannheim, N = 440 (45.5 years, 28.6% female); Hannover, N = 107 (48.1 years, 48.6% female). In our samples, the 2-factor solution of the PACS-G version is more stable than the internationally assumed 1-factor solution. The resulting two PACS-G subscores 'difficulty to resist' (items 4 and 5) and 'thoughts about alcohol' (items 1, 2, and 3) have an internal consistency (Cronbach's alpha) of 0.80 ≤ α ≤ 0.90, m = 0.86 and 0.86 ≤ α ≤ 0.91, m = 0.89 with an overlap of R2 = 62%. We found good convergent validity assessed via the Craving Automatized Scale-Alcohol and the Obsessive-Compulsive Drinking Scale, but also correlations with depression and anxiety assessed via the Beck's Depression and Anxiety Inventories. This study is the first to provide evidence for a 2-factor solution ('difficulty to resist' and 'thoughts about alcohol') underlying the PACS-G version.