Craving is one of the most robust proximal predictors of both treatment dropout and relapse during early recovery for alcohol use disorder (AUD). Craving can onset rapidly, and the ability to accurately detect or modulate cravings varies significantly within- and between-persons. Because of this, craving management is a central feature of most current AUD treatment models. However, impaired interoceptive awareness, which is common in early AUD recovery, can stymie individuals' capacity to implement craving management strategies. Measurement and detection of craving through passive biosensor monitoring could support novel just-in-time adaptive interventions that can mitigate this vulnerability. This study sought to characterize the biosignatures of craving through the measurement of heart rate variability (HRV) using a combination of ambulatory electrocardiogram (ECG) monitoring and ecological momentary assessment (EMA) in individuals in the first year of a current AUD recovery attempt (N = 40, observations = 400). A multilevel negative binomial regression analysis was conducted to estimate correlations between craving and HRV. Results demonstrated that, at the within-person level, high-frequency HRV (HF-HRV; IRR = 1.01, p = 0.013) and SD1 (IRR = 0.97, p = 0.020) were associated with craving at the same moment. Findings highlight HRV as a viable target for passive monitoring in interventions aimed at supporting craving mitigation in early AUD recovery, particularly at the momentary level.
Betel quid (BQ) is classified as a Group 1 carcinogen, underscoring a significant public health challenge. Neuroimaging evidence demonstrated that betel quid dependence (BQD) was linked to alterations in reward-related brain regions. However, resting-state functional connectivity (FC) in the reward circuit and their neural correlates with pathophysiological characteristics of BQD remain largely unexplored. We recruited 53 male BQD chewers and 53 male healthy controls (HCs) to participate in this study. Eleven reward circuit seeds, such as ventral striatum (VS), ventromedial prefrontal cortex (VMPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and others, were selected. Resting-state functional magnetic resonance imaging (rs-fMRI) data were analysed to evaluate FC between predefined seed regions and the whole brain. Association between aberrant FC and clinical features was further investigated. Relative to HCs, individuals with BQD exhibited altered FC in the reward circuit, mainly in VS, VMPFC, ACC, PCC and thalamus (Th). Correlation analysis indicated that FC between right Th and PCC was negatively correlated with BQD scales and dosage of BQ use in BQD subjects. Our findings provided the first empirical evidence that individuals with BQD showed aberrant resting-state FC in the reward circuit. Additionally, decreased connectivity between right Th and PCC was negatively associated with dependence degree and dosage of BQ use. These results highlighted the importance of the reward circuit in the pathophysiology of BQD and suggested that reward circuit dysfunction could serve as a potential circuit-level biomarker.
Objective Prenatal substance use is associated with negative outcomes for both the pregnant person and child. Entering substance use treatment during pregnancy is associated with improved outcomes but there are many barriers to treatment such as stigma. To improve prevention and treatment outcomes, it is critical to understand the relationship between risk/protective factors for substance use during pregnancy and to look for temporal changes in these relationships.Method Pregnant people (N = 32) with substance use disorder and a history of trauma exposure were included in this secondary analysis. Participants completed ecological momentary assessment (EMA), three times per day for 28 days. We used time-varying effects models (TVEMs) to examine the effects of craving on substance use, PTSD symptoms on craving, prenatal bonding on craving, and PTSD symptoms on prenatal bonding.Results Craving predicted substance use from gestational weeks 19.58 to 26.96. The relationship decreased over time and was not significant after week 27. PTSD symptoms predicted cravings at three times (weeks: 19.96-20.30, 23.36-31.68, 36.22-36.79). Maternal-fetal quality of attachment predicted craving from weeks 19.58-25.63. Maternal-fetal intensity of preoccupation predicted craving from weeks 19.58-22.42 and 31.31-31.87. PTSD symptoms predicted maternal fetal quality of attachment between weeks 25.06-26.20. There was no relationship between PTSD symptoms and maternal-fetal intensity of preoccupation over time.Conclusions These findings support prior research on the relationship between risk/protective factors for substance use during pregnancy. However, these relationships appear to fluctuate over time indicating that other factors might impact substance use during pregnancy.
The underlying neurobiological mechanisms of chronic alcohol consumption, particularly neuroinflammation and immune system dysregulation, have been extensively studied in recent years. In this process, the identification of objective biomarkers that can predict treatment response and enable personalized medicine approaches is of critical importance. This study aimed to evaluate the potential predictive value of tenascin-C (TNC), an extracellular matrix protein, neopterin, a marker of cellular immune activation and pro-inflammatory cytokines interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), during the treatment process for alcohol use disorder (AUD). This prospective observational cohort study included 30 patients admitted to an AUD treatment centre and 31 healthy controls. Serum TNC, IL-6, TNF-α and IFN-γ levels were measured using the ELISA method. Clinical outcomes were assessed using the SCL-90-R and API-K scales. Serum samples were collected from patients at admission and on the 7th day of detoxification treatment. Baseline serum TNC levels in the alcohol group (131.78 ± 50.92 ng/mL) were significantly higher than in the healthy control group (63.92 ± 23.85 ng/mL). In the alcohol group, TNC (p = 0.007) and AST (p = 0.025) levels decreased significantly, while vitamin B12 (p = 0.002) and platelet count (p = 0.012) increased. No significant difference was observed in neopterin and cytokine levels (TNF-α, IL-6 and IFN-γ) between baseline and follow-up measurements. Clinical assessments showed significant improvements in depression (p = 0.041), anxiety (p = 0.014) and total symptom scores (p = 0.026) on the SCL-90-R scale. ROC analysis showed that a reduction of 28.22% or more in TNC predicted clinical improvement with an overall accuracy rate of 73.33%.
4F-ABUTINACA, a fourth-generation synthetic cannabinoid, has been identified in branded herbal smoking mixtures and e-cigarettes seized in China. However, its potential for abuse and its corresponding neurotoxic effects remain poorly understood. In the present study, we evaluated the abuse potential of 4F-ABUTINACA using the intravenous self-administration (IVSA) model and assessed anxiety-like behaviour using the open-field test (OFT) and the elevated plus maze test (EPM). Additionally, neuronal injury, apoptosis, alterations in glia expression and the BDNF-TrkB-AKT signalling pathway in multiple brain regions were assessed simultaneously. Rats acquired stable nose-poke operant response for self-administering 4F-ABUTINACA (0.00625 mg·kg-1·infusion-1) and showed significant drug-seeking behaviour induced by conditioned cues. Persistent anxiety-like behaviours were observed both immediately after drug-taking (SA group) and cue-induced reinstatement testing after a 14-day extinction period (CIR group). Histochemical analysis revealed more pronounced neuronal injury and apoptosis in the hippocampus, prefrontal cortex (PFC) and nucleus accumbens (NAc) in the SA group than in the CIR group. Reactive astrogliosis and microgliosis were observed in the hippocampus and the PFC in the SA group, whereas the numbers of microglia and astrocytes decreased in the NAc of the CIR group. We also found the distinct region-specific alterations in the BDNF-TrkB-AKT signalling pathway expression profile between the SA and CIR groups. The present results demonstrate that 4F-ABUTINACA exhibits significant potential for abuse and produces anxiety-like behaviour during both the active drug-taking and cue-induced relapse stages, which are associated with the neuropathological alterations in specific brain regions.
Alcohol use disorder (AUD) is linked to cognitive deficits that can persist even after prolonged abstinence. Research highlighted associations between plasma apolipoproteins and cognition in AUD. This study examines the longitudinal evolution of plasma apolipoproteins and inflammation in AUD patients during early and prolonged abstinence and their association with cognitive recovery. Thirty-three AUD patients from an outpatient hospital alcoholism programme were evaluated at baseline (t = 0), 6 months (t = 1) and 12 months (t = 2), along with 34 healthy controls. Cognitive performance was assessed using the TEDCA test, which measures general cognitive function (GCF). Biological assessments included plasma pro-inflammatory biomarkers (LPS and LBP) and several apolipoproteins (APOAI, APOAII, APOB, APOCII, APOE, APOJ and APOM). AUD patients showed elevated plasma LPS, APOAI, APOE, APOJ and downregulated APOM, which all normalized at t = 1, whereas cognitive improvement was significant at t = 2 compared to controls. Mixed-effects models including all covariates and within-between person decomposition, followed by correlation matrix and reduced mixed models sensitivity analysis support robust associations between better GCF and (1) the duration of abstinence and (2) within-person reductions in LPS, although apolipoprotein changes should be considered exploratory at this level. Prolonged abstinence in AUD patients normalizes plasma peripheral inflammation and apolipoprotein levels and improves cognition. Although APOAI and APOM showed opposite trajectories, as opposite biomarkers in AUD diagnosis reported previously, only the duration of abstinence and normalization of within-person blood LPS levels over time emerged as predictors of cognitive recovery.
Sleep disturbances are common in individuals with Internet gaming disorder (IGD), yet the neurobiological links between poor sleep quality and addictive symptoms remain unclear. The glymphatic system contributes to cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, processes that are closely related to sleep physiology. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) provides a non-invasive MRI-based marker related to glymphatic system function. In parallel, middle frontal gyrus (MFG)-centred functional connectivity may reflect prefrontal network alterations associated with cognitive control and addiction severity in IGD. The study included 30 individuals with IGD and 37 demographically matched healthy controls (HCs). All participants underwent diffusion tensor imaging and resting-state functional MRI. DTI-ALPS was used to assess glymphatic system-related function. Resting-state functional connectivity analysis was performed using the MFG as the seed region. Group differences in ALPS indices were tested while controlling for age, education years and mean framewise displacement. Within the IGD group, correlation analyses were conducted to examine associations among ALPS indices, PSQI scores, MFG-centred functional connectivity and IAT scores. Individuals with IGD showed significantly lower mean and left ALPS indices than HCs. The right ALPS index showed a non-significant trend towards reduction. Within the IGD group, higher PSQI scores were associated with lower mean, left and right ALPS indices, suggesting that poorer subjective sleep quality was related to reduced glymphatic system-related function. MFG-centred functional connectivity analysis showed increased connectivity mainly involving medial and superior frontal regions and decreased connectivity involving subcortical regions. Stronger MFG-centred functional connectivity was positively correlated with IAT scores, indicating an association with greater addiction severity. This study integrates DTI-ALPS and MFG-centred resting-state functional connectivity to examine sleep-related glymphatic alterations and prefrontal network changes in IGD. Lower ALPS indices were associated with poorer sleep quality, whereas stronger MFG-centred connectivity was associated with greater addiction severity. These findings support a potential sleep-glymphatic-prefrontal network framework for understanding IGD. Longitudinal and interventional studies are needed to clarify the directionality of these associations.
Cues associated with alcohol consumption can trigger cravings, seeking behaviour and relapse after abstinence in individuals with alcohol use disorder (AUD). These conditioned responses can be attenuated through extinction learning, a core component of cue exposure therapy (CET). CET is effective in some individuals with AUD but not all, so it is necessary to develop strategies to identify and intervene with individuals unlikely to benefit from CET. Another method for attenuating conditioned responding is retrieval‐extinction, which renders the original associative memory labile via distinct neural mechanisms. We recently demonstrated that CO 2 reactivity predicts extinction memory for both fear and food cues, and fear memory after retrieval‐extinction, and CO 2 ‐induced orexin/c‐Fos colocalization predicts fear extinction memory. The purpose of the current study was to examine whether the predictive power of CO 2 reactivity might extend to alcohol‐seeking behaviour after extinction or retrieval‐extinction in male and female rats. We also examined the relationship between CO 2 reactivity, return of alcohol‐seeking behaviour and CO 2 ‐induced orexin/c‐Fos colocalization. Male and female rats first underwent alcohol drinking induction in the homecage followed by dependence via exposure to chronic intermittent ethanol vapour or control air and homecage drinking. All rats then underwent Pavlovian alcohol conditioning followed by either standard extinction or retrieval‐extinction. They then received a long‐term memory (LTM) test and CO 2 challenge followed by euthanasia for brain harvesting. CO 2 reactivity differentially predicted LTM after extinction and retrieval‐extinction. There were no relationships between orexin/c‐Fos colocalization and CO 2 reactivity or LTM. The predictive power of CO 2 reactivity extends to alcohol‐seeking behaviour after extinction and retrieval‐extinction in alcohol dependent and nondependent male and female rats, while its relationship with orexin/c‐Fos colocalization does not. CO 2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for CET or a retrieval‐extinction–based approach.
Cocaine use disorder (CUD) is a serious global public health problem, characterized by compulsive drug seeking and impaired cognitive control. Previous studies using voxel-based morphometry (VBM) or surface-based morphometry (SBM) have identified regional alterations in grey matter volume and cortical thickness (CT); purely local morphological analyses are insufficient to capture coordinated patterns of interregional change. In this study, we employed structural covariance networks (SCNs) analysis to investigate abnormalities in the macroscopic topological organization of the brain in individuals with CUD, based on CT measures. A total of 68 patients with CUD and 52 healthy controls (HCs) were included from the OpenNeuro database. The results demonstrated that the CUD group exhibited a significantly reduced global clustering coefficient and a shift in small-world properties, with network topology becoming more closely aligned with a lattice-like configuration. In addition, CUD showed disrupted rich-club connectivity, particularly within core frontoparietal regions. Notably, no significant group differences were observed in network robustness against random failure or targeted attack. Together, these findings indicated an imbalance between network integration and segregation in the structural brain networks of individuals with CUD, providing a novel network-level perspective on the pathophysiology of addiction and suggesting potential utility as a diagnostic neurobiological marker.
Underage drinking has become a global public health concern. One of the major causes of underage drinking is stress. The orexin system has been reported to be involved in both alcohol addiction and stress. However, few studies have examined this system, especially among adolescents. Therefore, we constructed protein-protein interaction (PPI) networks to confirm that orexin receptors are connected to stress- and alcohol dependence-related genes, providing a theoretical basis for our experimental approach. Animal experiments employed the conditioned place preference (CPP), the foot-shock stress model and the enzyme-linked immunosorbent assay (ELISA), to elucidate the role of the orexin system in the stress-induced alcohol addiction-related behaviour among adolescent mice. Our results revealed that there were interactions among orexin system, chronic/acute stress and alcohol dependence related proteins. Otherwise, chronic stress can increase the animals' vulnerability to alcohol addition-related behaviour. Additionally, acute foot-shock can promote alcohol-seeking behaviour reinstatement and facilitate orexin concentrations in brain regions that have been shown to be associated with reward and addiction. Moreover, the inhibition of orexin receptors can attenuate the formation and reinstatement of alcohol addiction-like behaviour among adolescent mice. Collectively, our findings indicate that orexin system may be a pivotal target for preventing stress-induced alcohol addiction and reinstatement among the adolescents.
Pavlovian and operant learning mechanisms promote and maintain alcohol intake despite aversive consequences. Here, we review the evidence for drug-associated modifications of basic learning mechanisms during the initiation and maintenance of alcohol use disorders in humans. We discuss how neuroadaptive effects elicited by chronic alcohol intake in the so-called brain reward system can bias learning and decision making towards drug consumption and contribute to the relapse risk after detoxification. Robustness of results and limitations of the respective neurobiological or imaging techniques are addressed. We opine that studying the effects of alcohol intake on Pavlovian and reinforcement learning can inform psychotherapeutic interventions and help to better understand some new neurobiological interventions. We argue that a focus on drug effects biassing basic learning mechanisms can help to reduce the stigma associated with drug consumption and emphasize behavioural and neurobiological interventions that take individual learning mechanisms into account when promoting alternative coping strategies.
Longer treatment engagement is associated with improved recovery outcomes in alcohol use disorder (AUD), making patient retention a critical determinant of reduced return to drinking. This study aimed to identify factors predicting outpatient treatment engagement, operationalized as the number of follow-up visits, among individuals with AUD following inpatient care. We applied a five-step analytic framework integrating random forest modelling (RFM) and Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify predictors of outpatient visit frequency. Clinical, psychological and physiological variables (n = 177 per participant) collected during inpatient treatment prior to discharge were included. RFM ranked variables associated with follow-up visits, with LASSO used for validation and complementary selection. Over a 5-year period, 119 treatment-seeking patients with AUD (mean age = 45.8) returned for outpatient care, averaging 5.14 visits, following a medical treatment inpatient stay. Positive urgency (VIP = 44.31) and positive life events (VIP = 41.19) emerged as the strongest predictors; both inversely associated with visit frequency. LASSO confirmed positive urgency as a significant predictor (coefficient: -0.03296). Greater alcohol use severity and higher haemoglobin levels were also associated with fewer outpatient visits, whereas higher depressive symptom severity predicted increased follow-up engagement. Using complementary machine learning and regression approaches, this study identified affective traits, alcohol use severity and physiological factors as key determinants of outpatient engagement following inpatient AUD treatment. Interestingly, positive urgency and positive life events, often considered markers of recovery or resilience, were linked to reduced outpatient attendance, suggesting that certain personality or motivational factors may diminish perceived need for continued care. These findings highlight the importance of integrating psychological and motivational variables into postdischarge planning to enhance retention and improve early recovery outcomes.
Despite sedative-hypnotic use disorder (SHUD) being a major public health priority due to its high abuse liability, the underlying causal neurobiological mechanisms of individual susceptibility remain largely unknown. We conducted a large-scale, bidirectional two-sample Mendelian randomization (MR) study utilizing genome-wide association study (GWAS) summary statistics for 3935 brain imaging-derived phenotypes (IDPs) from the UK Biobank (N = 33 000 participants) and SHUD data from the FinnGen R10 release (N = 2258 cases). Causal effects were primarily estimated using the inverse-variance weighted (IVW) method, which was supplemented by a suite of sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Multiple testing was controlled via Benjamini-Hochberg false discovery rate (FDR) correction ( q < 0.05 $$ q<0.05 $$ ). Forward MR identified 34 brain IDPs with significant causal associations with SHUD risk. Specifically, increased susceptibility was linked to structural metrics in the temporal and limbic regions, including higher cortical thickness in the left transverse temporal sulcus (OR = 1.35, 95% CI 1.09-1.67, FDR = 0.04) and right middle temporal gyrus (OR = 1.30, 95% CI 1.07-1.58, FDR = 0.04), as well as elevated white-to-grey matter intensity contrast in the right insula (OR = 1.31, 95% CI 1.13-1.51, FDR = 0.02) and left parahippocampal gyrus (OR = 1.29, 95% CI 1.08-1.54, FDR = 0.04). Conversely, protective effects were observed for brainstem volume (OR = 0.74, 95% CI 0.61-0.91, FDR = 0.04) and white matter integrity in the left cingulum (OR = 0.73, 95% CI 0.57-0.92, FDR = 0.04). Functional connectivity analyses revealed that higher node activity in the salience network (OR = 0.70, 95% CI 0.53-0.92, FDR = 0.04) and strengthened connectivity between the visual and somatomotor networks (OR range: 0.54-0.74) predicted reduced risk. In contrast, specific edges within the default mode network and visual network were positively associated with SHUD susceptibility (OR = 1.56 and 1.48, respectively). Reverse MR analysis provided limited evidence for a causal effect of genetically predicted SHUD on right middle temporal gyrus thickness. Although a nominal association was observed (OR = 1.03, 95% CI 1.00-1.05, p = 0.02), this finding did not survive multiple testing correction (FDR = 0.56) and lacked robustness across sensitivity models. This research establishes a causal link between SHUD susceptibility and specific cortical morphologies, subcortical volumes and functional network topographies, emphasizing the pivotal roles of the temporal-limbic and salience systems. These findings provide novel mechanistic insights into the neurobiological foundations of SHUD while identifying potential imaging biomarkers for risk stratification and the advancement of therapeutic targets.
Relapse is a defining feature of substance use disorders, yet relapse risk varies widely across individuals. This variability has been linked to individual differences in incentive salience attribution to drug-related cues. We used fMRI to identify cortical and subcortical circuits underlying individual differences in incentive salience attribution among people with tobacco use disorder. Fifty daily cigarette users viewed pleasant, unpleasant, cigarette-related and neutral images during task-based fMRI and completed a resting-state scan. We extracted per-condition BOLD activity from a functionally defined extended visual region (Emotional > Neutral) and applied k-means clustering (k = 2) to derive neuroaffective profiles. Whole-brain voxelwise tests assessed Group × Content (cigarette vs. pleasant) effects. We compared groups' resting-state connectivity at the network level and for subcortical-cortical pairs. Individuals were clustered based on neuroaffective reactivity to drug-related and pleasant stimuli: The C > P profile showed larger BOLD responses to cigarette cues than to pleasant stimuli, whereas the P > C profile showed the opposite pattern. Whole-brain analyses showed significant Group × Content interactions that mirrored these profiles across left dorsolateral and medial prefrontal cortices and amygdala-hippocampal regions. At rest, individuals in the C > P profile showed weaker within-network connectivity of the frontoparietal control network (FPCN) and, in exploratory analyses, reduced FPCN-nucleus accumbens coupling. By replicating and extending prior psychophysiological work, this study identifies neuroaffective profiles that reflect the variation in incentive salience attribution central to neurobehavioral models of relapse. These findings provide convergent neurobiological markers that characterize distinct motivational pathways in substance use disorders.
Studies have used repetitive transcranial magnetic stimulation (rTMS) to stimulate the left dorsolateral prefrontal cortex (DLPFC) in patients with tobacco use disorder (TUD); consequently, decreased craving for smoking was observed. However, the neural mechanism underlying this process remains unclear. Functional MRI data were collected from 59 valid TUD participants (31 rTMS and 28 shams) when they performed a Go/No-go task before and after a continuous 5-day treatment (rTMS on the left DLPFC). Three approaches of data analyses were performed: event-related data analyses to identify the brain regions that are associated with rTMS treatment; functional connectivity (FC) analyses among the left DLPFC (the stimulate region) and other survived brain regions after group comparison; FC between the left DLPFC and all brain regions to find couplings among the brain regions. rTMS decreased the craving for smoking in patients with TUD. Comparing with the sham group, the rTMS group showed enhanced brain responses in the bilateral ACC, bilateral caudate and left thalamus to the No-go smoking cues. Further, FC analyses among the survived brain regions showed that rTMS enhanced the FC in DLPFC-caudate and caudate-left thalamus pathways. Notably, enhanced FC between the DLPFC and bilateral basal ganglia thalamus was observed. The current study demonstrated the effectiveness of rTMS in the treatment of TUD, which is associated with enhanced brain responses that are responsible for executive control and reward processing; it enhanced top-down control by reshaping the prefrontal-striatal pathways.
Long-acting naltrexone is a first-line pharmacotherapy for alcohol use disorder (AUD), but clinical response is heterogeneous and the underlying biology remains incompletely understood. In a randomised, double-blind, placebo-controlled trial of naltrexone implants (n = 70), the prespecified primary endpoint-percentage of heavy-drinking days (PHDD) over 24 weeks-favoured naltrexone (median 1.49% vs. 13.39%; p = 0.042). In a prespecified Week-12 mechanistic lipidomics substudy, untargeted liquid chromatography-mass spectrometry (LC-MS) profiling was performed in a responder-enriched subset comprising naltrexone responders (RN, n = 18), placebo-treated participants (PL, n = 10) and age- and BMI-matched healthy male controls (HC, n = 10). We derived membrane-related indices reflecting two prespecified axes of phospholipid remodelling: headgroup balance (PC/PE) and acyl-chain composition (arachidonic acid [AA] and n-3 polyunsaturated fatty acids within phospholipid pools). RN showed higher PC/PE and coordinated acyl-chain shifts versus PL, with species-level changes preferentially moving toward the healthy-control direction. Exploratory analyses in naltrexone nonresponders (NR, n = 10) revealed partial Lands-cycle-related shifts but lacked the broader dual-axis configuration observed in RN. In RN + PL (n = 28), higher n-3 in PE and lower AA in PE at Week 12 were prospectively associated with greater subsequent heavy-drinking burden. These findings support a dual-axis membrane remodelling phenotype associated with naltrexone response and prospectively linked to heavy-drinking burden in AUD, providing a biologically grounded framework for future mechanistic and biomarker studies.
Alcohol use disorder (AUD) is considered a chronic disorder with a highly variable course. Understanding this variability is crucial for identifying factors associated with persistence versus spontaneous remission. We analysed data from N = 462 individuals with AUD in an observational longitudinal cohort study to identify factors associated with spontaneous remission. All participants met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for AUD at study entry and were reassessed after 1 year, in which they were classified as being in spontaneous remission (n = 107), falling below the ≥ 2-criteria threshold for AUD (n = 87) or continuing to meet AUD criteria (n = 296). Groups were compared on socio-demographic, clinical and substance use variables at baseline and after 1 year. Additionally, we used machine learning models to identify baseline characteristics predicting a persistent course of AUD. Between-group comparisons revealed that individuals who experienced spontaneous remission reported significantly lower AUD severity (F(2,459) = 25.17, p < 0.001), lower levels of alcohol intake (F(2,459) = 8.31, p = 0.013) and fewer drinking days (F(2,459) = 11.91, p < 0.001) at baseline and after 1 year. Machine learning analysis demonstrated moderate classification performance (AUC = 0.679), with the Alcohol Use Disorders Identification Test (AUDIT) sum score being the most informative predictor for group classification. Our findings indicate significant differences between spontaneously remitted and non-remitted individuals on key alcohol-related variables, supporting the clinical validity of remission as defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). In addition, baseline characteristics may help identify individuals at risk of persistent AUD, enabling earlier identification of those who may benefit from specialized treatment. TRIAL REGISTRATION: DRKS number: DRKS00020580.
Millions of people worldwide are affected by betel quid dependence (BQD), a prevalent psychoactive substance-use disorder. To evaluate cerebral glymphatic dysfunction in BQD, this work used the coupling between global blood-oxygen-level-dependent (gBOLD) and cerebrospinal fluid (CSF) signals collected via resting-state functional MRI (rs-fMRI). Sixty-six participants (29 BQD individuals and 37 healthy controls) underwent rs-fMRI scanning. Cross-correlation analysis between cortical BOLD and CSF time series was carried out to compute the gBOLD-CSF coupling intensity. Group comparisons were performed via independent sample t-tests, and correlations with clinical features were assessed using exploratory Pearson's analysis. Bonferroni correction was applied to the five correlation analyses (BQDS, duration, daily consumption, HAMA-14 and HAMD-24). The corrected significance threshold was set at p < 0.01 (0.05/5). BQD individuals exhibited significantly reduced gBOLD-CSF coupling (t = -2.42, p = 0.019), and weaker coupling correlated with longer BQD duration (r = 0.4313, uncorrected p = 0.0195). After Bonferroni correction for multiple comparisons, the correlation between duration and gBOLD-CSF coupling (original p = 0.0195) did not reach the adjusted threshold. Chronic betel quid exposure may impair glymphatic function, reflecting disrupted brain-CSF interactions. The gBOLD-CSF coupling metric could be used as a noninvasive imaging biomarker to evaluate neurotoxic effects and glymphatic dysfunction in substance-use disorders.
Alcohol dependence (AD) is characterized by a high relapse rate. Virtual reality (VR) technology can provide immersive cue exposure therapy (VR-CET) and aversion therapy (VR-AT). This study aimed to evaluate the efficacy of VR-CET, VR-AT and their combination on craving, emotional and sleep states, attentional bias and relapse rate in patients with AD. In this single-centre randomized controlled trial, male inpatients with AD were randomly assigned to one of four groups: control, VR-CET, VR-AT or combined VR-CET + AT (target n = 25 per group; 80 completed, 20 per group). The interventions spanned 15 days with eight sessions (VR-CET + AT ~20 min/session; others ~10 min). Assessments were conducted before and after treatment using the Visual Analogue Scale (VAS), the Pennsylvania Alcohol Craving Scale (PACS), the Hamilton Depression Scale (HAMD), the Hamilton Anxiety Scale (HAMA) and the Pittsburgh Sleep Quality Index (PSQI). Eye-tracking and grasping indices in VR environments were used to assess attentional bias (e.g., alcohol-cue fixation time ratio). Relapse was evaluated by telephone at 4 and 12 weeks post-treatment. Statistical analyses used Shapiro-Wilk tests and ANOVA/Kruskal-Wallis tests with appropriate post hoc comparisons (α = 0.05). All groups showed significant pre- to post-treatment improvements in PACS, HAMD, HAMA, PSQI and VAS scores (all p < 0.001). Between-group comparisons at post-treatment revealed significant differences in alcohol-cue fixation time ratio (p < 0.05), with the VR-CET + AT group showing a lower fixation time ratio than the control group. VAS scores also differed among groups (p < 0.05), with the control group showing higher values than the VR-CET + AT group. Changes in alcohol-cue fixation time ratio from pre- to post-treatment were significantly greater in the VR-CET + AT group than in the control group. Relapse rates at 4 and 12 weeks (47/80 reached by telephone follow-up) did not significantly differ among groups (both p > 0.05). Combining VR-CET with VR-AT reduced craving (VAS) and attentional bias (alcohol-cue fixation time ratio) beyond standard care, whereas all groups improved on clinical scales. Larger and longer trials are warranted to further clarify relapse outcomes. Trial Registration: Chinese Clinical Trial Registry, ChiCTR2500110026. Registered 29 September 2025 (retrospectively registered).
Plasma neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), tau protein and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) are candidate biomarkers of alcohol withdrawal (AW)-associated brain toxicity, as they are biomarkers of axonal, neuronal or glial injury. The aim of this study was to investigate the changes of these biomarkers during AW in patients with severe alcohol use disorder (AUD). Plasma NFL, GFAP, tau and UCHL1 levels were measured, with SIMOA, at three times: on Day 1 (T1), on Day 3 or 4 (T2) and on Day 13, 14 or 15 (T3) of AW. They were analysed with a linear mixed model adjusted for age, sex and body mass index. Changes in these levels according to AW symptom severity were evaluated. Twenty-four inpatients with severe AUD were included: 20 men (83.3%), aged 47.4 years [±11.3], with symptoms requiring a median equivalent-diazepam dose of 0.81 mg/kg at T1. A significant increase was observed for NFL level from T1 to T2 (β = 0.349, p = 0.035), but not for GFAP, tau or UCHL1 levels. In AW symptom severity analyses, a significant positive association was found with equivalent-diazepam dose required × T1-T2 time interaction factor for NFL (β = 0.161, p = 0.028) and for GFAP (β = 0.400, p = 9.9 × 10-4). This longitudinal study provided preliminary indication that brain injury could occur within the first days of AW, especially in patients with severe pharmacological dependence. Plasma NFL and GFAP are promising biomarkers of AW-related brain pathology and should be investigated as biomarkers of therapeutic response to test innovative drug strategies for preventing this toxicity. Trial Registration: Clinical Trials: NCT05216705.
