Brain science research in China is at an unprecedented moment of opportunity, but existing data silos represent a systemic obstacle that impedes research and limits both scientific innovation and clinical translation. We believe the path ahead must be towards creating a fully standardized national brain health ecosystem. The pillars of this ecosystem are the standardized acquisition of multimodal data, a governance pipeline to translate raw data into secure, shareable knowledge, and large prospective cohorts as important tools for translational research. These components can help ensure that data are no longer just accumulated, but knowledge is actually found, and can enable a strategic shift in brain disease care from reactive, treatment-focused care to proactive, prevention-focused brain health.

INTRODUCTION:While smoking has been associated with many negative consequences to human health, one possible benefit is that nicotine could improve cognitive functions. Previous studies have suggested that smoking may influence brain-derived neurotrophic factor (BDNF) levels. However, the exact effects of smoking on BDNF and cognition, and the potential neurobiological mechanisms underlying the changes induced by nicotine, remain elusive. METHODS:Two tobacco products were used in the population to detect plasma BDNF, and the spatial memory was examined using the N-back test. Acute and chronic nicotine exposure and withdrawal models were established in rats. BDNF levels and relevant targets in serum, cerebrospinal fluid, and hippocampus were detected, and spatial memory and motor ability were evaluated by Y-maze test. Pharmacological blockage or genetic deletion of α7 nicotinic acetylcholine receptors (nAChR) was administered to rats to confirm its role in regulating the effects of nicotine on BDNF and memory levels. RESULTS:Our research revealed that tobacco product use led to an increase in working memory and human plasma BDNF levels. Furthermore, nicotine was responsible for the elevation in BDNF levels, which showed dose-dependent increases in both serum and the hippocampus, and improved memory performance. Conversely, BDNF levels decreased with prolonged withdrawal from nicotine, and resulted in impaired memory performance. However, when the α7 nAChR was inhibited by the receptor antagonist methyllycaconitine citrate (MLA) or genetic knockout, the elevation of BDNF levels caused by chronic nicotine exposures was blocked. CONCLUSIONS:The nicotine in tobacco can improve memory through α7 nAChR.

Methamphetamine (METH) is a widely abused stimulant that affects the central nervous system. The persistent maladaptive conditioned stimuli (CS, drug cues)-drug associative memories represent a primary factor precipitating relapse. Interfering with the reconsolidation of these memories may help disrupt and modify these maladaptive CS-drug associations, potentially reducing their influence on drug-seeking behavior. The present study explored the effect of CS-triggered memory retrieval-extinction on METH craving, potentially offering a new treatment strategy for addiction. This was a single-center, randomized, controlled trial involving individuals with METH use disorder (MUD). Participants completed one of three interventions on consecutive days (days 2 and 3): CS-triggered memory retrieval followed by extinction after a 10-min interval, CS-triggered memory retrieval followed by extinction after a 6-h interval, or extinction without prior retrieval. Self-report cue-induced craving for METH, salivary cortisol and sympathetic responses were measured at baseline (day 1), post intervention (day 4) and two follow-up timepoints (days 34 and 184), with cue-induced craving and salivary cortisol as primary outcomes. Ninety-eight MUD individuals (mean age 28.15 ± 6.31) were analyzed. After two-day’s interventions, cue-induced METH craving (time × cue interaction: F(1,94) = 60.02, p < 0.001) reduced in all groups. Results from follow-up data indicated, when the extinction was performed 10 min, but not 6 h after memory retrieval or no retrieval, the intervention decreased experimental cue-induced METH craving (intervention × time × cue: F(2,94) = 14.32, p < 0.001; intervention: F(2,94) = 24.28, p < 0.001) and saliva cortisol increases (F(2,90) = 9.51, p < 0.001), with effects lasting up to 6-month follow-up. The results revealed a substantial reduction in cue-elicited craving and saliva cortisol in the retrieval-10 min-extinction group over the 6-month follow-up. These findings provide compelling evidence that a brief reconsolidation-based intervention can effectively diminish METH-related craving and cortisol levels, underscoring its potential as a supportive measure in METH treatment. Salivary cortisol is a readily accessible and sensitive biomarker for evaluating intervention effects.

Depressive disorders (DD) are more prevalent among people with HIV (PWH) compared to the general population. Research in the general population has confirmed the association between depression and gray matter atrophy as well as reduced cortical thickness. However, there is a lack of neuroimaging studies investigating brain structural changes in PWH with comorbid DD (PWH-DD). This cross-sectional study included 69 HIV-positive men who have sex with men, categorized into PWH-DD (n = 29) and PWH control (n = 40) groups based on the diagnosis of DD. Participants underwent clinical, neuropsychiatric, and MRI evaluations. Voxel-based and surface-based morphometry techniques were applied to analyze gray matter volume (GMV) and cortical anatomical characteristics in structural MRI data. The imaging findings were ultimately correlated with the results of clinical assessments. Compared to participants in the PWH control group, those in the PWH-DD group showed higher scores in evaluation of depression, anxiety, sleep disturbances, childhood trauma, and mental health symptoms, indicating a greater burden of psychological and emotional distress. Comparisons of brain structure showed that participants in the PWH-DD group exhibited lower GMV in the left middle frontal gyrus, shallower sulcal depth in the left supramarginal and bilateral superior parietal regions, and lower fractal dimension in multiple frontal and temporal lobe areas compared to those in the PWH control group. Among all participants, correlation analysis demonstrated that GMV of the left middle frontal gyrus was significantly negatively correlated with Self-Rating Depression Scale scores. This study emphasizes that HIV-positive men who have sex with men with comorbid DD exhibit poorer mental health status and more severe brain structural alterations. However, further longitudinal studies are needed to explore the exact causal relationship between DD and brain structural injury in PWH.

BACKGROUND:Anxiety and depressive disorders contribute significantly to the global mental health burden. This study focuses and forecasts on the distribution of these disorders across regions, age groups, genders, and time periods. METHODS:We estimated the global burden of anxiety and depressive disorders from 1990 to 2021 using data from the Global Burden of Disease (GBD) 2021 study. Prevalence, disability-adjusted life years (DALYs), and regional trends were analyzed using Joinpoint regression, and projections for 2022-2040 were made with the Autoregressive Integrated Moving Average model. Decomposition analysis examined the impacts of population growth, aging, and epidemiological changes. FINDINGS:In 2021, global prevalence of anxiety and depressive disorders reached 359.2 million and 332.4 million cases, respectively, accounting for 9.1 % of all diseases and 63.1 % of mental health disorders. Middle and low SDI contributed the majority of global cases and DALYs. Between 1990 and 2021, the age-standardised DALY rate (ASDR) for anxiety disorders increased by 18.2 % and for depressive disorders by 13.4 %. Population growth accounted for the majority of this increase. The prevalence of these disorders rises with age, particularly in the 10-24 age group, with females experiencing higher rates. By 2040, global cases are projected to over 515 million for anxiety and over 466 million for depressive disorders, with middle and low SDI contributing the majority of cases. CONCLUSIONS:The global burden of anxiety and depressive continues to grow, with significant increases in middle and low SDI. Urgent mental health interventions are needed, especially in low-resource settings and among youth.

Background:A variety of symptoms, particularly cognitive, psychiatric and neurological symptoms, may persist for a long time among individuals recovering from COVID-19. However, the underlying mechanism of these brain abnormalities remains unclear. This study aimed to investigate the long-term neuroimaging effects of COVID-19 infection on brain functional activities using resting-state functional magnetic resonance imaging (rs-fMRI). Methods:Fifty-two survivors 27 months after infection (mild-moderate group: 25 participants, severe-critical: 27 participants), from our previous community participants, along with 35 healthy controls, were recruited to undergo fMRI scans and comprehensive cognitive function measurements. Participants were evaluated by subjective assessment of Cognitive Failures Questionnaire-14 (CFQ-14) and Fatigue Scale-14 (FS-14), and objective assessment of Montreal Cognitive Assessment (MoCA), N-back, and Simple Reaction Time (SRT). Each had rs-fMRI at 3T. Measures such as the amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were calculated. Findings:Compared with healthy controls, survivors of mild-moderate acute symptoms group and severe-critical group had a significantly higher score of cognitive complains involving cognitive failure and mental fatigue. However, there was no difference of cognitive complaints between two groups of COVID-19 survivors. The performance of three groups was similar on the score of MoCA, N-back and SRT. The rs-fMRI results showed that COVID-19 survivors exhibited significantly increased ALFF values in the left putamen (PUT.L), right inferior temporal gyrus (ITG.R) and right pallidum (PAL.R), while decreased ALFF values were observed in the right superior parietal gyrus (SPG.R) and left superior temporal gyrus (STG.L). Additionally, decreased ReHo values in the right precentral gyrus (PreCG.R), left postcentral gyrus (PoCG.L), left calcarine fissure and surrounding cortex (CAL.L) and left superior temporal gyrus (STG.L). Furthermore, significant negative correlations between the ReHo values in the STG.L, and CFQ-14 and mental fatigue were found. Interpretation:This long-term study suggests that individuals recovering from COVID-19 continue to experience cognitive complaints, psychiatric and neurological symptoms, and brain functional alteration. The rs-fMRI results indicated that the changes in brain function in regions such as the putamen, temporal lobe, and superior parietal gyrus may contribute to cognitive complaints in individuals with long COVID even after 2-year infection. Funding:The National Programs for Brain Science and Brain-like Intelligence Technology of China, the National Natural Science Foundation of China, Natural Science Foundation of Beijing Municipality of China, and the National Key Research and Development Program of China.

The exact relationship between nicotine metabolism and dependence is not fully understood but is known to be influenced at a molecular level by genetic factors. A sample comprising 274 Chinese adult male smokers was categorized into groups based on their metabolic rates, namely fast, intermediate, and slow metabolizers. We then measured their smoking topography, evaluated their nicotine dependence, and assessed the rewarding effects. Based on these findings, we proposed the hypothesis that the rate of nicotine metabolism could influence the level of dopamine release which in turn had repercussions on the pleasurable and rewarding effects. To test this hypothesis, male mice were selected with different nicotine metabolic rates that closely resembled in the smoker group. We evaluated their nicotine dependence and rewarding effects through conditioned place preference and withdrawal symptom tests, supplemented with dopamine release measurements. In both animal and human, the slow metabolism group (SMG) required less nicotine to maintain a comparable level of dependence than the fast metabolism group (FMG). The SMG could achieve similar rewarding effects to FMG despite consuming less nicotine. Comparable dopamine levels released were therefore critical in setting the nicotine acquisition behavior in this animal model and also for the smokers tested. Our findings suggested that even within the same ethnicity of established smokers (Chinese Han), differences in nicotine metabolism were an important parameter to modulate the degree of nicotine dependence.

Integrase strand transfer inhibitors (INSTIs) have emerged as the first-line choice for treating human immunodeficiency virus (HIV) infection due to their superior efficacy and safety. However, the impact of INSTIs on the development of neuropsychiatric conditions in people living with HIV (PLWH) is not fully understood due to limited data. In this study, we conducted a cross-sectional examination of PLWH receiving antiretroviral therapy, with a specific focus on HIV-positive men who have sex with men (MSM) on INSTI-based regimens (n = 61) and efavirenz (EFV)-based regimens (n = 28). Participants underwent comprehensive neuropsychiatric evaluations and multimodal magnetic resonance imaging (MRI) scans, including T1-weighted images and resting-state functional MRI. Compared to the EFV group, the INSTI group exhibited primarily reduced gray matter volume (GMV) in the right superior parietal gyrus, higher regional homogeneity (ReHo) in the left postcentral gyrus, lower ReHo in the right orbital part of the inferior frontal gyrus, and increased voxel-wise functional connectivity for the seed region in the left inferior temporal gyrus with clusters in the right cuneus. Furthermore, the analysis revealed a main effect of antiretroviral drugs on GMV changes, but no main effect of neuropsychiatric disorders or their interaction. The repeated analysis of participants who did not switch regimens confirmed the GMV changes in the INSTI group, validating the initial findings. Our study demonstrated gray matter atrophy and functional brain changes in PLWH on INSTI-based regimens compared to those on EFV-based regimens. These neuroimaging results provide valuable insights into the characteristics of brain network modifications in PLWH receiving INSTI-based regimens.

目的 研究慢性间歇性限制摄食对大鼠条件性恐惧记忆维持和焦虑样行为的影响.方法 雄性SD大鼠接受听觉条件性恐惧记忆训练,随后进行为期4周的间歇性限制摄食;之后进行恐惧记忆、高架迷宫和自发活动测试.结果 与正常摄食组大鼠相比,限制摄食4周大鼠的听觉恐惧记忆水平显著降低,进入高架迷宫开放臂的次数和时间显著增加,提示限制摄食降低恐惧记忆的维持,且降低动物的焦虑水平.结论 限制摄食能够降低恐惧记忆的维持,为治疗恐惧记忆相关疾病提供了新的思路.

Since their introduction in the United States and Europe in 2007, electronic cigarettes (E-Cigs) have become increasingly popular among smokers. Nicotine, a key component in both tobacco and e-cigarettes, can exist in two forms: nicotine-freebase (FBN) and nicotine salts (NS). While nicotine salt is becoming more popular in e-cigarettes, the effect of nicotine salts on reinforcement-related behaviors remains poorly understood. This study aimed to compare the reinforcing effects of nicotine and nicotine salts in animal models of drug self-administration and explore potential mechanisms that may contribute to these differences. The results demonstrated that three nicotine salts (nicotine benzoate, nicotine lactate, and nicotine tartrate) resulted in greater reinforcement-related behaviors in rats compared to nicotine-freebase. Moreover, withdrawal-induced anxiety symptoms were lower in the three nicotine salt groups than in the nicotine-freebase group. The study suggested that differences in the pharmacokinetics of nicotine-freebase and nicotine salts in vivo may explain the observed behavioral differences. Overall, this study provides valuable insights into the reinforcing effects of nicotine as well as potential differences between nicotine-freebase and nicotine salts.

This work presented a significant correlation between heroin and methamphetamine dependence (HD and MD) which distinguished with alcohol dependence (AD) at the genome-wide level. Three novel risk loci were identified for HD and MD. The shared polygenic risk with cognition and attention-deficit hyperactivity disorder (ADHD) further profiled the similar genetic characteristics between HD and MD compared to AD. Substance dependencies (SD) are one of the leading public health concerns worldwide. Drug markets are in a constant state of flux. The combined use of different addictive substances, especially illegal drugs, is common among addiction patients. Genetic factors contribute to approximately 40%–70% of the variance in persistent SD.1 Capturing the shared and specific genetic mechanism of different substance dependences is crucial for coping with the changeable types of addiction. In this study, genome-wide association meta-analyses (GWMA) were performed independently for HD, MD and AD based on two data sets (DS) of substance-specific dependence patients (1028 HD, 1750 MD, 537 AD and 2862 shared controls for DS1, 980 HD, 701 MD, 224 AD and 1111 shared controls for DS2) (Supplementary Tables S1 and S2, Supplementary Figures S1 and S2, supplementary methods). Consist with our previous study in DS12, One significant locus at chr12 ANKS1B was identified for both HD (peaked in rs112706556, pmeta = 4.99e-8) and MD (peaked in rs58720542, pmeta = 4.401e-9) (Table 1, Figure 1A and B); two well-known loci in chr4 ADH cluster and chr12 ALDH cluster were verified for AD (Supplementary Figure S3). Genetic correlation analysis using LD score regression3 showed MD and HD were significantly correlated (rg = 0.8618, p = 7.361e-5), but not for HD and AD, MD and AD. The cross-dataset pairwise polygenic risk score (PRS) analysis further validated these relationship patterns (Supplementary Table S3). Based on the high genetic correlation between HD and MD, the combined GWMA for HD&MD versus controls were analysed, in which HD and MD were grouped as cases and compared with controls (Table 1 and Figure 1). In addition to the ANKS1B locus (peaked in rs140254085, pmeta = 6.355e-10), another two novel loci located in chr2 locus (peaked in rs74330628 downstream of NRXN1, pmeta = 3.84e-8) and chr7 locus (peaked in GTF2IRD1 intron rs76965632, pmeta = 1.41e-8) were identified (Supplementary Table S4). The functional annotations for the three significant loci are shown in Table 1. Several regulatory features were located in the loci (Supplementary Figure S4), and eQTL data showed the loci regulated the expression of ANKS1B and NRXN1 in brain tissues (Supplementary Table S5, Figure 2A and Supplementary Figure S5). By comparison, the three significant loci of HD&MD were not associated with AD, while the chr4 ADH and chr12 ALDH loci were not associated with HD and MD or had a different direction in HD and MD with AD (Supplementary Figure S6). These findings are consistent with previous twin study that showed a closer genetic correlation across illicit drug dependences compared to alcohol dependence.4 Next, the association with addiction characteristics of the significant loci for HD&MD was examined (Supplementary Table S6 and Figure 2B). The protective allele (A) of rs74330628 in the NRXN1 locus was associated with a lower frequency of heroin usage (padj = .0167). The protective allele (C) of rs76965632 in the GTF2IRD1 locus was negatively associated with craving of MA (padj = .0256). Using the Human Connectome Project data, the SNPs of ANKS1B was associated with risk of ever used illicit drug (EverDrugs) (Supplementary Table S7), which was associated with the volume of the left and right amygdala (Supplementary Table S8). Mediation analysis showed the ANKS1B locus had an indirect effect on EverDrugs by the mediation of the left amygdala and right amygdala (Figure 2C). ANKS1B protein may be involved in the neural plasticity of the amygdala during drug use by affecting glutamatergic neurotransmission.5 Phenome-wide association analysis based on the GWAS Atlas6 further validated the association of ANKS1B, NRXN1 and GTF2IRD1 with psychiatric traits (Supplementary Figure S7 and Supplementary Tables S9–S11). We next explored the associated genes and pathways for the shared risk of HD and MD. ANKS1B, GRM7, RBFOX1 and CDH13 were shared by HD, MD and HD&MD (Supplementary Table S12). Enrichment analysis showed the HD- and MD-related 22 unique genes were significantly enriched in brain-related tissues, GO term ‘modulation of chemical synaptic transmission’ and drug abuse and neurodevelopmental disorder-related diseases (Supplementary Figure S8). These associated genes and pathways provide new candidates and clues for understanding the genetic mechanism of drug dependences. Additionally, polygenic associations with phenotypes of addiction-related traits, risk behaviour, cognition and psychiatric disorders (Supplementary Table S13) were performed for HD, MD and AD. The three alcohol-related traits were significantly associated with AD, but not with HD and MD (Figure 3A and Supplementary Table S14). Sexual and smoke behaviour risks were positively associated with the MD and HD&MD, but not with AD (Figure 3B and Supplementary Table S15). Cognition performance, education attainment and IQ were negatively associated with HD, MD and HD&MD but not with AD (Figure 3C and Supplementary Table S16). Our findings support that pre-existing cognition disruption could increase the risk of illicit drug dependence.7 For the eight psychiatric disorders, only the PRS of ADHD was positively associated with HD, MD and HD&MD, but not with AD (Figure 3D and Supplementary Table S17). Mendelian randomisation analysis further highlighted the causal effect of ADHD on HD and HD&MD (Supplementary Table S18). Our previous study also demonstrated that ADHD-relevant childhood behaviour was a risk factor for MA-induced psychosis.8 First-degree relatives of ADHD probands have an increased risk for drug dependence.9 This suggests that ADHD and drug dependence have shared genetic factors. Cluster analysis based on the standardised coefficient matrix from the PRS association results showed HD, MD and HD&MD were in one sub-cluster and were different from AD, which further highlighted the closer polygenic correlations between HD and MD compared to AD. In conclusion, at the genome-wide loci, genes and polygenic levels, we identified significant genetic overlap between HD and MD, which distinguished with AD. Notably, the combined HD&MD GWAS identified three common risk loci, located on ANSK1B, NRXN1 and GTF2IRD1 genes. At the polygenic level, HD and MD were significantly associated with cognition deficiency and ADHD, which distinguished them from AD. Our results would help with the fine-mapping of the common and unique genetic mechanisms underlying drug dependences and alcohol dependence and may provide clues for their prevention. This work was supported by the National Natural Science Foundation of China (No. 31871259, 82171488, U1802283, 81821092), the National Key Research and Development Program of China (No. 2021YFF0306500), and the Beijing Municipal Science and Technology Commission (No. Z181100001518005). The authors declare no competing interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Tobacco addiction has been largely attributed to nicotine, a component in tobacco leaves and smoke. However, extensive evidence suggests that some non-nicotine components of smoke should not be overlooked when considering tobacco dependence. Yet, their individual effect and synergistic effect on nicotine reinforcement remain poorly understood. The study herein focused on the role of non-nicotine constituents in promoting the effects of nicotine and their independent reinforcing effects. Denicotinized cigarettes were prepared by chemical extracting of cut tobacco, and the cigarette smoke extracts (CSE, used as a proxy for non-nicotine ingredients) were obtained by machine-smoking the cigarettes and DMSO extraction. The compositions of harmful components, nicotine, and other minor alkaloids in both cut tobacco and the CSE of experimental denicotinized cigarettes were examined by GC-MS, and compared with 3R4F reference cigarettes. individually and in synergy with nicotine were determined by conditioned place preference (CPP), dopamine (DA) level detection, the open field test (OFT), and the elevated plus maze (EPM). Finally, the potential enhancement mechanism of non-nicotinic constituents was investigated by nicotine metabolism and monoamine oxidase A (MAOA) activity inhibition in the striatum of mice and human recombinant MAOA. Thenicotine content in smoke from the experimental denicotinized cigarettes (under ISO machine-smoking conditions) was reduced by 95.1% and retained most minor alkaloids, relative to the 3R4F reference cigarettes. It was found that non-nicotine constituents increased acute locomotor activities. This was especially pronounced for DA levels in NAc and CPP scores, decreased the time in center zone. There were no differences in these metrics with DNC group when compared to the NS group. Non-nicotine constituents alone did not show reinforcing effects in CPP or striatum DA levels in mice. However, in the presence of nicotine, non-nicotine constituents further increased the reinforcing effects. Furthermore, non-nicotine constituents may enhance nicotine’s reinforcing effects by inhibiting striatum MAOA activity rather than affecting nicotine metabolism or total striatum DA content in mice. These findings expand our knowledge of the effect on smoking reinforcement of non-nicotine constituents found in tobacco products.

BACKGROUND:Trauma experience increases the risk of suicidal ideation, but little is known about potentially psychological mechanisms underlying this relationship. This study aims to examine the relationship between coronavirus disease 2019 (COVID-19)-related traumatic event (CTE) exposure and suicidal ideation among hospital workers, and identify mediating roles of sleep disturbances in this relationship.METHODS:Workers in seven designated hospitals in Wuhan, China, were invited to participate in an online survey from May 27, 2020, to July 31, 2020. Participants completed a self-report questionnaire to evaluate demographic characteristics, level of CTE exposures, nightmare frequency, insomnia severity, symptoms of depression and anxiety, and suicidal ideation. A series of correlation analyses were performed, and a mediation model was generated to examine correlations between CTE exposure, sleep disturbances, and suicidal ideation.RESULTS:A total of 16,220 hospital workers were included in the final analysis, 13.3% of them reported suicidal ideation in the past month. CTE exposure was significantly associated with insomnia severity, nightmare frequency, and suicidal ideation. After controlling potential confounders, nightmares but not insomnia, depression, or anxiety were shown to be independent risk factors for suicidal ideation. Pathway analyses showed that the relationship between CTE exposure and suicidal ideation was fully mediated by nightmares (proportion mediated 66.4%) after adjusting for demographic characteristics and psychological confounders.LIMITATIONS:Cross-sectional design precluded the investigation of causal relationships.CONCLUSIONS:CTE exposure increases risk of hospital workers' suicidal ideation that is mediated by nightmares, suggesting nightmares intervention might be considered as a component when developing suicide prevention strategies.

BackgroundOpioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP.MethodsIn the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate.FindingsMethadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01).InterpretationThe approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse.FundingNational Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800)

Background: University students who are exposed to coronavirus disease 2019 (COVID-19) could be mentally distressed. We aimed to evaluate the pattern and risk factors of mental health and suicidal behavior among students who experienced long-term school closure due to the COVID-19 pandemic. Methods: This large-sample, cross-sectional, online survey was conducted from June 29, 2020, to July 18, 2020. Eleven thousand two hundred fifty four participants were recruited from 30 universities located in Wuhan, Hubei Province, China. The prevalence of symptoms of depression, anxiety, insomnia, and posttraumatic stress disorder (PTSD) and suicidal behavior was evaluated using the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Insomnia Severity Index, Posttraumatic Stress Disorder Checklist for DSM-5, and questions about suicidal ideation and attempts, respectively. Logistic regression was used to explore risk factors for mental health problems and suicidal behavior. Results: The prevalence of mental health problems was 41.5% for depressive symptoms, 32.6% for anxiety symptoms, 35.0% for insomnia symptoms, 8.5% for PTSD symptoms, and 2.0% for suicidal behavior. Participants with high stress during the pandemic were at higher risk of symptoms of depression [adjusted odds ratio (OR) = 1.67, 95% confidence interval (CI) = 1.43–1.95, p < 0.01), anxiety (adjusted OR = 1.90, 95% CI = 1.63–2.23, p < 0.01), insomnia (adjusted OR = 1.64, 95% CI = 1.44–1.87, p < 0.01), PTSD (adjusted OR = 1.71, 95% CI = 1.38–2.11, p < 0.01) and suicidal behavior (adjusted OR = 3.51, 95% CI = 2.28–5.40, p < 0.01). Distant relationship with parents, changes in lifestyle and alcohol use during the pandemic were associated with higher risk of mental health symptoms and suicidal behavior, whereas regular physical exercise reduced the risk of mental health problems. Conclusions: The psychological symptoms and suicidal behavior were relatively high among students who attended university in Wuhan, China after 6 months of the COVID-19 outbreak in China. Comprehensive mental health services and suicide prevention strategies are essential for university students during the COVID-19 pandemic.

BACKGROUND:COVID-19 is still spreading worldwide and posing a threat to individuals' physical and mental health including problematic internet use (PIU). A potentially high-risk group for PIU are those with symptoms of attention deficit and hyperactivity (ADHD symptoms), because of restrictions in their physical activity levels and engagement in computer diversions requiring only short attention spans. METHODS:We used convenience sampling in a cross-sectional survey of university students from 30 universities in Wuhan, Hubei Province, China. We assessed PIU using the Internet Addiction Test and ADHD symptoms using the WHO Adult ADHD Self-Report Screening Scale. Using logistic regression and linear regression analyses we adjusted for demographic, epidemic-related and psychological covariates in models of the association between ADHD symptoms and PIU. RESULTS:Among 11,254 participants, we found a 28.4% (95% CI, 27.5%-29.2%) prevalence of PIU, relatively higher than before the pandemic. In our final logistic regression model, participants with ADHD symptoms had approximately two times the risk for PIU (OR: 2.31, 95% CI: 1.89-2.83). Similarly, individuals with depression, anxiety, insomnia, PTSD symptoms and feeling stress during the pandemic had a higher risk of PIU, while those exercising regularly during the pandemic had a lower risk. LIMITATIONS:The cross-sectional design and reliance on internet based self-reports for ADHD symptoms and PIU assessments, without direct structured interviews for validation, are limitations. CONCLUSIONS:The prevalence of PIU was high during COVID-19, and those people with ADHD symptoms and other mental illness symptoms appear to be at higher risk of PIU. Regular exercise may reduce that PIU risk and hence should be recommended during the COVID-19 pandemic.

The majority of smokers relapse even after successfully quitting because of the craving to smoking after unexpectedly re-exposed to smoking-related cues. This conditioned craving is mediated by reward memories that are frequently experienced and stubbornly resistant to treatment. Reconsolidation theory posits that well-consolidated memories are destabilized after retrieval, and this process renders memories labile and vulnerable to amnestic intervention. This study tests the retrieval reconsolidation procedure to decrease nicotine craving among people who smoke. In this study, 52 male smokers received a single dose of propranolol (n = 27) or placebo (n = 25) before the reactivation of nicotine-associated memories to impair the reconsolidation process. Craving for smoking and neural activity in response to smoking-related cues served as primary outcomes. Functional magnetic resonance imaging was performed during the memory reconsolidation process. The disruption of reconsolidation by propranolol decreased craving for smoking. Reactivity of the postcentral gyrus in response to smoking-related cues also decreased in the propranolol group after the reconsolidation manipulation. Functional connectivity between the hippocampus and striatum was higher during memory reconsolidation in the propranolol group. Furthermore, the increase in coupling between the hippocampus and striatum positively correlated with the decrease in craving after the reconsolidation manipulation in the propranolol group. Propranolol administration before memory reactivation disrupted the reconsolidation of smoking-related memories in smokers by mediating brain regions that are involved in memory and reward processing. These findings demonstrate the noradrenergic regulation of memory reconsolidation in humans and suggest that adjunct propranolol administration can facilitate the treatment of nicotine dependence. The present study was pre-registered at ClinicalTrials.gov (registration no. ChiCTR1900024412).

Continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation technique, can induce long-lasting changes in synaptic plasticity, vital for memory reconsolidation. For this study, a total of 170 participants completed four experiments by a randomized controlled design. Succeeding fear conditioning, the subjects received cTBS over the right dorsolateral prefrontal cortex (dlPFC) or vertex (control) with or without exposure to the conditioned stimulus to reactivate the original fear memory, and then underwent fear response tests. Compared with cTBS over the vertex and without memory reactivation, only cTBS over the right dlPFC after reactivation decreased the fear response for both recent and remote fear memories. This procedure was effective only during the reconsolidation window. The disruptive effect of cTBS over the right dlPFC on fear memory reconsolidation was delay-dependent. These findings demonstrate that cTBS time-dependently and delay-dependently prevents the return of fear and may have clinical potential for treating fear-related disorders.

BACKGROUND AND OBJECTIVES The adverse impact of chronic methamphetamine (MA) use on cognitive function has been described in previous studies, but limited evidence is available for abstinent users from prospective longitudinal studies. The aim of the present study was to assess cognitive function of varying abstinent duration. METHODS This prospective longitudinal study was conducted with baseline and four follow-up interviews every 6 months over 2 years in 358 MA users in Guangdong province, China. The Montreal Cognitive Assessment (MoCA) was used to measure cognitive function. Generalized estimating equation (GEE) analysis was used to examine within-subjects relationships between abstinence and cognitive consequences over time. RESULTS The repeated measure analysis of variance showed significant differences in the total MoCA score and all subscale scores (except Orientation) in the 24 months follow-up. The GEE model showed that abstinence from MA in the past 6 months predicted an increase of 0.66 (95% confidence interval [CI] = 0.29 to 1.05, p = .002) in MoCA score changes compared with the nonabstinence MA users. Abstinence in the past 12, 18, and 24 months predicted an increase in MoCA total score changes of 1.25 (95% CI = -0.23 to 2.74), 2.15 (95% CI = -0.79 to 5.09), and 5.28 (95% CI = -2.01 to 12.58), respectively, but none of these was statistically significant. DISCUSSION AND CONCLUSIONS Cognitive function was potentially improved following 6 months of MA abstinence. SCIENTIFIC SIGNIFICANCE This study extends prior research by long-term follow-up in big sample MA abstinence users. Findings from study support the need for a comprehensive measure to decrease MA use and promote the recovery of cognitive impairment.