Treadmill exercise training inhibits morphine CPP by reversing morphine effects on GABA neurotransmission in D2-MSNs of the accumbens-pallidal pathway in male mice.

Relapse is a major challenge in the treatment of drug addiction, and exercise has been shown to decrease relapse to drug seeking in animal models. However, the neural circuitry mechanisms by which exercise inhibits morphine relapse remain unclear. In this study, we report that 4-week treadmill training prevented morphine conditioned place preference (CPP) expression during abstinence by acting through the nucleus accumbens (NAc)-ventral pallidum (VP) pathway. We found that neuronal excitability was reduced in D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) following repeated exposure to morphine and forced abstinence. Enhancing the excitability of NAc D2-MSNs via treadmill training decreased the expression of morphine CPP. We also found that the effects of treadmill training were mediated by decreasing enkephalin levels and that restoring opioid modulation of GABA neurotransmission in the VP, which increased neurotransmitter release from NAc D2-MSNs to VP, decreased morphine CPP. Our findings suggest the inhibitory effect of exercise on morphine CPP is mediated by reversing morphine-induced neuroadaptations in the NAc-to-VP pathway.

Altered N-linked glycosylation in depression: A pre-clinical study.

BACKGROUND: Neuroimmune plays an important role in major depressive disorders (MDD). N-linked protein glycosylation (NLG) might contribute to depression by regulating the neuroinflammatory response. As microglia is the main executor of neuroimmune function in the central neural system (CNS), targeting the process of N-linked protein glycosylation of microglia in the mice used for studying depression might potentially offer new avenues for the strategy for MDD. METHODS: The chronic unpredictable mild stress (CUMS) mouse model was established for the whole brain microglia isolating. Then, RNA samples of microglia were extracted for transcriptome sequencing and mRNA analysis. Immunofluorescence (IF) was used to identify the expression level of NLG-related enzyme, B4galt1, in microglia. RESULTS: The data showed that NLG was positively related to depression. Moreover, the NLG-related gene, B4galt1 increased expression in the microglia of CUMS mice. Then, the inhibition of NLG reversed the depressive behavior in CUMS mice. The expression level of B4galt1 in CUMS mice was upregulating following the NLG-inhibitor treatment. Similar results haven't been observed in neurons. Information obtained from these experiments showed increasing expression of B4galt1 in microglia following depressive-like behaviors. CONCLUSIONS: These findings indicate that NLG in microglia is associated with MDD, and suggest that therapeutically targeting NLG might be an effective strategy for depression. LIMITATIONS: How to modulate the B4galt1 or NLG pathways in microglia efficiently and economically request new technologies.

Dynamics of N6-methyladenosine modification during Alzheimer's disease development.

N6-methyladenosine (m6A) modification is a common RNA modification in the central nervous system and has been linked to various neurological disorders, including Alzheimer's disease (AD). However, the dynamic of mRNA m6A modification and m6A enzymes during the development of AD are not well understood. Therefore, this study examined the expression profiles of m6A and its enzymes in the development of AD. The results showed that changes in the expression levels of m6A regulatory factors occur in the early stages of AD, indicating a potential role for m6A modification in the onset of the disease. Additionally, the analysis of mRNA m6A expression profiles using m6A-seq revealed significant differences in m6A modification between AD and control brains. The genes with differential methylation were found to be enriched in GO and KEGG terms related to processes such as inflammation response, immune system processes. And the differently expressed genes (DEGs) are negatively lryassociated with genes involved in microglia hemostasis, but positively associated with genes related to "disease-associated microglia" (DAM) associated genes. These findings suggest that dysregulation of mRNA m6A modification may contribute to the development of AD by affecting the function and gene expression of microglia.

Multiple mediation of the association between childhood emotional abuse and adult obesity by anxiety and bulimia - a sample from bariatric surgery candidates and healthy controls.

Bulimia, which means a person has episodes of eating a very large amount of food (bingeing) during which the person feels a loss of control over their eating, is the most primitive reason for being overweight and obese. The extended literature has indicated that childhood emotional abuse has a close relationship with adverse mood states, bulimia, and obesity. To comprehensively understand the potential links among these factors, we evaluated a multiple mediation model in which anxiety/depression and bulimia were mediators between childhood emotional abuse and body mass index (BMI). A set of self-report questionnaires, including the Childhood Trauma Questionnaire (CTQ), Beck Anxiety Inventory, Beck Depression Inventory (BDI), and Eating Disorder Inventory (EDI), was sent out. Clinical data from 37 obese patients (age: 29.65 ± 5.35, body mass index (BMI): 37.59 ± 6.34) and 37 demographically well-matched healthy people with normal body weight (age: 31.35 ± 10.84, BMI: 22.16 ± 3.69) were included in the investigation. We first performed an independent t-test to compare all scales or subscale scores between the two groups. Then, we conducted Pearson correlation analysis to test every two variables' pairwise correlation. Finally, multiple mediation analysis was performed with BMI as the outcome variable, and childhood emotional abuse as the predictive variable. Pairs of anxiety, bulimia, and depression, bulimia were selected as the mediating variables in different multiple mediation models separately. The results show that the obese group reported higher childhood emotional abuse (t = 2.157, p = 0.034), worse mood state (anxiety: t = 5.466, p < 0.001; depression: t = 2.220, p = 0.030), and higher bulimia (t = 3.400, p = 0.001) than the healthy control group. Positive correlations were found in every pairwise combination of BMI, childhood emotional abuse, anxiety, and bulimia. Multiple mediation analyses indicate that childhood emotional abuse is positively linked to BMI (ß = 1.312, 95% CI = 0.482-2.141). The model using anxiety and bulimia as the multiple mediating variables is attested to play roles in the relationship between childhood emotional abuse and obesity (indirect effect = 0.739, 95% CI = 0.261-1.608, 56.33% of the total effect). These findings confirm that childhood emotional abuse contributes to adulthood obesity through the multiple mediating effects of anxiety and bulimia. The present study adds another potential model to facilitate our understanding of the eating psychopathology of obesity.

The resting-state brain activity signatures for addictive disorders.

BACKGROUND: Addiction is a chronic and relapsing brain disorder. Despite numerous neuroimaging and neurophysiological studies on individuals with substance use disorder (SUD) or behavioral addiction (BEA), currently a clear neural activity signature for the addicted brain is lacking. METHODS: We first performed systemic coordinate-based meta-analysis and partial least-squares regression to identify shared or distinct brain regions across multiple addictive disorders, with abnormal resting-state activity in SUD and BEA based on 46 studies (55 contrasts), including regional homogeneity (ReHo) and low-frequency fluctuation amplitude (ALFF) or fractional ALFF. We then combined Neurosynth, postmortem gene expression, and receptor/transporter distribution data to uncover the potential molecular mechanisms underlying these neural activity signatures. FINDINGS: The overall comparison between addiction cohorts and healthy subjects indicated significantly increased ReHo and ALFF in the right striatum (putamen) and bilateral supplementary motor area, as well as decreased ReHo and ALFF in the bilateral anterior cingulate cortex and ventral medial prefrontal cortex, in the addiction group. On the other hand, neural activity in cingulate cortex, ventral medial prefrontal cortex, and orbitofrontal cortex differed between SUD and BEA subjects. Using molecular analyses, the altered resting activity recapitulated the spatial distribution of dopaminergic, GABAergic, and acetylcholine system in SUD, while this also includes the serotonergic system in BEA. CONCLUSIONS: These results indicate both common and distinctive neural substrates underlying SUD and BEA, which validates and supports targeted neuromodulation against addiction. FUNDING: This work was supported by the National Natural Science Foundation of China and Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health.

An Electroencephalography Profile of Paroxysmal Kinesigenic Dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) is associated with a disturbance of neural circuit and network activities, while its neurophysiological characteristics have not been fully elucidated. This study utilized the high-density electroencephalogram (hd-EEG) signals to detect abnormal brain activity of PKD and provide a neural biomarker for its clinical diagnosis and PKD progression monitoring. The resting hd-EEGs are recorded from two independent datasets and then source-localized for measuring the oscillatory activities and function connectivity (FC) patterns of cortical and subcortical regions. The abnormal elevation of theta oscillation in wildly brain regions represents the most remarkable physiological feature for PKD and these changes returned to healthy control level in remission patients. Another remarkable feature of PKD is the decreased high-gamma FCs in non-remission patients. Subtype analyses report that increased theta oscillations may be related to the emotional factors of PKD, while the decreased high-gamma FCs are related to the motor symptoms. Finally, the authors established connectome-based predictive modelling and successfully identified the remission state in PKD patients in dataset 1 and dataset 2. The findings establish a clinically relevant electroencephalography profile of PKD and indicate that hd-EEG can provide robust neural biomarkers to evaluate the prognosis of PKD.

Computational markers of risky decision-making predict for relapse to alcohol.

BACKGROUND: Relapse remains the major challenge in treatment of alcohol use disorder (AUD). Aberrant decision-making has been found as important cognitive mechanism underlying relapse, but factors associated with relapse vulnerability are unclear. Here, we aim to identify potential computational markers of relapse vulnerability by investigating risky decision-making in individuals with AUD. METHODS: Forty-six healthy controls and fifty-two individuals with AUD were recruited for this study. The risk-taking propensity of these subjects was investigated using the balloon analog risk task (BART). After completion of clinical treatment, all individuals with AUD were followed up and divided into a non-relapse AUD group and a relapse AUD group according to their drinking status. RESULTS: The risk-taking propensity differed significantly among healthy controls, the non-relapse AUD group, and the relapse AUD group, and was negatively associated with the duration of abstinence in individuals with AUD. Logistic regression models showed that risk-taking propensity, as measured by the computational model, was a valid predictor of alcohol relapse, and higher risk-taking propensity was associated with greater risk of relapse to drink. CONCLUSION: Our study presents new insights into risk-taking measurement and identifies computational markers that provide prospective information for relapse to drink in individuals with AUD.

An electroencephalographic signature predicts craving for methamphetamine.

Craving is central to methamphetamine use disorder (MUD) and both characterizes the disease and predicts relapse. However, there is currently a lack of robust and reliable biomarkers for monitoring craving and diagnosing MUD. Here, we seek to identify a neurobiological signature of craving based on individual-level functional connectivity pattern differences between healthy control and MUD subjects. We train high-density electroencephalography (EEG)-based models using data recorded during the resting state and then calculate imaginary coherence features between the band-limited time series across different brain regions of interest. Our prediction model demonstrates that eyes-open beta functional connectivity networks have significant predictive value for craving at the individual level and can also identify individuals with MUD. These findings advance the neurobiological understanding of craving through an EEG-tailored computational model of the brain connectome. Dissecting neurophysiological features provides a clinical avenue for personalized treatment of MUD.

Chronic stress hinders sensory axon regeneration via impairing mitochondrial cristae and OXPHOS.

Spinal cord injury (SCI) often leads to physical limitations, persistent pain, and major lifestyle shifts, enhancing the likelihood of prolonged psychological stress and associated disorders such as anxiety and depression. The mechanisms linking stress with regeneration remain elusive, despite understanding the detrimental impact of chronic stress on SCI recovery. In this study, we investigated the effect of chronic stress on primary sensory axon regeneration using a preconditioning lesions mouse model. Our data revealed that chronic stress-induced mitochondrial cristae loss and a decrease in oxidative phosphorylation (OXPHOS) within primary sensory neurons, impeding central axon regrowth. Corticosterone, a stress hormone, emerged as a pivotal player in this process, affecting satellite glial cells by reducing Kir4.1 expression. This led to increased neuronal hyperactivity and reactive oxygen species levels, which, in turn, deformed mitochondrial cristae and impaired OXPHOS, crucial for axonal regeneration. Our study underscores the need to manage psychological stress in patients with SCI for effective sensory-motor rehabilitation.

Metformin improves cognitive impairment in patients with schizophrenia: associated with enhanced functional connectivity of dorsolateral prefrontal cortex.

Cognitive impairment is a core feature of schizophrenia, which is aggravated by antipsychotics-induced metabolic disturbance and lacks effective pharmacologic treatments in clinical practice. Our previous study demonstrated the efficiency of metformin in alleviating metabolic disturbance following antipsychotic administration. Here we report that metformin could ameliorate cognitive impairment and improve functional connectivity (FC) in prefrontal regions. This is an open-labeled, evaluator-blinded study. Clinically stable patients with schizophrenia were randomly assigned to receive antipsychotics plus metformin (N = 48) or antipsychotics alone (N = 24) for 24 weeks. The improvement in cognition was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Its association with metabolic measurements, and voxel-wise whole-brain FC with dorsolateral prefrontal cortex (DLPFC) subregions as seeds were evaluated. When compared to the antipsychotics alone group, the addition of metformin resulted in significantly greater improvements in the MCCB composite score, speed of processing, working memory, verbal learning, and visual learning. A significant time × group interaction effect of increased FC between DLPFC and the anterior cingulate cortex (ACC)/middle cingulate cortex (MCC), and between DLPFC subregions were observed after metformin treatment, which was positively correlated with MCCB cognitive performance. Furthermore, the FC between left DLPFC A9/46d to right ACC/MCC significantly mediated metformin-induced speed of processing improvement; the FC between left A46 to right ACC significantly mediated metformin-induced verbal learning improvement. Collectively, these findings demonstrate that metformin can improve cognitive impairments in schizophrenia patients and is partly related to the FC changes in the DLPFC. Trial Registration: The trial was registered with ClinicalTrials.gov (NCT03271866). The full trial protocol is provided in Supplementary Material.

Transcriptional and epigenetic decoding of the microglial aging process.

As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, the longitudinal characteristics of microglia remain poorly understood. In this study, we mapped the transcriptional and epigenetic profiles of microglia from 3- to 24-month-old mice. We first discovered unexpected sex differences and identified age-dependent microglia (ADEM) genes during the aging process. We then compared the features of aging and reactivity in female microglia at single-cell resolution and epigenetic level. To dissect functions of aged microglia excluding the influence from other aged brain cells, we established an accelerated microglial turnover model without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cognitive decline. Collectively, our work provides a comprehensive resource for decoding the aging process of microglia, shedding light on how microglia maintain brain functions.

A visual circuit related to the habenula mediates the prevention of cocaine relapse by bright light treatment.

Despite significant advancements in our understanding of addiction at the neurobiological level, a highly effective extinction procedure for preventing relapse remains elusive. In this study, we report that bright light treatment (BLT) administered during cocaine withdrawal with extinction training prevents cocaine-driven reinstatement by acting through the thalamic-habenular pathway. We found that during cocaine withdrawal, the lateral habenula (LHb) was recruited, and inhibition of the LHb via BLT prevented cocaine-driven reinstatement. We also demonstrated that the effects of BLT were mediated by activating LHb-projecting neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL) or by inhibiting postsynaptic LHb neurons. Furthermore, BLT was found to improve aversive emotional states induced by drug withdrawal. Our findings suggest that BLT administered during the cocaine withdrawal may be a promising strategy for achieving drug abstinence.

Posttraumatic stress disorder symptoms among healthcare workers during the Omicron era.

Background: The COVID-19 pandemic has caused significant psychological stress among healthcare workers. This study aimed to clarify the factors that influenced health workers' posttraumatic stress disorder (PTSD) symptoms. Method: A total of 443 healthcare workers from eight Mental Health Centers in Shandong were recruited to attend an online survey. Participants completed self-evaluation measures of exposure to the COVID-19 environment and PTSD symptoms, as well as measures of potential protective factors such as euthymia and perceived social support. Results: About 45.37% of healthcare workers had severe symptoms of PTSD symptoms. Healthcare workers with more serious PTSD symptoms were significantly related to higher exposure to COVID-19 (r = 0.177, p < 0.001), as well as lower levels of euthymia (r = -0.287, p < 0.001) and perceived social support (r = -0.236, p < 0.001). The structural equation model (SEM) further revealed that the impact of exposure to COVID-19 on PTSD symptoms was partially mediated by euthymia, and moderated by perceived social support, especially from others (e.g., friends, leaders, relatives and colleagues). Conclusion: These findings suggested that improving the state of euthymia, getting social support from others could alleviate PTSD symptoms among healthcare workers during the COVID-19.

Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: A randomized double-blind trial and TMS-EEG study.

It has been 15 years since repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) was approved by the FDA for clinical depression treatment. Yet, the underlying mechanisms for rTMS-induced depression relief are not fully elucidated. This study analyzes TMS-electroencephalogram (EEG) data from 64 healthy control (HC) subjects and 53 patients with major depressive disorder (MDD) before and after rTMS treatment. Prior to treatment, patients with MDD have lower activity in the DLPFC, the hippocampus (HPC), the orbitofrontal cortex (OFC), and DLPFC-OFC connectivity compared with HCs. Following active rTMS treatment, patients with MDD show a significant increase in the DLPFC, HPC, and OFC. Notably, the increase in HPC activity is specifically associated with amelioration of depressive symptoms but not anxiety or sleep quality. The orbitofrontal-hippocampal pathway plays a crucial role in mediating depression relief following rTMS treatment. These findings suggest potential alternative targets for brain stimulation therapy against depression (chictr.org.cn: ChiCTR2100052007).

Intermittent theta burst stimulation to the left dorsolateral prefrontal cortex improves working memory of subjects with methamphetamine use disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation has been employed to treat drug dependence, reduce drug use and improve cognition. The aim of the study was to analyze the effectiveness of intermittent theta-burst stimulation (iTBS) on cognition in individuals with methamphetamine use disorder (MUD). METHODS: This was a secondary analysis of 40 MUD subjects receiving left dorsolateral prefrontal cortex (L-DLPFC) iTBS or sham iTBS for 20 times over 10 days (twice-daily). Changes in working memory (WM) accuracy, reaction time, and sensitivity index were analyzed before and after active and sham rTMS treatment. Resting-state EEG was also acquired to identify potential biological changes that may relate to any cognitive improvement. RESULTS: The results showed that iTBS increased WM accuracy and discrimination ability, and improved reaction time relative to sham iTBS. iTBS also reduced resting-state delta power over the left prefrontal region. This reduction in resting-state delta power correlated with the changes in WM. CONCLUSIONS: Prefrontal iTBS may enhance WM performance in MUD subjects. iTBS induced resting EEG changes raising the possibility that such findings may represent a biological target of iTBS treatment response.

The effects of childhood maltreatment on adolescent non-suicidal self-injury behavior: mediating role of impulsivity.

Background: Non-suicidal self-injury (NSSI) severely challenges mental health in adolescents. Childhood maltreatment experience acts as high-risk factor for adolescents to engage in NSSI behaviors. On the other hand, impulsivity or loss of control sets the threshold for NSSI execution. Here we examined the effects of childhood maltreatment on adolescent NSSI-related clinical outcomes and the potential role of impulsivity. Methods: We assessed the clinical data of 160 hospitalized NSSI adolescents and recruited 64 age-matched healthy subjects as a control group. The clinical symptoms of NSSI are expressed by the NSSI frequency, depression, and anxiety measured by the Ottawa Self-Injury Inventory, the Beck Depression Inventory, and the Beck Anxiety Inventory. Childhood maltreatment and impulsivity were assessed with Childhood Trauma Questionnaire and Barratt Impulsiveness Scale. Results: The results showed that when compared to HC group, NSSI group is more likely to experience childhood maltreatment. Notably, NSSI group with Childhood maltreatment accompanies higher trait impulsivity and exacerbated clinical outcomes, such as NSSI frequency, depression and anxiety symptoms. Mediation analyses indicated that the association between childhood maltreatment and NSSI-related clinical outcomes was partially explained by impulsivity. Conclusion: We found that NSSI adolescents have a higher proportion of childhood maltreatment. Impulsivity plays a mediating role between childhood maltreatment and NSSI behaviors.

Effect of transdermal drug delivery therapy on anxiety symptoms in schizophrenic patients.

Objective: To evaluate the efficacy and safety of transdermal drug delivery therapy for schizophrenia with anxiety symptoms. Methods: A total of 80 schizophrenic patients (34 males and 56 females) with comorbid anxiety disorders were randomly assigned to the treatment group (n = 40) and the control group (n = 40) with 6 weeks of follow-up. The patients in the treatment group received the standard antipsychotic drug treatment along with transdermal drug delivery therapy. The evaluation of the patients included the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD-17), and treatment emergent symptom scale (TESS) at baseline, 3 weeks, and 6 weeks after transdermal drug delivery therapy. The Positive and Negative Symptom Scale (PANSS) was assessed at baseline and after 6 weeks of treatment. Results: After 3 and 6 weeks of treatment, the HAMA scale scores in the treatment group were lower than those in the control group (p < 0.001). However, there were no significant differences in the HAMD-17 scale scores, PANSS total scores, and subscale scores between the two groups (p > 0.05). Additionally, no significant differences in adverse effects were observed between the two groups during the intervention period (p > 0.05). After 6 weeks of penetration therapy, there was a low negative correlation between total disease duration and the change in HAMA scale score (pretreatment-posttreatment) in the treatment group. Conclusion: Combined traditional Chinese medicine directed penetration therapy can improve the anxiety symptoms of patients with schizophrenia and has a safe profile.