ABSTRACT Background Accurately predicting environmental dangers is a fundamental ability for animal and human survival. Fear memory could be disrupted by various stimuli, including inflammation, which can be mimicked by lipopolysaccharide (LPS) injection. LPS, which can activate microglia and disrupt the blood‐brain barrier (BBB), can impair contextual fear memory consolidation when injected immediately after fear conditioning. However, the mechanism is not clear. Minocycline, a tetracycline derivative, can reduce inflammation and microglial activation. This study aims to explore the role of microglial activation in LPS‐induced contextual fear memory consolidation impairment and BBB disruption. Methods Immediately after the fear conditioning training, 0.5 or 1 mg/kg LPS was injected i.p., and the contextual fear memory was tested 24 h later, followed by biochemical and histological test. Results The results showed that LPS impaired contextual fear memory consolidation, which was accompanied by a significant leakage of immunoglobulin G (IgG) in the hippocampus 24 h after LPS treatment. In addition, significantly decreased levels of claudin‐5 and occludin, and significantly upregulated levels of caveolin‐1, microglial activation, and the levels of pro‐inflammatory factors interleukin‐1β (IL‐1β) and tumor necrosis factor‐α (TNF‐α) were found in the hippocampus. In contrast, minocycline, which could inhibit microglial activation, reduce LPS‐induced memory impairment and BBB damage. Conclusions In summary, the study provides preliminary evidence that LPS can impair the consolidation of contextual fear memory by causing microglial activation, releasing pro‐inflammatory factors IL‐1β and TNF‐α, and leading to BBB disruption in the hippocampus of mice.
ABSTRACT Objective This systematic review aimed to assess the cost‐effectiveness of decompressive craniectomy (DC) in severe traumatic brain injury (TBI) patients by analyzing relevant economic studies. Methods The authors conducted a comprehensive search across multiple databases and included economic evaluation studies, clinical trials, observational studies, or modeling studies that focused on patients who underwent DC for severe TBI. The quality of included studies was assessed using the Drummond checklist, and potential publication bias was examined. Data on total hospital costs, quality‐adjusted life years (QALY), cost per QALY, and patient demographics were extracted and analyzed. Results The included studies were of moderate to high quality. Total hospital costs increased with a higher likelihood of unfavorable outcomes. A cost–utility analysis demonstrated that DC led to a higher expected QALY gain compared to medical management. At 12 months, though, DC was the costlier option. In the Finnish cohort, the estimated cost of continued care ran to several times that of the initial admission, which raised the all‐in cost per QALY well above the figure for neurosurgical treatment alone. Cost‐effectiveness varied with the severity of TBI. Conclusions DC may be cost‐effective in the management of severe TBI in selected patients, particularly those at lower risk of an unfavorable outcome, although the available evidence is limited and heterogeneous. That value falls as injury severity rises, and at the extreme end of severity the procedure is no longer cost‐effective. Decisions about DC in severe TBI therefore turn on both the expected clinical benefit and the cost, not on either alone. Longer follow‐up would help, since much of both the cost and the recovery in these patients accrues years after surgery.
ABSTRACT Background and Purpose Poststroke delirium (PSD) is common and prognostically relevant, yet under‐detected. Mechanistic and biomarker research is constrained by reliance on an intermittently observed binary phenotype, while delirium reflects one severity level on a continuum of delirium‐related encephalopathy. Quantitative EEG (qEEG) may capture encephalopathy endotypes more directly and enable severity‐spectrum characterization. Methods In this prospective, single‐center, observational cohort study, 87 consecutive patients with acute ischemic stroke or transient ischemic attack were assessed within 48 h using the Confusion Assessment Method (CAM). A 64‐channel EEG was recorded at enrollment; spectral power (delta/theta/alpha/beta) and functional connectivity metrics (phase lag index; amplitude envelope correlation corrected [AECc]) were computed. Neuroinflammatory and systemic biomarkers were quantified from routine serum sampling in an exploratory, add‐on subcohort (n = 31). Results PSD occurred in 28 of 87 (32%). PSD was characterized by spectral slowing and altered AECc. A multivariable qEEG model discriminated PSD with AUC = 0.892 (p < 0.001) and overall accuracy of 81.4% (non‐delirium 89.8%, delirium 63.0%). In the paired EEG plus serum subset, nominal exploratory correlations between qEEG metrics and selected biomarkers suggested links between network dysfunction and inflammatory signaling, including inverse correlations of theta‐band AECc with VILIP‐1 (r = −0.454, p = 0.045) and CX3CL1 (r = −0.604, p = 0.005), whereas biomarker–phenotype associations were less consistent. Conclusions qEEG connectivity provides an encephalopathy‐proximal readout that can detect PSD and may characterize delirium‐related endotypes beyond the intermittently observed clinical phenotype. Findings require validation in larger, multicenter cohorts.
BACKGROUND:Chronic cough, a distressing symptom of allergic asthma, possibly arises from the abnormal activation of airway-projecting sensory neurons. Levels of interleukin (IL)-31, a Th2 cytokine known for its neuronal effects in pruritus, are elevated in allergic disorders; however, its role in asthma-related cough remains unclear. Therefore, in this study, we aimed to determine the mechanism by which IL-31 influences cough-associated neuronal sensitization using a Dermatophagoides farinae (Derf)-induced asthma model. METHODS:Wild-type (WT) and Il31 knockout (KO) C57BL/6N mice were intranasally administered the Derf extract repeatedly. Lung tissues, bronchoalveolar lavage fluid, and hilar lymph nodes were analyzed via histology, flow cytometry, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction. Vagal and dorsal root ganglia were assessed via immunofluorescence assay and Ca2 + imaging. RESULTS:Protease-activated receptor (PAR)-2 activity was evaluated using the agonist SLIGRL-NH2. Derf upregulated Il31 levels in airway tissues. Notably, immune and histological parameters were comparable between WT and Il31 KO mice, indicating that IL-31 deficiency did not alter Th2-driven inflammation. In contrast, Derf-challenged WT mice exhibited increased Il31ra and F2rl1 (PAR-2) levels and PAR-2-positive neuron proportions in vagal ganglia, changes that were not observed in Il31 KO mice. Ca2 + imaging confirmed that PAR-2 responsiveness to SLIGRL-NH2 was enhanced only in WT asthma model mice. CONCLUSION:Overall, IL-31 modulated the neuronal, rather than immune, components of allergic asthma by enhancing the PAR-2-dependent excitability of vagal sensory neurons. These findings highlight the IL-31-PAR-2-vagal pathway as the potential mechanism of and therapeutic target for allergen-driven cough.
ABSTRACT Purpose: Peripheral nerve injuries (PNIs) pose a major clinical challenge, especially when nerve gaps exceed 5 mm and spontaneous regeneration is inadequate. This study aimed to evaluate the regenerative potential of novel bone‐derived nerve guidance conduits (NGCs) fabricated from rat femoral diaphysis and chicken ulna as alternatives to conventional autologous and allogeneic grafts. Methods: Demineralized and decellularized bone scaffolds were characterized for collagen preservation, luminal geometry, and mechanical and electrical properties. In vivo, the conduits were implanted to bridge 10 mm sciatic nerve gaps in rats. Functional recovery was assessed over 16 weeks using sciatic functional index (SFI), hot‐plate latency, and gastrocnemius muscle mass ratio. Histological analysis and RT‐qPCR profiling of ECM‐related genes (COL1A1, FN1, LAMB2, and Tenascin‐C) were performed to evaluate tissue integration and molecular responses. Findings: Chicken‐derived conduits showed superior tensile strength and elasticity, while both scaffold types supported hydration‐dependent ionic conductivity. In vivo results demonstrated progressive conduit resorption and nerve tissue replacement. Treated groups showed significant motor and sensory recovery compared to axotomy controls. Histology revealed early axonal infiltration, neovascularization, and remyelination. Gene expression analysis indicated scaffold‐specific temporal regulation aligned with regenerative phases. Conclusion: Bone‐derived NGCs from rat femur and chicken ulna effectively supported structural, electrophysiological, and functional nerve regeneration. These findings highlight their promise as accessible, biocompatible alternatives to traditional grafts and provide a foundation for future translational research in peripheral nerve repair.
BACKGROUND:Ischemic stroke (IS) is one of the leading causes of death and long-term disability worldwide. Electrolyte fluctuations, particularly in sodium and potassium, may play a critical role in the mortality of IS. METHODS:This retrospective cohort study utilized the MIMIC-IV database and NWICU to examine the association between sodium and potassium variability (coefficient of variation [CV]) and mortality in IS patients. A total of 3266 IS patients were included. The study focused on 30-, 90-, and 360-day all-cause mortality. Patients were stratified into quartiles based on CV values for sodium and potassium variability. Multivariable Cox proportional-hazards models were used to assess associations. Cumulative incidence was estimated using Kaplan-Meier methods. Restricted cubic spline (RCS) analyses were conducted to examine the associations of sodium and potassium CVs with the primary outcomes. Sensitivity analyses further examined the impact of electrolyte levels and variability on mortality. RESULTS:In this study, 2593 patients from MIMIC-IV and 673 patients from NWICU were analyzed by sodium and potassium fluctuation quartiles. Sodium and potassium variability were significantly associated with mortality at 30-day, 90-day, and 360-day intervals, with continuous sodium variability showing HRs of 1.22 (30-day), 1.18 (90-day), and 1.17 (360-day), and Q4 significantly increasing risk (HR = 1.78, 1.51, 1.49, respectively). In NWICU, Q4 sodium variability was an independent risk factor for 30-day mortality (HR = 4.04, p < 0.001). Sensitivity analyses confirmed that both high and low sodium and potassium levels were associated with increased mortality risks. CONCLUSIONS:Fluctuations in sodium and potassium levels were strongly linked to increased short-term and long-term mortality risk in intensive care unit (ICU) patients. Patients with high variability in both electrolytes had the worst prognosis.
INTRODUCTION:Greater brain resilience-the capacity of the brain to maintain normal functioning and cognition with aging-is associated with a slower cognitive decline. Cognitive reserve (CR) is one component of brain resilience and may be supported by educational, occupational, and leisure experiences. PURPOSE:This exploratory, cross-sectional study examined associations among psychological well-being, engagement in leisure activities associated with cognitive reserve, and cognitive performance in older community dwellers (older adults living independently) in Spain. General brain resilience was tapped on by measuring performance in memory and attention cognitive tasks. METHOD:We used the depression, anxiety and stress scale (DASS-21), life satisfaction scale (SWLS), loneliness scale (UCLA), and cognitive reserve scale (CRS) as proxy measures for psychological well-being and cognitive reserve in 80 people (33 men) between 65 and 101 years of age. The CRS was used as a proxy measure of the leisure-activity contribution to cognitive reserve rather than as a comprehensive or direct measure of cognitive reserve. To probe cognitive performance, we administered a memory-span task and spatial-cueing tasks measuring endogenous and exogenous attention. FINDINGS:Among males, higher CRS scores were associated with lower perceived stress and greater reported loneliness, whereas comparable associations were not observed among females. Higher CRS scores were also associated with selected measures of attention. No significant association was observed between CRS scores and memory span. Given the exploratory design and sample size, sex-specific findings should be interpreted cautiously. CONCLUSION:We discuss these findings and outline a research agenda for more hypotheses-driven studies to investigate the intricate relationships among different aspects of brain resilience, psychological well-being and cognitive performance in older individuals. Better understanding of intricate associations between cognitive performance and psychological factors (feeling of loneliness, subjective stress and anxiety, and life satisfaction) may contribute to our understanding of how lifestyle and cognitive reserve are related.
INTRODUCTION:Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous. METHODS:This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework. RESULTS:Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (β = -0.03, p = 0.006) and memory performance (β = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower Aβ42/Aβ40 was associated with poorer memory performance (β = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (± evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis. CONCLUSIONS:The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and Aβ42/Aβ40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.
BACKGROUND:Anxiety and depressive symptoms frequently accompany Parkinson's disease (PD), yet the biological processes underlying these affective complications and their potential peripheral indicators remain incompletely understood. This study evaluated whether circulating concentrations of vasoactive intestinal peptide (VIP), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) differed according to the presence of anxiety and depressive symptoms among individuals with PD. METHODS:This exploratory study included 56 individuals with PD and 40 neurologically healthy participants matched for age and sex who were enrolled at the same institution. Clinical characterization included Hoehn-Yahr staging, assessment of daily living function (ADL), cognitive evaluation using MMSE, and measurement of anxiety and depressive symptoms with HAMA-14 and HAMD-17. PD-AD status was determined when participants simultaneously met the predefined cutoff values for both anxiety and depression assessment scales. Circulating concentrations of VIP, TNF-α, and IL-1β were measured using enzyme-linked immunosorbent assays. Relationships between biomarkers and clinical variables were examined through Spearman correlation testing, binary logistic regression modeling, and receiver operating characteristic (ROC) analysis. RESULTS:Relative to healthy participants, the PD group showed lower circulating VIP concentrations and higher IL-1β and TNF-α concentrations, with all comparisons reaching statistical significance (p < 0.01). Among participants with PD, those meeting criteria for anxiety and depression showed an additional reduction in VIP accompanied by increased IL-1β concentrations. Lower VIP concentrations were associated with higher HAMA-14 and HAMD-17 scores (r = -0.559 and r = -0.853, respectively), whereas IL-1β concentrations demonstrated positive relationships with both symptom scales. ROC analysis identified VIP as the biomarker with the strongest ability to distinguish PD-AD from PD patients without affective symptoms (AUC = 0.892, 95% CI: 0.799 to 0.986; sensitivity: 0.842; specificity: 0.814). IL-1β demonstrated a moderate capacity for classification, with an AUC of 0.796 (95% CI: 0.666 to 0.926). CONCLUSION:These results suggest that alterations in VIP and IL-1β are associated with affective symptoms in PD and may contribute to biomarker-based recognition of PD-AD in clinical practice. Nevertheless, interpretation of these findings is limited by the observational cross-sectional design and relatively small cohort size; future studies involving larger longitudinal populations are required for validation.
PURPOSE:Boredom is increasingly emerging as a clinically relevant construct in psychiatry, yet it remains insufficiently integrated into contemporary psychopathological models. Rather than reflecting a trivial or purely situational state, boredom may be conceptualized as an aversive condition arising when individuals desire meaningful engagement but are unable to sustain it. This review examines boredom across major psychiatric disorders, with particular attention to its neurophysiological, neurobiological, and clinical correlates. METHODS:A narrative synthesis of conceptual, neurophysiological, neuroimaging, autonomic, and clinical literature on boredom was conducted, considering findings across major psychiatric disorders. FINDING:Available evidence suggests that boredom is associated with alterations in attentional regulation, motivational processing, and internally oriented cognition. EEG studies report increased alpha activity, altered theta dynamics, and reduced indices of cognitive control, whereas functional neuroimaging findings highlight greater involvement of the default mode network and reduced engagement of fronto-parietal control systems. Autonomic data further indicate that boredom is not a uniform low-arousal state, but a dynamic psychophysiological condition characterized by fluctuating patterns of disengagement and re-engagement. Clinically, boredom appears to cut across diagnostic categories, including attention-deficit/hyperactivity disorder, mood and anxiety disorders, psychotic spectrum conditions, addictions, eating disorders, personality disorders, and suicidality. Across these conditions, it may function both as a vulnerability factor and as a mechanism contributing to maladaptive coping, impaired functioning, and poorer treatment adherence. CONCLUSION:Overall, the literature supports the view that boredom may represent a dimensional and transdiagnostic construct of potential relevance for psychiatric research and practice. A more systematic assessment of boredom may improve psychopathological characterization and help identify novel therapeutic targets.
OBJECTIVE:Protein O-fucosyltransferase 1 (POFUT1) has been implicated in several malignancies, but its functional and prognostic significance in glioma remains insufficiently defined. This study evaluated whether POFUT1 expression is associated with glioma progression, patient outcome, and PI3K/AKT pathway activity. METHODS:Public glioma transcriptome datasets from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) were analyzed and compared with clinical samples collected from 123 glioma patients. POFUT1 protein levels in clinical specimens were determined by immunohistochemical staining, and its association with patient outcome was analyzed using survival curves. In vitro, glioma cell growth, motility, and invasiveness were examined using MTT and Transwell assays. The effect of POFUT1 on tumor formation was further tested in a subcutaneous xenograft model. RNA sequencing, KEGG pathway enrichment, and pharmacological inhibition were then used to explore the mechanism linking POFUT1 to PI3K/AKT signaling. RESULTS:POFUT1 expression was higher in glioma than in normal brain tissue and increased with tumor grade. Patients with high POFUT1 levels had shorter overall survival, and multivariate Cox analyses supported POFUT1 as an independent prognostic indicator. Incorporating POFUT1 into a nomogram improved prediction of 1-, 3-, and 5-year survival. Functionally, POFUT1 knockdown reduced glioma cell growth, motility, invasion, and xenograft expansion, whereas POFUT1 overexpression produced the opposite phenotype. Transcriptomic and protein analyses indicated that POFUT1 enhanced PI3K/AKT signaling. The PI3K inhibitor LY294002 weakened the tumor-promoting effects caused by POFUT1 overexpression. CONCLUSION:POFUT1 as a key driver of glioma malignancy, predominantly through activating the PI3K-AKT signaling pathway. These findings highlight POFUT1 as a promising novel therapeutic target for aggressive glioma.
OBJECTIVES:To explore the association of stellate ganglion block with platelet-rich plasma plus lidocaine with clinical outcomes in adults with chronic migraine, in comparison to lidocaine alone. METHODS:This multicenter prospective exploratory study enrolled 200 adults with chronic migraine scheduled for stellate ganglion block across three hospitals from October 2024 to September 2025. Treatment allocation was based on patient preference within a prespecified quota design, with 100 patients per group receiving either platelet-rich plasma plus lidocaine or lidocaine alone. Propensity score matching was performed to balance confounders. The primary outcome was the mean change from baseline in monthly headache days at 1 month post-intervention. Secondary outcomes included headache frequency, pain intensity, headache duration, response rate, analgesic consumption, functional status, and safety. RESULTS:After propensity score matching, 66 patients per group were analyzed. At one month, the platelet-rich plasma plus lidocaine group showed a significantly greater reduction in monthly headache days compared with lidocaine alone (mean difference, 1.84 days; 95% confidence interval [CI], 0.68-2.99; p = 0.002). This advantage persisted at two and three months. The combination group also demonstrated superior improvements in pain intensity, headache duration, response rate, and analgesic reduction at all time points, along with better functional status at 1 and 2 months (all nominal P < 0.05). Baseline disability was a negative predictor of one-month response. No significant differences in safety outcomes were observed. CONCLUSION:In this exploratory study, stellate ganglion block with platelet-rich plasma plus lidocaine was associated with clinically meaningful improvements in headache outcomes and functional status compared with lidocaine alone in patients with chronic migraine, with a favorable safety profile. These findings warrant validation in a definitive randomized trial.
BACKGROUND:Religious and spiritual practices are among the most ancient and universal human behaviors, yet their neurobiological substrates remain incompletely characterized. Neurotheology-the scientific study of the relationship between spiritual experience and brain function-has produced growing evidence that such practices generate measurable, systematic, and neuroplastic changes in brain structure and function. However, prior reviews have been limited to single practice types, narrow evidence bases, or narrative methods, with none synthesizing the full spectrum of traditions, practices, and neuroimaging modalities in a single review. METHODS:Adhering to the PRISMA 2020 guidelines and registered on the Open Science Framework, Scopus, PubMed/MEDLINE, and ProQuest (23 sub-databases) were searched from inception to June 30, 2026. Eligible studies comprised those using objective neuroimaging or neurophysiological techniques. After multi-stage screening, 105 studies (1998-2026) were synthesized narratively using the synthesis without meta-analysis (SWiM) framework, given substantial heterogeneity. RESULTS:Studies spanned Buddhist, Christian, Islamic, Hindu, Santo Daime, Spiritist, Sant Mat, and mixed traditions, examining meditation, prayer, chanting, recitation, worship, retreat, mystical experience, mediumistic trance, and ritual altered states. Consistent engagement appeared across the prefrontal cortex, anterior cingulate, default mode network (DMN), insula, amygdala, hippocampus, temporoparietal junction, and dopaminergic/serotonergic systems. Practice-specific signatures emerged: meditation (DMN suppression, prefrontal augmentation), prayer (social-cognition networks), chanting/recitation (limbic deactivation, gamma/delta enhancement), and mystical states (most distributed profiles). Long-term practitioners showed structural neuroplasticity, and clinical-population studies linked these circuits to depression, anxiety, and stress. CONCLUSIONS:Religious and spiritual practices produce consistent, practice-specific, and neuroplastic modifications to brain systems governing attention, emotion regulation, self-referential processing, and reward-supporting a plausible mechanistic link between spiritual engagement and mental health, and positioning neurotheology as an empirically grounded dialogue between contemplative tradition and clinical neuroscience.
AIM:As the cornerstone of cognition, emotion, and social well-being, brain health faces escalating threats from aging, neurodegenerative diseases, and sedentary lifestyles. Non-pharmacological interventions have attracted growing interest owing to their favorable safety profiles and potential for widespread implementation. This review aims to examine the individual and synergistic effects of music and exercise on brain health. METHODS:This narrative review integrates literature identified through searches of PubMed and Web of Science using terms related to music, exercise or physical activity, and brain health and offers a concept-driven synthesis of the underlying neurobiological mechanisms and potential combined effects. FINDINGS:Music modulates neurotransmitters and neural oscillations via reward and emotion networks, while exercise enhances neuroplasticity by improving energy metabolism, neurotrophic signaling, and cerebrovascular function. Their potential synergistic interaction may arise from music's capacity to temporally structure and modulate the neurochemical and metabolic states induced by exercise. Combined interventions may further enhance synaptic plasticity and network integration by mitigating neuroinflammation and oxidative stress. They may offer additional benefits for cognition, mood, and motor control beyond either intervention alone. Dance, a prototypical integration of music and movement, activates multisensory and social networks and has shown potential benefits in Alzheimer's disease, Parkinson's disease, depression, and autism. CONCLUSION:Music and exercise may engage convergent and potentially interacting mechanisms, including neuroplasticity, metabolic regulation, and neuroinflammatory modulation, forming an integrated framework for brain health. Dance exemplifies this music-movement integration by engaging multisensory and socio-emotional networks, highlighting its translational potential for promoting brain function.
OBJECTIVE:This review systematically elaborates multi-system interactive mechanisms underlying comorbid chronic low back pain (CLBP) and major depressive disorder (MDD), synthesizes recent advances in diagnosis, treatment, and management, and proposes precision medicine directions to address clinical challenges, including missed diagnosis, treatment resistance, and poor prognosis. METHOD:We reviewed 86 studies published between 2015 and 2025 from the PubMed, Embase, and CNKI databases. We focused on basic research and clinical trials, integrating multi-omics data to construct mechanistic frameworks and therapeutic evidence. RESULT:The comorbid pathogenesis of CLBP and MDD is driven by dysregulation of the "neural-immune-endocrine-gut-brain axis" network. Spinal dorsal horn N-methyl-D-aspartate (NMDA) receptor NR2B phosphorylation amplifies pain signals 2- to 3-fold, while anterior cingulate cortex (ACC)-insula connectivity correlates positively with depression severity. Microglial toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) activation increases cerebrospinal fluid interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) by 3.2- and 2.7-fold, respectively. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction causes a flattened cortisol rhythm, with glucocorticoid receptor gene (NR3C1) hypermethylation reducing glucocorticoid sensitivity by 45%. Gut dysbiosis decreases short-chain fatty acids (SCFAs) by 30% and increases plasma lipopolysaccharide (LPS) by 2.3-fold, accompanied by abnormal proliferation of pro-inflammatory E. coli and Desulfovibrio as well as depletion of anti-inflammatory Prevotella. Duloxetine reduces visual analog scale (VAS) pain scores by 40% and Hamilton Depression Rating Scale (HAM-D) scores by 35% relative to placebo. Closed-loop spinal cord stimulation (SCS) improves treatment response rates to 68% compared with open-loop stimulation. Electroacupuncture at BL23/LR3 alleviates clinical symptoms in 75% of patients relative to sham acupuncture. At the 12-month follow-up, duloxetine's pain relief efficacy slightly declined from 40% to 38%, a phenomenon speculated to be linked to serotonin transporter upregulation. At the 1-year follow-up, closed-loop SCS efficacy decreases to 55%, which may be associated with secondary neural circuit re-remodeling. At the 6-month follow-up, electroacupuncture treatment carries a 22% symptom recurrence rate, which researchers hypothesize arises from secondary gut microbiota re-dysbiosis featuring reduced Prevotella abundance. CONCLUSION:Pathological progression of concurrent CLBP and MDD relies on multi-level remodeling of molecular, cellular, and systemic biological networks. Precision interventions targeting neural circuits, neuroinflammation, and the gut-brain axis, combined with multidisciplinary clinical collaboration, represent core strategies to break through current diagnostic and therapeutic bottlenecks.
PURPOSE:Overtraining Syndrome (OTS) is a chronic maladaptive condition characterized by persistent performance decline due to excessive training and inadequate recovery. OTS is associated with mood disturbances, but the underlying neurobiological mechanisms remain unclear. This study investigated whether a 6-week overtraining (OT) protocol induces anxiety-like behavior and changes in hippocampal BBB-related tight junction proteins in mice. METHODS:Eight-week-old male C57BL/6J mice were assigned to sedentary (SED, n = 5), moderate exercise (ME, n = 5), or overtraining (OT; downhill treadmill running, initially n = 10) groups and completed a 6-week training protocol. The final OT sample size was n = 4 after 6 of the 10 mice were excluded due to tail or hindlimb injuries. Endurance capacity was assessed using an incremental loading test (ILT). Anxiety-like behaviors were evaluated using the nest building test (NBT), open-field test (OFT), and elevated plus maze (EPM). Hippocampal tight junction (TJ) proteins zonula occludens-1 (ZO-1), occludin, claudin-5, as well as tumor necrosis factor-alpha (TNF-α) were quantified by Western blot analysis. RESULTS:After 6 weeks, endurance performance in the OT group significantly decreased from baseline (p < 0.01) and was lower than that of the ME group at Week 6 (p < 0.0001). In the quadriceps, TNF-α protein levels were significantly elevated in the OT group compared with both the SED (p < 0.05) and ME groups (p < 0.01). In the OFT, OT mice exhibited fewer center entries and reduced time spent in the center zone versus the SED and ME groups (p < 0.05), indicating increased anxiety related behavioral change. In the hippocampus, zonula occludens-1 (ZO-1) levels were reduced and TNF-α levels were elevated in OT compared with SED (p < 0.01 and p < 0.05, respectively), whereas claudin-5 levels were higher in ME than SED (p < 0.05). CONCLUSION:OT was associated with anxiety-like behavioral alterations and changes in hippocampal BBB-related tight junction proteins. Reduced expression of TJ proteins and increased neuroinflammation may contribute to affective symptoms observed in OTS. However, given the small final sample size in the OT group, these findings should be interpreted with caution.
INTRODUCTION:Non-central nervous system (non-CNS) cancer patients experienced cognitive impairment, both subjectively and objectively. However, they are only weakly correlated. Previous studies indicated that subjective cognitive complaints (SCCs) could be a distinct neural phenotype from objective neuropsychological function. To explore what underlies SCCs, we examined the relationship between SCCs and objective neuropsychological assessment in this systematic review. METHODS:Following the PRISMA guidelines, we searched multiple databases from September 2000 to November 2024 for cross-sectional studies that directly investigated SCCs and neuropsychological assessment, excluding those involving neurological conditions. Sixteen of the 202 articles met the criteria; the total sample included 2093. We used multilevel meta-analysis in R to analyze 156 correlation coefficients and estimated the sampling error variance, within-study variance, and between-study variance from the analysis. RESULTS:The correlations between SCCs and objective neuropsychological examinations were low but significant. When using cognitive domains, female ratio, and age disparity as variables, 57.18% of the variance was attributed to within-study variance. As the female ratio increased, correlations between SCCs and executive function were inconsistent but consistent with attention and memory. When considering the relationship with age disparity, the trend would be corrected. CONCLUSIONS:Different cognitive domains may show distinct trends, suggesting that neuropsychological functions can be predicted by SCCs when controlling for specific conditions. Potential mechanisms include hormonal influences, age-related biological and psychosocial changes, and differences in emotional vulnerability across the lifespan. The present study highlights the importance of carefully evaluating subjective cognitive complaints within evidence-based decision-making processes.
BACKGROUND:The aim of this study is to investigate the effects of hypobaric hypoxia (simulated altitude of 3600 m) on regional cerebral blood flow (CBF) and cognitive function, and to explore the regulatory role of transcutaneous vagus nerve stimulation (tVNS). METHODS:Forty-three healthy Han Chinese males (18-45 years) were enrolled at the Chinese PLA General Hospital (June 2024-December 2025). During 24-h hypobaric hypoxia exposure via a specialized hypobaric chamber, participants were randomly assigned to tVNS (n = 23) or non-tVNS (n = 20) groups. A non-exposure cohort (n = 18) was included to correct for cognitive learning effects. Arterial spin labeling quantified CBF in the anterior, middle, and posterior cerebral artery territories and hippocampus at baseline, exposure, and post-exposure; the Repeatable Battery for the Assessment of Neuropsychological Status assessed cognitive function at the same time points. RESULTS:Hypoxia-induced compensatory CBF increases across all examined regions in the control group (p < 0.05). In the tVNS group, CBF modulation was region-specific: frontotemporal CBF was higher at exposure than post-exposure and higher at post-exposure than baseline; occipital and hippocampal CBF were higher at exposure than at both other time points, with no difference between post-exposure and baseline. Only temporal lobe CBF was significantly higher in the tVNS group than the control group (76.22 ± 7.49 vs. 70.88 ± 8.93, p = 0.039). Hypoxia impaired visuospatial ability, language, and attention and delayed memory (all p < 0.05), but tVNS did not ameliorate these deficits. CONCLUSIONS:Simulated 3600 m hypobaric hypoxia induces compensatory regional CBF elevations. tVNS selectively increases temporal lobe perfusion but does not ameliorate cognitive impairment, warranting optimized studies to clarify its neuroprotective role.
PURPOSE:Cognitive impairment is a growing global health concern associated with aging, neurodegenerative diseases, stroke, and traumatic brain injury. Existing pharmacological treatments, including cholinesterase inhibitors and memantine, provide limited and variable benefits. This review aims to evaluate the mechanistic basis, clinical efficacy, and safety profile of oxiracetam as a potential therapeutic agent for cognitive dysfunction across a range of neurological disorders. METHODS:A narrative review was conducted by synthesizing available preclinical and clinical literature on oxiracetam. Mechanistic studies evaluating its pharmacodynamics, including effects on cholinergic and glutamatergic pathways, synaptic plasticity, neuroinflammation, and oxidative stress, were analyzed. Clinical evidence from trials involving patients with traumatic brain injury, stroke, vascular cognitive impairment, and dementia was reviewed. FINDINGS:Oxiracetam demonstrates multimodal mechanisms of action, including enhancement of cholinergic neurotransmission, modulation of AMPA receptors, and promotion of synaptic plasticity and long-term potentiation. Additionally, it exhibits antioxidant and anti-inflammatory effects contributing to neuroprotection. Clinical studies suggest potential cognitive benefits in several neurological conditions; however, results are heterogeneous, with some trials showing significant improvement and others demonstrating no superiority over placebo. CONCLUSION:Oxiracetam is a promising neurocognitive modulator with a favorable safety profile and potential therapeutic applications across multiple neurological disorders. Nevertheless, current evidence is limited by methodological constraints and inconsistent outcomes. Further large-scale, multicenter clinical trials are required to establish its definitive efficacy and clinical utility.
BACKGROUND:Previous studies suggested links between obesity, glucose regulation, and autoimmune diseases, but the associations of weight and glucose levels with myasthenia gravis (MG) remain uncertain. We examined these associations and a potential indirect pathway through glucose levels. OBJECTIVE:We investigated the associations of weight and glucose levels with MG risk using Mendelian randomization (MR) and a retrospective case-control study. METHODS:We conducted two-sample MR analyses using genome-wide association study summary statistics from European populations. The clinical component retrospectively included patients with MG and healthy controls and used propensity-score matching and logistic regression. RESULTS:The MR analyses suggested associations among genetically predicted weight, glucose levels, and MG risk. They also yielded a small indirect estimate through glucose levels that was opposite in direction to the direct and total effects. This opposing-direction indirect estimate was sensitive to the inferential method and was not observed in the retrospective case-control analysis. In the clinical analysis, MG cases had higher weight and lower glucose levels than controls, and both variables were associated with MG status. CONCLUSION:Two-sample MR suggested that genetically predicted higher weight was associated with higher odds of MG, whereas genetically predicted higher glucose levels were associated with lower odds of MG. The retrospective case-control analysis showed directionally similar associations for measured weight and fasting glucose, but the indirect pathway suggested by MR was not observed in the clinical analysis.
