ABSTRACT Background Childhood trauma (CT) is a recognized risk factor for adverse psychiatric and physical health outcomes in individuals with bipolar disorder (BD). However, few prospective studies have examined how CT relates to the longitudinal course of metabolic dysregulation in BD. This study aimed to describe the association between CT exposure and the progression of metabolic disturbances over 36 months in adults with BD. Methods In this prospective cohort study, 305 adults diagnosed with BD (Types I and II) were followed across 13 visits over 36 months. Participants were stratified according to CT exposure using the Childhood Trauma Questionnaire—Short Form (CTQ—SF). Metabolic outcomes (HbA1c, BMI, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and hs‐CRP) were analyzed with inverse probability of treatment weighting (IPTW) and linear mixed‐effects models incorporating a group‐by‐time interaction. Results Of the 305 participants enrolled, 53 (17.4%) were lost to follow‐up. Longitudinal analyses showed significant CT‐by‐time interactions for all metabolic markers (p < 0.001). At 36 months, participants exposed to CT showed greater increases than non‐exposed participants in HbA1c (adjusted least‐squares mean difference 1.11%, 95% CI 0.89–1.33), BMI (4.46 kg/m2, 95% CI 3.90–5.03), and hs‐CRP (2.68 mg/L, 95% CI 2.52–2.84), together with unfavorable changes in the lipid profile. Effect sizes were large (Cohen's d > 0.8). These associations persisted after IPTW weighting for measured baseline covariates. Conclusions In this observational cohort, CT exposure was associated with an accelerated trajectory of metabolic deterioration in individuals with BD after weighting for measured baseline characteristics. Because the design is observational and several behavioral, socioeconomic, and illness‐course determinants of metabolic risk were not measured, these findings should be interpreted as associations rather than as causal effects. They nonetheless support the value of early trauma‐informed assessment and of integrated care strategies addressing both psychiatric and physical health in BD. Future research should incorporate detailed lifestyle and treatment‐exposure data, additional inflammatory biomarkers, and preventive interventions to mitigate long‐term cardiometabolic risk in this vulnerable population.
ABSTRACT Introduction Patients with recent noncardioembolic ischemic stroke or high‐risk transient ischemic attack (TIA) remain at risk of recurrent events despite antiplatelet therapy. Oral factor XIa (FXIa) inhibitors may reduce thrombotic risk while limiting bleeding, but their adjunctive efficacy and safety require clarification. Methods PubMed, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov were searched through May 2026 for randomized, double‐blind, placebo‐controlled trials of oral FXIa inhibitors added to antiplatelet therapy. Primary efficacy and safety outcomes were recurrent ischemic stroke and major bleeding. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random‐effects models. Results Three trials randomized 16,501 participants overall, of whom 14,239 contributed to the primary selected‐dose efficacy analysis. FXIa inhibition reduced recurrent ischemic stroke (413/6927 vs. 579/7312; RR 0.74, 95% CI 0.65–0.84; I2 = 0%; p < 0.00001). No statistically significant differences were observed in major bleeding (RR 1.12, 95% CI 0.87–1.44), major or clinically relevant non‐major bleeding (RR 1.40, 95% CI 0.91–2.15), clinically relevant non‐major bleeding (RR 1.49, 95% CI 0.85–2.60), minor or non‐actionable bleeding (RR 0.94, 95% CI 0.84–1.05), intracranial or intracerebral hemorrhage (RR 1.16, 95% CI 0.75–1.79), or fatal bleeding (RR 1.75, 95% CI 0.74–4.17); however, confidence intervals for several bleeding outcomes were wide and did not exclude clinically important harm. Findings remained consistent in the all‐dose sensitivity analysis (RR 0.77, 95% CI 0.68–0.86; I2 = 0%). Conclusions In patients with recent noncardioembolic ischemic stroke or high‐risk TIA receiving antiplatelet therapy, pooled randomized evidence showed a reduction in recurrent ischemic stroke with oral FXIa inhibition; however, the estimate was predominantly driven by the phase 3 asundexian trial, limiting certainty regarding generalization across individual FXIa inhibitors. Major bleeding and other safety outcomes were not significantly increased, although rare‐event estimates were imprecise and clinically important harm cannot be excluded.
ABSTRACT Introduction Resting‐state EEG aperiodic parameters characterize the broadband background component of neural activity. The offset reflects overall broadband power and has been linked to population‐level firing, whereas the exponent is often interpreted, within a theoretical framework, as an indirect proxy for cortical excitation/inhibition (E/I) balance. These measures may therefore provide candidate neurophysiological trait markers of negative affective vulnerability, but it remains unclear whether their associations with trait anxiety and trait depression are direct or are statistically accounted for by stable personality traits. Methods A total of 164 healthy adults completed measures of the Big Five personality traits, trait anxiety, and trait depression and underwent eyes‐closed resting‐state EEG recording. Aperiodic exponent and offset were estimated at the whole‐brain and regional levels using spectral parameterization. Partial correlations, hierarchical regression analyses, and bootstrap mediation analyses were conducted controlling for sex, age, and years of education. Results Neuroticism showed the strongest and most spatially widespread positive associations with the aperiodic exponent. Trait anxiety showed more limited associations, mainly with whole‐brain and frontal aperiodic parameters. The association between whole‐brain exponent and trait anxiety was no longer significant after the Big Five personality traits were entered into the model. Bootstrap mediation analyses identified significant indirect effects in this association through personality traits, with neuroticism showing the largest indirect effect and conscientiousness also showing a significant indirect effect. Trait depression was not directly associated with aperiodic parameters, although significant indirect effects through personality traits were observed. Conclusions Resting‐state EEG aperiodic activity, particularly the exponent, was more consistently associated with stable personality dispositions than with negative affective vulnerability directly. Personality traits, especially neuroticism, may statistically account for part of the association between aperiodic exponent and trait anxiety. Because the data were cross‐sectional, the temporal and causal direction of these associations cannot be determined.
ABSTRACT Background Cognitive impairment is a common and disabling manifestation of multiple sclerosis (MS), yet its structural correlates remain incompletely understood in routine clinical practice. Although advanced neuroimaging has improved our understanding of the underlying mechanisms, its limited accessibility restricts widespread clinical implementation. We aimed to investigate whether conventional MRI markers are associated with domain‐specific cognitive impairment in patients with MS. Methods In this exploratory cross‐sectional study, 25 adults with clinically confirmed multiple sclerosis underwent cognitive assessment using the standard Persian Montreal Cognitive Assessment (MoCA), version 7.1, and conventional 1.5‐T brain MRI. Conventional MRI measures included lesion burden, lesion topography, and visually rated cortical atrophy. Associations between MRI markers and MoCA‐derived cognitive domains were assessed using Spearman rank correlation with false discovery rate adjustment for multiple testing. Findings Twenty‐five patients with clinically confirmed MS completed cognitive and MRI assessments. Mean age was 42.4 ± 9.1 years, 56% were women, and the mean MoCA score was 22 ± 7. Periventricular (88%) and juxtacortical/cortical (84%) lesions were the most frequent MRI findings, total T2/FLAIR lesion burden showed only weak correlations with cognitive performance (ρ range −0.02 to 0.29; all FDR‐adjusted p > 0.65). The largest lesion‐based association was observed between infratentorial lesions and concentration (ρ = −0.48, unadjusted p = 0.018; FDR‐adjusted p = 0.405). Among atrophy measures, GCA showed the strongest association with visuospatial performance (ρ = 0.51, unadjusted p = 0.012; FDR‐adjusted p = 0.405), with additional moderate trends for concentration (ρ = 0.40, p = 0.052) and executive function (ρ = 0.40, p = 0.052). No MRI marker remained statistically significant after correction for multiple comparisons. Interpretation Although no MRI–cognitive association remained statistically significant after correction for multiple comparisons, several unadjusted associations showed moderate effect sizes and may warrant further investigation. The strongest exploratory associations involved infratentorial lesions and concentration (ρ = −0.48) and global cortical atrophy and visuospatial performance (ρ = 0.51). The absence of consistent relationships between overall lesion burden or individual regional MRI markers and cognitive performance suggests that focal structural measures alone may not fully capture the neural substrates of cognitive dysfunction in MS. This pattern provides a rationale for further investigation of distributed, network‐level mechanisms of cognitive dysfunction, while the present findings should be considered hypothesis‐generating rather than confirmatory. Conventional MRI may therefore provide complementary structural information in the clinical assessment of cognitive dysfunction in MS. Larger, adequately powered studies using comprehensive neuropsychological assessment and quantitative, network‐sensitive MRI measures are needed to determine whether these observed patterns are reproducible and clinically meaningful.
ABSTRACT Background Depression and dyspepsia are highly comorbid in clinical practice, and their occurrence and progression are closely associated with dysfunction of the brain–gut axis. Electroacupuncture (EA) can improve depression and gastrointestinal dysfunction at the same time. However, whether its therapeutic effects are mediated through regulation of the brain–gut axis remains unclear. Methods We established a rat model of comorbid depression‐like and dyspepsia‐like symptoms using SD rats. Behavioral tests were used to evaluate anxiety‐ and depression‐like states in rats. Gastric emptying rate, small intestinal propulsion rate, and gastrointestinal hormones were measured to assess gastrointestinal motility. Histomorphological changes in the hippocampus, stomach, and duodenum were observed by hematoxylin–eosin (HE) staining and Nissl staining. Immunofluorescence (IF), Western blotting, quantitative real‐time polymerase chain reaction (RT‐qPCR), and biochemical assays were used to determine the activation status of hippocampal microglia and mitochondrial reactive oxygen species (mtROS)/NOD‐like receptor family pyrin domain containing 3 (mtROS/NLRP3) pathway‐related indicators. Enzyme‐linked immunosorbent assay was used to determine central and peripheral levels of 5‐hydroxytryptamine (5‐HT) and inflammatory factors. Gut microbiota diversity and composition were analyzed by 16S rRNA sequencing. The expression of duodenal mucosal barrier‐related proteins was detected by immunofluorescence, and the ultrastructure of the duodenum was observed by transmission electron microscopy. Results EA significantly alleviated anxiety‐ and depression‐like behaviors and improved gastrointestinal motility in model rats. EA ameliorated hippocampal neuronal injury, increased Nissl body number, reduced mtROS and malondialdehyde levels, enhanced mitochondrial membrane potential and superoxide dismutase activity, and suppressed microglial activation and NLRP3 inflammasome signaling. In addition, EA increased central and peripheral 5‐HT levels while decreasing Interleukin‐6 (IL‐6) and tumor necrosis factor‐α expression. EA also modulated gut microbiota composition by reducing opportunistic pathogens and enriching beneficial bacteria. Moreover, EA improved duodenal ultrastructure and upregulated the tight junction proteins ZO‐1 and Occludin. Conclusion EA can improve depression‐like behaviors and dyspepsia‐like symptoms in comorbid rats. These behavioral and gastrointestinal improvements were accompanied by reduced hippocampal oxidative stress and neuroinflammation, altered gut microbiota composition, and improved duodenal mucosal barrier. These findings suggest that the therapeutic mechanism of EA may involve regulation of the brain–gut axis, although the specific causal relationships among its individual components remain to be elucidated.
