Brain, Behavior, and Immunity

BackgroundMajor depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune-metabolic processes. AimsTo identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune-metabolic biomarkers of MDD. MethodsShotgun metagenomics with taxonomic profiling was performed in MDD versus controls us...

BackgroundMajor depressive disorder (MDD) is a neuro-immune-metabolic-oxidative (NIMETOX) disorder. Nevertheless, the effects of alterations in immune responsiveness, oxidative stress, antioxidant defenses, gut-derived short-chain fatty acids (SCFAs), metabolic hormones and adipokines on metabolomic modules and the MDD phenome have remained elusive. MethodsSerum samples from 125 MDD inpatients and 40 healthy controls were analyzed using high-resolution metabolomics assays (liquid chromatography...

BackgroundMajor depressive disorder (MDD) severely impairs individual health and creates heavy societal burdens. Diagnostic and therapeutic research remains hindered by MDDs marked heterogeneity and the absence of valid biomarkers. As a neuro-immune, metabolic, and oxidative stress (NIMETOX) disorder, MDD exhibits metabolomic signatures as a final common pathway in the Chinese population. ObjectivesTo identify lipidomic profile differences between MDD patients and healthy controls and examine a...

BackgroundMajor depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. ObjectivesTo identify metabolic abnormalities that differentiate inpatients with severe MDD from healthy controls through h...

Major depressive disorder (MDD) involves dysregulated neuroimmune, metabolic, and oxidative stress (NIMETOX) pathways. Recently, it was shown that NIMETOX pathways should be evaluated in MDD patients stratified for metabolic syndrome (MetS). The current study aims to characterize the metabolic hormone and adipokine profiles of Chinese MDD patients stratified for MetS and to delineate their associations with overall severity of depression (OSOD), suicidal ideation (SI), recurrence of illness (ROI...

ObjectiveTo identify immunomodulatory drug targets with genetic evidence in major depressive disorder (MDD), probe symptom-level heterogeneity in their effects, and identify drug repurposing opportunities. MethodsWe used cis-Mendelian randomisation to evaluate the targets of 204 immunomodulatory compounds, including immunosuppressants, cytokine inhibitors, and anti-infectives. As exposures, we selected genetic instruments from nine genome-wide association studies (GWASs) of protein or gene tran...

BackgroundAdverse life events and psychosocial stressors contribute to a range of neuropsychiatric disorders. However, the role of inflammatory dynamics around stress exposure remains unclear. Using TriNetX, a large international electronic health records database, we examined how systemic inflammatory activity and its temporal dynamics relate to subsequent risk of mental illness and somatic symptoms. MethodsWe compared 36,772 individuals with records of adverse life events and leukocytosis in ...

BackgroundPsycho-affective symptoms and repetitive negative thinking (RNT) may increase Alzheimers disease (AD) risk. As sleep plays a key role in emotional regulation, we investigated both cross-sectional and longitudinal associations between sleep disturbances and psycho-affective health, according to amyloid-beta (A{beta}) status. MethodsOne hundred and thirty-four cognitively unimpaired older adults from the Age-Well interventional study (mean age = 68.8 {+/-} 3.8 years; 82 women; 37 A{beta...

BackgroundAntenatal depressive symptoms (ADS) are common and underdiagnosed, particularly in low- and middle-income countries, and are associated with adverse maternal and offspring outcomes. Current screening relies on subjective symptom reporting, limiting early identification and prevention. Epigenetic modifications, particularly DNA methylation, offer a promising avenue for objective, early biomarkers of depression risk during pregnancy. MethodsIn this nested case-control design within the ...

The plasma metabolome represents a valuable molecular readout of a persons physiological state, yet its relation to health, stress and lifestyle remains underexplored collectively. Here, we conducted an untargeted metabolomics analysis using 3804 paired samples from 1902 participants of the Netherlands Study of Depression and Anxiety at baseline and 6-year follow-up, quantifying 680 plasma metabolites. We characterised five metabolome profiles using principal component analysis, three with disti...

BackgroundMild behavioural impairment (MBI), characterized by later-life emergence of persistent neuropsychiatric symptoms (NPS), is an early clinical indicator of dementia risk. MBI as a global construct has been associated with Alzheimer disease (AD) pathology; studies have also explored MBI domains. Prior work has linked MBI-apathy to cerebrospinal fluid (CSF) biomarkers of AD, but whether similar associations are detectable using plasma-based biomarkers such as phosphorylated tau (p-tau) is ...

BackgroundMajor depressive disorder (MDD) involves immune-metabolic dysregulation, psychosocial adversity, and multidomain cognitive disturbances, yet single cognitive indices often show small and inconsistent effects. We derived a multivariate Cambridge Neuropsychological Test Automated Battery (CANTAB)-based cognitive phenotype ("cognitype") and tested whether it adds explanatory value beyond adverse childhood experiences (ACEs) and an acute-phase protein (APP) index in acute-phase MDD. Metho...

ObjectiveSubthreshold depression (StD) in adolescence is a potent risk factor for major depressive disorder, yet its neurobiological mechanisms remain unclear. The glymphatic system, a brain-wide waste clearance pathway, has been implicated in psychiatric disorders but has not been investigated integratively in StD. This study aimed to characterize glymphatic function in adolescents with StD using a multimodal neuroimaging approach. MethodsA total of 107 adolescents (71 with StD and 36 healthy ...

BackgroundEarly detection of individuals at risk for clinical deterioration in first-episode psychosis (FEP) remains a vital challenge in psychiatric care. Emerging evidence indicates that immune dysregulation might play a crucial role in the pathophysiology and progression of psychotic disorders. AimsThis study examined the predictive potential of a plasma cytokine and chemokine panel in anticipating clinical stage transition of FEP patients. MethodUsing multiplex immunoassays, plasma samples...

Neuroimaging has revealed that major depression is underpinned by dysfunctional brain networks, with symptom variability stemming from altered interactions within and between brain regions. While the effect of depression severity is well-studied, the effect of depression duration (chronicity) is relatively neglected, despite its clinical significance. This study examined how severity, chronicity, and their interaction affect brain network connectivity and grey matter volume. Forty-six patients (...

BackgroundLight plays a critical role in mental health, as the primary input to the circadian system, which regulates mood, energy, and the sleep-wake cycle. Altered light sensitivity is a potential mechanism in circadian-associated mental disorders. MethodsActigraphy-derived sleep, physical activity, and circadian rhythm correlates of the pupillary light reflex were explored in young people with emerging mental disorders. Participants were 27 healthy controls (Mean age=25.67 {+/-} 2.83, 52% fe...

ImportanceTraumatic brain injury (TBI) increases the risk of developing psychiatric symptoms such as post-traumatic stress disorder (PTSD), depression and anxiety, however biological risk and resiliency factors that explain the significant heterogeneity in outcomes are limited. Although 5-10% of the population carries natural autoantibodies to the NMDA receptor (anti-NMDAR1) it is unknown if carrying anti-NMDAR1 autoantibodies modifies risk for psychiatric outcomes after TBI. ObjectiveSince TBI...

IntroductionLactate plays dual roles in neuronal energy metabolism and signalling. The dorsal anterior cingulate cortex (dACC), a region with high baseline glycolytic activity implicated in psychiatric disorders, may exhibit dynamic lactate responses to graded cognitive-emotional demands. Because mitochondrial function declines with age, aging may model whether fMRS-derived lactate dynamics can detect latent neurometabolic vulnerabilities. MethodsUsing fMRS, we monitored dACC metabolite changes...

ObjectiveDigital cognitive behavioral therapy for insomnia (CBT-I) is an effective and scalable treatment for chronic insomnia. However, treatment outcomes are typically evaluated using aggregated symptom scores, which obscure differential effects on individual symptoms and limit insights into underlying mechanisms. This study applied network intervention analysis (NIA) to investigate how somnovia, a self-guided digital CBT-I intervention, is associated with changes in individual symptoms of ins...

BackgroundBrain perivascular spaces (PVS) are emerging MRI markers of microvascular function and waste metabolite clearance. While PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphology reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. In this study, we investigated whether PVS morphometry captures these familial characteristics, further modulated by i...