Brain, Behavior, and Immunity

Background Observational studies have reported an association between inflammation and postoperative complications but it is unclear whether these associations are causal. It is also unknown whether postoperative outcomes share a causal architecture with chronic, all-cause disease. Methods We performed bi-directional two-sample Mendelian randomization to investigate potential causal effects of 19 genetically-proxied inflammatory markers on postoperative acute kidney injury, atrial fibrillation (AF), delirium, myocardial infarction, stroke and surgical site infection, and their all-cause equivalents. Genetic instruments for inflammatory markers were sourced from nine GWAS of up to 204,402 European participants with outcome data derived from UK Biobank. Results The primary postoperative analysis showed a protective effect of down-regulated IL-6 signalling on stroke risk (OR (95% CI) 0.27 (0.11--0.69), p=0.006). However, in the all-cause analysis a causal effect on stroke was not present (OR (95% CI) 1.14 (0.75--1.24), p=0.78), whilst a robust protective effect was seen for down-regulated IL-6 with AF across all three instruments studied (all p<0.009). In postoperative and all-cause analyses, genome-wide variants for CRP showed a protective effect on delirium that was not present in cis-restricted analyses. Conclusions We found evidence supporting a potential causal role for IL-6 signalling in perioperative stroke. However, the divergence in IL-6 effects between postoperative and all-cause outcomes suggests that the inflammatory architecture of acute postoperative complications may differ from chronic disease states. Furthermore, our findings suggest previously reported associations between CRP and delirium likely represent horizontal pleiotropy rather than direct causation. Future work should interrogate local tissue responses and the immediate perioperative period.

BackgroundSickness behavior comprises a coordinated constellation of motivational, cognitive, and social alterations that emerge during systemic inflammation. Although reductions in locomotion, feeding, and social engagement have been extensively characterized, how inflammation affects ultrasonic vocal communication--an ethologically relevant index of social motivation in rodents--remains insufficiently understood. Here, we investigated how systemic immune activation alters male-female social communication in mice by jointly assessing ultrasonic vocalizations (USVs) and approach behavior. MethodsSexually experienced male mice received an intraperitoneal injection of lipopolysaccharide (LPS), and their interactions with a novel estrous female were evaluated 24 h later by quantifying USVs and approach behavior. ResultsLPS administration robustly suppressed both the total number of USVs and the duration of male approach behavior, indicating a pronounced reduction in social motivation. Beyond this quantitative suppression, LPS also induced qualitative changes in vocal output, including shifts in the proportional use of specific USV subtypes and alterations in acoustic features such as sound pressure. ConclusionsThese findings demonstrate that USVs capture multiple dimensions of inflammation-induced disruption of social communication, reflecting not only diminished motivation to engage socially but also changes in the structure of communicative signals themselves. By revealing that systemic immune activation reshapes both social approach behavior and vocal communication patterns, this study establishes USV analysis as a sensitive and translationally relevant behavioral readout for probing neuroimmune mechanisms underlying the social and communicative disturbances characteristic of sickness behavior. More broadly, our results highlight the utility of vocal communication analyses for elucidating how inflammatory processes perturb social circuits and communicative function in health and disease.

Background. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and irritable bowel syndrome (IBS) frequently co-occur following infection, yet shared genetic architecture at the locus level has not been systematically characterised. Aims. To estimate global and local genetic correlations between ME/CFS (including infection-onset subgroup), IBS, major depressive disorder (MDD) and loneliness/isolation, and characterise ME/CFS cell-type heritability enrichment. Method. GWAS summary statistics: DecodeME (15,579 ME/CFS; 9,738 infection-onset), FinnGen R9 (9,296 IBS), PGC MDD Wave 2 (45,396) and UK Biobank loneliness (N=455,364). LDSC for global correlations; LAVA for local correlations across 2,495 loci; MAGMA for cell-type enrichment (Descartes Human atlas); coloc.abf for colocalisation. Results. All pairwise global correlations were significant after Bonferroni correction, including ME/CFS-all-MDD (rg=0.598, 95% CI 0.46-0.74) and ME/CFS-all-IBS (rg=0.573, 0.39-0.75). Of 4,232 local tests, 16 reached FDR<0.05; two lonelinessxMDD loci were Bonferroni-significant. ME/CFS-MDD showed three FDR-significant local correlations, but all were boundary-estimated and non-Bonferroni-significant. A borderline infection-onset ME/CFS-IBS signal occurred at chr12q24.22 ({rho}=1.000, FDR=0.046), but colocalisation did not support a shared causal variant (PP.H4=0.007). ME/CFS heritability was enriched in inhibitory neurons (P=1.210x-7) and enteric nervous system neurons (FDR=0.004), with no FDR-significant peripheral immune cell-type enrichment in the atlas used. Conclusions. High global ME/CFS-MDD correlation was accompanied by limited, boundary-estimated, non-Bonferroni-robust local sharing; the data do not support reducing ME/CFS to depression at the genetic-architecture level. Neural enrichment, including enteric nervous system neurons, supports involvement of neural components in ME/CFS susceptibility without excluding immune mechanisms. A borderline ME/CFS-IBS signal at a NOS1-containing region generated hypotheses requiring replication.

Background: Psychiatric disorders and neurodegenerative diseases, including bipolar disorder (BD), schizophrenia spectrum disorders (SSD), Parkinson's disease (PD), and Alzheimer's disease (AD), are associated with substantial impairments in functioning and quality of life. Increasing evidence suggests that low-grade systemic inflammation and gut microbiome dysregulation are shared mechanisms across these brain disorders, providing a rationale for transdiagnostic interventions targeting the gut-brain axis. Objective: This study was designed to evaluate the efficacy of an anti-inflammatory dietary pattern (AIDP), termed the BrAIN diet, on global functioning and a comprehensive set of secondary clinical, cognitive, inflammatory, and gut-health outcomes across relevant patient populations. Methods: We designed an open-label, randomized controlled, two-period crossover trial with 12-week intervention periods, a 24-week washout period and 12-week follow-up. We aimed to enrol 100 adult outpatients (25 per diagnosis: BD, SSD, PD, and AD) aged 18-80 years, recruited through outpatient clinics and patient organisations in the northern Netherlands. Participants were randomized 1:3 to either start the BrAIN diet immediately (Group 1, BrAIN/diet-as-usual [DaU] sequence) or after 36-weeks (Group 2, DaU/BrAIN sequence). The BrAIN diet is based on Shivappa's Dietary Inflammatory Index, components of the MIND diet, and Dutch dietary guidelines, and is delivered through weekly home-delivered food boxes, recipes, and weekly dietitian counselling. The primary outcome is global functioning measured with the Outcome Questionnaire-45 (OQ-45). The treatment effect is estimated from the timepoint x treatment interaction in a linear mixed-effects model that uses all observed timepoints, with participant as a random intercept and period and sequence as fixed effects. Secondary outcomes include Global Assessment of Functioning (GAF), cognition (Brief Assessment of Cognition, Stroop, Trail Making), quality of life (EQ-5D), fatigue (FSS), gastrointestinal symptoms (GSRS), gut-permeability biomarkers, faecal microbiome composition, inflammatory and metabolic markers, and disease-specific symptom scales. Assessments occur at weeks 0 (V1, baseline period 1), 12 (V2, end of period 1), 24 (V3, mid-washout), 36 (V4, baseline period 2), 48 (V5, end of period 2), and 60 (V6, follow-up). The trial protocol was developed in 2021 and approved by the accredited Medical Research Ethics Committee on 11 January 2022. The trial is reported in accordance with the SPIRIT 2013 guideline in effect at the time of protocol development. Results: The trial received favourable ethical opinion from Medical Research Ethics Committee BeBo Assen (NL78755.056.21) on 11 January 2022 and was registered prospectively at OMON (NL-OMON52339). Recruitment commenced in February 2022; the first participant was enrolled on 7 March 2022 and the last on 6 May 2024. Follow-up was completed on 5 September 2025. A total of 107 participants were enrolled. Data analysis is ongoing; primary results are expected to be submitted for publication in summer 2026. Conclusions: This study provides evidence on whether an anti-inflammatory dietary intervention targeting shared inflammatory and gut-microbiome pathways can improve global functioning and a broad set of clinical and mechanistic outcomes in psychiatric and neurodegenerative populations. The crossover design ensures all participants ultimately receive the intervention while serving as their own controls, maximising statistical power within a heterogeneous patient population. If effective, the BrAIN diet could provide a safe, accessible adjunct to standard care in neuropsychiatric and neurodegenerative populations.

BackgroundTraumatic brain injury (TBI) initiates a rapidly evolving neuroinflammatory response; however, the temporal relationship between early innate immune activation, T cell polarization, and neurobehavioural recovery remains poorly understood. Here, we hypothesize that interleukin-1{beta} (IL-1{beta}) is a critical upstream mediator that polarizes T cells towards pro-inflammatory and cytotoxic effector functions following TBI. MethodsUsing a controlled cortical impact model in adult male C57BL/6J mice, we mapped post-injury immune dynamics and investigated whether targeting key innate inflammatory compartments influenced subsequent T cell programming and neurological outcomes. We conducted longitudinal immune profiling by multiparameter spectral flow cytometry and quantitative polymerase chain reaction up to 10 days post-injury. Antibody-based immune depletion strategies were used to investigate neutrophil and monocyte contributions to the post-traumatic T cell response, while pharmacological inhibition of NLRP3 inflammasome by MCC950 treatment was used to investigate the contribution of IL-1{beta}. ResultsTBI elicited a structured early innate immune response, marked by rapid chemokine induction, followed by temporally distinct infiltration of neutrophils, monocytes, and dendritic cells. Neutrophils and monocytes were the predominant early IL-1{beta}-producing infiltrating populations. This was followed by a delayed adaptive phase characterized by sustained recruitment of T cell subsets (CD4+, CD8+, {gamma}{delta}+), alongside dynamic effector cytokine production (IL-17, IFN-{gamma}). Neutrophil depletion altered the early myeloid composition but did not result in durable improvements in T cell effector responses or neurobehavioral outcomes. Depletion of CCR2-dependent inflammatory monocytes reduced acute monocyte accumulation and attenuated early downstream T cell responses; however, these effects were not sustained and only resulted in modest neurobehavioural benefits. In contrast, inhibition of the NLRP3 inflammasome suppressed microglial IL-1{beta} production, without significantly altering leukocyte recruitment or subacute T cell effector phenotypes. These phenotypic changes were associated with improvements in motor and cognitive function recovery. ConclusionWe show that early monocyte IL-1{beta} signalling actively regulates downstream T cell infiltration and effector function after TBI. In addition, inhibition of NLRP3 inflammasome after TBI attenuates microglial IL-1{beta}-associated immune activation and results in behavioural improvement despite ongoing leukocyte recruitment, indicating that targeting the nature and cellular source of IL-1{beta} signalling can dissociate immune cell burden from neurological outcomes. Collectively, our findings identify myeloid IL-1{beta}-linked pathways as a viable bridge between innate and adaptive immunity post-TBI, and underscore cellular compensation as a critical design consideration for next-generation immunotherapies.

BackgroundSpinal cord injury (SCI) triggers remote pathological changes in supraspinal regions, including neuroendocrine dysfunction that manifests clinically as hyponatremia and central diabetes insipidus. Clinical observations of lesion-level dependency and sequential transformation between these disorders suggest a temporally ordered hypothalamic cascade in which a compensatory arginine vasopressin (AVP)-driven neuroendocrine surge may precede a later neuroinflammation and endoplasmic reticulum (ER) stress-mediated neuronal exhaustion. Direct transcriptomic evidence for the temporal ordering of these events, however, has been lacking. MethodsWe performed a dual-cohort transcriptomic analysis. A discovery cohort (NCBI Sequence Read Archive PRJNA953752) comprised hypothalamic tissue from adult male Sprague-Dawley rats subjected to high-thoracic (T3) SCI, low-thoracic (T10) SCI, or sham surgery, sampled at post-injury day 7 and analyzed with edgeR/DESeq2 (|log2FC| > 1, Padj < 0.05). An independent chronic-phase validation cohort (Gene Expression Omnibus GSE297887) of hippocampal tissue from SCI and sham mice was interrogated as a sensitive supraspinal proxy for remote neuroinflammatory and ER-stress signatures. Pre-defined gene panels covered neuroendocrine, neuroinflammation, and ER-stress/unfolded-protein-response categories. ResultsIn the discovery cohort, high-thoracic SCI produced a lesion-level-dependent neuroendocrine surge in the hypothalamus: Avp (fold change 7.23; Padj = 0.002), Oxt (fold change 14.25; Padj = 2.3 x 10-7), and Ucn3 (fold change 9.22; Padj = 0.002) were among the most significantly upregulated genes genome-wide, whereas low-thoracic SCI failed to reach significance for any of these targets. Classical neuroinflammation markers and canonical ER-stress effectors remained transcriptionally silent (all Padj > 0.69). The PERK-pathway sentinel genes Trib3 and Ppp1r15a/GADD34 exhibited coordinated sub-threshold trends indicative of early activation, and Avp expression was tightly correlated with Mmp9 (r = 0.833; P = 0.0004). In the chronic-phase validation cohort, microglial P2ry12 and ferroptosis signatures were significantly upregulated (P2ry12 fold change 1.33; P = 0.008) suggesting a primed microglial state, while ER-stress effectors remained silent. ConclusionsThese data support a temporally ordered hypothalamic cascade after SCI in which an early compensatory neuroendocrine surge precedes -- and may precipitate, through biosynthetic overload and blood-brain-barrier disruption -- a subsequent neuroinflammation and ER-stress crisis. The defined molecular window between neuroendocrine activation and inflammatory/ER-stress engagement identifies a candidate therapeutic window for early neuroprotective intervention in acute SCI.

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Pregnancy requires tightly regulated immune adaptation, which may be altered by maternal adiposity and HIV infection. In high HIV prevalence settings with rising obesity rates, overlapping metabolic and infectious inflammation may shape gestational immune trajectories. We examined patterns of C-reactive (CRP), serum amyloid A (SAA), and interferon-gamma inducible protein-10 (IP-10) among 527 pregnant women living with HIV in Cape Town, South Africa. Immune markers were measured at up to four antenatal visits. Maternal body mass index (BMI) was categorised as normal, overweight or obese. Antiretroviral therapy (ART) exposure was classified as initiation before conception or during pregnancy. Mixed-effects models assessed associations, adjusting for baseline CD4 cell count and viral load. CRP concentrations remained elevated across pregnancy and were significantly higher among obese women independent of ART timing. In contrast, IP-10 concentrations were strongly associated with ART timing, with higher levels observed prior to ART initiation and declining thereafter; no independent association with BMI was observed. SAA concentrations were modestly lower among obese women and among those on preconception ART. These divergent patterns persisted after adjustment for HIV disease severity. These findings suggest that metabolic and HIV-related inflammatory pathways operate in parallel during pregnancy, with adiposity predominantly influencing acute-phase responses and HIV-related immune activation shaping interferon-associated chemokines trajectories.

BackgroundExposure to prenatal maternal inflammation (PNMI) has been linked to neurodevelopmental alterations in human offspring. Preclinical studies suggest that PNMI disrupts reward circuitry, particularly within mesolimbic circuits. However, the effects of PNMI on mesolimbic circuits (i.e, ventral tegmental area (VTA) projections to the hippocampus (VTA-H) and limbic striatum (VTA-LS)) in humans are not yet known. MethodsData for PNMI biomarkers [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1ra), soluble TNF receptor-II (sTNF-RII)] from first trimester (T1) and second trimester (T2) maternal sera, and offspring MRI brain scans in late midlife (aged 57-63 years), were available for 89 mother-offspring dyads. Probabilistic tractography delineated bilateral VTA-H and VTA-LS tracts. Macrostructural tract measures were examined using hierarchical linear regressions. Microstructural integrity was assessed using neurite orientation dispersion and density imaging, and permutation-based cluster analyses. ResultsHigher T2 IL-1ra was associated with increased macrostructure (left VTA-H tract), whereas higher T2 sTNF-RII was associated with reduced macrostructure (right VTA-H and VTA-LS tracts) and higher T2 IL-8 (bilateral VTA-LS tracts). Microstructurally, higher T2 IL-6 was associated with increased neurite density (distal cluster, right VTA-H tract), while higher T1 IL-8 was associated with reduced neurite density (near the hippocampus in the left VTA-H tract, near the VTA in bilateral VTA-LS tracts). ConclusionsPNMI was associated with altered mesolimbic reward circuitry in offspring. This suggests that prenatal inflammation may contribute to affective and motivational disorders in offspring via alterations in mesolimbic circuitry.

Bidirectional communication between the nervous and immune systems has been demonstrated to limit or enhance immune cell function across organ systems and conditions. Although these neuroimmune circuits can become activated as an anti-inflammatory reflex, vagus nerve stimulation (VNS) reduces inflammation in models of endotoxemia, rheumatoid arthritis, and intestinal inflammation. In the spleen during endotoxemia, VNS activates a "cholinergic anti-inflammatory pathway" (CAIP), whereby choline acetyltransferase (ChAT)-expressing T cells release acetylcholine to reduce macrophage activation. VNS can also drive CAIP-independent pathways to reduce inflammation in the spleen and intestinal tract, although the circuitry modulating colonic inflammation remains underexplored. Here, we demonstrate that left cervical VNS reduces acute LPS-induced inflammation, evidenced by reduced Tnfa expression in colon and spleen and decreased circulating TNF. In the colon, these protective effects required efferent but not afferent VNS and were independent of ChAT+ T cells, IL10, {beta}-adrenergic signaling, and colonic sympathetic innervation. Critically, the ability of VNS to modulate colonic inflammation depended on prior tissue-specific inflammation. Mice recovering from DSS colitis, despite near-complete histological recovery, were refractory to the protective effects of VNS in the colon. This lack of efficacy in the colon was not reflected in measures of inflammation in the spleen or serum, highlighting the need for target-organ-specific monitoring. This loss of efficacy after colonic inflammation was transient, with restoration occurring upon complete recovery. These findings demonstrate that VNS efficacy in colonic inflammation depends on circuitry distinct from canonical systemic anti-inflammatory pathways, and that tissue responsiveness is shaped by anatomical site and inflammatory history. Key PointsO_LIElectrical stimulation of the left cervical vagus nerve reduces LPS-induced inflammation in the mouse colon. C_LIO_LIThis colonic anti-inflammatory effect requires vagal efferents but not afferent signaling. C_LIO_LIUnlike canonical splenic anti-inflammatory pathways, the colonic response does not require ChAT+ T cells, IL-10, {beta}-adrenergic signaling, or local sympathetic innervation. C_LIO_LIRecent DSS colitis abolishes colonic responsiveness to VNS despite preserved splenic and systemic anti-inflammatory effects. C_LIO_LIRecovery of VNS anti-inflammatory efficacy after colitis shows that neuroimmune responsiveness in the colon is dynamically shaped by inflammatory history. C_LI

Communication between gut microbiota and immune cells within the brain is essential for neurotypical development. Specifically, microglia are known to play a key role in regulating and supporting neural progenitor stem cell production during brain development, and are sensitive to changes in the maternal gut microbial composition during perinatal development. Here, we employed a germ-free (GF) porcine paradigm to examine how the absence of the microbiome affects microglial dynamics during a key epoch of brain development. We utilized automated software to evaluate microglial density and morphology across three developmentally significant regions: the ventricular/subventricular zone (VZ/SVZ), the prefrontal subcortical white matter (PFCSWM), and layers II/III of the prefrontal cortex (PFCII-III). We found no significant differences in microglial morphology or density in the VZ/SVZ or PFCSWM. In contrast, the PFCII-III of P16 piglets exhibited an increase in microglia density paired with morphologies indicative of an activated/reactive functional state. Notably, these effects were identified with no overall changes in microglial density in any of the regions assessed. Transcriptomics on RNA isolated from the PFCII-III revealed a significant upregulation of genes related to neuroinflammation, in agreement with a region-specific microglial and immune response in the absence of microbial colonization during postnatal development. Together, these findings build on the limited knowledge available on how microbiota influence brain development in large animal model organisms with high similarities to human brain anatomy and developmental trajectories. Significance StatementThe prefrontal cortex of porcine display unique, ramified microglia which are sensitive to germ-free conditions whereby they display alterations in morphology with a more transcriptionally reactive signature. These findings indicate that microglia are regionally sensitive to stimuli in the periphery, and studies in lissencephalic mammalian models may not be directly correlative to other higher-order species. The neuroanatomical heterogeneity of microglia across species is informative and understudied, but necessary, to draw conclusions on the array of perturbations spanning neurodevelopmental trajectories in health and disease.

Post-traumatic stress disorder (PTSD) has been linked to various alterations within the immune system, yet the metabolic programming of immune cells remains unexplored. In the current cross-sectional study, we interrogated immunometabolic function by applying cell-specific metabolic flow cytometry, serum biomarker profiling, and targeted gene expression analysis in peripheral blood mononuclear cells from patients with PTSD (N=34) compared with healthy controls (N=32). PTSD was associated with higher glycolysis- and oxidative pentose phosphate pathway-related markers across adaptive and innate immune cell subsets, as well as elevated circulating interleukin-6. Expression of inflammatory- and stress-related genes was largely comparable between groups. Together, these data provide preliminary evidence for immunometabolic alterations in PTSD at both cellular and systemic levels. These results could contribute to understanding potential pathophysiological mechanisms and support further investigation of immunometabolism in PTSD.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Its pathophysiology is incompletely understood and likely involves complex interactions between immune, autonomic, and metabolic dysregulation. Despite features with potential relevance for anesthesia and perioperative care, evidence to guide anesthetic management in individuals with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research. Methods: We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10 codes (G93.3 and U09.9) with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia. Results: Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. ME/CFS patients exhibited lower lowest recorded intraoperative systolic blood pressure (90 [82.5-95.0] mmHg in ME/CFS vs 100 [90.0-110.0] mmHg in controls, p = 0.044) as well as lower lowest heart rate (50 [40.0-57.5] bpm in ME/CFS vs 60 [50.0-65.0] bpm in controls, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] in ME/CFS vs 1.0 [0.0-4.0] in controls, p = 0.008) and more frequent opioid rescue analgesia (80% in ME/CFS vs 33% in controls, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups. Conclusions: General anesthesia appears hemodynamically well tolerated in individuals with ME/CFS. In contrast, postoperative pain burden is increased and may require tailored analgesic strategies. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured in this study and remains an important target for future research. These hypothesis-generating findings highlight the need for prospective studies to optimize perioperative management and evaluate patient-relevant outcomes in ME/CFS.

Reactive astrocytes contribute to neuroinflammation and synaptic dysfunction, but it remains unclear whether transient inflammatory stimulation causes a persistent reactive state after the initial inflammatory stimulus is removed. Here, we investigated whether transient exposure to a defined inflammatory cytokine/complement cocktail induces a persistent reactive astrocyte state and examined the signaling mechanism underlying its maintenance. Human astrocytes were exposed to the inflammatory stimulus and subsequently subjected to stimulus washout, followed by time-course analyses to compare the reversibility of inflammatory gene expression after stimulus removal. Following washout, the expression of several inflammatory response genes, including CXCL10 and NF-{kappa}B-associated genes such as NFKBIA, TNFAIP3, and RELB, returned toward baseline levels. In contrast, C3 expression remained elevated, indicating persistence of a post-inflammatory C3-high astrocyte state after withdrawal of the inflammatory stimulus. Pharmacological inhibition of JAK signaling reduced persistent C3 expression to near-baseline levels, supporting the involvement of JAK-dependent signaling in maintenance of this persistent state. Together, these findings suggest that transient inflammatory stimulation induces a post-inflammatory persistent C3-high astrocyte state that is maintained even after broader inflammatory gene responses have subsided. This persistent C3-high component is pharmacologically attenuated by JAK inhibition, identifying JAK-dependent pathways as modulators of persistent astrocyte inflammatory reactivity.

PurposePost-acute sequalae of SARS-CoV-2 (PASC) are associated with persistent neurological symptoms (neuroPASC). Perivascular spaces (PVS) in the brain may enlarge in the context of inflammation and vascular dysfunction, reflecting impaired glymphatic clearance, and have been linked to cognitive decline. SARS-CoV-2 may disrupt the blood-brain barrier and impair glymphatic function, contributing to PVS burden. This study used 7 Tesla MRI to segment and quantify PVS in neuroPASC participants and uninfected comparators and examined associations with cognitive performance. MethodsAdult participants (36 neuroPASC (44.3 {+/-} 12.7 years) and 33 comparators (38.4 {+/-} 13.0 years)) underwent a 7 Tesla MRI scan. White matter masks of the whole brain and four lobes were segmented, and semi-automated segmentation was used to quantify PVS count and volume. All participants completed cognitive testing including Trails A and B sequencing tasks; neuroPASC participants also self-reported brain fog, fatigue, anxiety, and depression. PVS count, PVS volume, and total white matter volume (WMV) between groups were compared and associations between PVS metrics and cognitive function were assessed controlling for age, sex, and intracranial volume and corrected for multiple comparisons. ResultsAmong neuroPASC participants, those reporting anxiety (p =0.009) and depression (p =0.01) had higher WMV than those without. Greater PVS burden was associated with worse cognitive performance in PASC, particularly processing speed (Trails A) and executive function (Trails B). Specifically, processing speed was negatively associated with whole-brain PVS count (p-FDR = 0.008, R2 = 0.27), frontal PVS count (p-FDR = 0.03, R2 = 0.25), and frontal PVS volume (p-FDR = 0.04, R2 = 0.23). Trails B was also negatively associated with whole-brain PVS count (p-FDR = 0.005, R2 = 0.26). In comparators, higher PVS burden (volume and count) across multiple lobes was associated with worse semantic fluency (Animal Naming). There were no other significant associations between PVS measures and neuropsychiatric tests among participants within any of the subgroups to report. ConclusionAlthough group-level differences in PVS were not observed, PVS burden was meaningfully negatively associated with cognitive performance in neuroPASC, with the strongest effects in frontal regions. These findings suggest that microvascular and glymphatic alterations may contribute to the characteristic processing speed and executive dysfunction seen in neuroPASC. Elevated WMV in those with anxiety and depression may reflect heightened inflammatory vulnerability. PVS may serve as a sensitive imaging marker of glymphatic dysfunction and neuroinflammation in neuroPASC, offering insight into the mechanisms underlying cognitive impairment and potential intervention targets.

BackgroundLoneliness is a psychosocial stressor associated with elevated risk of severe mental illness (SMI), including major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD). Loneliness is theorized to become biologically embedded via inflammation-related mechanisms, yet its causal relationship with SMI and the role of inflammatory signaling remain unclear. AimsTo investigate whether loneliness causally influences SMI risk and whether inflammatory cytokines mediate this relationship. MethodWe applied univariable Mendelian randomization (MR) to estimate the causal effect of loneliness on SMI and multivariable MR (MVMR) to assess mediation by inflammatory signaling. We integrated genome-wide association study (GWAS) summary statistics for loneliness and SMI with genetic instruments for inflammatory cytokines. MVMR models estimated the direct effect of loneliness after accounting for inflammatory signaling using eQTL and pQTLs for interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), IL-6 receptor (IL-6R), tumor necrosis factor alpha (TNF-), and TNF receptors (TNF-R1/2). Bidirectional MR examined potential reverse causal pathways between inflammation, SMI, and loneliness. ResultsMR provided evidence consistent with a causal effect of loneliness on SCZ and MDD. Results were also consistent with inflammatory cytokine pathways for IL-1RA, IL-6R, and TNF-R1, partially mediating the loneliness-SCZ and loneliness-MDD causal effect. No significant effects were identified for BD in UVMR or MVMR models. Bidirectional MR suggested evidence of reverse causation between SCZ and loneliness. ConclusionsThe findings support a causal risk-increasing effect of loneliness on SCZ and MDD, partially mediated by systemic inflammatory signaling, implicating pathways as a plausible mechanistic link between psychosocial stress and mental illness risk and highlighting potential opportunities for prevention and targeted intervention through inflammation and social pathways.

Despite their prevalence, the pathophysiology of depression and anxiety remains poorly understood. Although adversity is a known risk factor, the mechanisms and biological contexts through which it contributes to mood disorder symptoms remain unclear. Immune and mitochondrial adaptations have both been implicated in mood disorders, suggesting the biological embedding of adversity may involve both systems. However, inconsistencies in the literature remain, partly due to reliance on mixed peripheral blood mononuclear cell (PBMC) populations despite substantial variability in mitochondrial biology across immune cell subtypes. We therefore investigated associations between adversity, mood disorder symptoms, immune cell proportions, and immune cell-specific mitochondrial bioenergetics (enzyme activities and respirometry) in participants from the Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study (n=105, age 18-60, 68% female, 35% with mitochondrial disease). Depressive and anxiety symptoms were positively associated with the monocyte-to-lymphocyte ratio, suggesting a shift toward greater innate relative to adaptive immunity. Associations between mood disorder symptoms and immune cell count were stronger in those exposed to greater early life adversity. Mood disorder symptoms were negatively associated with lymphocyte maximal mitochondrial respiratory capacity (MRC). As expected, the associations between mood disorder symptoms and lymphocyte mitochondrial bioenergetics (enzyme-based MRC and respiratory measurements) were stronger and more consistent among individuals exposed to higher lifetime adversity compared to those with lower lifetime adversity. Overall, these results suggest a complex interplay between adversity, immune cell mitochondrial bioenergetics, and mood disorder symptoms, highlighting immune mitochondrial biology as a potential allostatic pathway linking adversity to psychiatric disorders.

Natural anti-NMDAR1 autoantibodies are present at varying levels in the general human population, but their effects on cognitive function remain unclear. Recent human studies reported significant associations between higher blood levels of natural anti-NMDAR1 autoantibodies and potential neuroprotective outcomes in Alzheimers disease, traumatic brain injury-associated depression and PTSD symptoms, and schizophrenia. However, whether these natural autoantibodies play a causal role in emotional and cognitive function has not been investigated. Since natural autoantibodies in human blood are predominantly of the IgM isotype, we immunized Aicda mutant mice to produce only IgM isotype anti-NMDAR1 autoantibodies without IgG and IgA isotypes. Mice were tested for sensorimotor gating and conditioned fear and extinction, cross species measures of information processing and emotional memory, respectively. Mice with higher levels of IgM anti-NMDAR1 autoantibodies exhibited significantly increased sensorimotor gating and improved fear extinction recall compared with mice with baseline levels of these autoantibodies. These findings indicate that IgM anti-NMDAR1 autoantibodies are pro-cognitive, unlike previous reports of poor cognition associated with IgG anti-NMDAR1 autoantibodies. Together, these studies suggest that IgM may hold therapeutic potential for a range of neurodegenerative, neurological, and psychiatric disorders.

BackgroundRecent multiomic analyses identify metformin-inducible genes, such as DDIT4, as predictors of delayed HIV rebound, suggesting a "cell-extrinsic" role for low systemic inflammation in viral control. We sought to validate this inflammatory "cooling" in a large-scale human population. MethodsUsing Olink proteomics from the UK Biobank (N = 502,493), we evaluated associations between metformin use and inflammatory markers (IL-6, CXCL10, GZMB) in a diabetic cohort (N = 18,548). Stepwise regression was used to adjust for co-medications (statins) and glycemic control (HbA1c). ResultsMetformin use was associated with significantly lower levels of IL-6 (p = 0.0049) and CXCL10 (p < 0.001) after adjusting for age, BMI, and statin use. In exploratory analyses of participants with HIV (N = 61), metformin users showed directionally lower mean IL-6 and CXCL10. However, associations in the primary cohort were attenuated upon adjustment for HbA1c, indicating that metformins systemic anti-inflammatory effect is largely mediated by its metabolic efficacy. ConclusionsMetformin use is associated with a reduction in master regulators of inflammation, independent of common co-medications. These findings suggest that metformin promotes the systemic "cell-extrinsic" environment required for HIV control via its metabolic effects, providing a population-level substrate for the "block-and-lock" mechanisms observed in clinical cohorts.

BackgroundAcute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. MethodsWe conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod-stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. FindingsThe RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.