Neuroscience & Biobehavioral Reviews

Abstract Background Negative symptoms are persistent determinants of disability in schizophrenia and often respond incompletely to antipsychotic treatment. Objective To compare the efficacy of pharmacological and non-pharmacological add-on treatments for prominent or persistent negative symptoms using network meta-analysis. Methods This systematic review followed PRISMA 2020 and PRISMA-NMA and was registered in PROSPERO (CRD420261422218). PubMed, Europe PMC, Semantic Scholar and Crossref were searched from inception to 29 July 2026, supplemented by citation chasing. Eligible studies were randomized controlled trials in adults with DSM/ICD schizophrenia or schizoaffective disorder, prominent or persistent negative symptoms, stable antipsychotic treatment and an adjunctive intervention. Outcomes were Positive and Negative Syndrome Scale negative subscale or Scale for the Assessment of Negative Symptoms scores. Random-effects frequentist networks estimated standardized mean differences (SMDs) with 95% confidence intervals (CIs); negative values favoured add-on treatment. Risk of bias was assessed with Cochrane RoB 2. Results Forty-nine unique RCTs met the clinical and design criteria, of which 28 (2,067 randomized; 1,933 analysable participants) contributed to the locked quantitative dataset. The primary connected network included 24 trials, 25 treatments and 31 comparison estimates. Fourteen add-ons had CIs excluding the null versus a broad control node. The highest P-scores were observed for mirtazapine (SMD -2.38, 95% CI -3.55 to -1.21), granisetron (-1.96, -2.74 to -1.17), tropisetron (-1.82, -2.59 to -1.05), minocycline (-1.78, -2.55 to -1.01) and memantine (-1.54, -2.28 to -0.80). Heterogeneity was low ({tau} = 0.119; {tau}2= 0.014), but the predominantly star-shaped network had zero inconsistency degrees of freedom. Overall RoB 2 judgements were low for eight trials, some concerns for 15 and high for five. Conclusions Several pharmacological and non-pharmacological add-ons showed potentially important efficacy signals. Because most nodes were informed by single small trials, direct active comparisons were scarce, inconsistency could not be evaluated and risk-of-bias concerns were common, the treatment hierarchy should be considered hypothesis-generating rather than a basis for firm clinical recommendations. Registration: PROSPERO CRD420261422218 Keywords: schizophrenia; negative symptoms; adjunctive treatment; network meta-analysis; randomized controlled trial; neurostimulation Key Points This review compares pharmacological and non-pharmacological adjuncts in adults selected for prominent or persistent negative symptoms while receiving stable antipsychotic medication. Mirtazapine, granisetron, tropisetron, minocycline and memantine had the highest P-scores, while tDCS, rTMS and body-oriented psychotherapy also showed efficacy signals versus broad control. The evidence network was sparse and star-shaped, most interventions were supported by one small trial, and inconsistency was not estimable; rankings therefore require cautious interpretation.

Background: Altered gamma-aminobutyric acid (GABA) neurotransmission is a proposed mechanism underlying autism spectrum disorder (ASD), prompting evaluation of several GABA-modulating pharmacotherapies. However, it remains unclear whether these interventions improve ASD broadly or preferentially affect specific symptom domains. Methods: We conducted a systematic review and random-effects meta-analysis of randomized controlled trials evaluating GABA-modulating pharmacotherapies in individuals with ASD. PubMed/MEDLINE, Embase, Scopus, and CENTRAL were searched from inception to April 1, 2026. Outcomes were prespecified as global autism severity, social communication, functional communication, restricted and repetitive behaviours (RRBs), adaptive behaviour, and irritability. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and certainty of evidence was evaluated using GRADE. Results: Thirteen randomized controlled trials evaluating three GABA-modulating interventions (bumetanide, arbaclofen, and valproate) were included. GABA-modulating therapies were associated with statistically significant improvements in global autism severity (Hedges' g = -0.25, 95% CI -0.46 to -0.03; p = 0.028) and adaptive behaviour (Hedges' g = -0.09, 95% CI -0.15 to -0.02; p = 0.023). No significant pooled effects were observed for social communication (Hedges' g = -0.26, p = 0.077), functional communication (Hedges' g = -0.01, p = 0.869), RRBs (Hedges' g = -0.21, p = 0.126), or irritability (Hedges' g = -0.07, p = 0.543). After Holm-Bonferroni step down procedure, neither global autism severity nor adaptive behaviour remained statistically significant (Holm-adjusted p = .140 and .138, respectively). Adverse events were predominantly gastrointestinal, neurological, metabolic, and appetite-related. Overall risk of bias was variable, and the certainty of evidence ranged from very low to moderate. Conclusions: GABA-modulating pharmacotherapies did not demonstrate a robust, multiplicity-corrected benefit in any of the six prespecified ASD symptom domains. Nominal, unadjusted improvements in global autism severity and adaptive behaviour did not withstand correction for multiple comparisons and should be regarded as hypothesis-generating rather than confirmatory. Larger, adequately powered randomized trials using standardized domain-specific outcome measures are needed to determine whether individual GABA-modulating agents provide clinically meaningful benefit.

Objectives To evaluate the positive and adverse effects of parent-mediated interventions (PMIs) versus care as usual for children with autism. Setting Systematic review and meta-analysis and Trial Sequential Analyses (TSA), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methods We searched for randomised clinical trials of PMIs for children with autism in the databases CENTRAL, EMBASE, LILACS, PsycINFO, MEDLINE, and SCI-EXPANDED (up to 13 August, 2025), complemented with manual searches. 12,359 articles were screened. Data were synthesised using meta-analyses and Trial Sequential Analyses (TSA), and risks of bias and certainty of the evidence were evaluated. Primary and secondary outcome measures The primary outcome was autism characteristics. Secondary outcomes were adverse effects, child adaptive functioning, child language, child and parent quality of life, and parental stress. Ten exploratory outcomes were included. Results 32 trials (N=1,625) comparing PMIs to usual care, waiting list, or no intervention were included. All trials had a high risk of bias. The multiplicity-adjusted threshold for statistical significance was p = 0.013 due to the number of outcomes. Meta-analyses and TSAs showed it could be rejected that PMIs reduced autism characteristics (MD = -0.88; 95% confidence interval -2.92 to 1.15; p = 0.05, 4 trials, N=353, low certainty), child adaptive functioning (7 trials, N=408), child language (4 trials, N=308), or parental stress (7 trials, N=385). Due to insufficient data, the remaining secondary meta-analyses could not be conducted. Meta-analyses of exploratory outcomes showed beneficial effects concerning child behaviour problems and parent sensitivity/synchronicity. Conclusions This meta-analysis found no benefits of PMIs on child autism characteristics, child adaptive functioning, child language, or parental stress. Benefits were found in reduction of child behaviour problems and improved parent sensitivity/synchronicity. The evidence remains uncertain, and more trials including outcomes of adverse effects and quality of life are needed.

Background: Placebo responding involves the reduction of symptoms in response to contextual features of an intervention (e.g., verbal suggestions), yet it is characterized by pronounced heterogeneity. Although verbal suggestions are widely recognised as a hallmark method for inducing placebo responses, an open question is whether variability in placebo responding can be partly attributed to individual differences in trait responsiveness to verbal suggestions (REVS). We conducted a pre-registered meta-analysis (PROSPERO registration number CRD420250654692) to quantitatively synthesize available research on the association between trait REVS and placebo responding. Methods: PsycInfo, PubMed, MEDLINE, and Embase were searched up to June 2026 for original clinical or experimental studies involving both the assessment of REVS and symptom measures (self-report, behavioural, and/or physiological) in response to an inactive intervention (placebo). Results: Of 1,512 search results, 24 articles presenting 66 correlations between REVS and placebo responding were analysed (N = 1,137). A multi-level meta-analysis revealed a significant, albeit weak, positive correlation between REVS and placebo responses, r = 0.18 [95% CI: 0.13, 0.24], such that individuals with higher REVS reported greater symptom relief in response to the placebo. Meta-regression analyses did not identify any significant moderators of the correlation between REVS and placebo responding and sensitivity analyses based on Bayesian subgroup estimates indicated that the aggregate correlation was stable across methodological quality indicators and study features. Conclusion: These findings suggest that individual differences in REVS may partly explain variability in symptom reduction in response to placebos, with implications for the sources of variance in placebo effects in experimental and applied contexts.

Background Spinal manipulation therapy (SMT) is widely used for low back pain (LBP), yet comparative effectiveness findings across trials remain inconsistent. One potential explanation is incomplete separation of treatment-specific effects from natural recovery and placebo response, which may differ between acute and chronic presentations. Methods We conducted a Bayesian hierarchical analysis of 120 randomized controlled trials (298 arms; 19,059 patients) evaluating SMT, exercise, medical management, physical modalities, self-care, and control conditions. Natural history (NH) trajectories were derived from independent observational cohorts and incorporated as external model components. Treatment effects were estimated as deviations from NH, and sham-corrected effects as deviations from control conditions. Results In acute LBP, NH trajectories predicted substantial improvement by 26 weeks. Estimated treatment effects relative to NH were negative across all categories, and sham-corrected effects were near zero, with credible intervals overlapping zero. In chronic LBP, NH trajectories predicted more gradual improvement. Control conditions exceeded NH, consistent with a substantial placebo response. Exercise and SMT demonstrated positive sham-corrected effects with credible intervals excluding zero; however, estimated magnitudes were modest and did not consistently exceed commonly cited thresholds for clinical importance. Higher study quality was associated with smaller estimated effects in chronic trials. Conclusions Modeling natural history as a structural component of treatment response alters estimates of comparative effectiveness in LBP. Improvements observed in acute LBP appear largely consistent with underlying recovery processes, whereas in chronic LBP, contextual and placebo-related effects contribute substantially to observed outcomes. Explicit separation of these components may help reconcile inconsistencies in the literature and inform interpretation of treatment effects.

Background Vitamin D may influence bone healing and recovery after spine surgery, but its clinical effects remain uncertain. Objective To evaluate clinical, functional, and bone-related outcomes associated with vitamin D status and supplementation in patients undergoing spine surgery. Methods This systematic review and meta-analysis was registered in PROSPERO (CRD420261467482) and reported according to PRISMA 2020. PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library were searched from inception through 1 June 2026. Random-effects meta-analyses used mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. Direct supplementation analyses were prioritized, while analyses combining supplementation, baseline vitamin D status, or co-interventions were considered exploratory. Risk of bias was assessed using design-specific Joanna Briggs Institute tools. Results Thirteen studies were included. Four supplementation studies involving 177 participants showed no significant reduction in postoperative pain (MD -0.82, 95% CI -2.50 to 0.86; I2 = 84.3%). Three studies involving 277 participants showed lower Oswestry Disability Index scores in an exploratory analysis (MD -6.40, 95% CI -10.41 to -2.39; I2 = 96.8%). Three supplementation studies involving 128 participants showed no significant improvement in fusion rate (RR 1.17, 95% CI 0.78 to 1.74; I2 = 31.5%). An exploratory four-study fusion analysis was also not statistically significant (RR 1.24, 95% CI 0.98 to 1.57; I2 = 45.5%). Conclusion Current evidence does not establish that vitamin D supplementation independently improves postoperative pain or fusion rates after spine surgery. Possible benefits for disability and other bone-related outcomes remain uncertain because of small study numbers, heterogeneity, co-interventions, and residual confounding. Larger randomized trials stratified by baseline vitamin D status are needed.

Purpose: We introduce the Temporal Index of Divergent Evidence (TIDE), a metric that evaluates how the topic center of gravity of a corresponding corpus of literature aligns with, or shifts relative to, a recommendation's semantics over time. Methods: TIDE computes annual mean cosine similarity using MedCPT embedding vectors between a recommendation and corresponding PubMed records binned by year (2000-2024), testing for monotonic temporal trend (Kendall {tau}). Three recommendations with expected divergent, stable, and convergent trajectories were examined: two-stage exchange for periprosthetic joint infection (PJI), emergent fasciotomy for acute compartment syndrome (ACS), and non-operative management of distal radius fractures (DRF) in adults [≥] 65 years. The signal was characterized by an additive per-token attribution, an isolated vs. in-context analysis, and an adversarial minimal-pair test. Results: PJI diverged ({tau} = -0.84, year-shuffle p = 0.001), DRF converged ({tau} = +0.42, p = 0.005), and ACS showed no detectable trend ({tau} = -0.07, p = 0.66). The two significant directions (PJI, DRF) held under matched input [CLS] pooling, while ACS remained near zero. Publication volume baselines did not distinguish the three trajectories (publication count was universally positive, {tau} = +0.77 to +0.97). A reversed-meaning minimal-pair control showed little cosine sensitivity to reversal. Paper-level TF-IDF recovered the qualitative three-case pattern. Conclusion: Embedding-based drift analysis is a proof-of-concept candidate pre-triage signal that tracks topical alignment, not evidentiary direction; superiority over TF-IDF remains unproven. The present study is hypothesis-generating, showing potential use of embedding representations as an analytical unit rather than simply for retrieval.

Background: Vitamin B12 is essential for one-carbon metabolism, deoxyribonucleic acid (DNA) synthesis, and myelination, and inadequate maternal status during pregnancy may influence fetal growth and child neurodevelopment. Objective: To evaluate the association between maternal vitamin B12 status and perinatal and child neurodevelopmental outcomes. Methods: We conducted a systematic review and meta-analysis of observational studies and randomized clinical trials. The main outcomes were preterm birth, low birth weight, small for gestational age (SGA), and cognitive/global development. For binary outcomes, the natural logarithm of the relative risk (logRR) was the primary analytical effect measure; for neurodevelopment, Hedges g was used. Random-effects models were fitted, between-study variance was estimated by restricted maximum likelihood (REML), and inference used Knapp-Hartung (KH) adjustment. Results: For preterm birth, nine estimates yielded a pooled logRR of 0.190 (95% confidence interval [95% CI] KH: -0.046 to 0.427; p = 0.101; I2 = 19.2%). For low birth weight, nine estimates yielded a pooled logRR of 0.136 (95% CI KH: -0.013 to 0.286; p = 0.069; I2 = 4.8%). For SGA, six estimates yielded a pooled logRR of 0.047 (95% CI KH: -0.083 to 0.177; p = 0.397; I2 = 0%). Cognitive/global development, assessed in five independent studies, showed a pooled Hedges g of 0.266 (95% CI KH: 0.034 to 0.499; p = 0.034; I2 = 55.7%). Conclusions: logRR estimates for preterm birth and low birth weight were directionally compatible with higher risk among mothers with lower vitamin B12 availability, but their 95% CIs included the null. No consistent association was observed for SGA. Higher maternal vitamin B12 availability or supplementation was associated with a small favorable effect on cognitive/global development, with moderate heterogeneity.

Consciousness is often studied by asking whether particular brain regions or systems are privileged. We tested a distributed, decentred and context-sensitive alternative using 579 consciousness-focused neuroimaging studies. Semantic clustering of titles and abstracts identified seven domains whose corrected meta-analytic maps showed limited overlap and no invariant cross-domain core. These maps occupied 18.0% of grey matter while extending across 91.0% of brain regions. After controlling for reporting topography, distributed cognitive, sensorimotor and organismic-affective maps reconstructed the residual consciousness landscape better than spatial surrogates. Organismic-affective maps contributed most, but functional contributions varied contextually across domains. Theory-associated regional loci added no additional meaningful prediction. Information carried by the functional families was both redundant and synergistic. Coactivation-network and hypergraph analyses revealed a shared network repertoire but context-dependent higher-order coalitions. These results argue against an invariant core, supporting a distributed neurobiology of consciousness in which specialised systems are weighted and combined differently across contexts.

Individuals with schizophrenia show well-documented impairment in metaphor comprehension, often exhibiting a bias toward concrete, literal interpretations. While this tendency has traditionally been linked to psychopathological and cognitive factors, the contribution of perceptual processes remains underexplored. Here, we tested the hypothesis that figurative language impairment reflects altered perceptual processing, whereby the visual representations evoked by metaphors remain abnormally active and hinder abstraction. A sample of 143 individuals with schizophrenia and healthy controls was administered a novel paradigm where metaphors (e.g., Wisdom is a flashlight) served as primes for target words related to the metaphor vehicle based on visual (e.g., microphone), action (e.g., remote), or semantic features (e.g., lamp). While in healthy participants metaphors activated semantically associated words, individuals with schizophrenia showed sustained visual priming, emerging 1000 ms after metaphor presentation and persisting up to 1400 ms, with both groups showing reverse priming for action targets. Critically, greater visual priming predicted lower metaphor comprehension in patients, whereas greater semantic priming was correlated with better metaphor skills in controls. These results suggest that visual-perceptual representations are not only overactivated in patients compared to controls during metaphor processing but may also interfere with figurative comprehension. We argue that concretism arises from an imbalance between bottom-up sensory signals and top-down contextual priors, leading to the persistence of the visual representations and impaired abstraction. More broadly, these results support multimodal and predictive accounts of metaphor processing and point to altered perceptual dynamics as a previously unappreciated mechanism contributing to pragmatic impairment in schizophrenia.

Frequent comparisons with idealized portrayals of others on social media may be linked to poorer mental health. To test this hypothesis, we systematically searched PsycInfo, MEDLINE, and Web of Science for studies published through April 28, 2026. A total of 149 observational studies (N = 76,262) and 77 experimental studies (N = 15,404) were included in meta-analytic syntheses. Upward social comparison tendency correlated cross-sectionally with mental health outcomes, including psychopathology (r = .32) and body dissatisfaction (r = .54). Worse comparative self-evaluations were associated with poorer mental health and vice versa, with moderate-to-large effect sizes. Across experimental studies, upward social comparisons adversely affected mental health. Results were robust in sub-group analyses (e.g., female or young samples). Across study designs, there was no evidence that downward comparisons were linked to mental health. These findings identify upward social comparisons as a robust correlate and potential risk factor for poor mental health.

Large language models (LLMs) screen titles and abstracts without review-specific training, but generating screening decisions as text takes processing time and incurs API charges. We evaluated Jev, a non-generative model returning classification probabilities, on 4527 records from two systematic reviews of bipolar disorder treatments. We used human reviewers' decisions to retain records for full-text assessment as the reference standard. In the primary analysis, we asked Jev yes-or-no questions ("Noul") about whether to retain each record. Records were retained when their retention probability was at least 50%, a cutoff specified before the final evaluation runs. We also evaluated lower retention thresholds. For comparison, we gave Jev explicit include/exclude options ("Choice") and used the same prompts with GPT-5 mini and GPT-6 Astra; both LLMs used default reasoning. In the primary analysis at 50%, sensitivity and specificity were 99.6% and 98.9% for light therapy and 93.2% and 93.5% for adjunctive pharmacotherapy. Lower cutoffs selected on these data retained all reference-positive records. Compared with assessing every record manually, these cutoffs reduced the number requiring human assessment by 96.9% for light therapy and 61.3% for adjunctive pharmacotherapy. For light therapy and adjunctive pharmacotherapy, sensitivity was 92.3% and 90.0% with Jev using explicit options at 50%, 87.2% and 90.0% with GPT-5 mini, and 92.3% and 80.8% with GPT-6 Astra. Costs for screening all 4527 records once were US$0.20 for Jev using explicit options, US$2.59 for GPT-5 mini, and US$33.45 for GPT-6 Astra. Jev's probabilities could provide graded information for reviewers assessing titles and abstracts.

Importance: Anhedonia, social withdrawal and executive deficits represent transdiagnostic symptoms in depression, schizophrenia and addition, yet transdiagnostic brain volumetric alterations and their contribution to these symptom domains have not been systematically characterized. Objective: To determine common and disorder-specific gray matter deficits in patients with schizophrenia (SZ), major depression disorder (MDD) and alcohol use disorder (AUD) compared to heathy controls. Data Sources: A comprehensive literature search using three databases including PubMed, Web of Science and PsycInfo (between January 2000 to March 2024) as well as searches on review articles. Study Selection: Studies had to be published in English, reporting whole-brain results, comparing patients and healthy controls. Data Extraction and Synthesis: This meta-analysis adhered to the PRISMA guidelines and was pre-registered (https://osf.io/s57uq) prior to data analysis. Data was independently extracted and verified by 3 contributors, and statistical brain maps were generated using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) random-effects model. 147 VBM studies encompassing 90 Schizophrenia, 44 MDD and 13 AUD studies were finally included. Main Outcomes and Measures: Statistical maps of common and disorder-specific gray matter deficits in patients versus healthy controls are presented. Statistical inference utilized permutation tests, with threshold at p < .0025 and cluster extent of 10 voxels. Heterogeneity was evaluated using the I2 statistic and publication bias using Eggers regression test. Results: Capitalizing on a coordinate-based meta-analysis involving n=13,041 participants, we found shared GMV alterations in the ventromedial prefrontal cortex, ventral anterior cingulate cortex, insula, superior temporal gyrus. On the network level, we found robust functional interactions of the identified shared regions with the cortical midline structures as well as social and theory of mind-related behavioral functions. Subsequent characterization analyses highlighted the involvement of dopaminergic and serotonergic neurotransmitters as well as associated genetic annotations. Conclusions and Relevance: Overall, the present meta-analysis found common as well as separate GMV abnormalities in schizophrenia, major depressive disorder and alcohol use disorder suggesting a common neurostructural substrate and treatment target for social withdrawal and anhedonia across these disorders. Keywords: alcohol-use disorder, depression, meta-analysis, schizophrenia, voxel-based morphometry

Background: Stimulant and non-stimulant medications increase fronto-striato-thalamic activation in youth with Attention-Deficit/Hyperactivity Disorder (ADHD). However, comparative effects of the more recently licensed stimulant lisdexamfetamine and non-stimulant guanfacine on functional magnetic resonance imaging (fMRI) correlates in ADHD are unknown. Methods: This exploratory randomised, placebo-controlled, double-blind, crossover study compared fMRI activation in youth with ADHD during a tracking stop-signal task (SST; N = 12), a working memory task (N-back; N = 11) and a sustained attention task (SAT; N = 10), after single clinical doses of either guanfacine extended-release, lisdexamfetamine, or placebo, with one-week washouts. Twenty-one demographically matched typically developing controls (TD) were assessed once to test for potential normalisation of case-control activation differences. Results: Region of interest analysis showed increased right caudate and putamen activation for lisdexamfetamine versus placebo during N-back and SAT, respectively. Both drugs shared an increase in left superior temporal activation versus placebo during N-back. In whole-brain analyses only lisdexamfetamine increased precuneus/posterior cingulate activation during SST versus guanfacine, and during N-back in pre- and postcentral and occipital cortices versus placebo. During SST, placebo-treated ADHD versus TD showed reduced putamen, insula, parietal and occipital activation that was potentially attenuated/normalised under lisdexamfetamine, while under guanfacine lingual gyrus underactivation remained, with additional precuneus and middle temporal underactivation. Also, only lisdexamfetamine improved and normalised SST performance. Conclusion: Lisdexamfetamine appears to have stronger and drug-exclusive upregulation and potential attenuation/normalisation effects than guanfacine on basal ganglia, posterior parieto-occipital and sensorimotor activations during ADHD-relevant executive function tasks with some shared putamen and superior temporal effects.

Background Although mental illness is primarily regarded as a disorder of the brain, body system dysfunction is increasingly recognized as a salient biomarker in psychiatry, often emerging before the onset of overt symptoms. Here, we systematically review studies on peripheral organ systems (cardiovascular, metabolic, immune, liver, kidneys, lungs and muskeloskeletal) in schizophrenia, major depressive disorder (MDD), bipolar disorder (BD) and generalized anxiety disorder (GAD), aiming to synthesize findings on the function of multiple body systems in the early stages of mental illness. Methods EMBASE, MEDLINE and PsycINFO were searched from inception until 19 November 2024, identifying case-control studies comparing physiological markers of peripheral organ systems (i.e., cardiovascular, metabolic, immune, liver, kidney, lung and muskeloskeletal) in adults with one of the four mental illnesses at first-episode and drug naive, with healthy controls. We followed the PRISMA 2020 guidelines (PROSPERO: CRD42023408594). Results Of 2,637 citations retrieved, 138 studies met inclusion criteria for review with 52 markers of immune (n=32), metabolic (n=11), cardiovascular (n=6), liver (n=2) and musculoskeletal (n=1) function identified. 105 studies were eligible for meta-analysis, including 80, 26, 4 and 0 studies on schizophrenia, MDD, BD and GAD respectively. Meta-analysis revealed increased HDL-cholesterol, waist-hip-circumference ratio, triglycerides, insulin, insulin resistance, 2-hr glucose, neutrophil, monocyte, white blood cell, IL-4 and systolic blood pressure, and reduced albumin in schizophrenia; increased TNF- and IL-10 in MDD; and increased IL-6 and IFN-{gamma} in both schizophrenia and MDD. Other results were narratively discussed. Conclusions Alterations in peripheral organ function across multiple systems characterizes the onset of psychiatric disorders. However, research on peripheral organ function in psychiatry is limited and primarily focusses on the immune and metabolic systems.

Introduction: Preterm birth is often associated with fetal membrane (FM) inflammation. Opioid-use disorder during pregnancy is a major public health issue as all opioids carry a risk for preterm birth. While maintenance therapy with methadone improves maternal outcomes, it also elevates the risk of preterm birth. We previously reported that the opioid, buprenorphine, induced human FM sterile inflammation. The goal of this study was to investigate if methadone also induced FM inflammation and to determine the mechanisms involved. Methods: Human FM explants were treated with or without methadone in the presence or absence of inhibitors to TLR4/MD2, TLR7, TLR8, NLRP3, the -opioid receptor, p65 NF{kappa}B, p38 MAPK, ERK or JNK. Supernatants were measured for cytokines/chemokines by ELISA. Tissues were analyzed by Western blot for NF{kappa}B and MAPK activity, and by RT-qPCR for the TLR7/8-activating miRs: miR-21a, miR-29a, miR-146a-3p, Let-7b. Pregnant C57BL/6 mice were injected with PBS or methadone on E15.5 and 6hrs later FMs were analyzed by RT-qPCR. Results: Methadone elevated human FM explant secretion of IL-1{beta}, TNF, MIP-1, GM-CSF, and PGE2, and expression of miR-21a. In vivo, methadone elevated mouse FM expression of MIP1A, KC, and COX2. TLR4/MD2 inhibition had no effect on human FM inflammation in response to methadone. NLRP3 inhibition reduced methadone-induced FM IL-1{beta}, TLR7 inhibition reduced methadone-induced FM TNF, and inhibition of either TLR8 or the -opioid receptor reduced methadone-induced secretion of TNF, MIP-1, GM-CSF, and PGE2, but not IL-1{beta} Methadone increased human FM activity of p65 NF{kappa}B, p38 MAPK, JNK, and ERK and inhibition of these signaling pathways collectively reduced methadone-triggered FM inflammation. Finally, naloxone reduced most of the methadone-induced FM inflammatory response. Conclusion: Methadone induces sterile inflammation in human and mouse FMs. In human FMs this inflammation is mediated through activation of innate immune TLR7, TLR8, and NLRP3; the -opioid receptor; and NF{kappa}B/MAPK signaling. These findings provide further insight into the mechanisms underlying the association between opioid use during pregnancy and preterm birth.

Background: Neuropathic pain (NP) remains a therapeutic challenge, with conventional repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) yielding a response rate of approximately 40%. Personalised targeting based on dysfunctional neurocircuitry offers a promising strategy to enhance efficacy, yet its application in NP is unexplored. This open-label trial investigated a novel targeting approach guided by the recently described cingulo-opercular and somato-cognitive action (CON-SCAN) network, a circuit integrating cognitive and affective dimensions of pain. Methods: Twenty patients with NP received 10 sessions of M1-rTMS over two weeks, with the stimulation site individually localised based on maximal functional connectivity to a CON template. Results: Increased CON-SCAN connectivity from baseline to post-treatment was associated with reduction in pain interference, anxiety and depression scores. The response rate was 50% post-treatment, which was maintained at the 1-month follow-up. Improvements were also observed in neuropathic pain symptoms, negative affect, and overall health. Conclusions: As the first connectivity-guided rTMS trial for NP, this study provides preliminary evidence that personalised targeting of the CON-SCAN network is feasible and associated with the analgesic effects of M1-rTMS, supporting further investigation in randomised controlled trials. Trial registration: Chinese Clinical Trial Registry, ChiCTR2500104679. Registered 20 June 2025, http://www.chictr.org.cn. Chinese Clinical Trial Registry, ChiCTR2400094568. Registered 24 December 2024, http://www.chictr.org.cn. Keywords: Personalised TMS; Pain; M1; CON; SCAN

Vaping of cannabis and its primary components, including {triangleup}9-tetrahydrocannabinol (THC), has increased during the last decade, especially among adolescents and adults. While the behavioral consequences of THC, including anxiety, depression, and associated impacts on reward-related signaling, are well documented, evaluation of additional pathways that have implications for neuronal function remains relatively unexplored. Further, despite evidence of the impact of THC on several physiologic processes, most studies have focused on the brain even though the endocannabinoid system with which THC interacts has widespread expression and functions throughout the body. To address these gaps, we obtained biological samples from adult female Sprague-Dawley rats (N=5-6 per group; all females) that were passively exposed to THC or vehicle vapor and then allowed to self-administer vaporized THC or vehicle intermittently for nine months. Animals were euthanized, and brain and peripheral organs were collected for analyses. We evaluated genes of endocannabinoid system-related receptors, modulators, ion channels, and metabolic enzymes, along with immune and microbiome-related pathways in 9 peripheral organs, 14 brain regions, and plasma. We observed that rats exposed to chronic intermittent THC vapor administration had widespread modulation of several endocannabinoid-system genes only in the brain, with most changes occurring in the dorsal striatum and hippocampus. In contrast, endocannabinoid-system gene expression in all evaluated peripheral organs remained unchanged after THC exposure. Similar findings occurred with immune-relevant genes, where il-1beta, il-6, ccl2, and mx1 were modulated only in the brain while expression in peripheral organs remained unchanged. Immune system modulation following chronic THC exposure significantly elevated plasma concentrations of IL-17A, gut microbiota dysbiosis, and global changes to circulating metabolites, including several amino acids, fatty acids, aminosugar, and nucleic acids. Our findings provide, for the first time, a whole-body evaluation of the molecular effects of chronic THC exposure throughout adulthood on the endocannabinoid and immune systems that have implications for cannabinoid-related behavioral effects.

Objective: Perceived injustice is a psychosocial risk factor associated with delayed recovery and poor occupational outcomes among workers with pain conditions. We examined a theory-informed pathway linking occupational stressors, perceived injustice, pain interference, depressive symptoms, and insomnia, while evaluating selected measurement properties of the Japanese Injustice Experience Questionnaire-Short Form (IEQ-SF-J). Methods: This cross-sectional online survey included 600 Japanese workers (300 with headache and 300 with low back pain). Structural validity of the IEQ-SF-J was evaluated using exploratory and confirmatory factor analyses (CFA) and item response theory. Construct validity was examined using Spearman correlations. Structural equation modelling (SEM) estimated indirect associations between job demands or low job control and pain interference, depressive symptoms, and insomnia, with perceived injustice specified as a latent intervening construct. Results: CFA supported a unidimensional structure (comparative fit index = 0.993; root mean square error of approximation = 0.080). Internal consistency was acceptable (Cronbach's ; = 0.82; McDonald's {omega}; = 0.90), and test-retest reliability was moderate (intraclass correlation coefficient = 0.60). IEQ-SF-J scores correlated significantly with pain interference, insomnia, and depressive symptoms. Job demands and low job control showed significant indirect associations with all three outcomes involving perceived injustice. Conclusions: The IEQ-SF-J showed supportive evidence for several measurement properties and occupied a theoretically coherent position in associations linking occupational stressors with pain interference, depressive symptoms, and insomnia among workers with headache or low back pain.

Neurological and cardiovascular disorders frequently coexist, yet targeted dual-system interventions remain underinvestigated. Transcranial magnetic stimulation (TMS), including intermittent and continuous theta-burst stimulation (iTBS/cTBS), non-invasively modulates primary motor cortex (M1) excitability. Concurrently, ketone monoesters (KME) show neuroprotective potential and alter cardiovascular hemodynamics. In a randomized, double-blind, placebo-controlled crossover study, 44 healthy young adults were stratified to receive iTBS or cTBS (n = 22/group). Participants completed two sessions separated by 1 week, consuming either a KME or placebo beverage, followed by TBS 1-hour post-ingestion. Motor evoked potentials (MEPs) from the right first dorsal interosseous muscle were tracked for 30 minutes post-stimulation. Blood pressure was measured every 3-5 minutes, heart rate was monitored continuously, and venous blood was sampled for glucose, beta-hydroxybutyrate (BHB), pro-BDNF, mature BDNF (mBDNF), and the BDNF rs6265 polymorphism. We found that KME significantly elevated blood BHB and heart rate while decreasing blood glucose and diastolic blood pressure. KME did not alter resting motor threshold, baseline MEP amplitude, or MEP latency. Factorial analysis showed no significant modification of post-TBS MEP time courses by KME. In exploratory within-condition analyses, placebo-cTBS induced significant late increases in MEP amplitude, whereas KME-cTBS showed a blunted post-stimulation response. Serum mBDNF and pro-BDNF concentrations remained unchanged. In conclusion, combining KME and TBS is feasible, well-tolerated, and may exert concurrent neurological and cardiovascular effects. This work opens the door to a novel metabolic-neuromodulatory avenue that merits confirmation in larger cohorts and establishment of clinical relevance in patients with comorbid neurological and cardiovascular disorders.