Schizophrenia Research

BackgroundNegative symptoms are core features of schizophrenia that relate strongly to functional impairment, yet interventions targeting these symptoms remain largely ineffective. Emerging theoretical work highlights how environmental factors may shape and maintain negative symptoms. Although racial disparities in schizophrenia diagnosis among Black Americans are well documented and linked to racial stress and psychosis, the impact of racial stress on negative symptoms has not been examined. This study provides an initial test of a novel theory proposing that racial stress - here measured by racial discrimination - influences negative symptom severity through exacerbation of negative cognitions about the self, particularly defeatist performance beliefs (DPB). Study DesignParticipants diagnosed with schizophrenia-spectrum disorder (SSD) (N = 208; 80 Black, 128 White) completed the Positive and Negative Syndrome Scale (PANSS), the Defeatist Beliefs Scale, and self-report measures of subjective racial and ethnic discrimination (Racial and Ethnic Minority Scale and General Ethnic Discrimination Scale). Relationships among variables were tested using linear regression and mediation analysis. Study ResultsBlack participants exhibited significantly greater total and experiential negative symptoms than White participants with no group difference in DPB. Racial discrimination explained 46% of the relationship between race and negative symptoms. Among Black participants, higher DPB were associated with greater negative symptom severity. Discrimination was positively related to both DPB and negative symptoms. DPB partially mediated the relationship between discrimination and negative symptoms. ConclusionsFindings suggest that racial stress contributes to negative symptom severity via defeatist beliefs among Black individuals, highlighting potential targets for culturally informed interventions.

Background: Diminished Expression (DE) and Amotivation/Apathy (AA) are widely recognized as two main factors of negative symptoms. This study aimed to 1) examine the longitudinal stability of the DE-AA structure and its variation throughout a 5-year follow-up in people with first-episode psychosis (FEP), and 2) investigate whether DE and AA have distinct predictive value compared with the unitary construct of negative symptoms. Study Design: 227 participants from the EUropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and Genetics and Psychosis (GAP) studies were included at FEP and were followed up 5 years later. One-factor (global negative symptoms), uncorrelated two-factor (DE-AA), and correlated two-factor structures were modelled using confirmatory factor analysis. Regression analyses were applied to examine the associations between these factors and negative symptom trajectories, functioning, and quality-of-life outcomes. Study Results: The correlated two-factor model composed of DE and AA best fitted the data and exhibited 5-year stability. The regression model adjusted for AA accounted for more variance (59.2%) than global negative symptoms (52.8%) in explaining the enduring course of negative symptoms. Baseline AA was the only negative symptom factor that significantly predicted individuals' functional outcome at follow-up (B=-1.76, p=0.037). All negative symptom dimensions negatively predicted employment status, whereas lower educational attainment was primarily related to AA severity at baseline. Conclusions: Our findings support the validity and longitudinal stability of the two-dimensional (DE-AA) approach to negative symptoms in individuals with FEP. AA in particular exhibited distinctive predictive value, underscoring its potential clinical utility for early identification and the development of targeted interventions.

BackgroundPsychosis has been conceptualised as a continuum extending from healthy individuals with psychotic-like experiences to clinical populations with schizophrenia. It is unclear which biological mechanisms found in chronic schizophrenia extend across the psychosis continuum to healthy individuals with high positive schizotypy (HS). In this study, we used computational modeling to test whether changes in effective connectivity and excitation/inhibition (E/I) balance reported in schizophrenia are also found in HS. MethodsA total of 2425 individuals from the general population were screened for HS. A subset (N=141) was invited for in-depth phenotyping. Resting-state functional magnetic resonance imaging (rsfMRI) and proton magnetic resonance spectroscopy (1H-MRS) were recorded in n=69 HS individuals and n=72 group-matched controls with low schizotypy (LS). We used dynamic causal modeling to estimate effective connectivity between bilateral primary auditory cortex (A1), superior temporal gyrus (STG), and inferior frontal gyrus (IFG). ResultsBilateral backward connectivity from IFG to STG was significantly reduced in HS compared to LS. Widespread cortical disinhibition in the auditory cortex-IFG network correlated with more severe positive schizotypy scores and impulsive nonconformity. Reduced excitability in the same network was correlated with stronger cognitive disorganisation. ConclusionsOur results favour a psychosis-continuum hypothesis, suggesting that reduced top-down drive from frontal cortex and compensatory allostatic upregulation of cortical excitability, as observed in chronic schizophrenia, also extend to groups with sub-clinical psychotic symptoms. Frontal cortex dysfunction may serve as a biologically interpretable biomarker of psychosis risk and a target for preventative interventions.

Background: The highly influential predictive processing theory of psychosis posits that symptoms arise from imbalances in the weighting of predictions (priors) and sensory evidence. Despite this theory's increasing prominence, studies often present conflicting results. This is particularly problematic as findings from single tasks with modest sample sizes are frequently used to advance a theory for a generalised altered reliance on priors in psychosis. Methods: This study presents a random-effects, multi-level meta-analysis (PROSPERO CRD42024574379) evaluating evidence for aberrant reliance on priors in psychosis across perceptual tasks. The search identified articles in Embase, MEDLINE, APA PsycINFO, and APA PsycArticles published between 1st January 2005 and 31st October 2024, with risk of bias assessed using the Newcastle-Ottawa Scale. Included articles (34 results from 27 studies) compared adults with schizophrenia-spectrum psychosis (SZ; n = 904) to healthy controls (n = 1,039) on behavioural measures representing reliance on priors. Results: Results provided no evidence for atypical reliance on priors in psychosis (g = .03, 95% CI [-0.27, 0.34]; p = .818) or associations with delusions (6 results; SZ = 183; r = -.16, 95% CI [-0.51, 0.19]; p = .293) or hallucinations (10 results; SZ = 370; r = .04, 95% CI [-0.28, 0.36]; p = .780). In contrast with the theory that psychosis may differentially affect priors at different levels of the cognitive hierarchy, a sub-group analysis indicated that a two-level hierarchical model of priors did not account for conflicting results (F(1,32) = 0.1, p = .758). Conclusion: These findings do not suggest that psychosis is associated with a generalised predictive processing deficit spanning multiple aspects of perception. Key words: psychosis, schizophrenia, predictive processing, prior expectations, perception

Schizophrenia is a serious mental disorder that changes the way people think, perceive, and manage daily life. Getting the diagnosis right is critical for proper treatment, but in practice it is often difficult. Current evaluations depend mostly on a clinicians judgment, and the overlap of symptoms with bipolar disorder or major depression makes the task even harder. EEG offers a safe and noninvasive way to study brain activity, yet no single EEG feature has been reliable enough to stand on its own. This makes it important to look at integrative approaches that bring together different aspects of brain dynamics. In this study, we analyzed EEG features to distinguish patients with schizophrenia from healthy controls. Spectral power was measured across {delta}, {theta}, , {beta}, and {gamma} bands. Temporal irregularity was quantified with Multiscale Permutation Entropy (MPE), which to our knowledge represents the first application of MPE to EEG in schizophrenia. Functional connectivity was estimated with the weighted Phase Lag Index in {theta}, , and {beta} bands, followed by extraction of graph measures including global efficiency, clustering coefficient, characteristic path length, and mean strength. These features were used to train Random Forest, Multi-Layer Perceptron, and Support Vector Machine classifiers. Among the models, Random Forest achieved the most reliable performance, reaching 99.7% accuracy under stratified 5-fold validation and 99.6% under leave-one-subject-out validation. Feature analysis showed that connectivity in {theta} and bands contributed most strongly to classification. Topographic maps of {theta}, , and {beta} activity also revealed regional group differences. Overall, the results suggest that combining spectral, entropy, and connectivity measures offers a promising framework for EEG-based detection of schizophrenia. Nevertheless, these findings are preliminary given the limited sample size (N=28), and replication in larger and more diverse cohorts is required before clinical translation.

Cognitive deficits are a core feature of schizophrenia, yet their neural mechanisms remain poorly understood. Network switching, a measure of how frequently brain networks change their interactions over time, has been linked to cognitive performance in healthy individuals and has been reported to be altered in schizophrenia. Recent evidence further suggests that the relationship between network switching and cognition depends on arousal, which is itself disrupted in schizophrenia. However, whether arousal-related alterations in network switching contribute to cognitive impairment in schizophrenia remains unclear. Here, we used concurrent resting-state functional MRI (fMRI) and pulse oximetry data from 39 healthy controls (HC), 27 psychiatric controls (PC), and 39 individuals with schizophrenia spectrum disorders (SSD) to examine whether network switching relates to indices of autonomic arousal. Additionally, in HC and SSD participants, we tested whether arousal moderated the association between network switching and performance on an attention task. We observed no group differences in autonomic arousal. However, PC exhibited higher dorsal default mode and anterior salience network switching rates compared to SSD participants. Additionally, autonomic arousal significantly moderated the relationship between network switching and cognitive performance in HC, an effect that was absent in SSD. Notably, these findings implicate network switching as a potential neural biomarker that differentiates PC from SSD. They also suggest that disrupted coupling between arousal state and network switching, rather than switching alone, may underlie cognitive dysfunction in SSD.

IntroductionTotal and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses (aff-P) cases could be a roadblock if these differ in cellular pathology. MethodsWe examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations (1H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis, including 20 schizophrenia and 13 aff-P cases. ResultsNP-aff and HC had similar total cognition (46.64{+/-}12.01 vs 41.10{+/-}17.88), both superior psychosis (28.34{+/-}12.34; ps<0.01). Metabolite concentrations were similar across all groups but showed significant within-group associations to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, ps<.05), although no biomarker predicted total cognition in the clinical groups. For NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). In all psychotic cases only reduced myelin/membrane concentrations predicted deficits (-.514, p<.05); but separating schizophrenia from aff-P, respectively showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) but higher myelin/membrane and neuronal integrity concentrations (.575, .581, ps<.05) in aff-P. ConclusionsSchizophrenia and aff-P significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.

Schizophrenia frequently follows a chronic relapsing-remitting course, comprising alternating episodes with and without psychotic symptoms (hereafter: psychosis and psychotic remission). One potential neurobiological correlate of this course is aberrant dopamine synthesis and storage (DSS) in the striatum, which can be estimated by 18F-DOPA positron emission tomography (PET). We hypothesised that striatal DSS in patients with schizophrenia decreases from psychosis to psychotic remission, with lower striatal DSS in patients during psychotic remission compared to healthy subjects. Additionally, we explored whether striatal DSS is associated with psychotic relapse after remission. 18F-DOPA PET scans and clinical assessments were conducted in 28 patients with schizophrenia at two timepoints, first during psychosis and second during early psychotic remission 6 weeks to 12 months after the first timepoint, as well as in 21 healthy controls, assessed twice in a comparable time interval. The averaged influx constant kicer as proxy for DSS was calculated for striatal subregions (i.e., nucleus accumbens, caudate, and putamen) using voxel-wise Patlak modelling with a cerebellar reference region. Mixed-effects models and post hoc analyses were used to test for longitudinal changes in kicer and cross-sectional group differences. An exploratory clinical follow-up 12 months after the second scan was conducted to assess psychotic relapse, and post hoc ANCOVAs were used to test for differences in kicer at each session between relapsing and non-relapsing patients. Kicer in both caudate and nucleus accumbens significantly changed from psychosis to psychotic remission compared to healthy controls, with a significant longitudinal decrease of caudate kicer in patients. Furthermore, kicer in both caudate and accumbens was significantly lower in patients during early psychotic remission compared to controls. At the exploratory clinical follow-up, 32% of patients had experienced a psychotic relapse; they showed higher caudate kicer compared to non-relapsing patients during psychosis, with no difference during psychotic remission. These findings provide evidence for the link between striatal, particularly caudate, DSS and the relapsing-remitting course of psychotic symptoms in schizophrenia, with lower caudate DSS during early psychotic remission. Data suggest altered striatal dopamine synthesis together with impaired DSS dynamics along the course of psychotic symptoms in schizophrenia.

BackgroundSchizophrenia is marked by impairments in emotional processing and social cognition, yet traditional neuroimaging paradigms often lack the ecological validity to capture these deficits in real-world contexts. MethodsIn this study, we used intersubject correlation (ISC) analysis of functional MRI data to examine shared neural representations of naturalistic visual narratives in individuals with schizophrenia and healthy controls. Participants viewed short films designed to evoke happy, sad, and emotionally neutral responses, allowing us to compare how synchronized brain activity varied with emotional content across and within groups. ResultsHealthy controls showed greater ISC in regions associated with affective salience, emotion recognition, and social understanding, including the amygdala, insula, and temporal cortices. In contrast, participants with schizophrenia displayed higher synchrony in visual, subcortical, and frontal areas, suggesting a reliance on perceptual and executive systems. To isolate the effects of emotion from general visual processing, we compared ISC during emotional clips relative to neutral videos. This revealed significantly reduced synchrony in the bilateral amygdala in patients, highlighting a core dysfunction in affective engagement. Interestingly, neutral stimuli elicited unexpectedly strong synchronization in frontal and limbic regions in the schizophrenia group, possibly reflecting altered salience attribution to ambiguous or emotionally ambiguous content. ConclusionsThese results point to a functional reorganization of affective processing in schizophrenia, where impaired limbic recruitment is accompanied by compensatory engagement of perceptual and cognitive control networks. ISC during naturalistic stimulation emerges as a powerful tool for capturing subtle disruptions in shared emotional experience in psychiatric populations.

Schizophrenia (SCZ) and type 2 diabetes mellitus (T2DM) are common comorbid disorders that severely impair patient prognosis and quality of life. This study aimed to explore the association between the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and MTHFR promoter methylation in patients with comorbid SCZ and T2DM. A total of 120 participants were enrolled from Liaocheng Fourth Peoples Hospital between January 2025 and June 2025, comprising 30 subjects in each of the four groups: SCZ group, T2DM group, SCZ-T2DM comorbid (SCZ+T2DM) group, and healthy control (CTL) group. Corresponding primers were designed for genetic analysis, and methylation-specific PCR (MSP) was performed to detect the methylation level of the MTHFR promoter. Genotype distribution of the MTHFR C677T polymorphism was consistent with Hardy-Weinberg equilibrium (HWE) (p>0.05). The C677T polymorphism was significantly associated with an elevated risk of SCZ and T2DM comorbidity (p<0.05). Notably, the methylation rate of the MTHFR promoter in the SCZ+T2DM group (95.00%) was not significantly higher than that in the CTL group (90.00%) (p>0.05). In conclusion, the MTHFR gene may serve as a susceptibility gene for SCZ-T2DM comorbidity, whereas MTHFR promoter methylation is not associated with the pathogenesis of this comorbid condition. These results indicate that genetic variation in MTHFR, rather than promoter methylation, contributes critically to the comorbidity of SCZ and T2DM in the Han Chinese population. Our findings may provide novel molecular insights into their shared pathophysiology and inform future clinical strategies for patients with this complex phenotype.

BackgroundSchizophrenia is associated with widespread cognitive impairments. Several early risk factors for schizophrenia have been identified, and some studies suggest associations between these early risk factors and cognition, yet the literature is sparse in psychosis. MethodsClinical cohorts of child/adolescent and adult patients with first-episode psychosis (FEP) and healthy controls (HC) were linked with register-based information (N=276). Gestational age, Apgar scores, birth weight and length, parental age, and season of birth were extracted from the Danish medical birth registry. Cognition was assessed at time of diagnosis using BACS, CANTAB, and WAIS-III/WISC-IV. Missing data was imputed using MICE. Canonical correlation analysis (CCA) was used to examine patterns of associations. Post hoc analyses explored group differences according to diagnosis, age, and sex. ResultsCCA resulted in two significant patterns of associations. CCA1 was stable across imputations (r=0.44, p=.036, pmin= .017, pmax= .055), and constituted by a risk profile of lower maternal age, lower birth length, being small for gestational age, and lower birth weight and a cognitive profile of lower estimated IQ and poorer working memory, mental flexibility, processing speed, verbal fluency, and motor latency. The pattern was more expressed in FEP compared to HC and in adults compared to children. CCA2 was more unstable across imputations (r=0.38, p=.033, pmin=.003, pmax=.168) and constituted by a broad pattern of minor loadings. ConclusionCognitive functioning later in life is associated with multiple early risk factors, underscoring the complexity of developmental processes and the importance of the early developmental context in shaping cognitive trajectories.

Background and Hypothesis: Environmental exposures linked to schizophrenia may play a role in shaping long-term clinical outcomes among individuals with psychotic disorders. This study examined whether the Maudsley Environmental Risk Score (ERS), a cumulative measure of five established environmental risk factors, predicts trajectories of symptoms, cognition, and psychosocial functioning over 25 years following first hospitalization for psychosis. Study Design: Participants were drawn from the Suffolk County Mental Health Project, a longitudinal cohort of individuals with first-admission psychosis assessed six times over two decades. A total of 516 participants had sufficient ERS data and repeated assessments of symptoms (SAPS, SANS), cognitive ability, and functioning (GAF). Study Results: Linear mixed-effects models showed that higher ERS was significantly associated with lower global functioning ({beta} = -0.104, p = 0.008), an effect that remained consistent over time. ERS also predicted more severe and worsening reality distortion ({beta} = 0.082, p = 0.023 for intercept; {beta} = 0.005, p = 0.032 for slope of time). No significant associations were observed between ERS and cognitive ability, disorganization, or negative symptoms. Conclusions: These findings highlight the contribution of environmental risk to functional impairment and persistent positive symptoms across the course of psychotic illness. Incorporating ERS into clinical risk models may aid the identification of individuals likely to experience a more severe illness trajectory, and inform long-term treatment planning.

ObjectiveTobacco use is a leading cause of mortality in schizophrenia, but treatments are partially effective. Default mode network (DMN) pathology is linked to tobacco use in schizophrenia, and transcranial magnetic stimulation (TMS) applied to the DMN affects craving in schizophrenia. To advance TMS therapeutics for tobacco use in schizophrenia, we used TMS experiments to 1) determine optimal stimulation parameters then 2) compare our optimal parameters against a well-established, effective TMS intervention for craving. MethodsIn Protocol Optimization TMS, nicotine-using individuals with schizophrenia (n=10) received single sessions of DMN-targeted TMS with pre/post neuroimaging and craving assessment. Neuroimaging analysis revealed bilateral parietal DMN connectivity was associated with craving change. In Comparative Effectiveness TMS (n=62), nicotine-using individuals with schizophrenia and non-psychosis controls participated in a crossover study comparing DMN-targeted and left dorsolateral prefrontal cortex (DLFPC)-targeted TMS with pre/post neuroimaging and craving assessment. Mixed effects models were used to determine effects of target, group, and relationship between craving change and connectivity change. ResultsIn Protocol Optimization TMS, increased craving was associated with increased bilateral parietal DMN connectivity (mean pFDR<0.012, r=0.60). In Comparative Effectiveness TMS, both interventions reduced craving (DLPFC: p=0.0015; DMN: p=0.0054) and bilateral parietal DMN connectivity (DLPFC: p=0.024; DMN: p=0.022). There was an interaction of bilateral parietal DMN connectivity change, group, and age (p=0.001) where connectivity change was associated with craving change in older individuals with schizophrenia (p=0.041) but not other groups. ConclusionsBilateral parietal DMN connectivity is a novel mechanism underlying craving in schizophrenia that can be engaged for therapeutic benefit.

Background Cognitive impairment is a core feature of schizophrenia and a major determinant of functional disability. Executive deficits affect approximately 85% of patients and are associated with reduced activity in the prefrontal cortex (hypofrontality). Current pharmacological treatments show limited efficacy in improving cognition, highlighting the need for alternative therapeutic approaches. Combining non-invasive brain stimulation with cognitive remediation may enhance neuroplasticity and improve cognitive outcomes. Methods This prospective, randomized, double-blind, sham-controlled, parallel-group superiority clinical trial. A total of 120 adults aged 18-65 years with clinically stable schizophrenia diagnosed according to DSM-5 criteria will be enrolled at a single clinical center. Participants will be randomly assigned in a 1:1 ratio to receive either active transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex followed by cognitive remediation therapy (CRT) using the RehaCom system, or sham stimulation followed by the same cognitive training. Assessments will be conducted at three time points: prior to the intervention (V1), immediately after the intervention (V2), and during the follow-up visit 8 weeks after the intervention (V3). The primary outcome is change in cognitive performance measured with the CANTAB battery. Secondary outcomes include symptom severity assessed with the PANSS, global clinical status (CGI-S), and neurophysiological changes measured by EEG. Written informed consent will be obtained from all participants, and the study has received ethics committee approval. Discussion This trial will evaluate whether tDCS administered prior to cognitive training enhances cognitive improvement compared with cognitive training alone. The findings may inform the development of more effective interventions targeting cognitive deficits in schizophrenia. Trial registration ClinicalTrials.gov Identifier: NCT07273175. Registered on 25 November 2025.

BackgroundSchizophrenia is a neurodevelopmental disorder shaped by immune-related mechanisms, particularly dysregulated complement-mediated synaptic pruning. Genome-wide association studies have identified CSMD1 as a major schizophrenia risk gene, an association robustly replicated across populations of diverse ancestries. As a complement regulator, CSMD1 further links genetic vulnerability to synaptic refinement processes. However, the transcriptional status of CSMD1 and its homolog CSMD2 in individuals with schizophrenia (SZ individuals) remains poorly characterized. We conducted a meta-analysis of gene-expression datasets to determine whether CSMD1 and CSMD2 are differentially expressed in brain and peripheral tissues, and to assess the concordance between central and peripheral transcriptional signals. MethodsTranscriptional data were obtained from gene expression omnibus. Random-effects meta-analyses were performed on CSMD1 and CSMD2 expression data from 854 postmortem brain samples derived from 348 SZ individuals and 346 healthy controls (HC), and 295 peripheral blood samples from 162 SZ individuals and 133 HC. Sex-stratified analyses and meta-regressions evaluated potential moderators. ResultsIn brain tissues, CSMD2 expression was significantly increased in SZ individuals vs. HC (SMD: 0.22 [0.05; 0.39], adj-p=0.026), whereas CSMD1 showed no differential expression. The female-only meta-analysis revealed nominal CSMD2 overexpression (p=0.037) in brain tissues, not surviving correction. No significant transcriptional differences were detected in peripheral blood. ConclusionIn schizophrenia, our findings point to a dissociation between genetic vulnerability and transcriptional activity within the CSMD gene family. Schizophrenia is associated with selective brain CSMD2 overexpression, contrasting with unchanged CSMD1 transcription and absent peripheral blood alterations. These findings support complement-related dysregulation as a central pathway in schizophrenia.

Weak inhibition of mitochondrial complex I (mtCI) has been shown to have neuroprotective effects in cellular and animal models of Alzheimers and Huntingtons diseases, at least in part by enhancing mitochondrial biogenesis and function. Mitochondrial dysfunction has also been demonstrated in schizophrenia patients and mouse models of schizophrenia. We tested whether weak inhibition of mtCI would ameliorate mitochondrial and behavioral phenotypes in a mouse model of schizophrenia. In mice with four copies of the Gldc gene, 8 weeks of treatment with the weak mtCI inhibitor, the small-molecule tricyclic pyrone compound CP2, reversed spontaneous alternation deficits in the Y maze, startle habituation deficits, and social novelty deficits in the three-chamber social interaction test. Consistent with the mechanism of action, Western blots revealed that CP2 reverses the reduced expression of PGC-1, a master regulator of mitochondrial biogenesis, and of the VDAC1, a primary gatekeeper for the exchange of metabolites, ions, and ATP between mitochondria and the cytosol. These findings suggest that the improvement of mitochondrial function may represent a novel strategy to reverse pathophysiological and behavioral deficits in schizophrenia.

Working memory depends on gamma oscillations generated across sensory and prefrontal cortices. In sensory cortices such as primary visual cortex (V1), stimulus-locked gamma oscillations encode stimulus information, while in prefrontal cortex (PFC), persistent gamma oscillations maintain this information after the stimulus is removed. In schizophrenia (SZ), gamma power is reduced in both V1 and PFC, consistent with deficits in sensory encoding and working memory maintenance in the illness. These two regimes of gamma oscillations arise from a canonical microcircuit involving pyramidal neurons (PNs) and parvalbumin-expressing interneurons (PVIs). Yet, whether stimulus-locked and persistent gamma oscillations are similarly or differentially vulnerable to synaptic alterations within this circuit in SZ remains unknown. To investigate this question, we used a mean-field model of the PN-PVI circuit generating either stimulus-locked or persistent gamma oscillations. We then assessed the effects of three synaptic alterations found in SZ: lower excitatory drive to PVIs (E[-&gt;]I), lower inhibitory drive to PNs (I[-&gt;]E), and greater variability in E[-&gt;]I synaptic strength. Each alteration produced larger gamma power deficits in the persistent regime than in the stimulus-locked regime. When applied together, these alterations interacted synergistically to reduce gamma power in both regimes, with the persistent regime exhibiting a more pronounced deficit. Among the three parameters, E[-&gt;]I synaptic strength was the strongest contributor to the synergistic loss of gamma power. Two-dimensional bifurcation analyses further revealed that this differential vulnerability arises from a narrower margin of oscillatory stability in the persistent regime, where the parameter values producing maximum gamma power sit closer to the Hopf bifurcation boundary. Together, these findings identify the persistent regime as intrinsically more fragile than the stimulus-locked regime, with the implications for understanding regional patterns of synaptic pathology and cortical gamma oscillations with distinct dynamics in SZ. Author summaryWorking memory depends on stimulus-locked gamma oscillations in sensory cortices such as primary visual cortex (V1) for encoding stimulus information, and persistent gamma oscillations in prefrontal cortex (PFC) for maintaining this information after stimulus offset. In schizophrenia (SZ), gamma power is reduced in both V1 and PFC, and postmortem human brain studies suggest that the underlying synaptic alterations are more severe in V1 than in PFC. Our computational modeling results suggest that this regional pattern arises because persistent gamma oscillations are intrinsically more fragile than stimulus-locked gamma oscillations, so that smaller synaptic alterations are sufficient to disrupt gamma oscillations in PFC while larger alterations are required to produce comparable disruption in V1. Together, these findings give rise to a differential vulnerability model of cortical gamma oscillations in SZ, linking the regional patterns of synaptic pathology to the deficits in gamma oscillations observed across sensory and prefrontal cortices in the illness.

Background: Psychotic disorders such as schizophrenia have been associated with older-appearing brain structure, commonly quantified using the brain-age paradigm. However, it remains unclear whether these alterations are present at illness onset and whether antipsychotic treatment modifies their trajectory. Methods: In this study, 61 (28 females and 33 males) antipsychotic-naive people with first-episode psychosis were randomised to receive either a second-generation antipsychotic (risperidone or paliperidone) or placebo over a 6-month treatment period, alongside intensive psychosocial therapy. A healthy control group (n = 27, 17 females, 10 males) was also recruited. Structural MRI scans were collected at baseline, 3 months, and 12 months. Brain age was estimated using two pretrained and validated models (Pyment and CentileBrain). Results: Brain-predicted age difference (brain-PAD) did not differ between patients and healthy controls at baseline (F(1,80) = 1.30; p = 0.26). There were also no significant effects of time, treatment group (antipsychotic, placebo, healthy control), or their interaction on brain-PAD across the first year (all p > 0.26). Findings were consistent across both brain-age models, and brain-PAD was not associated with clinical and lifestyle measures. Conclusion: These findings suggest that altered structural brain ageing is not evident during the earliest stages of psychosis and is not modified by early antipsychotic exposure over the first year of illness. Longer follow-up and approaches that account for illness heterogeneity may be needed to clarify when brain-age alterations emerge in psychotic disorders.

BACKGROUND: Predicting long-term outcomes in first-episode schizophrenia (FES) remains difficult, despite being especially important early in the illness, when timely intervention is most critical. Many potential predictors have been studied, but few are reliable enough to guide early treatment decisions. It also remains unclear how much data from the initial phase of illness is required to improve prognostic accuracy. METHODS: We analysed 68 patients with first-episode schizophrenia (FES) assessed at baseline (V1; mean 0.5 years post-onset, YPO), one-year follow-up (V2; mean 1.2 YPO), and outcome (V3; mean 4.9 YPO). We trained elastic-net models to predict three V3 outcomes-negative symptoms (PANSS Negative factor; Wallwork/Fortgang), global functioning (GAF), and quality of life (WHOQOL-BREF psychological domain)-using either 23 V1 predictors alone or V1 predictors plus V2 data (43 predictors). Performance was evaluated with nested cross-validation on held-out data. RESULTS: Using predictors from the first year (V1+V2), we achieved statistically significant out-of-sample prediction for all three V3 outcomes: PANSS Negative factor (Wallwork/Fortgang) R2=0.22 driven mainly by log(DUP), PANSS Negative at V1/V2, and PANSS Disorganized at V2; WHOQOL-BREF Psychological Health R2=0.22 driven mainly by WHOQOL Psychological Health at V2 and GAF at V2; and GAF R2=0.14 driven mainly by GAF at V2, PANSS Positive at V2, WHOQOL Psychological Health at V2, and hospitalization burden (before V1 and between V1-V2). With baseline-only predictors (V1), only PANSS Negative showed meaningful predictive power (R2=0.15); GAF and WHOQOL-BREF did not outperform the intercept-only baseline. CONCLUSION: In FES, long-term functioning (GAF) and quality of life (WHOQOL-BREF) can not be predicted well from first-episode (V1) measures; at least an additional 1 year of follow-up is needed, implying these outcomes are driven by changes after onset that V1 misses. Negative symptoms differ: they are comparatively stable after initial antipsychotic treatment, and duration of untreated psychosis is their strongest predictor beyond baseline severity-consistent with early biology and treatment timing shaping their level and persistence. These contrasting patterns indicate different outcome phenotypes.

Background and PurposeWhile inflammation has been generally considered to exacerbate symptoms of schizophrenia, some clinical observations suggest that acute inflammation may alleviate positive symptoms. However, animal models often use excessive inflammatory stimuli, and the effects of acute inflammation--comparable to levels observed in patients--remain unknown. Experimental ApproachTo address this, we examined whether acute inflammation induced under relatively mild, clinically relevant conditions suppresses behavioural sensitization in methamphetamine (METH)-sensitized mice, a model of psychostimulant-induced psychosis with relevance to certain aspects of positive symptoms of schizophrenia. We used a repeated METH (1 mg/kg) sensitized model to evaluate the effects of acute inflammation on behavioural sensitization. Acute inflammation was induced via two methods using either lipopolysaccharides (LPS; 1 g/kg) to mimic peripheral immune activation or restraint stress (RS; single 2-h exposure) to model the neuroinflammation induced by psychological stress. LPS doses were adjusted with reference to the magnitude of peripheral cytokine elevation reported in patients, and RS was applied in short single sessions to avoid excessive inflammation. Key ResultsBoth LPS and RS significantly suppressed behavioural sensitization, without inducing other behavioural abnormalities. This suppression was dependent on toll-like receptor-4 activation. LPS-mediated suppression involved cyclooxygenase-2, whereas RS-mediated suppression was linked to the microglia-derived tumour necrosis factor-. LPS did not alter, whereas RS significantly reduced the striatal extracellular dopamine levels. Conclusion and ImplicationsThese findings suggest that acute inflammation suppresses behavioural sensitization through distinct mechanisms depending on the inflammatory trigger, providing a framework for understanding how inflammation may influence psychosis-related processes, with potential relevance to schizophrenia.