Schizophrenia Research

Schizophrenia is associated with cognitive impairments, including deficits in implicit learning. Probabilistic serial reaction time tasks (SRTT) offer an objective approach to characterizing these deficits through both motor execution (ME) and motor imagery (MI), the mental simulation of movement without physical action. Whether implicit probabilistic sequence learning is impaired across both modalities in schizophrenia remains poorly understood. Thirty individuals with schizophrenia (ME: n=12; MI: n=13) and 40 healthy controls (ME: n=20; MI: n=20) completed an auditory probabilistic SRTT. Symptom severity was assessed with the PANSS and cognitive functioning with the MCCB. Healthy controls demonstrated a robust signature of implicit probabilistic sequence learning, whereas participants with schizophrenia exhibited weaker and less consistent learning signatures, particularly during motor imagery. Sensitivity to probabilistic structure differed significantly between groups during motor execution but not motor imagery. Participants with schizophrenia also showed significantly longer reaction times than controls across both modalities, consistent with generalized psychomotor slowing. Greater PANSS-General severity was associated with greater deviation from the probabilistic learning patterns observed in healthy controls during ME, whereas higher MCCB verbal learning scores were associated with greater similarity to these learning patterns during MI. These findings indicate that implicit probabilistic sequence learning is impaired in schizophrenia across both motor execution and motor imagery, and that these deficits are meaningfully associated with clinical symptom severity and cognitive functioning.

Background: Psychotic illnesses are among the most debilitating classes of psychiatric disorders, requiring targeted and effective treatment strategies. Although antipsychotics are the primary pharmacological therapy for psychosis, their full range of effects remain unclear, including effects within the frontal cortex, a brain region linked structurally and functionally to psychotic disorders. Methods: To examine the effects of antipsychotic treatment on the frontal cortex, we conducted a meta-analysis of publicly available rodent (rat, mice) transcriptional profiling datasets (microarray, RNA-Seq). Five datasets (GSE45229, GSE93918, GSE2547, GSE4031.1, GSE66275) were identified within the Gemma database using pre-specified search terms and inclusion/exclusion criteria (date: 7/7/2024), yielding differential expression results for eight drug vs. control comparisons (collective n=68). A random-effects meta-analysis model was fit to the log2 fold changes for each gene, and p-values adjusted for false discovery rate (FDR), with follow-up analyses exploring robustness, heterogeneity, and publication bias. To increase the power and generalizability of our findings, an exploratory meta-analysis was also run incorporating antipsychotic effects from both rodents and nonhuman primates (collective n=101), and compared to findings from individuals with schizophrenia. Results: Our meta-analysis yielded stable estimates for 12,190 genes, identifying 63 genes that were differentially expressed following antipsychotic treatment ("DEGs", FDR<0.05). Differential expression included genes important for serotonergic and cholinergic signalling, and was enriched within pathways linked to oligodendrocyte development and myelination, physiological and cellular stress responses, and cardiovascular function. An exploratory meta-analysis combining rodent and nonhuman primate results confirmed these observations and yielded additional findings (117 DEGs total). Comparisons with human post-mortem findings suggested that some schizophrenia-related gene expression may instead reflect antipsychotic treatment. Conclusion: Further validation is necessary, but our findings suggest that antipsychotics may assist in the regulation of specific structural and functional changes within the frontal cortex linked to psychotic disorders.

Apathy is a major driver of long-term disability in schizophrenia, yet existing accounts focus on how patients evaluate the cost of action while neglecting their capacity to generate options for action in the first place. Using a brief, culture-fair option generation task (OGT) within the international CHANSS study, we examined this process in 150 patients with different stages of schizophrenia and 100 healthy controls across the UK, Spain, and China. The OGT requires drawing as many different paths as possible between two points on a touchscreen, yielding two measures: fluency (the number of paths that they generate) and uniqueness (the distinctiveness of those paths). Patients drew as many paths as controls but produced options roughly half as unique. Across patients, uniqueness was positively associated with verbal fluency and depressive symptom severity, but negatively associated with self-reported behavioural apathy. This suggests that increased apathy is associated with reduced ability to generate unique options (paths on the task). To examine the cognitive mechanisms further, we decomposed uniqueness into four exploratory measures: roaming entropy (spatial breadth of exploration), option elaboration (within-path development), perseveration (local repetition), and novelty maintenance (sustaining diversity over time). Together these explained 69% of the variance in motor-residualised uniqueness and attenuated the group difference by 80%, with roaming entropy as the dominant contributor. K-means clustering revealed three distinct patient profiles, each with a different clinical signature. A small subgroup generated options much like the control group. A larger subgroup retained spatial exploration but developed each option less and reported more depressive symptoms. A third subgroup showed broadly impaired exploration and the lowest verbal fluency. These findings establish option generation as a measurable behavioural phenotype in schizophrenia that relates to apathy and can be decomposed into specific cognitive mechanisms. They suggest that an impoverished option space, marked by reduced generation of unique possibilities for action, may be a remediable component of apathy.

Objective: This study examined the prevalence of psychotic experiences (PE) and how early onset and persistence of PE contribute to risk and severity of mental disorders in adolescents at familial high-risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and adolescents from a population-based control group (PBC). Methods: This is the second follow-up of a nationwide cohort study including 522 children at FHR-SZ (N=202), FHR-BP (N=120), and PBC (N=200). Participants were assessed at ages 7, 11, and 15 using a semi-structured interview to evaluate PE and mental disorders. Results: At age 15, adolescents at FHR-SZ reported more PE than PBC over the past six months (current) and the past four years, while adolescents at FHR-BP only reported more current PE. PE reported at two or three timepoints (persistent PE) predicted any Axis I disorder in mid-adolescence, corresponding to three- (OR 2.9, 95% CI [1.5-5.7]) and 21-fold (OR 21.4, 95% CI [2.8-162.3]) increased risks, respectively. Persistent PE also predicted multimorbidity, with three- (OR 2.8, 95% CI [1.0-7.6]) and four-fold (OR 4.1, 95% CI [1.2-14.1]) increased risks, respectively. This was after adjustment for sex, early mental disorders, and familial risk. Conclusions: This study demonstrates a strong link between persistent PE and mid-adolescence mental disorders. Our findings emphasize PE as important risk markers for mental disorders during mid-adolescence and highlight the importance of monitoring children with PE before age 7 who develop persistent symptoms.

Background: Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods: Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results: In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions: DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.

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.

Introduction: Disturbed interpersonal attunement is a core but poorly operationalised feature of the psychopathology of schizophrenia. Language Style Matching (LSM), the largely unconscious alignment of two speakers' function words during ordinary conversation, offers an observable, dialogue-derived index of this dyadic attunement. An open question is where altered alignment mark who a patient (a stable trait of inner experience) is or how they are (a fluctuating state that shifts with symptom severity)? Objective: To characterise LSM over 12 months in early psychosis relative to controls, and to test, at both between- and within-person levels, whether alignment covaries with core psychopathological dimensions across self-referential (autobiographical) and externally directed discourse. Methods: First-episode and recent-onset patients (n = 109) and controls (n = 60) completed semi-structured interviews at baseline and 12 months. LSM was computed per context and modelled with linear mixed-effects; a Mundlak decomposition partitioned the LSM-symptom association into between- and within-person components. Results: LSM is not a fixed trait: groups were indistinguishable at baseline but diverged by 12 months (Group x Timepoint {beta}=-0.018, p = .029), and the deficit was specific to autobiographical speech. Within individuals, autobiographical alignment tightened as formal thought disorder rose above a patient's own average and as negative symptoms worsened, independent of antipsychotic dose. Conclusion: Patients aligned less than controls when speaking about themselves, yet aligned more as symptoms deteriorated, a shift from self-generated toward partner-scaffolded speech when self-organisation fails. LSM indexes disordered self-anchoring and interpersonal attunement in the negative-disorganized dimension of psychosis.

BackgroundSocial dysfunction is a major source of disability in schizophrenia, yet the neural mechanisms that contribute to impaired social understanding remain poorly understood. Converging evidence points to the role of the default mode network (DMN) in integrating social information over time to construct interpretations of social behaviors. Here, we tested the hypothesis that individuals with schizophrenia show reduced stimulus-driven coordination between brain regions within the DMN during free viewing of naturalistic social stimuli. MethodsA sample of 124 adults (schizophrenia: n=63; healthy controls: n=61) viewed naturalistic video clips during fMRI. Inter-subject functional connectivity (ISFC) was computed within the two groups. Group differences were identified via permutation testing. We also explored group differences in other brain networks to examine whether effects were specific to the DMN. ResultsIndividuals with schizophrenia showed weaker stimulus-driven coupling within the DMN compared to healthy controls, specifically between areas such as the parahippocampal gyrus, precuneus, and medial prefrontal cortex. Group differences in ISFC were specific to the DMN. Furthermore, no between-group differences emerged for within-participant functional connectivity in the DMN, suggesting that the observed effects reflect reduced stimulus-driven coordination among DMN regions when processing social stimuli rather than a more general decline in DMN connectivity. ConclusionsSchizophrenia is characterized by impaired coordination within the DMN as it dynamically integrates social information over time, which could contribute to difficulties in constructing coherent interpretations of real-world social situations. These findings suggest that disrupted stimulus-driven network coordination might underlie social cognitive impairments in schizophrenia, highlighting the value of naturalistic paradigms for revealing network-level dysfunction under conditions that closely approximate real-world experience.

Resting-state electroencephalography (EEG) studies consistently report increased slow-wave activity and reduced alpha power in schizophrenia. However, the regional distribution of EEG relative power (RP) across finer frequency bands, particularly in adolescent schizophrenia, remains poorly characterized. We analyzed a publicly available resting-state EEG dataset comprising 45 male adolescents with schizophrenia (SCZ; mean age: 12.3 {+/-} 1.2 years) and 39 age- and sex-matched healthy controls (CON; mean age: 12.3 {+/-} 1.3years), recorded using 16 scalp electrodes (10-20 system). Following band-pass filtering, artefact subspace reconstruction, spline interpolation, average re-referencing and independent component analysis, RP was computed for nine frequency bands across five cortical regions (frontal, central, parietal, temporal, and occipital). Group differences were assessed using three-way repeated-measures analysis of variance (ANOVA), followed by Bonferroni false discovery rate (FDR)-corrected post-hoc pairwise comparisons using estimated marginal means (emmeans). Compared to controls, the SCZ group showed significantly higher delta RP in the frontal, parietal, and occipital regions and significantly lower alpha2 RP, dissociable from alpha1, in the central, parietal, temporal, and occipital regions (all FDR < 0.001). The occipital cortex showed the greatest increase in delta RP (|Cohens d|=0.82) and the greatest reduction in alpha2 RP (|d|=0.73), with moderate-to-large effect sizes. Topographic maps demonstrated widespread delta enhancement and attenuated occipito-parietal alpha2 activity in the SCZ group. These findings demonstrate region-specific alterations in resting-state EEG relative power in adolescent schizophrenia, particularly within the occipital cortex, and suggest that regional RP may serve as a promising neurophysiological feature for early-onset schizophrenia. HighlightsO_LIResting-state EEG relative power was analyzed in adolescent schizophrenia. C_LIO_LIDelta relative power increased (occipital > parietal > frontal). C_LIO_LIAlpha2, but not alpha1, relative power decreased (occipital > parietal > temporal > central). C_LIO_LIOccipital cortex showed the largest EEG spectral abnormalities. C_LIO_LINine-band analysis improved regional spectral characterization. C_LI

Recent computational approaches to speech in psychosis generate large multidimensional feature spaces capturing semantic and acoustic aspects of language production. However, the clinical relevance of individual measures often becomes difficult to interpret due to redundancy, interaction effects, and high intercorrelation among features. Building upon previous work constructing a single composite index derived from semantic features based on language model embeddings, we here build a second acoustic index derived from speech acoustic features. Our aim was to evaluate the differential performance of both indices in conjunction in PANSS symptom prediction in psychosis in a cross-linguistic setting, including positive symptoms (P1, P2, P3), negative symptoms (N1, N4, N6), and general measures (G5, G9). The dataset comprised five languages and 221 patients with schizophrenia spectrum disorder (SSD). Both indices showed predictive power for individual PANSS scores, while also demonstrating clinically important complementarity: semantic indices were more strongly associated with positive symptom dimensions (P2, P3, Total Positive), whereas acoustic indices showed stronger relationships with negative and general symptoms (N1, N4, G5, G9). Both domains shared predictive overlap for global measures, such as PANSS Total scores. These findings suggest that both indices capture complementary and partially overlapping dimensions of psychopathology. The proposed composite index framework contributes to the advancement of low-dimensional speech-derived markers of symptom severity variation, potentially informing vulnerability to relapse and remission in psychosis.

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.

Relatively preserved insight distinguishes individuals at risk for psychosis from those with full-blown psychosis. Metacognitive processes thought to support insight and uncertainty monitoring may therefore serve as early markers of illness progression. Yet findings have been inconsistent, perhaps partly due to reliance on explicit confidence ratings that introduce reflection and response biases. To address these limitations, we used a novel implicit confidence measure derived from post-decision gaze in a virtual-reality probabilistic learning task. Gaze-based confidence quantifies the alignment between spatial predictions and gaze direction. We assessed first-order learning and gaze-based metacognition in four groups: clinical high-risk for psychosis (CHR-P), first episode psychosis (FEP), help-seeking controls (HSC), and healthy controls (HC). We tested whether implicit metacognition differentiates psychosis risk from psychosis. Learning accuracy was reduced in both CHR-P and FEP compared to control groups. At the metacognitive level, CHR-P confidence levels were approximately commensurate with their reduced first-order performance, indicating preserved confidence calibration, along with preserved metacognitive sensitivity--the ability to distinguish correct from incorrect decisions. In contrast, FEP showed impaired confidence calibration and reduced metacognitive sensitivity. Metacognitive calibration and sensitivity distinguished CHR-P from FEP and provided predictive value in distinguishing CHR-P from FEP, whereas learning accuracy did not. These findings reveal a dissociation between first-order cognitive processes and distinct aspects of implicit metacognition, including confidence calibration and metacognitive sensitivity, across the psychosis continuum. This dissociation may refine early clinical characterization and improve identification of preserved insight-related mechanisms in psychosis risk.

Serotonergic psychedelics (SP) are increasingly used in clinical research and naturalistic settings, but their psychotic-like side effects, including persisting perceptual abnormalities (PPAs), are poorly understood. Psychosis-associated hallucinations are associated with susceptibility to conditioned hallucinations and computationally-estimated overweighting of perceptual expectations, or priors. However, SPs are widely argued to reduce prior weighting. We surveyed 186 naturalistic SP users on prior SP use, SP-associated PPA history, and current PPAs. Participants completed the visual conditioned hallucinations (VCH) task, in which conditioning induces perception of absent stimuli. Behavioral data were used to fit parameters of a computational model to estimate latent states driving percepts and responses. Past and current PPAs were associated with younger age at first use and higher SP doses, lower visual thresholds, higher VCH rate and confidence, and reduced sensory discrimination. Among model parameters, however, only reduced decision precision tracked both measures and mediated the dose-PPA relationship; relative prior weighting rose equivocally, as expected when priors and sensory evidence gain precision together. SP-related PPAs may therefore arise from a noisy visual system biased toward detection, in which priors act as templates that convert sensory noise into expected percepts. These findings may point to a tractable model for how psychotic-like perception emerges.

In about a quarter of people with schizophrenia-spectrum disorder (SSD), the illness is unresponsive to standard antipsychotic treatment, yet the biological mechanisms underlying this remain poorly understood. Although such treatment-resistant schizophrenia (TRS) shares a substantial genetic liability with treatment-responsive schizophrenia, the limited efficacy of dopamine antagonists in TRS indicates that mechanisms beyond dopamine signalling likely contribute to treatment-resistance, requiring the identification of alternative biological pathways. This is the first cross-ancestry genetic study to investigate the genetic architecture of TRS, by directly comparing patients with treatment-resistant and treatment-responsive schizophrenia in two independent Hong Kong (N=798) and STRATA-G consortium (N=1243) cohorts. Using an integrated multi-level analytic framework, we conducted a genome-wide association study (GWAS) with gene-based and gene set-based analyses, pathway polygenic-risk-scores, and transcriptome-wide association study (TWAS). We further conducted gene-set enrichment analysis focusing on expert-curated synaptic pathways and brain tissues. Genetic signals at the gene, pathway, and genetically predicted expression levels were identified within each ancestry. Whereas limited power constrained individual loci discovery and cross-ancestry concordance, enrichment analyses indicated heterogeneous signals across cohorts, including differences in effect direction, but highlighted cohort-specific, synapse-related biology, particularly pathways involved in presynaptic vesicle dynamics, neurotransmission, and synaptic organization. Collectively, these findings highlight synaptic biology as one potential pathway-level signal from common-variant genetic effects associated with treatment resistance in SSD, despite minimal SNP-level discovery. Our work suggests there is promise in pathway-level and multi-omics approaches to elucidate biologically meaningful heterogeneity within SSD and provides support for synaptic mechanisms as potential targets for understanding and stratifying treatment-resistance.

Background: Traumatic brain injury (TBI) is common in older adults and frequently co-occurs with neurological conditions such as dementia, stroke, and Parkinson's disease. Both TBI and neurological disease independently increase vulnerability to psychiatric disorders, yet the long-term impact of lifetime TBI exposure on mental health outcomes within these neurological populations remains poorly understood. Methods: Using data from the UK Biobank cohort (N = 502,154), we examined associations between TBI and subsequent psychiatric diagnoses in individuals diagnosed with dementia, stroke, or Parkinson's disease. Participants were assigned to one of four exposure groups (no TBI and no neurological disease, TBI only, neurological disease only, TBI plus neurological disease), and mixed-effects logistic regression estimated psychiatric risk across these groups and within each neurological condition. Kaplan-Meier curves and Cox proportional hazards models assessed 10-year cumulative risk. All analyses were adjusted for demographic and socioeconomic factors. Results: The combined presence of TBI and neurological disease produced the greatest psychiatric risk, exceeding that observed for either condition alone. Across dementia, stroke, and Parkinson's disease, TBI most reliably increased the odds of mood disorders, while associations for anxiety were less consistent. Ten-year cumulative incidence analyses demonstrated higher risk of mood and overall mental health disorders across all three neurological cohorts. Conclusions: Lifetime TBI exposure is associated with increased likelihood and long-term risk of psychiatric disorders in individuals with dementia, stroke, and Parkinson's disease, with mood disorders being the most consistent outcome across conditions. These findings highlight the importance of recognising TBI history when assessing and managing psychiatric risk in ageing neurological populations and underscore the need for integrated clinical pathways that address both neurological and mental health needs.

Psychosis has been linked to changes in diffusion-derived fractional anisotropy (FA) across multiple white matter tracts, yet most evidence is cross-sectional. Longitudinal findings are inconsistent, and the clinical relevance of white matter changes over time remains unclear. To address this gap, we investigated longitudinal white matter changes and their clinical correlates in early psychosis in a large, multi-centre diffusion-tensor imaging study. Across 18 sites, 407 participants (healthy controls: n = 97, 59.8% men, mean age 23.9{+/-}4.6 years; clinical high risk of psychosis: n = 158, 53.5% men, mean age 23.0{+/-}4.9 years; first-episode psychosis: n = 152, 71.1% men, mean age 25.1{+/-}5.4 years) were scanned at up to three time points over 12 months. FA was assessed in the cingulum bundle, the superior longitudinal fasciculus, the inferior fronto-occipital fasciculus, and at the whole brain level. FA trajectories were analysed using linear mixed-effects models to test effects of group, social and occupational functioning, and (attenuated) psychotic symptoms, while controlling for demographic and socioeconomic covariates. No significant group differences in FA were observed, either globally or within tracts (p > .05). Longitudinal FA trajectories were not associated with changes in (attenuated) psychotic symptoms or functioning (p > .05). In contrast, higher baseline antipsychotic medication dose was significantly associated with lower FA (pcorr < .05). Overall, these findings indicate that white matter microstructure is relatively stable during the clinical-high-risk and first-episode phases of psychosis, and that it is not clearly associated with variation in symptom severity or functional outcomes over time.

Psychosis has long been conceptualized as a disorder of disrupted hierarchical integration across distributed brain systems, yet it remains unclear whether alterations in macroscale cortical hierarchy are already present before illness onset and are associated with subsequent transition to psychosis. Using connectome gradient mapping, we characterized baseline cortical hierarchical architecture along the unimodal-to-transmodal axis in 580 participants from the NAPLS-3 cohort, including converters (CHR-C, n = 56), non-converters (CHR-NC, n = 434), and healthy controls (HC, n = 90). Group differences were assessed at regional, network, and global levels. Group comparisons revealed that CHR-C individuals, relative to the other two groups, exhibited bidirectional alterations selectively along the sensorimotor-to-association gradient, with reduced values in the visual network alongside elevated values in the default mode network, indicating greater separation between sensory and transmodal systems along the gradient. At the global level, CHR-C showed increased explained variance, range, and variation of this gradient, collectively indicating hierarchical expansion. Notably, greater explained variance of this gradient was associated with a shorter time to conversion to psychosis, while increased gradient range and variation were associated with higher positive symptom severity across CHR individuals. These findings indicate that expansion of the sensorimotor-to-association connectome hierarchy is already present before psychosis onset in individuals who subsequently convert to psychosis. This altered hierarchical organization may reflect greater decoupling between sensory and transmodal systems and may characterize neurobiological changes associated with progression from a clinical high-risk state to psychotic illness.

Introduction: Auditory verbal hallucinations (AVH) affect 60-80% of people with schizophrenia, yet existing assessment tools inadequately capture their phenomenological complexity. Aim: To determine whether individuals with schizophrenia spectrum disorders could accurately match auditory verbal hallucination loudness to an external audio track, and to explore participant perspectives on this approach. Methods: Eight participants with schizophrenia spectrum disorders and active AVHs rated loudness via a Likert scale and by adjusting a headphone audio track to match their experience. Structured interviews and thematic analysis captured participant viewpoints. Results: No significant correlation was found between audio tool and Likert scale scores. Seven of eight participants reported the audio tool provided greater precision in quantifying AVH loudness and better enabled them to convey their internal experience to others. Discussion: Audio-matching tools may offer meaningful advantages over traditional scales for quantifying AVH loudness, even where statistical convergence with existing measures is absent. Limitations: Small sample size; loudness alone cannot fully capture the qualitative experience of hearing voices. Implications: This tool shows promise for longitudinal tracking of AVH loudness. Recommendations: Further investigation of digital approaches to AVH assessment is warranted.

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.

Schizophrenia is characterized by persistent executive dysfunction and atypical engagement of prefrontal circuits underlying attentional control. However, the neural dynamics of executive processing during ecologically relevant tasks remain underexplored. This study examined frontal theta/beta oscillatory patterns and trial level EEG responsiveness as indices of adaptive cognitive control in schizophrenia compared to healthy controls. Thirty adults with schizophrenia (M age = 39.9, SD = 9.10 years) and a matched healthy control group (N = 30; M age = 32.25, SD = 6.50 years) underwent quantitative EEG during an eyes-open resting state and while performing two executive tasks: an augmented reality visuomotor challenge (LCAR) and a mobile guided daily routine task (B2B). Frontal theta/beta ratios (TBR) at Fz and Cz indexed attentional engagement. Trial level responsiveness was assessed via discrete Stimulus Response Events (SREs). Results: Both LCAR and B2B elicited significant TBR increases relative to eyes open rest at midline frontal sites (p < .001), reflecting elevated executive demand. Compared to healthy controls, participants with schizophrenia exhibited higher baseline TBR and reduced modulation across task segments. In contrast, controls showed stronger SRE linked variability and greater memory gains, indicating more efficient task locked cognitive adaptation. Age related effects were also observed, with participants under 40 years showing higher resting TBR at Fp1 (p =.01). Conclusion: Findings advance understanding of prefrontal theta/beta modulation as a neurophysiological marker of adaptive executive control during complex, ecologically valid tasks. By integrating real-world paradigms with trial level EEG analyses, this study contributes to models of dynamic information processing and cognitive resource allocation in schizophrenia. Keywords: schizophrenia; healthy controls; theta/beta ratio; QEEG; executive function; augmented reality; neural biomarkers