Schizophrenia Research

Background and ObjectivesEmerging preclinical evidence suggests that vagal signals contribute to the development of schizophrenia-related abnormalities in brain and behavior. Whether vagal communication in general, and its impairment in particular, is a risk factor for schizophrenia in humans remains, however, unclear. Vagotomy, the surgical lesion of the vagus nerve, was routinely performed as a treatment for peptic ulcer before modern treatment options were available. Hence, the primary aim of this study was to investigate whether vagotomy modulates the subsequent risk of developing schizophrenia. Moreover, given the existence of diverse vagotomy techniques (i.e., "truncal" or "selective"), our secondary goal was to test whether the extent of denervation modulates the risk of schizophrenia. MethodsUsing a nationwide retrospective matched cohort design, we identified 8,315 vagotomized individuals from the Swedish National Patient Register during the period 1970-2020 and 40,855 non-vagotomized individuals matching for age, sex and type of peptic ulcer. The risk of being diagnosed with schizophrenia and associated psychoses (ICD10 codes F20-29) was analyzed using Cox proportional hazards regression models, including death as competing risk. ResultsWhen considering all types of vagotomy together, vagotomy was not significantly associated with schizophrenia (HR: 0.91 [0.72; 1.16]). However, truncal vagotomy (which denervates all subdiaphragmatic organs) significantly increased the risk of developing schizophrenia by 69% (HR: 1.69 [1.08; 2.64]), whereas selective vagotomy (which only denervates the stomach) showed no significant association (HR: 0.80 [0.61; 1.04]). DiscussionOur results provide epidemiological support for the hypothesis that impairments in vagal functions could increase the risk of schizophrenia. Notably, the finding that truncal but not selective vagotomy is associated with an increased risk of schizophrenia raises the possibility that the activity of subdiaphragmatic non-gastric vagal branches may be of particular relevance for the development of schizophrenia.

Cognitive deficits are established as a fundamental feature of schizophrenia; however, their pattern and how they are affected by chronicity are still unclear. Although a generalized stable impairment affecting multiple cognitive domains is commonly seen from the onset, some longitudinal studies have shown evidence of neuroprogression, and selective deterioration in certain cognitive domains. We assessed cognitive performance in patients with recent-onset (n = 17, duration of illness [&le;] 2 years) and chronic schizophrenia (n = 14, duration [&ge;] 15 years), and healthy adults (n = 16) using the Global Neuropsychological Assessment and examined correlations between cognitive scores and gray matter volumes computed from T1-weighted MRI images. We also measured and analyzed differences between patient groups for negative and positive symptoms, psychotic exacerbations, and medication exposure, and studied their correlations with cognitive performances. We observed cognitive deficits affecting multiple domains in both recent-onset and chronic schizophrenia samples. Selectively greater impairment of perceptual comparison/processing speed was found in adults with chronic schizophrenia (p = 0.009, {eta}2partial = 0.25). In the full sample (n = 47), perceptual comparison speed correlated significantly with gray matter volumes in the anterior and medial temporal lobes, predominantly on the left side (TFCE, FWE p < 0.01). These results indicate that along with generalized deficit across multiple cognitive domains, selectively greater impairment of perceptual comparison/processing speed appears to characterize chronic schizophrenia. This pattern might indicate an accelerated or premature cognitive aging. Gray matter volumetric deficits in the anterior-medial temporal lobes especially of left side might underlie the impaired perceptual comparison/processing speed seen in schizophrenia.

BackgroundSchizophrenia is categorized into qualitatively distinct classes, i.e. major (MNP) and simple (SNP) neurocognitive psychosis. MNP is accompanied by more severe neurocognitive deficits and symptomatology, activated immune-inflammatory and oxidative stress pathways, and induction of the tryptophan catabolite (TRYCAT) pathway with increased quinolinic acid (QA) and lowered kynurenic acid (KA) levels. AimsTo examine whether MNP and increased QA levels are associated with increased brain injury markers, including S100 calcium-binding protein B (S100B), neuroepithelial stem cell protein (Nestin), neuron-specific enolase (NSE), phosphorylated tau217 (pTau217), and glial fibrillary acidic protein (GFAP). MethodsThis case-control study included 52 MNP subjects, 68 SNP subjects, and 60 healthy controls and assessed the above brain injury biomarkers and TRYCATs. ResultsNSE and GFAP were significantly higher in MNP than in SNP, and in both MNP or SNP than in controls. Serum S100B levels were substantially higher in MNP than in controls and SNP. The results indicate injuries to neurofilaments in MNP and SBP, and that MNP is additionally characterized by damage to cell bodies, axons, glial cell projections, reduced neurogenesis and synaptic plasticity as compared with SNP. Increased QA levels and lowered KA predict increased pTau217, NSE and GFAP. The QA/KA ratio is the best predictor of these three brain injury markers ConclusionsThese findings validate the differentiation between the two distinct subclasses with MNP being characterized by more profound injuries to brain cells and structures as compared with SNP. Increases in peripheral QA levels may contribute to these brain injuries in MNP.

For decades, schizophrenia has been primarily conceptualized as a disorder of high-order cognitive functions with deficits in executive brain regions. Yet due to the increasing reports of early sensory processing deficit, recent models focus more on the developmental effects of impaired sensory process on high-order functions. The present study examined whether this pathological interaction relates to an overarching system-level imbalance, specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. We applied a novel combination of connectome gradient and stepwise connectivity analysis to resting-state functional magnetic resonance imaging (rsfMRI) to characterize the sensorimotor-to-transmodal cortical hierarchy organization (96 patients vs. 122 controls). Using these techniques, we demonstrated compression of the cortical hierarchy organization in schizophrenia, with a prominent compression from the sensorimotor region and a less prominent compression from the frontal-parietal region, resulting in a diminished separation between sensory and fronto-parietal cognitive systems. Further analyses suggested reduced differentiation related to atypical functional connectome transition from unimodal to transmodal brain areas. Specifically, we found hypo-connectivity within unimodal regions and hyper-connectivity between unimodal regions and frontoparietal and ventral attention regions along the classical sensation-to-cognition continuum established in prior neuroanatomical work. The compression of cortical hierarchy organization represents a novel and integrative system-level substrate underlying the pathological interaction of early sensory and cognitive function in schizophrenia. This abnormal cortical hierarchy organization suggests cascaded impairments stemming from the disrupted somatosensory-motor system and inefficient integration of bottom-up sensory information with attentional demands and executive control processes partially account for high-level cognitive deficits characteristic of schizophrenia.

BackgroundRare variants are likely to contribute to schizophrenia (SCZ), given the large discrepancy between the heritability estimated from twin and GWAS studies. Furthermore, the nature of the rare-variant contribution to SCZ may vary with the "age-at-onset" (AAO), since early-onset has been suggested as being indicative of neurodevelopment deviance. ObjectiveTo examine the association of rare deleterious coding variants in early- and adult-onset SCZ in a Chinese sample. MethodExome sequencing was performed on DNA from 197 patients with SCZ spectrum disorder and 82 healthy controls (HC) of Chinese ancestry recruited in Hong Kong. We also gathered AAO information in the majority of SCZ samples. Patients were classified into early-onset (EOS, AAO<18) and adult-onset (AOS, AAO>18). We collapsed the rare variants to improve statistical power and examined the overall association of rare variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels by Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was also conducted. We focused on variants which were predicted to have a medium or high impact on the protein-encoding process as defined by Ensembl. We applied a 100000-time permutation test to obtain empirical p-values, with significance threshold set at p < 1e-3 to control family-wise error rates. Moreover, we compared the burden of targeted rare variants in significant risk genes and gene sets in cases and controls. ResultsBased on several binary-trait association tests (i.e., SCZ vs HC, EOS vs HC and AOS vs HC), we identified 7 candidate risk genes and 20 gene ontology biological processes (GOBP) terms, which exhibited higher burdens in SCZ than in controls. Based on quantitative rare-variant association tests, we found that alterations in 5 candidate risk genes and 7 GOBP pathways were significantly correlated with AAO. Based on biological and functional profiles of the candidate risk genes and gene sets, our findings suggested that, in addition to the involvement of perturbations in neural systems in SCZ in general, altered immune responses may be specifically implicated in EOS. ConclusionDisrupted immune responses may exacerbate abnormal perturbations during neurodevelopment and trigger the early onset of SCZ. We provided evidence of rare variants increasing SCZ risk in the Chinese population.

Schizophrenia is a serious psychotic disorder caused by both individuals genetic background and their living environment. However, how the cognitive and negative symptoms can be treated is still a challenge since most anti-psychotic drugs are only effective for positive symptoms. Previous epidemic studies have demonstrated that plant exposure could decrease the risk of schizophrenia and shorten the length of psychiatric hospital admissions for patients. However, it is still unknown whether plant exposure could improve cognition-related defects in schizophrenia, with no related animal studies. In the present study, we first induced a schizophrenia mice model by giving mice long-term (2 weeks) injections of the antagonist of the NMDA receptor: MK801. We then raised the animals in environments containing plants (4 weeks) including Epipremnum aureum and rosemary, and tested their locomotive, anxious and social behaviors. We found that plant exposure did not change the locomotion behaviors of wild-type animals, but significantly reduced the schizophrenia-related social and anxious behaviors in the schizophrenic animals. In addition, we tested the expression of c-Fos in animals exposed to plants after social behavioral testing and found that the deficits in c-Fos expression in both the hippocampus and prefrontal cortex were partially rescued after plant exposure. These results indicate plant exposure will be a new tool to improve the clinical deficits of schizophrenia.

BackgroundSchizophrenia (SCZ) is characterized by a disconnect from reality that manifests as various clinical and cognitive symptoms, and persistent neurobiological abnormalities. Sex-related differences in clinical presentation imply separate brain substrates. The present study characterized deep brain morphology using shape features to understand the independent effects of diagnosis and sex on the brain, and to determine whether the neurobiology of schizophrenia varies as a function of sex. MethodsThis study analyzed multi-site archival data from 1,871 male (M) and 955 female (F) participants with SCZ, and 2,158 male and 1,877 female healthy controls (CON) from twenty-three cross-sectional samples from the ENIGMA Schizophrenia Workgroup. Harmonized shape analysis protocols were applied to each sites data for seven deep brain regions obtained from T1-weighted structural MRI scans. Effect sizes were calculated for the following main contrasts: 1) Sex effects;2) Diagnosis-by-Sex interaction; 3) within sex tests of diagnosis; 4) within diagnosis tests of sex differences. Meta-regression models between brain structure and clinical variables were also computed separately in men and women with schizophrenia. ResultsMass univariate meta-analyses revealed more concave-than-convex shape differences in all regions for women relative to men, across diagnostic groups (d = -0.35 to 0.20, SE = 0.02 to 0.07); there were no significant diagnosis-by-sex interaction effects. Within men and women separately, we identified more-concave-than-convex shape differences for the hippocampus, amygdala, accumbens, and thalamus, with more-convex-than-concave differences in the putamen and pallidum in SCZ (d = -0.30 to 0.30, SE = 0.03 to 0.10). Within CON and SZ separately, we found more-concave-than-convex shape differences in the thalamus, pallidum, putamen, and amygdala among females compared to males, with mixed findings in the hippocampus and caudate (d = -0.30 to 0.20, SE = 0.03 to 0.09). Meta-regression models revealed similarly small, but significant relationships, with medication and positive symptoms in both SCZ-M and SCZ-F. ConclusionsSex-specific variation is an overriding feature of deep brain shape regardless of disease status, underscoring persistent patterns of sex differences observed both within and across diagnostic categories, and highlighting the importance of including it as a critical variable in studies of neurobiology. Future work should continue to explore these dimensions independently to determine whether these patterns of brain morphology extend to other aspects of neurobiology in schizophrenia, potentially uncovering broader implications for diagnosis and treatment. Key PointsO_LIStatistical analyses revealed significant main effects for diagnosis and sex in deep brain shape morphology. Among patients with schizophrenia, there was a pattern of thinning and surface contraction in the bilateral hippocampus, amygdala, accumbens, and thalamus, and a pattern of significant thickening and surface expansion in the bilateral putamen and pallidum compared to healthy control participants. Between males and females, there was a pattern of significant thinning and surface contraction in the bilateral thalamus, pallidum, putamen, and amygdala in females compared to males. C_LIO_LIThere was no significant interaction between diagnosis and biological sex, suggesting that sex differences in deep brain shape and asymmetry among patients with schizophrenia reflect those observed in healthy individuals. C_LIO_LISmall but statistically significant relationships exist between brain structure and clinical correlates of schizophrenia were similar for both men and women with the disease, such that higher CPZ was associated with shape-derived thinning and surface contraction in the caudate, accumbens, hippocampus, amygdala, and thalamus, and elevated positive symptoms were associated with shape-derived thinning and surface contraction in the bilateral caudate, right hippocampus, and right amygdala. C_LI

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.

Schizophrenia has been linked to reality monitoring confusions, particularly misattributions of internal productions to external sources. We hypothesized that these misattributions may be related to deficits in processing acoustic cues that distinguish the subjective experience of a sound source inside or outside the head, i.e., sound externalization. This study aimed to investigate sound externalization in patients with schizophrenia, particularly for emotional sounds, as emotion influences auditory perception. In an externalization task, twenty-three patients with schizophrenia and twenty-five healthy controls were exposed to neutral and emotional sounds processed to be perceived as: internalized (diotic) or externalized (filtered with either an anechoic head-related transfer function -HRTF- or a binaural room impulse response -BRIR). Participants had to indicate whether the sound source was perceived inside or outside their head. Exploratory analyses also examined the relationships between externalization, reality monitoring, and symptom severity. Compared to controls, patients with schizophrenia rated the filtered sounds (HRTF, BRIR) as less externalized (pbonf < .001) and the diotic sounds as more externalized (pbonf = 0.004), regardless of emotional content. No significant correlation was found between externalization and reality monitoring. In patients, greater symptom severity was associated with reduced externalization of sounds simulated as originating outside the head. These findings suggest an abnormal perception of sound sources in patients with schizophrenia, who confuse sounds inside and outside the head to a greater extent. Further research is needed to elucidate the relationship between sound externalization and symptoms such as hallucinations.

BackgroundMismatch negativity (MMN) is elicited upon detecting background irregularities in the sensory environment and subsequent updating of the sensory context. Auditory MMN amplitude is reliably attenuated in schizophrenia patients. However, due to diversity in MMN deviant types (duration, frequency, intensity, gap, etc.), considerable variability exists in MMN findings reported from the early course and chronic samples. MMN is sometimes reported to be impaired or associated with schizotypy, but MMN and schizotypy are yet to be well examined in unaffected first-degree relatives of schizophrenia patients. MethodsFifty-two schizophrenia patients (SZ) were compared with thirty-six unaffected first-degree relatives (FDR) of schizophrenia patients and thirty-two age and sex-matched healthy controls (HC) on MMN indices using a two-tone passive auditory oddball paradigm with two conditions - duration deviant (MMNd) and frequency deviant (MMNf) event-related potential experiment. SZ sample was further split into two sub-groups 1) early-course/drug-naive or drug-free (dSZ), and 2) chronic/medicated (cSZ) to examine the effect of illness chronicity and medication on MMN indices. We also checked whether schizotypy scores associated with MMNd and MMNf amplitudes in the FDR group. ResultsAt baseline, SZ group had significantly diminished MMNd amplitude compared to both HC and FDR groups (p<0.001). The SZ group also had significantly lower MMNd latency than the FDR group (p<0.014). The cSZ and dSZ groups did not differ from each other on MMN amplitude or latency, though cSZ group had lower MMN amplitude. Only cSZ patients showed negative correlation of MMNd amplitude with hallucinations scores and total duration of illness. In FDRs, MMNd and MMNf amplitudes showed negative correlation with the cognitive-perceptual factor of schizotypy. DiscussionDeficient MMNd in SZ patients adds further support to the prediction error estimation abnormalities in schizophrenia. MMNd is a more robust measure than MMNf in differentiating SZ from FDR and HC. MMNd amplitude could be more impaired in hallucinating SZ patients and associate with illness chronicity. Though unaffected FDRs have MMN comparable to healthy controls, higher schizotypy in FDR is associated with lower MMN amplitude. MMN and schizotypy are potentially linked and deserve a nuanced examination.

To comprehensively investigate the white matter (WM) features of cerebellum in patients with schizophrenia, and further assess the correlation between altered WM features and clinical and cognitive assessments. Forty-two patients and fifty-two matched healthy controls (HCs) of the Collaborative Informatics and Neuroimaging Suite Data Exchange tool were involved in this study. The cerebellar WM volume was calculated by voxel-based morphometry. And tract-based spatial statistics was used to analysis the diffusion changes in patients when compared to HCs. Furthermore, we investigated the correlation between altered imaging feature and clinical, cognitive assessments. Compared to HCs, the schizophrenia patients did not reveal difference in cerebellar WM volume and schizophrenia patients showed decreased fractional anisotropy and increased radial diffusivity in left middle cerebellar peduncles and inferior cerebellar peduncles in voxel-wise but not in tract-wise. Critically, these cerebellar changes were associated with disease duration in schizophrenia patients. And significant correlation between the altered cerebellar WM features and cognitive assessments only revealed in HCs but disrupted in schizophrenia patients. The present findings suggested that the voxel-wise WM integrity analysis might was the more sensitive way to investigate the structural abnormalities in schizophrenia patients. Middle cerebellar peduncles and inferior cerebellar peduncles may be a crucial neurobiological substrate of cognition and thus might be regarded as a biomarker for treatment.

BackgroundSchizophrenia is a severe neuropsychiatric disorder. Efforts to describe the underlying biology and establish diagnostic markers through non-invasive neuroimaging methods are ongoing, resulting in a range of theoretical brain-based frameworks. Prominent frameworks for aberrant schizophrenia-associated functional connectivity in resting-state functional magnetic resonance imaging (rsfMRI) include the dysconnectivity hypothesis, theory of cognitive dysmetria, and triple network theory. Although informative, prior work can be improved by increasing sample size, avoiding confirmation bias, and accounting for individual variability and the effects of medication and chronicity. MethodsWith these recommendations in mind, we employed a data-driven, whole-brain approach using a large multi-site rsfMRI dataset (N = 2,656; schizophrenia = 1,248). We used reference-guided independent component analysis (ICA) to generate subject-specific whole-brain functional network connectivity (FNC) and extract imaging markers of similarity to schizophrenia patterns. We modeled the relationship between medication dosage, age of onset, chronicity, symptom severity, and cognitive performance and FNC. ResultsOur analysis identified a reliable schizophrenia-FNC signature characterized by aberrantly stronger negative cerebellothalamic and positive thalamocortical connectivity, implicating sensory, motor, and associative cortical circuits. While medication and chronicity were significantly associated with these signatures, the core cerebellothalamic disruptions remained a robust marker of schizophrenia. ConclusionsThis work represents the largest schizophrenia-specific rsfMRI study to date, refines existing theoretical frameworks with a more nuanced map of how clinical variables interact with brain connectivity, and provides a high-fidelity template of schizophrenia-related connectivity. We have released this template as an open-source resource to facilitate reproducibility and accelerate the development of reliable rsfMRI-based schizophrenia biomarkers.

The aetiology of schizophrenia-spectrum disorders (SSD) involves genetic and environmental factors impacting neurodevelopmental trajectories. Dermatoglyphic pattern deviances have been associated with SSD and considered vulnerability markers for these disorders based on the shared ectodermal origin of the epidermis and the central nervous system. The endocannabinoid system participates in epidermal differentiation, is sensitive to the prenatal environment and is associated with SSD. We assessed whether the Cannabinoid receptor 1 (CNR1) gene is a common denominator in dermatoglyphic pattern configurations and SSD risk and whether it modulates the dermatoglyphics-SSD association. In a sample of 112 controls and 97 SSD patients, three dermatoglyphic markers were assessed: the total palmar a-b ridge count (TABRC), the a-b ridge count fluctuating asymmetry (ABRC-FA), and the pattern intensity index (PII). Two CNR1 polymorphisms were genotyped: rs2023239-A/G and rs806379-A/T. We tested the CNR1 association with SSD and with the dermatoglyphic variability within diagnostic groups. Secondly, we assessed the CNR1 x dermatoglyphic measures interaction on SSD susceptibility. Both polymorphisms were associated with the risk for SSD, and within controls, rs2023239 and rs806379 modulated the PII and TABRC, respectively. Lastly, our data showed that rs2023239 modulated the relationship between PII and SSD: a high PII score was associated with a lower SSD risk within G-allele-carriers and a higher SSD risk within AA-homozygotes. These novel results highlight the endocannabinoid systems role in the development and variability of dermatoglyphic patterns. The identified interaction encourages combining genetic and dermatoglyphics to assess neurodevelopmental alterations predisposing to SSD.

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on functional connectivity between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer tracts along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer fibers on the left side. In addition, there were significant positive correlations between PANSS scores and tract length, tract volume, and number of streamlines for the posterior AF segment on the left side. It is concluded that the present structural results complement previous functional findings of fronto-temporal connectivity in AVH patients.

BackgroundThere has been increasing interest in the study of brain gyrification in schizophrenia since it may provide additional useful information on the cytoarchitecture and connectivity of the brain. Various methods have been developed to estimate brain gyrification that, so far, have yielded mixed and inconclusive results in schizophrenia studies. To the best of our knowledge, an alternative method to compute brain gyrification, known as surface ratio (SR), has not yet been applied to a schizophrenia sample. Our aim in this study was to assess whether SR could provide new insights on the brain structure of schizophrenia patients and the severity of symptoms. We also computed a more established brain gyrification measure, namely absolute mean curvature (AMC), for comparison. MethodWe processed and analyzed a total of 63 magnetic resonance images, 25 from schizophrenia patients with treatment-resistant auditory verbal hallucinations (SCH-H), 18 from schizophrenia patients without hallucinations (SCH-NH), and 20 from healthy controls (HC). We estimated brain gyrification with SR and AMC employing CAT software. ResultsThe SR measure mainly revealed that SCH-H patients had a more folded orbitofrontal cortex than SCH-NH patients and HC. Gyrification in this region was also negatively associated with positive symptoms, specifically with the delusions and conceptual disorganization items, only in the SCH-H group. Conversely, SCH-NH and HC showed more SR than SCH-H in other frontal areas. As for the AMC measure, we identified two areas where HC showed more gyrification than SCH-H patients, but no relationships arose with symptoms. DiscussionWe hypothesize that the hypergyrification of the orbitofrontal cortex displayed by SCH-H patients, as captured by the SR measure, suggests aberrant and/or excessive wiring in these patients, which in turn could give rise to auditory verbal hallucinations. Alternatively, we comment on potential compensatory mechanisms that may better explain the negative association between orbitofrontal gyrification and positive symptomatology. Importantly, the estimation of brain gyrification with the SR measure seems to capture the most relevant differences and associations, making it a promising biomarker in schizophrenia research.

BackgroundSchizophrenia is a complex mental disorder characterized by cognitive deficits, persistent symptoms, and functional impairment. Caffeine, a commonly consumed psychoactive substance, has plausible effects on cognition and mood. However, its impact on individuals with schizophrenia remains unclear. This review evaluates caffeines impact on cognition, symptomatology, and functional outcomes in schizophrenia. MethodA systematic literature search was conducted for articles published up to 30 December 2024 across PubMed, Cochrane Library, PsycINFO, Embase, Emcare, and Medline. We included English-language studies in adults with schizophrenia that compared different caffeine intake levels and reported outcomes on cognition, symptoms, or functioning. Cohort, cross-sectional, and clinical trial designs were included. Data were synthesized using a random-effects model with Hedges g for effect size and I{superscript 2} statistics for heterogeneity. ResultsOf 252 articles screened, eleven studies (n=1,406) met inclusion criteria. Findings were mixed. Some studies reported improvements in cognitive performance and working memory, while others observed increases in positive symptoms or inconsistent associations with overall symptom management. Meta-analyses revealed a non-significant increase/decrease in overall symptom severity (measured with Brief Psychiatric Rating Scale (BPRS) and Nurses Observation Scale for Inpatient Evaluation (NOSIE). Physiologically, caffeine was found to reduce cerebral blood flow, with no statistically significant effects on blood pressure or pulse. ConclusionCaffeine may have mixed effects on schizophrenia, with potential positive effects on cognitive and negative symptoms while possibly worsening positive symptoms. Functional and physiological impacts are unclear, warranting further research to guide clinical recommendations.

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.

Limited therapeutic advancements in Schizophrenia (SCZ) depend on the heterogeneous nature of the disorder, impacting drug development and clinical trials that assume uniform therapy response, neglecting individual genetic and epigenomic variability. Disease modeling using human induced pluripotent stem cells (hiPSCs) is ideally suited for precision medicine, enabling individualized treatment approaches. Here, we describe the generation of patient-specific lines from somatic cells of SCZ individuals with well-defined diverse clinical trajectories using a Sendai virus-based reprogramming system. Karyotypically and CGH-array validated, the generated hiPSCs expressed diagnostic markers and demonstrated functional pluripotency. Converting these hiPSCs into neural progenitor cells enables the identification of aberrant cellular phenotypes associated with specific pathologically relevant neural phenotypes. This collection of hiPSC lines serves as a platform for developing therapeutic compounds targeting neural populations, potentially addressing early-stage disease alterations.

ObjectiveThe study evaluated behavioural phenotypes and the level of Superioxde Dismutase activity in repeated sub-anaesthetic dose of ketamine administered to model schizophrenia in animal study. MethodAnimals were divided into groups (n=6), control group received distilled water (10mL/kg) as vehicle (VEH), Ketamine treated group (KET) received sub-anaesthetic dose of ketamine (20mg/kg) for 14 days consecutively. Animals in risperidone treated group (KET+RISP) were pre-treated with sub-anaesthetic dose of ketamine (20mg/kg) alone for 7 consecutive days, and from day 8-14, risperidone (0.5mg/kg) was administered 1 hour post-ketamine treatment. All treatment were administered intraperitoneally (i.p). Twenty-four (24) hours after the last treatment, Behavioural phenotypes (locomotor activity and cognition) were assessed in locomotor activity cage and elevated maze plus. Thereafter level of superioxde dismutase (SOD) activity was evaluated in homogenized brain tissue of each mouse using spectrophotometric analysis. ResultKET group showed significant (p<0.05) increase in movement counts and number of rearing events in locomotor activity test, also prolonged latency to enter the open arms in cognitive assessment compared to animals that received distilled water (10mg/kg), and risperidone (0.5mg/kg) treatment. The level of Superioxide Dismutase (SOD) activity was significantly elevated in KET group compare with vehicle control and risperidone treated animals. ConclusionRepeated dose of ketamine may pose differential effect on endogenous antioxidant system which may elevate superioxide dismutase activity in ketamine induced schizophrenic rodent as positive control mechanism.

Understanding factors that predict the course of schizophrenia remains essential for improving long-term clinical management. Rate and severity of symptom exacerbations vary widely across individuals, and although prior studies have examined potential predictors, findings have been inconsistent and often limited by small samples, infrequent assessments, and non-standardized measures. Using data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), which includes a large cohort with monthly standardized evaluations, this study investigated whether baseline negative symptom severity predicts risk of symptom exacerbation over time. Participants were 1139 adults aged 18-65 years meeting DSM-IV criteria for schizophrenia. Symptoms worsening or exacerbation was defined as a [&ge;]12-point increase from baseline on the PANSS total score. Cox regression survival models examined the association between baseline PANSS negative symptom tertiles and time to exacerbation, adjusting for age, sex, PANSS positive and general psychopathology subscales, and CGI-Severity. Overall, 25.5% of participants experienced exacerbation over a 18-month period of follow-up. Survival curves demonstrated significant separation across negative symptom tertiles (p=0.047), with higher baseline negative symptoms associated with longer time to exacerbation. Compared with the lowest tertile, medium and high negative symptom groups showed reduced exacerbation risk (HR=0.73 and HR=0.69, respectively; both p=0.03). Findings indicate that greater baseline negative symptom severity is associated with a lower likelihood of short-term symptom worsening, suggesting a relatively stable illness course among individuals with more severe negative symptoms. These results have implications for prognosis and treatment planning, while underscoring the persistent functional burden imposed by negative symptoms despite lower exacerbation risk.