Search

Schizophrenia is a mental disorder characterized by cognitive impairments, specifically deficits in social recognition memory (SRM). Abnormal hippocampal neurogenesis has been implicated in these deficits. Due to the pathogenetic heterogeneity of schizophrenia, studying the hippocampal neurogenesis and SRM in two models with prenatal and postnatal defects could enhance our understanding of the developmental aspects of the biological susceptibility to schizophrenia. Here, we examined SRM and hippocampal neurogenesis in two developmental models of schizophrenia: gestational exposure to methylazoxymethanol acetate (MAM) and postweaning social isolation (SI). Our findings revealed that gestational MAM exposure induced a decay of social memory while postweaning SI led to impaired social memory formation and decay. In both models, we observed a correlation between impaired SRM and reduced number, and abnormal differentiation and less complex morphology of hippocampal neurons. These results indicate that aberrant hippocampal neurogenesis may contribute to the deficits of SRM in both models, and these abnormalities may be a shared underlying pathogenic factor in developmental models of schizophrenia, regardless of prenatal and postnatal pathogenesis., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Optical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk., Methods: Optical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter., Results: The sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude., Conclusions: This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

White matter (WM) abnormalities are an emerging feature of schizophrenia, yet the underlying pathophysiological mechanisms are largely unknown. Disruption of ErbB signaling, which is essential for peripheral myelination, has been genetically associated with schizophrenia and WM lesions in schizophrenic patients. However, the roles of ErbB signaling in oligodendrocytes remain elusive. Here, we used an in vivo pan-ErbB inhibition strategy and demonstrated the functions of endogenous ErbB receptors in oligodendrocytes. Through analyses of the cellular, histological, biochemical, behavioral, and electrophysiological differences in mice with manipulated ErbB activities in oligodendrocytes at different differentiation stages, we found that ErbB signaling regulates myelination and aerobic glycolysis in oligodendrocytes, and both functions are required for working memory. ErbB inhibition in oligodendrocytes at early differentiation stages induces hypomyelination by suppressing the myelinating capacity of newly formed oligodendrocytes. In contrast, ErbB inhibition in mature oligodendrocytes alters neither myelination nor oligodendrocyte numbers, but accelerates axonal conduction decline under energy stress. Mechanistically, ErbB inhibition attenuates K-Ras activities, leading to the reduced expression of lactate dehydrogenase A that promotes aerobic glycolysis in mature oligodendrocytes. Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings emphasize the indispensable roles of ErbB signaling in WM integrity and function and provide insights into the multifaceted contributions of WM abnormalities to cognitive impairment., Competing Interests: Competing interests statement:The authors declare no competing interest.

Schizophrenia (SCZ) is a complex psychiatric disorder that involves an inflammatory response thought to be characterized by microglial activation. The inflammasome complex may play critical roles in the pathomechanism of neuroinflammation but how this relates to SCZ remains unclear. In this study, we performed an immunohistochemical (IHC) analysis to compare the expression of inflammasome proteins in brain tissue from donors with SCZ (n = 16) and non-psychiatric donors (NP; n = 13) isolated from the superior frontal cortex (SFC), superior temporal cortex, and anterior cingulate cortex brain regions. To assess changes in the cell populations that express key inflammasome proteins, we performed IHC analyses of apoptosis-associated speck-like protein containing a CARD (ASC), nod-like receptor protein 3 (NLRP3), and interleukin (IL)-18 to determine if these proteins are expressed in microglia, astrocytes, oligodendrocytes, or neurons. Inflammasome proteins were expressed mainly in microglia from SCZ and NP brains. Increased numbers of microglia were present in the SFC of SCZ brains and exhibited higher inflammasome protein expression of ASC, NLRP3, and IL-18 compared to NPs. These findings suggest that increased inflammasome signaling may contribute to the pathology underlying SCZ., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Subtle craniofacial dysmorphology has been reported in schizophrenia patients. This dysmorphology includes midline facial elongation, frontonasal anomalies and a sexually dimorphic deviation from normal directional asymmetry of the face, with male patients showing reduced and female patients showing enhanced facial asymmetry relative to healthy control subjects. GFAP.HMOX1 0-12m transgenic mice (Mus musculus) that overexpress heme oxygenase-1 in astrocytes recapitulate many schizophrenia-relevant neurochemical, neuropathological and behavioral features. As morphogenesis of the brain, skull and face are highly interrelated, we hypothesized that GFAP.HMOX1 0-12m mice may exhibit craniofacial anomalies similar to those reported in persons with schizophrenia. We examined craniofacial anatomy in male GFAP.HMOX1 0-12m mice and wild-type control mice at the early adulthood age of 6-8 months. We used computer vision techniques for the extraction and analysis of mouse head shape parameters from systematically acquired 2D digital images, and confirmed our results with landmark-based geometric morphometrics. We performed skull bone morphometry using digital calipers to take linear distance measurements between known landmarks. Relative to controls, adult male GFAP.HMOX1 0-12m mice manifested craniofacial dysmorphology including elongation of the nasal bones, alteration of head shape anisotropy and reduction of directional asymmetry in facial shape features. These findings demonstrate that GFAP.HMOX1 0-12m mice exhibit craniofacial anomalies resembling those described in schizophrenia patients, implicating heme oxygenase-1 in their development. As a preclinical mouse model, GFAP.HMOX1 0-12m mice provide a novel opportunity for the study of the etiopathogenesis of craniofacial and other anomalies in schizophrenia and related disorders., (© 2024 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Schizophrenia (SZ) is a complex mental illness characterized by disturbances in thinking, emotionality, and behavior, significantly impacting the quality of life for individuals affected and those around them. The etiology of SZ involves intricate interactions between genetic and environmental factors, although the precise mechanisms remain incompletely understood. Genetic predisposition, neurotransmitter dysregulation (particularly involving dopamine and serotonin), and structural brain abnormalities, including impaired prefrontal cortex function, have been implicated in SZ development. However, increasing evidence reveals the role of environmental factors, such as nutrition, during critical periods like pregnancy and lactation. Epidemiological studies suggest that early malnutrition significantly increases the risk of SZ symptoms manifesting in late adolescence, a crucial period coinciding with peak myelination and brain maturation. Prenatal undernutrition may disrupt myelin formation, rendering individuals more susceptible to SZ pathology. This review explores the potential relationship between prenatal undernutrition, myelin alterations, and susceptibility to SZ. By delineating the etiopathogenesis, examining genetic and environmental factors associated with SZ, and reviewing the relationship between SZ and myelination disorders, alongside the impact of malnutrition on myelination, we aim to examine how malnutrition might be linked to SZ by altering myelination processes, which contribute to increasing the understanding of SZ etiology and help identify targets for intervention and management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Schizophrenia (SCZ) is a psychiatric disorder with a strong genetic determinant. A major hypothesis to explain disease aetiology comprises synaptic dysfunction associated with excitatory-inhibitory imbalance of synaptic transmission, ultimately contributing to impaired network oscillation and cognitive deficits associated with the disease. Here, we studied the morphological and functional properties of a highly defined co-culture of GABAergic and glutamatergic neurons derived from induced pluripotent stem cells (iPSC) from patients with idiopathic SCZ. Our results indicate upregulation of synaptic genes and increased excitatory synapse formation on GABAergic neurons in co-cultures. In parallel, we observed decreased lengths of axon initial segments, concordant with data from postmortem brains from patients with SCZ. In line with increased synapse density, patch-clamp analyses revealed markedly increased spontaneous excitatory postsynaptic currents (EPSC) recorded from GABAergic SCZ neurons. Finally, MEA recordings from neuronal networks indicate increased strength of network activity, potentially in response to altered synaptic transmission and E-I balance in the co-cultures. In conclusion, our results suggest selective deregulation of neuronal activity in SCZ samples, providing evidence for altered synapse formation and synaptic transmission as a potential base for aberrant network synchronization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) are two major psychotic disorders with similar symptoms and tight associations on the psychopathological level, posing a clinical challenge for their differentiation. This study aimed to investigate and compare the structural connectivity patterns of the limbic system between SCZ and PBD, and to identify specific regional disruptions associated with psychiatric symptoms., Methods: Using sMRI data from 146 SCZ, 160 PBD, and 145 healthy control (HC) participants, we employed a data-driven approach to segment the hippocampus, thalamus, hypothalamus, amygdala, and cingulate cortex into subregions. We then investigated the structural connectivity patterns between these subregions at the global and nodal levels. Additionally, we assessed psychotic symptoms by utilizing the subscales of the Brief Psychiatric Rating Scale (BPRS) to examine correlations between symptom severity and network metrics between groups., Results: Patients with SCZ and PBD had decreased global efficiency (E glob ) (SCZ: adjusted P<0.001; PBD: adjusted P = 0.003), local efficiency (E loc ) (SCZ and PBD: adjusted P<0.001), and clustering coefficient (Cp) (SCZ and PBD: adjusted P<0.001), and increased path length (Lp) (SCZ: adjusted P<0.001; PBD: adjusted P = 0.004) compared to HC. Patients with SCZ showed more pronounced decreases in E glob (adjusted P<0.001), E loc (adjusted P<0.001), and Cp (adjusted P = 0.029), and increased Lp (adjusted P = 0.024) compared to patients with PBD. The most notable structural disruptions were observed in the hippocampus and thalamus, which correlated with different psychotic symptoms, respectively., Conclusion: This study provides evidence of distinct structural connectivity disruptions in the limbic system of patients with SCZ and PBD. These findings might contribute to our understanding of the neuropathological basis for distinguishing SCZ and PBD., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Previous studies have shown that microstructural alterations in white matter (WM) could contribute to the symptom manifestation and support the dysconnectivity hypothesis in schizophrenia patients. These alterations were pervasive, non-specific, and reported inconsistently across the literature. This study aimed to specifically investigate the microstructure alterations of the posterior limb of the internal capsule (PLIC) in first-episode, drug-naive schizophrenia patients. Utilizing a multicompartmental biophysical model, we further explored the correlation between these alterations and syndrome scale scores., Methods: Thirty-two individuals with first-episode, drug-naive schizophrenia (FES) and thirty demographically matched healthy controls were enrolled. High-resolution multi-shell diffusion MRI data were collected, followed by the application of a three-compartment Neurite Orientation Dispersion and Density Imaging (NODDI) model to scrutinize the alterations in white matter microstructure. Changes in sensory and motor fibers within the PLIC were specifically focused on. Additionally, the correlation between these pathological changes and scores on the Positive and Negative Syndrome Scale (PANSS) was investigated., Results: The Neurite density index (NDI) in the left PLIC was significantly lower in FES patients compared to healthy individuals, and positively correlated with PANSS positive syndrome scores (r = 0.0379, p = 0.046). In the sensory component (left superior thalamic radiation within PLIC, STR&#95;P), the NDI was significantly elevated (p < 0.0001). Conversely, the NDI in the motor component (left corticospinal tract within PLIC, CST&#95;P) was reduced (p = 0.007) in FES patients compared to healthy individuals, and strongly correlated with PANSS positive syndrome scores (p < 0.020) and PANSS total scores (p < 0.045). Moreover, the NDI deviation of STR from total PLIC (f STR&#95;P ) and NDI deviation in STR&#95;P and CST&#95;P compared to PLIC region (f PLIC ) were significantly higher in FES patients than in healthy controls (p < 0.00001), with an area under the curve (AUC) of f PLIC reaching 0.872., Conclusion: The study's findings provided new insights into the discrepancy of white matter microstructure changes associated with the sensory and motor fibers in the PLIC region in FES patients. These results contribute to the growing body of evidence suggesting that WM microstructural alterations play a critical role in schizophrenia pathophysiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Schizophrenia is a neuropsychiatric illness characterized by altered neurotransmission, in which adenosine, a modulator of glutamate and dopamine, plays a critical role that is relatively unexplored in the human brain. In the present study, postmortem human brain tissue from the anterior cingulate cortex (ACC) of individuals with schizophrenia ( n = 20) and sex- and age-matched control subjects without psychiatric illness ( n = 20) was obtained from the Bronx-Mount Sinai NIH Brain and Tissue Repository. Enriched populations of ACC pyramidal neurons were isolated using laser microdissection (LMD). The mRNA expression levels of six key adenosine pathway components-adenosine kinase (ADK), equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), ectonucleoside triphosphate diphosphohydrolases 1 and 3 (ENTPD1 and ENTPD3), and ecto-5'-nucleotidase (NT5E)-were quantified using real-time PCR (qPCR) in neurons from these individuals. No significant mRNA expression differences were observed between the schizophrenia and control groups ( p > 0.05). However, a significant sex difference was found in ADK mRNA expression, with higher levels in male compared with female subjects (Mann-Whitney U = 86; p < 0.05), a finding significantly driven by disease (t (17) = 3.289; p < 0.05). Correlation analyses also demonstrated significant associations ( n = 12) between the expression of several adenosine pathway components ( p < 0.05). In our dementia severity analysis, ENTPD1 mRNA expression was significantly higher in males in the "mild" clinical dementia rating (CDR) bin compared with males in the "none" CDR bin (F (2, 13) = 5.212; p < 0.05 ). Lastly, antipsychotic analysis revealed no significant impact on the expression of adenosine pathway components between medicated and non-medicated schizophrenia subjects ( p > 0.05). The observed sex-specific variations and inter-component correlations highlight the value of investigating sex differences in disease and contribute to the molecular basis of schizophrenia's pathology.

Background: Schizophrenia is a chronic severe mental disorder characterized by impairment in cognition, emotion, perception, and other aspects of behavior. In light of the association of craniofacial dysmorphology with schizophrenia, mandibular morphology may provide clues about the role of neurodevelopment in the pathophysiology of schizophrenia. This retrospective cross-sectional study aimed to compare the mandibular morphology of patients with schizophrenia with controls using digital panoramic radiography (DPR)., Methods: 302 recorded diagnostic panoramic images obtained from 143 schizophrenia patients (98 males, 45 females), and 159 controls (73 males, 86 females), aged 18-45 years, were evaluated. Seven mandibular measurements consisting of ramus height, condylar height, gonial angle, antegonial angle, antegonial notch depth, ramal notch depth and bigonial width were measured from the DPRs in a double-blinded manner. Bivariate comparisons were carried out using the Independent t-test and Mann-Whitney U test. Logistic regression analysis was used for multivariate comparisons., Results: Linear measurements were higher while angular measurements were lower in schizophrenia patients. Regression analyses indicated that female patients had greater ramus height (OR = 1.243; P = 0.001), condylar height (OR = 1.463; P = 0.048) and bigonial width (OR = 1.082; P < 0.001); male patients had greater ramus heights (OR = 1.216; P = 0.001) and bigonial width (OR = 1.076; P < 0.001) as well as lower antegonial angle (OR = 0.908; P = 0.012) compared to their respective controls., Conclusion: Quantitative differences in mandibular morphology in schizophrenia patients versus controls deserve attention and corroborate with the concept of abnormal neurodevelopment in schizophrenia., (© 2024. The Author(s).)

The caudate nucleus is a part of the striatum, and striatal hyperdopaminergia is considered central to the pathophysiology of schizophrenia. How caudate volume is affected in schizophrenia and what role antipsychotics play remains unclear. In early-onset schizophrenia (EOS), where psychosis emerges during a neurodevelopmentally critical phase, the caudate may exhibit a heightened vulnerability to the effects of antipsychotic medications. We hypothesized effects of both antipsychotic medication use and age of onset on caudate in schizophrenia. We included adult patients with EOS (n = 83) and adult-onset schizophrenia (AOS) (n = 246), adult healthy controls (HC, n = 774), adolescent patients with non-affective psychosis (n = 56) and adolescent HC (n = 97). We obtained T1-weighted MRI scans using a 1.5T Siemens scanner and General Electric 3T scanners. In our main analysis, we tested for main and interaction effects of diagnosis and current antipsychotic medication use on caudate volume. Adult patients with EOS (p < 0.001) and AOS (p = 0.002) had both larger caudate than HC. Age of onset (EOS/AOS) interacted with antipsychotic use (p = 0.004) which was associated with larger caudate in EOS (p < 0.001) but not in AOS (p = 0.654). Conversely, among medicated patients only, EOS had larger caudate than AOS (p < 0.001). No other subcortical structures showed differences between medicated EOS and AOS. Medicated adolescent patients with non-affective psychosis and medicated adult patients with EOS showed similar caudate volumes. The results may indicate a schizophrenia-related and a medication-induced caudate increase, the latter restricted to patients with EOS and possibly occurring already in adolescence shortly after disease onset., (© 2024. The Author(s).)

Objective: In schizophrenia, impaired working memory is associated with transcriptome alterations in layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC). Distinct subtypes of L3PNs that send axonal projections to the DLPFC in the opposite hemisphere (callosal projection [CP] neurons) or the parietal cortex in the same hemisphere (ipsilateral projection [IP] neurons) play critical roles in working memory. However, how the transcriptomes of these L3PN subtypes might shift during late postnatal development when working memory impairments emerge in individuals later diagnosed with schizophrenia is not known. The aim of this study was to characterize and compare the transcriptome profiles of CP and IP L3PNs across developmental transitions from prepuberty to adulthood in macaque monkeys., Methods: The authors used retrograde labeling to identify CP and IP L3PNs in the DLPFC of prepubertal, postpubertal, and adult macaque monkeys, and used laser microdissection to capture these neurons for RNA sequencing., Results: At all three ages, CP and IP L3PNs had distinct transcriptomes, with the number of genes differentially expressed between neuronal subtypes increasing with age. For IP L3PNs, age-related shifts in gene expression were most prominent between prepubertal and postpubertal animals, whereas for CP L3PNs such shifts were most prominent between postpubertal and adult animals., Conclusions: These findings demonstrate the presence of cell type-specific profiles and developmental trajectories of the transcriptomes of PPC-projecting IP and DLPFC-projecting CP L3PNs in monkey DLPFC. The evidence that IP L3PNs reach a mature transcriptome earlier than CP L3PNs suggests that these two subtypes differentially contribute to the maturation of working memory performance across late postnatal development and that they may be differentially vulnerable to the disease process of schizophrenia at specific stages of postnatal development., Competing Interests: Dr. Lewis receives investigator-initiated research support from Merck. The other authors report no financial relationships with commercial interests.

Significant evidence links obesity and schizophrenia (SZ), but the brain associations are still largely unclear. 48 people with SZ were divided into two subgroups: patients with lower waist circumference (SZ-LWC: n = 24) and patients with higher waist circumference (SZ-HWC: n = 24). Healthy controls (HC) were included for comparison (HC: n = 27). Using tract-based spatial statistics, we compared fractional anisotropy (FA) of the whole-brain white matter skeleton between these three groups (SZ-LWC, SZ-HWC, HC). Using Free Surfer, we compared whole-brain cortical thickness and the selected subcortical volumes between the three groups. FA of widespread white matter and the mean cortical thickness in the right temporal lobe and insular cortex were significantly lower in the SZ-HWC group than in the HC group. The FA of regional white matter was significantly lower in the SZ-LWC group than in the HC group. There were no significant differences in mean subcortical volumes between the groups. Additionally, the cognitive performances were worse in the SZ-HWC group, who had more severe triglycerides elevation. This study provides evidence for microstructural abnormalities of white matter, cortical thickness and neurocognitive deficits in SZ patients with excessive abdominal obesity., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cognitive impairments affect functional capacity in individuals with schizophrenia (SZH), but their neural basis remains unclear. The Wisconsin Card Sorting Test (WCST), and the Stroop Task (SCWT), are paradigmatic tests which have been used extensively for examining executive function in SZH. However, few studies have explored how deficits on these tasks link to brain volume differences commonly seen in SZH. Here, for the first time, we tested associations between FreeSurfer-derived frontal brain volumes and performance on both WCST and SCWT, in a well-matched sample of 57 SZH and 32 control subjects. We also explored whether these associations were dissociable from links to symptom severity in SZH. Results revealed correlations between volumes and task performance which were unique to SZH. In SZH only, volumes of right middle frontal regions correlated with both WCST and Stroop performance: correlation coefficients were significantly different to those present in the control group, highlighting their specificity to the patient group. In the Stroop task, superior frontal regions also showed associations with Stroop interference scores which were unique to SZH. These findings provide important detail around how deficits on these two paradigmatic executive function tasks link to brain structural differences in SZH. Results align with converging evidence suggesting that neuropathology within right middle frontal regions (BA9 and BA46) might be of particular import in SZH. No volumetric associations with symptom severity were found, supporting the notion that the structural abnormalities underpinning cognitive deficits in SZH differ from those associated with symptomatology., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Schizophrenia spectrum disorders (SSD) are debilitating, with auditory verbal hallucinations (AVHs) being a core characteristic. While gray matter volume (GMV) reductions are commonly replicated in SSD populations, the neural basis of AVHs remains unclear. Using previously published data, this study comprises two main analyses, one of GMV dissimilarities between SSD and healthy controls (HC), and one of GMV differences specifically associated with AVHs. Structural brain images from 71 adults with (n = 46) and without (n = 25) SSD were employed. Group differences in GMVs of the cortex, anterior cingulate (ACC), superior temporal gyrus (STG), hippocampi, and thalami were assessed. Additionally, volumes of left Heschl's gyrus (HG) in a subgroup experiencing AVHs (AVH+, n = 23) were compared with those of patients who did not (AVH-, n = 23). SSD patients displayed reduced GMVs of the cortex, ACC, STG, hippocampi, and thalami compared to HC. AVH+ had significantly reduced left HG volume when compared to AVH-. Finally, a right-lateralized ventral prefrontal cluster was found to be uniquely associated with AVH severity. This study corroborates previous findings of GMV reductions in SSD cohorts. Chiefly, our secondary analysis suggests that AVHs are associated with language areas and their contralateral homologues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Offspring of parents with severe mental illness (e.g., bipolar disorder or schizophrenia) are at increased risk of developing psychopathology. Structural brain alterations have been found in child and adolescent offspring of patients with bipolar disorder and schizophrenia, but the developmental trajectories of brain anatomy in this high-familial-risk population are still unclear. 300 T1-weighted scans were obtained of 187 offspring of at least one parent diagnosed with bipolar disorder (n=80) or schizophrenia (n=53) and offspring of parents without severe mental illness (n=54). The age range was 8 to 23 years old; 113 offspring underwent two scans. Global brain measures and regional cortical thickness and surface area were computed. A generalized additive mixed model was used to capture non-linear age trajectories. Offspring of parents with schizophrenia had smaller total brain volume than offspring of parents with bipolar disorder (d=-0.20, p=0.004) and control offspring (d=-0.22, p=0.005) and lower mean cortical thickness than control offspring (d=-0.23, p<0.001). Offspring of parents with schizophrenia showed differential age trajectories of mean cortical thickness and cerebral white matter volume compared with control offspring (both p's=0.003). Regionally, offspring of parents with schizophrenia had a significantly different trajectory of cortical thickness in the middle temporal gyrus versus control offspring (p<0.001) and bipolar disorder offspring (p=0.001), which was no longer significant after correcting for mean cortical thickness. These findings suggest that particularly familial high risk of schizophrenia is related to reductions and deviating developmental trajectories of global brain structure measures, which were not driven by specific regions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome., (© 2024. The Author(s).)

Increased activation of inflammatory macrophages and altered expression of dopamine markers are found in the midbrains of people with schizophrenia (SZ). The relationship of midbrain macrophages to dopamine neurons has not been explored, nor is it known if changes in midbrain macrophages are also present in bipolar disorder (BD) or major depressive disorder (MDD). Herein, we determined whether there were differences in CD163+ cell density in the Substantia Nigra (SN), and cerebral peduncles (CP) of SZ, BD, and MDD compared to controls (CTRL). We also analyzed whether CD163 protein and dopamine-synthesizing enzyme tyrosine hydroxylase (TH) mRNA levels differed among diagnostic groups and if they correlated with the density of macrophages. Overall, perivascular CD163+ cell density was higher in the gray matter (SN) than in the white matter (CP). Compared to CTRL, we found increased density of parenchymal CD163+ cells in the SN of the three psychiatric groups and increased CD163 protein levels in SZ. CD163 protein was positively correlated with density of perivascular CD163+ cells. TH mRNA was reduced in SZ and BD and negatively correlated with parenchymal CD163+ cell density. We provide the first quantitative and molecular evidence of an increase in the density of parenchymal macrophages in the midbrain of major mental illnesses and show that the presence of these macrophages may negatively impact dopaminergic neurons., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA., (© 2024. The Author(s).)

Background: Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively., Results: We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10 -7 ). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10 -6 ). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively., Conclusions: We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction., (© 2024. The Author(s).)

Background: The onset of schizophrenia is concurrent with multiple key processes of brain development, such as the maturation of inhibitory networks. Some of these processes are proposed to depend on the development of perineuronal nets (PNNs), a specialized extracellular matrix structure that surrounds preferentially parvalbumin-containing GABAergic interneurons (PVIs). PNNs are fundamental to the postnatal experience-dependent maturation of inhibitory brain circuits. PNN abnormalities have been proposed as a core pathophysiological finding in SCZ, being linked to widespread consequences on circuit disruptions underlying SCZ symptoms., Objective: Here, we systematically evaluate PNN density in postmortem brain studies of subjects with SCZ., Methods: A systematic search in 3 online databases (PubMed, Embase, and Scopus) and qualitative review analysis of case-control studies reporting on PNN density in the postmortem brain of subjects with SCZ were performed., Results: Results consisted of 7 studies that were included in the final analysis. The specific brain regions investigated in the studies varied, with most attention given to the dorsolateral prefrontal cortex (DLPFC; 3 studies) and amygdala (2 studies). Findings were mostly positive for reduced PNN density in SCZ, with 6 of the 7 studies reporting significant reductions and one reporting a tendency towards reduced PNN density. Overall, tissue processing methodologies were heterogeneous., Conclusions: Despite few studies, PNN density was consistently reduced in SCZ across different brain regions. These findings support evidence that implicates deficits in PNN density in the pathophysiology of SCZ. However, more studies, preferably using similar methodological approaches as well as replication of findings, are needed., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Schizophrenic individuals display disrupted myelination patterns, altered oligodendrocyte distribution, and abnormal oligodendrocyte morphology. Schizophrenia is linked with dysregulation of a variety of genes involved in oligodendrocyte function and myelin production. Single-nucleotide polymorphisms (SNPs) and rare mutations in myelination-related genes are observed in certain schizophrenic populations, representing potential genetic risk factors. Downregulation of myelination-related RNAs and proteins, particularly in frontal and limbic regions, is consistently associated with the disorder across multiple studies. These findings support the notion that disruptions in myelination may contribute to the cognitive and behavioral impairments experienced in schizophrenia, although further evidence of causation is needed., (© 2024 International Society for Neurochemistry.)

Background: Schizophrenia (SZ) is characterized by disconnected cerebral networks. Recent studies have shown that functional connectivity between the cerebellar dorsal dentate nucleus (dDN) and cerebrum is correlated with psychotic symptoms, and processing speed in SZ patients. Dynamic effective connectivity (dEC) is a reliable indicator of brain functional status. However, the dEC between the dDN and cerebrum in patients with SZ remains largely unknown., Methods: Resting-state functional MRI data, symptom severity, and cognitive performance were collected from 74 SZ patients and 53 healthy controls (HC). Granger causality analysis and sliding time window methods were used to calculate dDN-based dEC maps for all subjects, and k-means clustering was performed to obtain several dEC states. Finally, between-group differences in dynamic effective connectivity variability (dECV) and clinical correlations were obtained using two-sample t-tests and correlation analysis., Results: We detected four dEC states from the cerebrum to the right dDN (IN states) and three dEC states from the right dDN to the cerebrum (OUT states), with SZ group having fewer transitions in the OUT states. SZ group had increased dECV from the right dDN to the right middle frontal gyrus (MFG) and left lingual gyrus (LG). Correlations were found between the dECV from the right dDN to the right MFG and symptom severity and between the dECV from the right dDN to the left LG and working memory performance., Conclusions: This study reveals a dynamic causal relationship between cerebellar dDN and the cerebrum in SZ and provides new evidence for the involvement of cerebellar neural circuits in neurocognitive functions in SZ., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in conducting this study or preparing the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: The cerebellum is involved in higher-order mental processing as well as sensorimotor functions. Although structural abnormalities in the cerebellum have been demonstrated in schizophrenia, neuroimaging techniques are not yet applicable to identify them given the lack of biomarkers. We aimed to develop a robust diagnostic model for schizophrenia using radiomic features from T1-weighted magnetic resonance imaging (T1-MRI) of the cerebellum., Methods: A total of 336 participants (174 schizophrenia; 162 healthy controls [HCs]) were allocated to training (122 schizophrenia; 115 HCs) and test (52 schizophrenia; 47 HCs) cohorts. We obtained 2568 radiomic features from T1-MRI of the cerebellar subregions. After feature selection, a light gradient boosting machine classifier was trained. The discrimination and calibration of the model were evaluated. SHapley Additive exPlanations (SHAP) was applied to determine model interpretability., Results: We identified 17 radiomic features to differentiate participants with schizophrenia from HCs. In the test cohort, the radiomics model had an area under the curve, accuracy, sensitivity, and specificity of 0.89 (95% confidence interval: 0.82-0.95), 78.8%, 88.5%, and 75.4%, respectively. The model explanation by SHAP suggested that the second-order size zone non-uniformity feature from the right lobule IX and first-order energy feature from the right lobules V and VI were highly associated with the risk of schizophrenia., Conclusion: The radiomics model focused on the cerebellum demonstrates robustness in diagnosing schizophrenia. Our results suggest that microcircuit disruption in the posterior cerebellum is a disease-defining feature of schizophrenia, and radiomics modeling has potential for supporting biomarker-based decision-making in clinical practice., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)

The prevalence of pyramidal cells (PCs) in the mammalian cerebral cortex underscore their value as they play a crucial role in various brain functions, ranging from cognition, sensory processing, to motor output. PC morphology significantly influences brain connectivity and plays a critical role in maintaining normal brain function. Pathological alterations to PC morphology are thought to contribute to the aetiology of neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. This review explores the relationship between abnormalities in PC morphology in key cortical areas and the clinical manifestations in schizophrenia and ASD. We focus largely on human postmortem studies and provide evidence that dendritic segment length, complexity and spine density are differentially affected in these disorders. These morphological alterations can lead to disruptions in cortical connectivity, potentially contributing to the cognitive and behavioural deficits observed in these disorders. Furthermore, we highlight the importance of investigating the functional and structural characteristics of PCs in these disorders to illuminate the underlying pathogenesis and stimulate further research in this area., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Given the shared ectodermal origin and integrated development of the face and the brain, facial biomarkers emerge as potential candidates to assess vulnerability for disorders in which neurodevelopment is compromised, such as schizophrenia (SZ) and bipolar disorder (BD). The sample comprised 188 individuals (67 SZ patients, 46 BD patients and 75 healthy controls (HC)). Using a landmark-based approach on 3D facial reconstructions, we quantified global and local facial shape differences between SZ/BD patients and HC using geometric morphometrics. We also assessed correlations between facial and brain cortical measures. All analyses were performed separately by sex. Diagnosis explained 4.1 % - 5.9 % of global facial shape variance in males and females with SZ, and 4.5 % - 4.1 % in BD. Regarding local facial shape, we detected 43.2 % of significantly different distances in males and 47.4 % in females with SZ as compared to HC, whereas in BD the percentages decreased to 35.8 % and 26.8 %, respectively. We detected that brain area and volume significantly explained 2.2 % and 2 % of facial shape variance in the male SZ - HC sample. Our results support facial shape as a neurodevelopmental marker for SZ and BD and reveal sex-specific pathophysiological mechanisms modulating the interplay between the brain and the face., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Thalamic abnormalities in schizophrenia are recognized, alongside cognitive deficits. However, the current findings about these abnormalities during the prodromal period remain relatively few and inconsistent. This study applied multimodal methods to explore the alterations in thalamic function and structure and their relationship with cognitive function in first-episode schizophrenia (FES) patients and ultra-high-risk (UHR) individuals, aiming to affirm the thalamus's role in schizophrenia development and cognitive deficits., Methods: 75 FES patients, 60 UHR individuals, and 60 healthy controls (HC) were recruited. Among the three groups, gray matter volume (GMV) and functional connectivity (FC) were evaluated to reflect the structural and functional abnormalities in the thalamus. Pearson correlation was used to calculate the association between these abnormalities and cognitive impairments., Results: No significant difference in GMV of the thalamus was found among the abovementioned three groups. Compared with HC individuals, FES patients had decreased thalamocortical FC mostly in the thalamocortical triple network, including the default mode network (DMN), salience network (SN), and executive control network (ECN). UHR individuals had similar but milder dysconnectivity as the FES group. Furthermore, FC between the left thalamus and right putamen was significantly correlated with execution speed and attention in the FES group., Conclusions: Our findings revealed decreased thalamocortical FC associated with cognitive deficits in FES and UHR subjects. This improves our understanding of the functional alterations in thalamus in prodromal stage of schizophrenia and the related factors of the cognitive impairment of the disease., Trial Registration: ClinicalTrials.govNCT03965598; https://clinicaltrials.gov/ct2/show/NCT03965598., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We examined the relationship between genetic risk for schizophrenia (SZ), using polygenic risk scores (PRSs), and retinal morphological alterations. Retinal structural and vascular indices derived from optical coherence tomography (OCT) and color fundus photography (CFP) and PRSs for SZ were analyzed in N = 35,024 individuals from the prospective cohort study, United Kingdom Biobank (UKB). Results indicated that macular ganglion cell-inner plexiform layer (mGC-IPL) thickness was significantly inversely related to PRS for SZ, and this relationship was strongest within higher PRS quintiles and independent of potential confounders and age. PRS, however, was unrelated to retinal vascular characteristics, with the exception of venular tortuosity, and other retinal structural indices (macular retinal nerve fiber layer [mRNFL], inner nuclear layer [INL], cup-to-disc ratio [CDR]). Additionally, the association between greater PRS and reduced mGC-IPL thickness was only significant for participants in the 40-49 and 50-59 age groups, not those in the 60-69 age group. These findings suggest that mGC-IPL thinning is associated with a genetic predisposition to SZ and may reflect neurodevelopmental and/or neurodegenerative processes inherent to SZ. Retinal microvasculature alterations, however, may be secondary consequences of SZ and do not appear to be associated with a genetic predisposition to SZ., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steven M. Silverstein reports financial support was provided by Empire State Development. Kelsey V. Stuart reports financial support was provided by Fight for Sight. Pearse A. Keane reports financial support was provided by UK Research and Innovation Future Leaders Fellowship. Pearse A. Keane reports financial support was provided by NIHR Moorfields Biomedical Research Centre. Pearse A. Keane reports financial support was provided by University College London Institute of Ophthalmology. Anthony P. Khawaja reports financial support was provided by UK Research and Innovation Future Leaders Fellowship. Anthony P. Khawaja reports financial support was provided by Alcon Research Institute. Anthony P. Khawaja reports financial support was provided by Lister Institute of Preventive Medicine. Anthony P. Khawaja reports financial support was provided by NIHR Moorfields Biomedical Research Centre. Anthony P. Khawaja reports financial support was provided by University College London Institute of Ophthalmology. Siegfried K. Wagner reports financial support was provided by Medical Research Council Clinical Research Training Fellowship. Brittany A. Blose declares that she has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified., Methods: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (n cases  = 169 and n controls  = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning., Results: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences., Conclusions: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The profiles of cortical gyrification across schizophrenia, bipolar I disorder, and schizoaffective disorder have been studied to a limited extent, report discordant findings, and are rarely compared in the same study. Here we assess gyrification in a large dataset of psychotic disorder probands, categorized according to the DSM-IV. Furthermore, we explore gyrification changes with age across healthy controls and probands., Methods: Participants were recruited within the Bipolar-Schizophrenia Network of Intermediate Phenotypes study and received T1-MPRAGE and clinical assessment. Gyrification was measured using FreeSurfer 7.1.0. Pairwise t-tests were conducted in R, and age-related gyrification changes were analyzed in MATLAB. P values <0.05 after false discovery rate correction were considered significant., Results: Significant hypogyria in schizophrenia, bipolar disorder, and schizoaffective disorder probands compared to controls was found, with a significant difference bilaterally in the frontal lobe between schizophrenia and bipolar disorder probands. Verbal memory was associated with gyrification in the right frontal and right cingulate cortex in schizophrenia. Age-fitted gyrification curves differed significantly among psychotic disorders and controls., Conclusions: Findings indicate hypogyria in DSM-IV psychotic disorders compared to controls and suggest differential patterns of gyrification across the different diagnoses. The study extends age related models of gyrification to psychotic disorder probands and supports that age-related differences in gyrification may differ across diagnoses. Fitted gyrification curves among probands categorized by DSM-IV significantly deviate from controls, with the model capturing early hypergyria and later hypogyria in schizophrenia compared to controls; this suggests unique disease and age-related changes in gyrification across psychotic disorders., Competing Interests: Declaration of competing interest The authors Rychagov, Zeng, Oykhman, Dr. del Re, Dr. Yassin, Dr. Lizano, Dr. Sweeny, Dr. Gershon, Dr. Pearlson, Dr. McDowell, and Dr. Clementz reported no potential conflicts of interest. Dr. Keshavan reports serving as an advisor to Alkermes, Takeda, and Vanna Inc. Dr. Tamminga reports the following financial disclosures: American Psychiatric Association – Deputy Editor; Astellas – Ad Hoc Consultant; Autifony – Ad Hoc Consultant; The Brain and Behavior Foundation – Council Member; Eli Lilly Pharmaceuticals – Ad Hoc Consultant; Intra-cellular Therapies (ITI, Inc.) – Advisory Board, drug development; Institute of Medicine – Council Member; National Academy of Medicine – Council Member; Pfizer – Ad Hoc Consultant; Sunovion – Investigator Initiated grant funding., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The pathogenesis of schizophrenia begins in early neurodevelopment and leads to excitatory-inhibitory imbalance. It is therefore essential that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar neurochemical deficits. One approach to improved preclinical modelling incorporates dual-hit neurodevelopmental insults, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress). We recently showed that male Lister-hooded rats exposed to PCP-Iso exhibit reduced hippocampal expression of the GABA interneuron marker calbindin. The current study expanded on this by investigating changes to additional populations of GABAergic interneurons in frontal cortical and hippocampal tissue from the same animals (by immunohistochemistry) as well as levels of GABA itself (via ELISA). Because inflammatory changes are also implicated in schizophrenia, we performed additional immunohistochemical evaluations of Iba-1 positive microglia as well as ELISA analysis of IL-6 in the same brain regions. Single-hit isolation-reared and dual-hit PCP-Iso rats both showed reduced parvalbumin immunoreactivity in the prelimbic/infralimbic region of the frontal cortex. However, this was more widespread in PCP-Iso, extending to the medial/ventral and lateral/dorsolateral orbitofrontal cortices. Loss of GABAergic markers was accompanied by increased microglial activation in the medial/ventral orbitofrontal cortices of PCP-Iso, together with frontal cortical IL-6 elevations not seen following single-hit isolation rearing. These findings enhance the face validity of PCP-Iso, and we advocate the use of this preclinical model for future evaluation of novel therapeutics-especially those designed to normalise excitatory-inhibitory imbalance or reduce neuroinflammation., (© 2024. The Author(s).)

Rationale and Objectives: To differentiate early-onset schizophrenia (EOS) from early-onset bipolar disorder (EBD) using surface-based morphometry measurements and brain volumes using machine learning (ML) algorithms., Method: High-resolution T 1 -weighted images were obtained to measure cortical thickness (CT), gyrification, gyrification index (GI), sulcal depth (SD), fractal dimension (FD), and brain volumes. After the feature selection step, ML classifiers were applied for each feature set and the combination of them. The SHapley Additive exPlanations (SHAP) technique was implemented to interpret the contribution of each feature., Findings: 144 adolescents (16.2 ± 1.4 years, female=39%) with EOS (n = 81) and EBD (n = 63) were included. The Adaptive Boosting (AdaBoost) algorithm had the highest accuracy (82.75%) in the whole dataset that includes all variables from Destrieux atlas. The best-performing algorithms were K-nearest neighbors (KNN) for FD subset, support vector machine (SVM) for SD subset, and AdaBoost for GI subset. The KNN algorithm had the highest accuracy (accuracy=79.31%) in the whole dataset from the Desikan-Killiany-Tourville atlas., Conclusion: This study demonstrates the use of ML in the differential diagnosis of EOS and EBD using surface-based morphometry measurements. Future studies could focus on multicenter data for the validation of these results., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Thalamic abnormalities have been repeatedly implicated in the pathophysiology of schizophrenia and other neurodevelopmental disorders. Uncovering the etiology of thalamic abnormalities and how they may contribute to illness phenotypes faces at least two obstacles. First, the typical developmental trajectories of thalamic nuclei and their association with cognition across the lifespan are largely unknown. Second, modest effect sizes indicate marked individual differences and pose a significant challenge to personalized medicine. To address these knowledge gaps, we characterized the development of thalamic nuclei volumes using normative models generated from the Human Connectome Project Lifespan datasets (5-100+ years), then applied them to an independent clinical cohort to determine the frequency of thalamic volume deviations in people with schizophrenia (17-61 years). Normative models revealed diverse non-linear age effects across the lifespan. Association nuclei exhibited negative age effects during youth but stabilized in adulthood until turning negative again with older age. Sensorimotor nuclei volumes remained relatively stable through youth and adulthood until also turning negative with older age. Up to 18% of individuals with schizophrenia exhibited abnormally small (i.e., below the 5th centile) mediodorsal and pulvinar volumes, and the degree of deviation, but not raw volumes, correlated with the severity of cognitive impairment. While case-control differences are robust, only a minority of patients demonstrate unusually small thalamic nuclei volumes. Normative modeling enables the identification of these individuals, which is a necessary step toward precision medicine., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Schizophrenia is a mental disorder that causes considerable morbidity, whose risk largely results from genetic factors. Setd1a is a gene implicated in schizophrenia., Objective: To study the gene expression changes found in heterozygous Setd1a ± knockout mice in order to gain useful insight into schizophrenia pathogenesis., Methods: We mined a single-cell RNA sequencing (scRNAseq) dataset from the prefrontal cortex (PFC) and striatum of Setd1a ± mice and identified cell type-specific differentially expressed genes (DEGs) and differential transcript usage (DTU). DEGs and genes containing DTU found in each cell type were used to identify affected biological pathways using Ingenuity Pathway Analysis (IPA)., Results: We identified 273 unique DEGs across all cell types in PFC and 675 unique gene peaks containing DTU. In striatum, we identified 327 unique DEGs across all cell types and 8 unique gene peaks containing DTU. Key IPA findings from the analysis of DEGs found in PFC and striatum implicate processes involved in protein synthesis, mitochondrial function, cell metabolism, and inflammation. IPA analysis of genes containing DTU in PFC points to protein synthesis, as well as cellular activities involving intracellular signaling and neurotransmission. One canonical pathway, 'EIF2 Signaling', which is involved in the regulation of protein synthesis, was detected in PFC DEGs, striatum DEGs, and PFC genes containing DTU, drawing attention to its importance in schizophrenia pathophysiology., Conclusion: Processes involving protein synthesis in general and the 'EIF2 Signaling' pathway in particular could be targets for the development of new research strategies and biomarkers in schizophrenia., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Cognitive dysfunction constitutes a core characteristic of schizophrenia spectrum disorders (SZ). Specifically, deficits in updating generative models (i.e., cognitive flexibility) and shielding against distractions (i.e., cognitive stability) are considered critical contributors to cognitive impairment in these patients. Here, we examined the structural integrity of frontostriatal networks and their associations with reduced cognitive stability and flexibility in SZ patients. In a sample of 21 patients diagnosed with SZ and 22 healthy controls, we measured gray matter volume (GMV) using structural MRI. Further, cognitive stability and flexibility were assessed using a switch-drift paradigm, quantifying the successful ignoring of distracters and detection of rule switches. Compared to controls, patients showed significantly smaller GMV in the whole brain and three predefined regions of interest: the medial prefrontal cortex (mPFC), inferior frontal gyrus (IFG), and caudate nucleus (CN). Notably, GMV in these areas positively correlated with correct rule-switch detection but not with ignoring rule-compatible drifts. Further, the volumetric differences between SZ patients and controls were statistically explainable by considering the behavioral performance in the switch-drift task. Our results indicate that morphological abnormalities in frontostriatal networks are associated with deficient flexibility in SZ patients and highlight the necessity of minimizing neurodevelopmental and progressive brain atrophy in this population., (© 2024 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Background: Major depressive disorder (MDD) and schizophrenia (SCZ) are heritable brain disorders characterized by alterations in cortical thickness. However, the shared genetic basis for cortical thickness changes in these disorders remains unclear., Methods: We conducted a systematic literature search on cortical thickness in MDD and SCZ through PubMed and Web of Science. A coordinate-based meta-analysis was performed to identify cortical thickness changes. Additionally, utilizing summary statistics from the largest genome-wide association studies for depression (N case  = 268,615, N control  = 667,123) and SCZ (N case  = 53,386, N control  = 77,258), we explored shared genomic loci using conjunctional false discovery rate (conjFDR) analysis. Transcriptome-neuroimaging association analysis was then employed to identify shared genes associated with cortical thickness alterations, and enrichment analysis was finally carried out to elucidate the biological significance of these genes., Results: Our search yielded 34 MDD (N case  = 1621, N control  = 1507) and 19 SCZ (N case  = 1170, N control  = 1043) neuroimaging studies for cortical thickness meta-analysis. Specific alterations in the left supplementary motor area were observed in MDD, while SCZ exhibited widespread reductions in various brain regions, particularly in the frontal and temporal areas. The conjFDR approach identified 357 genomic loci jointly associated with MDD and SCZ. Within these loci, 55 genes were found to be associated with cortical thickness alterations in both disorders. Enrichment analysis revealed their involvement in nervous system development, apoptosis, and cell communication., Conclusion: This study revealed the shared genetic architecture underlying cortical thickness alterations in MDD and SCZ, providing insights into common neurobiological pathways. The identified genes and pathways may serve as potential transdiagnostic markers, informing precision medicine approaches in psychiatric care., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Hypothesis: Cognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia., Study Design: Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (n = 27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n = 26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify (1) numbers of PVI across the cortical mantle (20 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 unaffected comparison, 18 schizophrenia)., Study Results: In schizophrenic patients, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and total DLPFC gray matter., Conclusions: Our findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Hypothesis: Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms., Study Design: We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms., Study Results: We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes., Conclusions: Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background and Hypothesis: The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear., Study Design: Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms., Study Results: The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes., Conclusions: These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Hypothesis: Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness., Study Design: In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined., Study Results: Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (P < .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (P < .05, false discovery rate correction)., Conclusions: Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Schizophrenia (SZ) and bipolar disorder (BD) are characterized by major symptomatic, cognitive, and neuroanatomical changes. Recent studies have used optical coherence tomography (OCT) to investigate retinal changes in SZ and BD, but their unique and shared changes require further evaluation. Articles were identified using PubMed and Google Scholar. 39 studies met the inclusion criteria. Diagnostic groups were proband (SZ/BD combined), SZ, BD, and healthy control (HC) eyes. Meta-analyses utilized fixed and random effects models when appropriate, and publication bias was corrected using trim-and-fill analysis ("meta" package in R). Results are reported as standardized mean differences with 95% CIs. Data from 3145 patient eyes (1956 SZ, 1189 BD) and 3135 HC eyes were included. Studies identified thinning of the peripapillary retinal nerve fiber layer (pRNFL, overall and in 2 subregions), m-Retina (overall and all subregions), mGCL-IPL, mIPL, and mRPE in SZ patients. BD showed thinning of the pRNFL (overall and in each subregion), pGCC, and macular Retina (in 5 subregions), but no changes in thickness or volume for the total retina. Neither SZ nor BD patients demonstrated significant changes in the fovea, mRNFL, mGCL, mGCC, mINL, mOPL, mONL, or choroid thicknesses. Moderating effects of age, illness duration, and smoking on retinal structures were identified. This meta-analysis builds upon previous literature in this field by incorporating recent OCT studies and examining both peripapillary and macular retinal regions with respect to psychotic disorders. Overall, this meta-analysis demonstrated both peripapillary and macular structural retinal abnormalities in people with SZ or BD compared with HCs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Brain disorders are often associated with changes in brain structure and function, where functional changes may be due to underlying structural variations. Gray matter (GM) volume segmentation from 3D structural MRI offers vital structural information for brain disorders like schizophrenia, as it encompasses essential brain tissues such as neuronal cell bodies, dendrites, and synapses, which are crucial for neural signal processing and transmission; changes in GM volume can thus indicate alterations in these tissues, reflecting underlying pathological conditions. In addition, the use of the ICA algorithm to transform high-dimensional fMRI data into functional network connectivity (FNC) matrices serves as an effective carrier of functional information. In our study, we introduce a new generative deep learning architecture, the conditional efficient vision transformer generative adversarial network (cEViT-GAN), which adeptly generates FNC matrices conditioned on GM to facilitate the exploration of potential connections between brain structure and function. We developed a new, lightweight self-attention mechanism for our ViT-based generator, enhancing the generation of refined attention maps critical for identifying structural biomarkers based on GM. Our approach not only generates high quality FNC matrices with a Pearson correlation of 0.74 compared to real FNC data, but also uses attention map technology to identify potential biomarkers in GM structure that could lead to functional abnormalities in schizophrenia patients. Visualization experiments within our study have highlighted these structural biomarkers, including the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DL-PFC), and cerebellum. In addition, through cross-domain analysis comparing generated and real FNC matrices, we have identified functional connections with the highest correlations to structural information, further validating the structure-function connections. This comprehensive analysis helps to understand the intricate relationship between brain structure and its functional manifestations, providing a more refined insight into the neurobiological research of schizophrenia., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to declare in relation to this manuscript. This includes any financial, personal, or professional interests that could be construed to influence the work reported in this paper. We confirm that the content of the manuscript has not been influenced by any external interests, and all research was conducted in accordance with ethical standards. This statement is true to the best of our knowledge and belief, and any potential conflicts will be disclosed promptly should they arise in the future., (Copyright © 2024. Published by Elsevier Inc.)

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response., Competing Interests: Declaration of competing interest There are no funding, employment or personal financial interests of any kind that would undermine the objectivity, integrity or perceived value of the submitted publication. In order of authorship listing: Edgardo Torres Carmona declaration of interest: none. Shinichiro Nakajima declaration of interest: none. Yusuke Iwata declaration of interest: none. Fumihiko Ueno declaration of interest: none. Cristiana Stefan declaration of interest: none. Jianmeng Song declaration of interest: none. Ali Abdolizadeh declaration of interest: none. Michel Teruki Koizumi declaration of interest: none. Yasman Kambari declaration of interest: none. Aron Amaev declaration of interest: none. Sri Mahavir Agarwal declaration of interest: none. Wanna Mar declaration of interest: none. Vincenzo de Luca declaration of interest: none. Gary Remington has received advisory board support from HLS Therapeutics and consultant fees from Mitsubishi Tanabe Pharma Corporation. Philip Gerretsen declaration of interest: none. Ariel Graff-Guerrero declaration of interest: none., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A substantial portion of schizophrenia spectrum disorder (SSD) patients exhibit resistance to antipsychotic treatments, emphasizing the need for reliable treatment response biomarkers. Previous magnetic resonance imaging (MRI) studies have identified various imaging predictors in SSD. This study focuses on evaluating the effectiveness of diffusion MRI sequences, diffusion tensor imaging (DTI) and diffusion-weighted imaging (DWI), in predicting antipsychotic response in SSD patients. A systematic search for relevant articles was conducted in PubMed, Embase, Scopus, and Web of Science on February 11, 2024. Twelve studies involving a total of 742 patients were systematically reviewed. The baseline DTI/DWI biomarkers revealed significant associations with antipsychotic treatment response. Notably a consistent negative link was found between response and baseline fractional anisotropy (FA) in fronto-temporo-limbic white matter tracts, specifically the superior longitudinal fasciculus, providing moderate-level evidence. In addition, weak-level evidence was found for the negative association between the treatment response and baseline FA in the corpus callosum, internal, and external capsule tracts. Collectively, this review demonstrated that obtaining pre-treatment brain diffusion MRI scans, particularly from white matter tracts of fronto-temporo-limbic network, can assist in delineating the treatment response trajectory in patients with SSD. However, additional larger randomized controlled trials are required to further substantiate these findings., Competing Interests: Declaration of competing interest No potential conflict of interests is declared., (Copyright © 2024. Published by Elsevier B.V.)

Background: Structural covariance network disruption has been considered an important pathophysiological indicator for schizophrenia. Here, we introduced a novel individualized structural covariance network measure, referred to as a texture similarity network (TSN), and hypothesized that the TSN could reliably reveal unique intersubject heterogeneity and complex dysconnectivity patterns in schizophrenia., Methods: The TSN was constructed by measuring the covariance of 180 three-dimensional voxelwise gray-level co-occurrence matrix feature maps between brain areas in each participant. We first tested the validity and reproducibility of the TSN in characterizing the intersubject variability in 2 longitudinal test-retest healthy cohorts. The TSN was further applied to elucidate intersubject variability and dysconnectivity patterns in 10 schizophrenia case-control datasets (609 schizophrenia cases vs. 579 controls) as well as in a first-episode depression dataset (69 patients with depression vs. 69 control participants)., Results: The test-retest analysis demonstrated higher TSN intersubject than intrasubject variability. Moreover, the TSN reliably revealed higher intersubject variability in both chronic and first-episode schizophrenia, but not in depression. The TSN also reproducibly detected coexistent increased and decreased TSN strength in widespread brain areas, increased global small-worldness, and the coexistence of both structural hyposynchronization in the central networks and hypersynchronization in peripheral networks in patients with schizophrenia but not in patients with depression. Finally, aberrant intersubject variability and covariance strength patterns revealed by the TSN showed a missing or weak correlation with other individualized structural covariance network measures, functional connectivity, and regional volume changes., Conclusions: These findings support the reliability of a TSN in revealing unique structural heterogeneity and complex dysconnectivity in patients with schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest No conflict of interest.