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Background: Structural and functional neurobiological abnormalities have been observed in schizophrenia. Previous studies have concentrated on specific illness stages, obscuring relationships between functional/structural changes and disorder progression. The present study aimed to quantify structural and functional abnormalities across different clinical stages using functional near-infrared spectroscopy (fNIRS) and structural magnetic resonance imaging (sMRI)., Methods: Fifty-four participants with first-episode schizophrenia (FES), 120 with clinically high risk of psychosis (CHR), and 111 healthy controls (HCs) underwent functional near-infrared spectroscopy (fNIRS) to measure oxyhemoglobin (Oxy-Hb) during the verbal fluency task. Among them, 28FES, 64CHR and 55HC also finished sMRI. Oxy-Hb and gray matter volume (GMV) were compared among the three groups while controlling for covariates, including age, sex, years of education, and task performance. Mediation analysis was utilized to determine the mediating effect of GMV on Oxy-Hb and cognition., Results: Compared with the HC group, CHR and FES groups showed significantly reduced brain activity. However, there were no significant differences between the FES and CHR. Pronounced GMV increase in the right frontal pole area (F = 4.234, p = 0.016) was identified in the CHR and FES groups. Mediation analysis showed a significant mediation effect of the right frontal pole GMV between Channel 31 Oxy-Hb and processing speed (z = 2.105, p = 0.035) and attention/vigilance (z = 1.992, p = 0.046)., Conclusions: Brain activation and anatomical deficits were observed in different brain regions, suggesting that anatomical and functional abnormalities are dissociated in the early stages of psychosis. The relationship between neural activity and anatomy may reflect a specific pathophysiology related to cognitive deterioration in schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Abnormalities in cortical excitability and plasticity have been considered to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) can provide a direct evaluation of cortical responses to TMS. Here, we employed TMS-EEG to investigate cortical responses to orbitofrontal cortex (OFC) stimulation in schizophrenia., Methods: In total, we recruited 92 drug-naïve patients with first-episode schizophrenia and 51 age- and sex-matched healthy individuals. For each participant, one session of 1-Hz repetitive TMS (rTMS) was delivered to the right OFC, and TMS-EEG data were obtained to explore the change in cortical-evoked activities before and immediately after rTMS during the eyes-closed state. The MATRICS Consensus Cognitive Battery was used to assess neurocognitive performance., Results: The cortical responses indexed by global mean field amplitudes (i.e., P30, N45, and P60) were larger in patients with schizophrenia than in healthy control participants at baseline. Furthermore, after one session of 1-Hz rTMS over the right OFC, the N100 amplitude was significantly reduced in the healthy control group but not in the schizophrenia group. In the healthy control participants, there was a significant correlation between modulation of P60 amplitude by rTMS and working memory; however, this correlation was absent in patients with schizophrenia., Conclusions: Aberrant global cortical responses following right OFC stimulation were found in patients with drug-naïve first-episode schizophrenia, supporting its significance in the primary pathophysiology of schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal 'trajectory' of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors., (© 2024. The Author(s).)

Schizophrenia lacks a clear definition at the neuroanatomical level, capturing the sites of origin and progress of this disorder. Using a network-theory approach called epicenter mapping on cross-sectional magnetic resonance imaging from 1124 individuals with schizophrenia, we identified the most likely "source of origin" of the structural pathology. Our results suggest that the Broca's area and adjacent frontoinsular cortex may be the epicenters of neuroanatomical pathophysiology in schizophrenia. These epicenters can predict an individual's response to treatment for psychosis. In addition, cross-diagnostic similarities based on epicenter mapping over of 4000 individuals diagnosed with neurological, neurodevelopmental, or psychiatric disorders appear to be limited. When present, these similarities are restricted to bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. We provide a comprehensive framework linking schizophrenia-specific epicenters to multiple levels of neurobiology, including cognitive processes, neurotransmitter receptors and transporters, and human brain gene expression. Epicenter mapping may be a reliable tool for identifying the potential onset sites of neural pathophysiology in schizophrenia.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Response inhibition deficits in schizophrenia (SZ) are accompanied by reduced neural activities using event-related potential (ERP) measurements. However, it remains unclear whether the reduction in inhibition-related ERPs in SZ is contingent upon prepotent motor tendencies. This study aimed to examine the relationship between ERP markers of prepotent motor activity (lateralised readiness potential, LRP) and response inhibition (P3) by collecting behavioural and EEG data from healthy control (HC) subjects and SZ patients during a modified Go/No-Go task. A trial-averaged analysis revealed that SZ patients made more commission errors in No-Go trials compared with HC subjects, although there was no significant difference in the inhibition-related P3 effect (i.e. larger P3 amplitudes in No-Go compared with Go trials) between the two groups. Subsequently, No-Go trials were sorted and median-split into bins of stronger and weaker motor tendencies. Both HC and SZ participants made more commission errors when faced with stronger motor tendencies. The LRP-sorted P3 data indicated that HC subjects exhibited larger P3 effects in response to stronger motor tendencies, whereas this trial-by-trial association between P3 and motor tendencies was absent in SZ patients. Furthermore, SZ patients displayed diminished P3 effects in No-Go trials with stronger motor tendencies but not in trials with weaker motor tendencies, relative to HC subjects. Taken together, these findings suggest that SZ patients are unable to dynamically adjust inhibition-related neural activities in response to changing inhibitory control demands and emphasise the importance of considering prepotent motor activity when investigating the neural mechanisms underlying response inhibition deficits in SZ., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Dynamic functional connectivity (FC) analyses have provided ample information on the disturbances of global functional brain organization in patients with schizophrenia. However, our understanding about the dynamics of local FC in never-treated first episode schizophrenia (FES) patients is still rudimentary. Dynamic Regional Phase Synchrony (DRePS), a newly developed dynamic local FC analysis method that could quantify the instantaneous phase synchronization in local spatial scale, overcomes the limitations of commonly used sliding-window methods. The current study performed a comprehensive examination on both the static and dynamic local FC alterations in FES patients (N = 74) from healthy controls (HCs, N = 41) with resting-state functional magnetic resonance imaging using DRePS, and compared the static local FC metrics derived from DRePS with those calculated from two commonly used regional homogeneity (ReHo) analysis methods that are defined based on Kendall's coefficient of concordance (KCC-ReHo) and frequency coherence (Cohe-ReHo). Symptom severities of FES patients were assessed with a set of clinical scales. Cognitive functions of FES patients and HCs were assessed with the MATRICS consensus cognitive battery. Group-level analysis revealed that compared with HCs, FES patients exhibited increased static local FC in right superior, middle temporal gyri, hippocampus, parahippocampal gyrus, putamen, and bilateral caudate nucleus. Nonetheless, the dynamic local FC metrics did not show any significant differences between the two groups. The associations between all local FC metrics and clinical characteristics manifested scores were explored using a relevance vector machine. Results showed that the Global Assessment of Functioning score highest in past year and the Brief Visuospatial Memory Test-Revised task score were statistically significantly predicted by a combination of all static and dynamic features. The diagnostic abilities of different local FC metrics and their combinations were compared by the classification performance of linear support vector machine classifiers. Results showed that the inclusion of zero crossing ratio of DRePS, one of the dynamic local FC metrics, alongside static local FC metrics improved the classification accuracy compared to using static metrics alone. These results enrich our understanding of the neurocognitive mechanisms underlying schizophrenia, and demonstrate the potential of developing diagnostic biomarker for schizophrenia based on DRePS.

Background and Hypothesis: Visual fixation is a dynamic process, with the spontaneous occurrence of microsaccades and macrosaccades. These fixational saccades are sensitive to the structural and functional alterations of the cortical-subcortical-cerebellar circuit. Given that dysfunctional cortical-subcortical-cerebellar circuit contributes to cognitive and behavioral impairments in schizophrenia, we hypothesized that patients with schizophrenia would exhibit abnormal fixational saccades and these abnormalities would be associated with the clinical manifestations., Study Design: Saccades were recorded from 140 drug-naïve patients with first-episode schizophrenia and 160 age-matched healthy controls during ten separate trials of 6-second steady fixations. Positive and negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognition was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB)., Study Results: Patients with schizophrenia exhibited fixational saccades more vertically than controls, which was reflected in more vertical saccades with angles around 90° and a greater vertical shift of horizontal saccades with angles around 0° in patients. The fixational saccades, especially horizontal saccades, showed longer durations, faster peak velocities, and larger amplitudes in patients. Furthermore, the greater vertical shift of horizontal saccades was associated with higher PANSS total and positive symptom scores in patients, and the longer duration of horizontal saccades was associated with lower MCCB neurocognitive composite, attention/vigilance, and speed of processing scores. Finally, based solely on these fixational eye movements, a K-nearest neighbors model classified patients with an accuracy of 85%. Conclusions: Our results reveal spatial and temporal abnormalities of fixational saccades and suggest fixational saccades as a promising biomarker for cognitive and positive symptoms and for diagnosis of schizophrenia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Repetitive transcranial magnetic stimulation (rTMS) has been used in the treatment of patients with schizophrenia. The conventional targets of rTMS treatment are the dorsolateral prefrontal cortex (DLPFC) and temporoparietal cortex (TPC). However, the efficacy of these two treatment strategies was quite heterogeneous. Structural and functional abnormalities of the orbitofrontal cortex (OFC) in schizophrenia are closely related to negative symptoms. We sought to determine whether 1 Hz rTMS over the right OFC is effective in treating patients with first-episode schizophrenia. In this study, eighty-nine patients with drug-naïve, first-episode schizophrenia were randomly divided into the rTMS (n = 47) or sham stimulation (n = 42) groups, with both groups receiving twenty sessions of 1 Hz rTMS treatment. The PANSS was assessed at baseline, day 10, and day 20, and MATRICS Consensus Cognitive Battery (MCCB) was implemented to assess the cognitive impairment at baseline and day 20. Results showed that patients in the active rTMS group had more improvement in clinical symptoms and cognitive deficits than patients in sham group at day 20. In conclusion, 1 Hz rTMS over OFC can improve psychotic symptoms and cognitive functions in schizophrenic patients. Our study provides a new alternative for the treatment of negative symptoms and cognitive deficits in schizophrenia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

The impact of the duration of untreated psychosis on the outcomes of schizophrenia has been extensively studied. However, there is a notable gap in the current understanding of the relationship between the duration of untreated prodromal symptoms (DUPrS) and the development of psychosis in individuals at clinical high risk (CHR). A sample of 704 individuals with CHR was identified through a structured interview, of who 145 (20.6 %) converted to psychosis (CHR-C) during the 3-year follow-up. The DUPrS was defined as the period between the onset of the first attenuated psychotic positive symptom and the commencement of professional assistance at mental health services. Quantile regression was applied for quantile levels between 0.1 and 0.9, and adjusted for age, sex, and education.The overall sample had a mean DUPrS of 7.1 months. No significant differences were observed in the DUPrS between the CHR-C and non-converter (CHR-NC) groups. Quantile regression analysis highlighted variations in the effects of the DUPrS on clinical variables across the different quantiles. We observed a positive association between DUPrS rank and positive symptoms below the 0.3 quantile, while a positive association between DUPrS rank and negative symptoms above the 0.3 quantile (except 0.7 and 0.9 quantile). A longer DUPrS (> 3 months) was associated with younger age (odds ratio [OR] = 0.948, p = 0.003), a higher proportion of women (OR = 1.474, p = 0.003), higher baseline global function (OR = 1.044, p = 0.003), lower previous global function (OR = 0.921, p < 0.001), and higher negative symptoms (OR = 1.061, p = 0.001). This study sheds light on the pivotal role of DUPrS as a potential intermediary factor in the complex pathway of psychosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure., Methods: 71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP., Results: Baseline imaging data from 63 FES patients and 55 HC met quality standards and were analyzed. FES patients exhibited less negative connectivity and increased positive connectivity between the right anterior GPi and several cortical and subcortical areas at baseline compared to HC (P FWE  < 0.05). Positive functional connectivity between the right anterior GPi and several brain areas, including the right dorsal anterior cingulate gyrus, was associated with severity of positive symptoms (P FWE  < 0.05) and predicted treatment response after 8 weeks (n = 28, adjusted R 2  = 0.486, p < 0.001)., Conclusions: Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis., Competing Interests: Declaration of competing interest Dr. Zhe Chen reports grants from the National Institutes of Health (NIH) and National Science Foundation (NSF) during the conduct of the study. Dr. Chen is also a founder and CEO of NeuroThX, LLC. Dr. Chen also received cloud computing resources supported by the Oracle for Research Award. These funders had no role in the design and conduct of the study, collection and analysis of data and decision to publish the manuscript. Unrelated to this work, Dr. Castellanos is on the Scientific Advisory Board of BOL Pharma, Israel. He is conducting a study of cannabidiol with medication provided by Greenwich Biosciences at no cost through an investigator-initiated study. He also serves as co-chief field editor of Frontiers in Neuroimaging. Dr. Goff has received no research funding or honoraria from commercial entities over the past three years. No other disclosures were reported., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: Schizophrenia (SZ) and intellectual disability (ID) are both included in the continuum of neurodevelopmental disorders (NDDs). DNA methylation is known to be important in the occurrence of NDDs. The family study is conducive to eliminate the effects of relative epigenetic backgrounds, and to screen for differentially methylated positions (DMPs) and regions (DMRs) that are truly associated with NDDs., Methods: Four monozygotic twin families were recruited, and both twin individuals suffered from NDDs (either SZ, ID, or SZ plus ID). Genome-wide methylation analysis was performed in all samples and each family. DMPs and DMRs between NDD patients and unaffected individuals were identified. Functional and pathway enrichment analyses were performed on the annotated genes., Results: Two significant DMPs annotated to CYP2E1 were found in all samples. In Family One, 1476 DMPs mapped to 880 genes, and 162 DMRs overlapping with 153 unique genes were recognised. Our results suggested that the altered methylation levels of FYN , STAT3 , RAC1 , and NR4A2 were associated with the development of SZ and ID. Neurodevelopment and the immune system may participate in the occurrence of SZ and ID., Conclusions: Our findings suggested that DNA methylation participated in the development of NDDs by affecting neurodevelopment and the immune system.

Neurocognitive deficits differ with age during the early stages of psychosis. This study aimed to explore age-related differences (9-35 years old) in the neurocognitive performance of a large clinical population. In total, 1059 individuals with first-episode psychosis (FEP), 794 individuals with a clinical high risk of psychosis (CHR), and 774 well-matched healthy controls (HC) were recruited between 2016 and 2021. Neurocognitive assessments were performed using the Chinese version of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Battery(MCCB). The MCCB subtest scores differed significantly among the groups across the age span. The mean scores of subtests in CHR individuals were approximately one standard deviation(SD) lower than that of HC, while that of FEP patients was approximately two SDs. The adolescents performed better than the adults in the HC, CHR, and FEP groups. In the HC group, a stronger correlation was found between age and cognitive function, and more neurocognitive domains were affected by age than in the CHR and FEP groups. These results emphasize that neurocognitive deficits in psychosis are present at the pre-onset stage and deteriorate at the first-episode stage across the age span, implicating the development of specific strategies that could monitor the cognitive trajectory in early psychosis., Competing Interests: Declaration of Competing Interest The authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Antipsychotic treatment has been shown to yield hippocampal and amygdalar volumetric changes in first-episode schizophrenia (FES). However, whether antipsychotic induced volumetric changes interact with age remains unclear., Methods: The current study includes data from 120 medication naïve FES patients and 110 matched healthy controls (HC). Patients underwent MRI scans before (T1) and after (T2) antipsychotic treatment. HCs underwent MRI scans at baseline only. The hippocampus and amygdala were segmented via Freesurfer 7. General linear models were conducted to investigate the effect of age by diagnosis interaction on baseline volume. Linear mixed models (LMM) were used to detect the effect of age on volumetric changes from pre to post treatment in FES., Results: GLM revealed a trending effect (F = 3.758, p = 0.054) of age by diagnosis interaction on the baseline volume of the left (whole) hippocampus, with older FES patients showing smaller hippocampal volumes, relative to HC, when controlled sex, education years, and ICV. LMM showed a significant age by time-point interaction effect (F = 4.194, estimate effect = -1.964, p = 0.043) on left hippocampal volume in all FES and significant time effect(F = 6.608,T1-T2(estimate effect) = 62.486, p = 0.011), whereby younger patients showed greater hippocampal volumetric decreases following treatment. At the subfield level, a significant time effect emerged in left molecular&#95;layer&#95;HP (F = 4.509,T1-T2(estimate effect) = 12.424, p = 0.032, FDR corrected) and left cornu ammonis(CA)4 (F = 4.800,T1-T2(estimate effect) = 7.527, p = 0.046, FDR corrected), implying volumetric reduction after treatment in these subfields., Conclusions: Our findings suggest that age plays an important role in the neuroplastic mechanisms of initial antipsychotics on the hippocampus and amygdala of schizophrenia., 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 © 2023. Published by Elsevier Inc.)

Background and Hypothesis: Cognitive deficits in visuospatial learning (VSL) are highly associated with an increased risk of developing psychosis among populations with clinical high risk (CHR) for psychosis. Early interventions targeting VSL enhancement are warranted in CHR but remain rudimentary. We investigated whether personalized transcranial magnetic stimulation (TMS) over the left parieto-hippocampal network could improve VSL performance in CHR patients and if it could reduce the risk of psychosis conversion within 1 year., Study Design: Sixty-five CHR patients were randomized to receive active or sham TMS treatments using an accelerated TMS protocol, consisting of 10 sessions of 20 Hz TMS treatments within 2 days. TMS target was defined by individual parieto-hippocampal functional connectivity and precisely localized by individual structural magnetic resonance imaging. VSL performance was measured using Brief Visuospatial Memory Test-Revised included in measurement and treatment research to improve cognition in schizophrenia consensus cognitive battery (MCCB). Fifty-eight CHR patients completed the TMS treatments and MCCB assessments and were included in the data analysis., Study Results: We observed significant VSL improvements in the active TMS subgroup (Cohen's d = 0.71, P < .001) but not in the sham TMS subgroup (Cohen's d = 0.07, P = .70). In addition, active TMS improved the precision of VSL performance. At a 1-year follow-up, CHR patients who received active TMS showed a lower psychosis conversion rate than those who received sham TMS (6.7% vs 28.0%, χ2 = 4.45, P = .03)., Conclusions: Our findings demonstrate that personalized TMS in the left parieto-hippocampal network may be a promising preventive intervention that improves VSL in CHR patients and reduces the risk of psychosis conversion at follow-up., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Schizophrenia is one of the most common and disabling mental disorders. About 20% of people with schizophrenia do not respond to antipsychotics, which are the mainstay of the treatment for schizophrenia today, and need to seek other treatment options. Magnetic seizure therapy (MST) is one of the novel non-invasive brain stimulation techniques that are being investigated in recent years.  OBJECTIVES: To evaluate the efficacy and tolerability of MST for people with schizophrenia., Search Methods: On 6 March 2022, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on CENTRAL, CINAHL, ClinicalTrials.Gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed, and WHO ICTRP., Selection Criteria: All randomised controlled trials (RCTs) comparing MST alone or plus standard care with ECT or any other interventions for people with schizophrenia.  DATA COLLECTION AND ANALYSIS: We performed reference screening, study selection, data extraction and risk of bias and quality assessment in duplicate. We calculated the risk ratios (RRs) and their 95% confidence intervals (CIs) for binary outcomes and the mean difference (MD) and their 95% CIs for continuous outcomes. We used the original risk of bias tool for risk of bias assessment and created a Summary of findings table using GRADE., Main Results: We included one four-week study with 79 adults in acute schizophrenia, comparing MST plus standard care to ECT plus standard care in this review. We rated the overall risk of bias as high due to high risk of bias in the domains of selective reporting and other biases (early termination and baseline imbalance) and unclear risk of bias in the domain of blinding of participants and personnel. We found that MST and ECT may not differ in improving the global state (n = 79, risk ratio (RR) 1.12, 95% confidence interval (CI) 0.73 to 1.70), overall (n = 79, mean difference (MD) -0.20, 95% CI -8.08 to 7.68), the positive symptoms (n = 79, MD 1.40, 95% CI -1.97 to 4.77) and the negative symptoms (n = 79, MD -1.00, 95% CI -3.85 to 1.85) in people with schizophrenia.  We found  that MST compared to ECT may cause less delayed memory deficit and less cognitive deterioration (n = 79, number of people with a delayed memory deficit, RR 0.63, 95% CI 0.41 to 0.96; n = 79, mean change in global cognitive function, MD 5.80, 95% CI 0.80 to 10.80), but also may improve more cognitive function (n = 47, number of people with any cognitive improvement, RR 3.30, 95% CI 1.29 to 8.47).  We found that there may be no difference between the two groups in terms of leaving the study early due to any reason (n = 79, RR 2.51, 95% CI 0.73 to 8.59), due to adverse effects (n = 79, RR 3.35, 95% CI 0.39 to 28.64) or due to inefficacy (n = 79, RR 2.52, 95% CI 0.11 to 60.10).  Since all findings were based on one study with high risk of bias and the confidence in the evidence was very low, we were not sure these comparable or favourable effects of MST over ECT were its true effects.  AUTHORS' CONCLUSIONS: Due to the paucity of data, we cannot draw any conclusion on the efficacy and tolerability of MST for people with schizophrenia. Well-designed RCTs are warranted to answer the question., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Schizophrenia is a severely debilitating psychiatric disorder with high heritability and polygenic architecture. A higher polygenic risk score for schizophrenia (SzPRS) has been associated with smaller gray matter volume, lower activation, and decreased functional connectivity (FC). However, the effect of polygenic inheritance on the brain white matter microstructure has only been sparsely reported., Methods: Eighty-four patients with first-episode schizophrenia (FES) patients and ninety-three healthy controls (HC) with genetics, diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI) data were included in our study. We investigated impaired white matter integrity as measured by fractional anisotropy (FA) in the FES group, further examined the effect of SzPRS on white matter FA and FC in the regions connected by SzPRS-related white matter tracts., Results: Decreased FA was observed in FES in many commonly identified regions. Among these regions, we observed that in the FES group, but not the HC group, SzPRS was negatively associated with the mean FA in the genu and body of corpus callosum, right anterior corona radiata, and right superior corona radiata. Higher SzPRS was also associated with lower FCs between the left inferior frontal gyrus (IFG)-left inferior temporal gyrus (ITG), right IFG-left ITG, right IFG-left middle frontal gyrus (MFG), and right IFG-right MFG in the FES group., Conclusion: Higher polygenic risks are linked with disrupted white matter integrity and FC in patients with schizophrenia. These correlations are strongly driven by the interhemispheric callosal fibers and the connections between frontotemporal regions.

Objective: This paper aims to model the anatomical circuits underlying schizophrenia symptoms, and to explore patterns of abnormal connectivity among brain networks affected by psychopathology., Methods: T1 magnetic resonance imaging (MRI), diffusion weighted imaging (DWI), and resting-state functional MRI (rsfMRI) were obtained from a total of 126 patients with schizophrenia who were recruited for the study. The images were processed using the Omniscient software (https://www.o8t. com). We further apply the use of the Hollow-tree Super (HoTS) method to gain insights into what brain regions had abnormal connectivity that might be linked to the symptoms of schizophrenia., Results: The Positive and Negative Symptom Scale is characterised into 6 factors. Each symptom is mapped with specific anatomical abnormalities and circuits. Comparison between factors reveals co-occurrence in parcels in Factor 1 and Factor 2. Multiple large-scale networks are involved in SCZ symptomatology, with functional connectivity within Default Mode Network (DMN) and Central Executive Network (CEN) regions most frequently associated with measures of psychopathology., Conclusion: We present a summary of the relevant anatomy for regions of the cortical areas as part of a larger effort to understand its contribution in schizophrenia. This unique machine learning-type approach maps symptoms to specific brain regions and circuits by bridging the diagnostic subtypes and analysing the features of the connectome., Competing Interests: Declaration of Competing Interest Six authors (HT, PN, OT, IY, SD and MS) are employees of Omniscient Neurotechnology. SD and MS are co-founders and directors of Omniscient Neurotechnology., (Copyright © 2023. Published by Elsevier B.V.)

Eye movement abnormalities have been established as an "endophenotype" of schizophrenia. However, less is known about the possibility of these abnormalities as biomarkers for psychosis conversion among clinical high risk (CHR) populations. In the present study, 108 CHR individuals and 70 healthy controls (HC) underwent clinical assessments and eye-tracking tests, comprising fixation stability and free-viewing tasks. According to three-year follow-up outcomes, CHR participants were further stratified into CHR-converter (CHR-C; n = 21) and CHR-nonconverter (CHR-NC; n = 87) subgroups. Prediction models were constructed using Cox regression and logistic regression. The CHR-C group showed more saccades of the fixation stability test (no distractor) and a reduced saccade amplitude of the free-viewing test than HC. Moreover, the CHR-NC group exhibited excessive saccades and an increased saccade amplitude of the fixation stability test (no distractor; with distractor) compared with HC. Furthermore, two indices could effectively discriminate CHR-C from CHR-NC with an area under the receiver-operating characteristic (ROC) curve of 0.80, including the saccade number of the fixation stability test (no distractor) and the saccade amplitude of the free-viewing test. Combined with negative symptom scores of the Scale of Prodromal Symptoms, the area was 0.81. These findings support that eye movement alterations might emerge before the onset of clinically overt psychosis and could assist in predicting psychosis transition among CHR populations., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objectives: Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES., Methods: FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields., Results: Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity., Conclusions: Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The hippocampus is a core region of interest for all major mental disorders, and its subfields implement distinctive functions. It is unclear whether the mental disorders exhibit common patterns of hippocampal impairments, and we lack knowledge on whether and how hippocampal subfields represent deficit spectra across mental disorders., Methods: Using brain images of 1123 individuals scanned on a single magnetic resonance imaging scanner, we examined the commonality, specificity, and symptom associations of the volume of hippocampal subfields across patients with schizophrenia, patients with obsessive-compulsive disorder, patients with bipolar disorder, patients with major depressive disorder, and healthy control subjects. We further performed a transdiagnostic analysis of the individual variability of the volume of hippocampal subfields to reflect cross-disease gradients in the hippocampus., Results: We found common and disease-specific abnormalities in a few hippocampal fields and identified 2 reliable transdiagnostic factors in the hippocampal subfields, each reflecting a spectrum of mental disorders. The plane spanned by the 2 most reliable factors provided a clearer view of hippocampal volume abnormality spectra among the major mental disorders. In addition, functional and genetic enrichment analyses supported the different roles of the 2 hippocampal factors in mental disorders., Conclusions: The volume of hippocampal subfields reflected some commonality and specificity among the 3 major mental disorders. We propose a new pathophysiological dimensional view of the hippocampus, reflecting at least 2 spectra of mental disorders, suggesting multivariate links among the diseases. This work highlights the value of the complementary categorical and dimensional views of the hippocampal deficits in mental disorders., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Individuals at clinical high risk (CHR) for psychosis exhibit a compromised mismatch negativity (MMN) response, which indicates dysfunction of pre-attentive deviance processing. Event-related potential and time-frequency (TF) information, in combination with clinical and cognitive profiles, may provide insight into the pathophysiology and psychopathology of the CHR stage and predict the prognosis of CHR individuals. A total of 92 individuals with CHR were recruited and followed up regularly for up to 3 years. Individuals with CHR were classified into three clinical subtypes demonstrated previously, specifically 28 from Cluster 1 (characterized by extensive negative symptoms and cognitive deficits), 31 from Cluster 2 (characterized by thought and behavioral disorganization, with moderate cognitive impairment), and 33 from Cluster 3 (characterized by the mildest symptoms and cognitive deficits). Auditory MMN to frequency and duration deviants was assessed. The event-related spectral perturbation (ERSP) and inter-trial coherence (ITC) were acquired using TF analysis. Predictive indices for remission were identified using logistic regression analyses. As expected, reduced frequency MMN (fMMN) and duration MMN (dMMN) responses were noted in Cluster 1 relative to the other two clusters. In the TF analysis, Cluster 1 showed decreased theta and alpha ITC in response to deviant stimuli. The regression analyses revealed that dMMN latency and alpha ERSP to duration deviants, theta ITC to frequency deviants and alpha ERSP to frequency deviants, and fMMN latency were significant MMN predictors of remission for the three clusters. MMN variables outperformed behavioral variables in predicting remission of Clusters 1 and 2. Our findings indicate relatively disrupted automatic auditory processing in a certain CHR subtype and a close affinity between these electrophysiological indexes and clinical profiles within different clusters. Furthermore, MMN indexes may serve as predictors of subsequent remission from the CHR state. These findings suggest that the auditory MMN response is a potential neurophysiological marker for distinct clinical subtypes of CHR., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Impaired sensitivity of the skin flush response to niacin is found in approximately 30% of patients with schizophrenia. Although the niacin response abnormality (NRA) may serve as a useful endophenotype for schizophrenia, few studies have directly replicated NRA in patients with first-episode psychosis (FEP)., Methods: In total, 204 patients with FEP, 16 with psychotic mood disorder (PMD), and 68 healthy controls (HC) were included. The log 10 (EC 50 ) values represent the concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response, and the MBF value was calculated. The NRA was defined as having log 10 (EC 50 ) molar value above the 90% and an MBF value below the 60% of those in the HC group., Results: In total, 13.7% of the FEP, 12.5% of the PMD, and 7.4% of the HC group met the definition of NRA. Significant differences were found in the log 10 (EC 50 ) values between the FEP and HC groups (p = .014) and in the MBF between the FEP and PMD groups (p = .011). Patients with FEP and NRA had more severe negative symptoms than those with a normal niacin response., Discussion: These data represent the NRA in patients with FEP, defining a small subgroup of patients with early-phase psychosis possessing a clinically significant phospholipid-signaling defect., (© 2022 John Wiley & Sons Australia, Ltd.)

We studied brain changes during an N-back task before and after 10 sessions of transcranial direct current stimulation (tDCS) and its relation to cognitive changes. This was a double-blind, sham-controlled, randomized study of tDCS in 27 patients with schizophrenia. They performed an N-back task in a 3 T scanner before and after receiving the 10 tDCS sessions. Cognitive performance outside the fMRI session was assessed using the MATRICS Consensus Cognitive Battery and other tests at baseline and several time points after 10 sessions of tDCS. During the N-back task performed during fMRI scans, comparing the 0-back vs. the 2-back task, the active tDCS group demonstrated a significantly increased activation in the right fusiform, left middle frontal, left inferior frontal gyrus (opercular part) and right inferior frontal gyrus (triangular part) and reduced activation in the left posterior cingulum gyrus with most of these results primarily due to increases in activation during the 0-back rather than 2-back task. There were also significant positive or negative correlations between some of the brain changes and cognitive performance. tDCS modulated prefrontal activation at low working memory load or attention mode, but default mode network at higher working memory load. Changes in brain activation measured during the N-back task were correlated with some dimensions of cognitive function immediately after 10 tDCS sessions and at follow-up times. The results support tDCS could offer a potential novel approach for modulating cortical activity and its relation to cognitive function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Schizophrenia is a neurodevelopmental disorder manifesting differing impairments at early onset and chronic disease stages. Brain imaging research suggests a core pathological region in patients with first-episode schizophrenia is Broca's area. With disease progression, alterations in thalamic connectivity becomes more prevalent. Understanding the common circuitry underlying pathology in these two groups might highlight a critical common network and novel targets for treatment. In this study, 937 subject samples were collected including patients with first-episode schizophrenia and those with chronic schizophrenia. We used hypothesis-based voxel-level functional connectivity analyses to calculate functional connectivity using the left Broca's area and thalamus as regions of interest in those with first-episode and chronic schizophrenia, respectively. We show for the first time that in both patients with first-episode and chronic schizophrenia the greatest functional connectivity disruption ended in the pre- and postcentral regions. At the early-onset stage, the core brain region is abnormally connected to pre- and postcentral areas responsible for mouth movement, while in the chronic stage, it expanded to a wider range of sensorimotor areas. Our findings suggest that expanding the focus on the low-order sensory-motor systems beyond high-order cognitive impairments in schizophrenia may show potential for neuromodulation treatment, given the relative accessibility of these cortical regions and their functional and structural connections to the core region at different stages of illness., (Copyright © 2022. Published by Elsevier Inc.)

Hippocampal deficits and metabolic dysregulations such as dyslipidemia have been frequently reported in schizophrenia and are suggested to contribute to the pathophysiology of schizophrenia. Hippocampus is particularly susceptible to environmental challenges including metabolism and inflammation. However, evidence linking hippocampal alterations and metabolic dysregulations are quite sparse in drug-naïve schizophrenia. A total of 166 drug-naïve patients with first-episode schizophrenia (FES) and 78 healthy controls (HC) underwent measures for several serum metabolic markers, structural and resting-state functional magnetic resonance imaging (rs-fMRI), as well as diffusion tensor imaging (DTI). Seed-to-voxel functional connectivity (FC) and probabilistic tractography were performed to assess the functional and microstructural connectivity of the bilateral hippocampi. Clinical symptoms were evaluated with Positive and Negative Syndrome Scale (PANSS). Patients with FES showed significantly decreased total cholesterol (Chol) level. Patients showed elevated FC between the left hippocampus and bilateral thalami while showing decreased microstructural connectivity between the left hippocampus and bilateral thalami. Multiple regression analyses showed that FC from the left hippocampus to the right superior frontal gyrus (SFG), bilateral frontal pole (FP), and right thalamus were negatively associated with the Chol level, while no association was observed in the HC group. Our study validated alterations in both functional and microstructural thalamo-hippocampal connectivities, and abnormal cholesterol level in FES. Moreover, decreased cholesterol level is associated with elevated thalamo-hippocampal functional connectivity in patients with FES, suggesting that dyslipidemia may interact with the hippocampal dysfunction in FES., (Copyright © 2022. Published by Elsevier Ltd.)

Electroconvulsive therapy (ECT) can effectively reduce the symptoms of schizophrenia, but may also impair cognitive function. A potential alternative is magnetic seizure therapy (MST), which has shown comparable efficacy with less severe cognitive disruption. This study compared ECT to MST for clinical efficacy and cognitive side effects. In addition, we examined the possible contributions of hippocampal volume changes and enhanced brain derived neurotrophic factor (BDNF) signaling to the therapeutic responses. Thirty-four confirmed schizophrenia patients were allocated to receive ECT (n = 16) or MST (n = 18) over a 4-week period. Schizophrenia symptoms were measured by PANSS, cognition by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and serum BDNF and its precursor proBDNF by ELISA at baseline and following ECT or MST. Both treatments reduced PANSS scores with comparable efficacy, while MST was superior for preservation of RBANS language score. ECT significantly increased the volumes of the bilateral hippocampus and multiple subfields, while MST had no effect on hippocampal volume. The change in right hippocampal volume was correlated with proBDNF change among ECT and MST non-responders (< 25% decrease in PANSS score). MST reduced schizophrenia symptoms as effectively as ECT with slightly better preservation of cognitive function., (Copyright © 2022. Published by Elsevier B.V.)

The lack of objective diagnostic markers has long been a challenge in the clinical management of schizophrenia (SZ). The current bivariate cut-offs method is an objective quantification of niacin skin flush abnormality (NFA) for identifying the SZ subgroup. However, the sensitivity of approximately 30% limits the application of NFA as a marker for detecting SZ. A laser Doppler flowmeter was employed to test the niacin skin-flushing response in 123 patients with first-episode psychosis including first-episode SZ (FES, n = 82) and psychotic bipolar disorders (PBP, n = 41), and non-psychiatric comparisons (NPC, n = 80). We modified the bivariate cut-offs using a combination of the niacin concentration corresponding to the half-maximal blood flow response (EC 50 ) and a new quantitative indicator called the overall trend area (OTA). The NFA used this study method predicted FES in the NPC group with 57% sensitivity, 89% specificity, and 73% accuracy compared to the 28% sensitivity, 91% specificity, and 59% accuracy of the existing method. This novel method could discern FES from the PBP group with an accuracy of 62%, compared with the 45% of the old method. In addition, we also discuss whether the bivariate cut-offs were occasional by adjusting the cut-offs threshold. The experimental results showed that the sensitivity and specificity were most stable when using the study method. The study indicates that NFA using modified bivariate cut-offs may be a potential objective marker in FES, and the niacin skin test could be feasible for early diagnosis and treatment of SZ., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: For decades, the dopamine D2 receptor (D2R) has been known as the main target of antipsychotic medications, but the mechanism for antipsychotic effects beyond this pharmacological target remains unclear. Disrupted-in-schizophrenia 1 ( DISC1 ) is a gene implicated in the etiology of schizophrenia, and we have found elevated levels of the D2R-DISC1 complex in the postmortem brain tissue of patients with schizophrenia., Methods: We used coimmunoprecipitation to measure D2R-DISC1 complex levels in peripheral blood samples from patients with schizophrenia and unaffected controls in 3 cohorts (including males and females) from different hospitals. We also used label-free mass spectrometry to conduct proteomic analysis of these samples., Results: Levels of the D2R-DISC1 complex were elevated in the peripheral blood samples of patients with schizophrenia from 3 independent cohorts, and were normalized with antipsychotic treatment. Proteomic analysis of the blood samples from patients with high D2R-DISC1 complex levels that were normalized with antipsychotic treatment revealed a number of altered proteins and pathways associated with D2R, DISC1 and the D2R-DISC1 complex. We identified additional proteins and pathways that were associated with antipsychotic treatment in schizophrenia, and that may also be novel targets for schizophrenia treatment., Limitations: Sample sizes were relatively small, but were sufficient to detect associations between D2R-DISC1 levels, schizophrenia and treatment response. The relevance of leukocyte changes to the symptoms of schizophrenia is unknown. The coimmunoprecipitation lanes included several nonspecific bands., Conclusion: Levels of the D2R-DISC1 complex were elevated in patients with schizophrenia and reduced with antipsychotic treatment. This finding reinforces the independent role of each protein in schizophrenia. Our results enhanced our understanding of the molecular pathways involved in schizophrenia and in antipsychotic medications, and identified novel potential molecular targets for treating schizophrenia., Competing Interests: Competing interests: A.H.C. Wong reports consulting fees and stock from FSD Pharma. No other competing interests declared., (© 2022 CMA Impact Inc. or its licensors.)

Recent evidence highlights the role of the cerebellum-cerebral loop in the pathophysiology of schizophrenia (SZ). Electroconvulsive therapy (ECT) is clinically applied to augment the effect of antipsychotic drugs. The study aims to address whether the cerebellum-cerebral loop is involved in the mechanisms of ECT's augmentation effect. Forty-two SZ patients and 23 healthy controls (HC) were recruited and scanned using resting-state functional MRI (rs-fMRI). Twenty-one patients received modified ECT plus antipsychotics (MSZ group), and 21 patients took antipsychotics only (DSZ group). All patients were re-scanned four weeks later. Brain functional network was constructed according to the graph theory. The sub-network exhibited longitudinal changes after ECT or medications were constructed. For the MSZ group, a sub-network involving default-mode network and cerebellum showed significant longitudinal changes. For the DSZ group, a different sub-network involving the thalamus, frontal and occipital cortex was found to be altered in the follow-up scan. In addition, the changing FC of the left cerebellar crus2 region was correlated with the changing scores of the psychotic symptoms only in the MSZ group but not in the DSZ group. In conclusion, the cerebral-cerebellum loop is possibly involved in the antipsychotic mechanisms of ECT for schizophrenia., (Copyright © 2022. Published by Elsevier B.V.)

Patients with schizophrenia show widespread impairments in clinical, cognitive and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are two neurophysiological biomarkers widely used to inform diagnosis, guide treatments and track response to interventions in schizophrenia. However, evidence for the test-retest reliability of these indices across multiple sessions in schizophrenia patients remains scarce. In the present study, we included 34 schizophrenia patients (17 females) and obtained duration MMN (dMMN), frequency MMN (fMMN) and 40-Hz ASSR data across three sessions with intervals of 2 days. Event-related spectrum perturbation (ERSP) and inter-trial coherence (ITC) were calculated following Morlet wavelet time-frequency decomposition of ASSR data. The intra-class correlation coefficient (ICC) was used to quantify the reliability of MMN and ASSR measures among the three sessions. We found fair to good reliability for dMMN amplitudes but poor reliability for fMMN amplitudes. For the ASSR measures, ERSP showed good to excellent test-retest reliability while ITC had poor to fair test-retest reliability. In addition, the average of dMMN amplitudes was significantly correlated with that of ERSP across the three sessions. In summary, we established for the first time the short-term test-retest reliability of MMN and ASSR measures in schizophrenia patients. These findings demonstrate that dMMN amplitudes and ERSP of ASSR are reliable indices which may be used in longitudinal observational studies., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cortical thickness reductions are evident in schizophrenia (SZ). Associations between antipsychotic medications (APMs) and cortical morphometry have been explored in SZ patients. This raises the question of whether the reconfiguration of morphological architecture by APM plays potential compensatory roles for abnormalities in the cerebral cortex. Structural magnetic resonance imaging was obtained from 127 medication-naive first-episode SZ patients and 133 matched healthy controls. Patients received 12 weeks of APM and were categorized as responders (n = 75) or nonresponders (NRs, n = 52) at follow-up. Using surface-based morphometry and structural covariance (SC) analysis, this study investigated the short-term effects of antipsychotics on cortical thickness and cortico-cortical covariance. Global efficiency was computed to characterize network integration of the large-scale structural connectome. The relationship between covariance and cortical thinning was examined by SC analysis among the top-n regions with thickness reduction. Widespread cortical thickness reductions were observed in pre-APM patients. Post-APM patients showed more reductions in cortical thickness, even in the frontotemporal regions without baseline reductions. Covariance analysis revealed strong cortico-cortical covariance and higher network integration in responders than in NRs. For the NRs, some of the prefrontal and temporal nodes were not covariant between the top-n regions with cortical thickness reduction. Antipsychotic effects are not restricted to a single brain region but rather exhibit a network-level covariance pattern. Neuroimaging connectomics highlights the positive effects of antipsychotics on the reconfiguration of brain architecture, suggesting that abnormalities in regional morphology may be compensated by increasing interregional covariance when symptoms are controlled by antipsychotics., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

White matter abnormality has been widely reported in patients with schizophrenia (Sz). However, few studies have focused on the relationship between the white matter deficit and formal thought disorder (FTD). Moreover, the role of genetic high risk in FTD-related white matter deficit remains unclear. The present study recruited 46 Sz patients, 18 unaffected first-degree relatives of Sz patients, and 29 healthy controls. There was a widespread fractional anisotropy (FA) reduction in Sz. In addition, reduced FA in the left anterior corona radiata was related to more severe FTD symptoms in Sz. However, the genetic high-risk group only showed lower mean FA in the left anterior limb of the internal capsule than healthy controls. Our findings suggest that abnormality in the left anterior corona radiata may only occur in Sz but not in the genetic high-risk group. Such an abnormality might be associated with the severity of FTD symptoms. Meanwhile, genetic vulnerability may contribute to the abnormality in the left anterior limb of the internal capsule. Better analytical methods are needed to validate our results., (Copyright © 2021. Published by Elsevier B.V.)

Interpersonal communication is a specific scenario in which patients with psychiatric symptoms may manifest different behavioral patterns due to psychopathology. This was a pilot study by eye-tracking technology to investigate attentive bias during social information processing in schizophrenia. We enrolled 39 patients with schizophrenia from Shanghai Mental Health Center and 42 age-, gender- and education-matched healthy controls. The experiment was a free-viewing task, in which pictures with three types of degree of interpersonal communication were shown. We used two measures: 1) initial fixation duration, 2) total gaze duration. The Positive and Negative Syndrome Scale (PANSS) was used to determine symptom severity. The ratio of first fixation duration for pictures of communicating vs. non-communicating persons was significantly lower in patients than in controls (Mann-Whitney U = 512, p = 0.004). We found that male patients showed a significantly lower ratio of first fixation duration than male controls (Mann-Whitney U = 190, p = 0.028), while it was marginally lower in female patients than female controls (Mann-Whitney U = 77, p = 0.057). The ratio of first fixation duration for pictures of communicating persons vs. no persons was negatively correlated with PANSS negative symptoms in male patients (rho = -0.458, p = 0.024). In contrast, it was negatively correlated with PANSS positive symptoms in female patients (-0.701, p = 0.004). These findings suggest altered attentive bias during social information processing with a pattern of avoidance at first sight towards pictures of communicating persons in schizophrenia. It is worthwhile to note that social functioning impairment is associated with the severity of symptoms., (Copyright © 2021. Published by Elsevier B.V.)

Reliable mapping of system-level individual differences is a critical first step toward precision medicine for complex disorders such as schizophrenia. Disrupted structural covariance indicates a system-level brain maturational disruption in schizophrenia. However, most studies examine structural covariance at the group level. This prevents subject-level inferences. Here, we introduce a Network Template Perturbation approach to construct individual differential structural covariance network (IDSCN) using regional gray-matter volume. IDSCN quantifies how structural covariance between two nodes in a patient deviates from the normative covariance in healthy subjects. We analyzed T1 images from 1287 subjects, including 107 first-episode (drug-naive) patients and 71 controls in the discovery datasets and established robustness in 213 first-episode (drug-naive), 294 chronic, 99 clinical high-risk patients, and 494 controls from the replication datasets. Patients with schizophrenia were highly variable in their altered structural covariance edges; the number of altered edges was related to severity of hallucinations. Despite this variability, a subset of covariance edges, including the left hippocampus-bilateral putamen/globus pallidus edges, clustered patients into two distinct subgroups with opposing changes in covariance compared to controls, and significant differences in their anxiety and depression scores. These subgroup differences were stable across all seven datasets with meaningful genetic associations and functional annotation for the affected edges. We conclude that the underlying physiology of affective symptoms in schizophrenia involves the hippocampus and putamen/pallidum, predates disease onset, and is sufficiently consistent to resolve morphological heterogeneity throughout the illness course. The two schizophrenia subgroups identified thus have implications for the nosology and clinical treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Schizophrenia is a complex and highly heterogeneous mental illness with a prodromal period called clinical high risk (CHR) for psychosis before onset. Metabolomics is greatly promising in analyzing the pathology of complex diseases and exploring diagnostic biomarkers. Therefore, we conducted salivary metabolomics analysis in 83 first-episode schizophrenia (FES) patients, 42 CHR individuals, and 78 healthy controls with ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The mass spectrometry raw data have been deposited on the MetaboLights (ID: MTBLS3463). We found downregulated aromatic amino acid metabolism, disturbed glutamine and nucleotide metabolism, and upregulated tricarboxylic acid cycle in FES patients, which existed even in the CHR stage and became more intense with the onset of the schizophrenia. Moreover, differential metabolites can be considered as potential diagnostic biomarkers and indicate the severity of the different clinical stages of disease. Furthermore, three disordered pathways were closely related to peripheral indicators of inflammatory response, oxidative stress, blood-brain barrier damage, and salivary microbiota. These results indicate that the disorder of oral metabolism occurs earlier than the onset of schizophrenia and is concentrated and intensified with the onset of disease, which may originate from the dysbiotic salivary microbiota and cause the onset of schizophrenia through the peripheral inflammatory response and redox system, suggesting the importance of oral-brain connection in the pathogenesis of schizophrenia.

Prolactin increase is a common side effect in antipsychotic treatment of schizophrenia, which crucially impacts drug choice and treatment compliance. As previous reviews by our group on this topic have included only few Chinese studies, we aimed to compare and rank antipsychotics based on broader evidence. This systematic review pooled data of 92 included studies from previous systematic review by Huhn et al. and 38 newly-added studies from Chinese-database search, including Chinese databases of China National Knowledge Infrastructure (CNKI), WANFANG DATA, WEIPU Journal Net (VIP) and Sino Biomedicine Service System (SinoMed) up to 20 May 2020. We conducted both network meta-analysis (NMA) and pairwise meta-analysis. The primary outcome was prolactin increase (continuous data). We calculated mean differences (MDs) for prolactin level with 95% confidence intervals (CIs) using random-effects model as primary analysis. 130 RCTs with 25,610 participants were included. Newer antipsychotics (risperidone, amisulpride and paliperidone) and older antipsychotics (chlorpromazine, haloperidol and sulpride) increase prolactin levels with large effect sizes. The SMD results were not identical to the MD results because consistency and heterogeneity assumption was tested to be different in calculations. Sensitivity analyses removing two studies with massive baseline imbalance or removing Chinese studies with high risk of bias did not affect the result. In contrast to a previous review clozapine and zotepine were no longer associated with decreased prolactin levels compared to placebo. Risperidone's ranking has more implications supported by CINeMA. This NMA draws the conclusion with larger sample size and extends evidence to more literature in this field., (Copyright © 2021. Published by Elsevier B.V.)

Background: Brain dynamics abnormalities in the triple-network, which involves the salience network (SN), the default mode network (DMN) and the central executive network (CEN), have been reported in schizophrenia. However, it remains to be clarified how antipsychotics affect dynamic functional connectivity (DFC) within the triple-network and whether differences in clinical outcomes are associated with varying levels of network model dysfunction., Methods: Resting-state functional magnetic resonance imaging scans were obtained from 64 first-episode schizophrenia patients (SZ) and 67 healthy controls (HC). All patients were scanned before and after 12-week antipsychotic treatment and the HC were scanned only at baseline., Results: At baseline, SZ participants showed significantly reduced dynamic functional interactions across the triple-network compared to HC. The SZ group displayed a pattern of reduction in resting-state DFC among the triple-network compared with HC. After medication, the mean dynamic network interaction index (dNII) value was improved. A significant quadratic relation was observed between longitudinal change of mean dNII and the reduction ratio of PANSS total score within the SZ group. The DFC within inter-network (between DMN and SN, and between DMN and CEN) and intra-network connections of DMN were significantly higher relative to baseline. Intra-SN DFC, intra-DMN DFC and DFC between SN and DMN were found to be predictive of clinical features at baseline. Intra-CEN DFC and DFC between DMN and CEN were predictive of treatment response., Conclusions: Aberrant brain dynamics in the triple-network could be regulated with medication. DFC organization in the triple network was found to predict the clinical outcome., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia., Methods: We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis., Results: RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated., Conclusions: We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

D-amino acid oxidase activator (DAOA) gene, which plays a crucial role in the process of glutamatergic transmission and mitochondrial function, is frequently linked with the liability for schizophrenia. We aimed to investigate whether the variation of DAOA rs2391191 is associated with alterations in white matter integrity of first-episode schizophrenia (FES) patients; and whether it influences the association between white matter integrity, cognitive function and clinical symptoms of schizophrenia. Forty-six patients with FES and forty-nine healthy controls underwent DTI and were genotyped for DAOA rs2391191. Psychopathological assessments were performed by Brief Psychiatric Rating Scale (BPRS) and Scale for Assessment of Negative Symptoms (SANS). Cognitive function was assessed by MATRICS Consensus Cognitive Battery (MCCB). Schizophrenia patients presented lower fractional anisotropy (FA) and higher radial diffusivity (RD), mainly spreading over the corpus callosum and corona radiata compared with healthy controls. Compared with patients carrying G allele, patients with AA showed lower FA in the body of corpus callosum, and higher RD in the genu of corpus callosum, right superior and anterior corona radiata, and left posterior corona radiata. In patients carrying G allele, FA in body of corpus callosum was positively correlated with working memory, RD in genu of corpus callosum was negatively associated with the speed of processing, working memory, and the composite score of MCCB, while no significant correlations were found in AA homozygotes. In our study, patients with FES presented abnormal white matter integrity in corpus callosum and corona radiata. Furthermore, this abnormality was associated with the genetic variation of DAOA rs2391191, with AA homozygotes showing less white matter integrity in the corpus callosum. Our findings possibly provide further support to the evidence that DAOA regulates the process of glutamatergic neurotransmission and mitochondrial function in the pathophysiological mechanism of schizophrenia., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Deficits in executive control have long been regarded as one of the hallmark cognitive characteristics in people with schizophrenia (SZ), and current neurocognitive models of SZ generally regard the dysfunctional anterior cingulate cortex (ACC) as the possible neural mechanism. This however, contrasts with recent studies showing that conflict processing, a key component of executive functions that relies on ACC, remains relatively intact in SZ. The current study aimed to investigate this issue through two well-known electrophysiological signatures of conflict processing that have been suggested to originate from ACC, i.e., the N2 component of event-related potentials (ERPs) and frontal midline theta (FMθ) oscillations. We recorded 64-channel scalp electroencephalography from 29 SZ (17 women; mean age: 30.4 years) and 31 healthy control subjects (HC; 17 women; mean age: 29.1 years) performing a modified flanker task. Behavioral data revealed no significant differences in flanker conflict effects (lower accuracy and longer reaction times in incongruent trials than in congruent trials) between HC and SZ. Trial-averaged ERP and spectral analysis suggested that both N2 and FMθ were significantly impaired in SZ relative to HC. Furthermore, by sorting incongruent trials according to their reaction times within individual subjects, we found that the trial-by-trial modulation of N2 (larger amplitude and longer latency in slower trials) which was observed and localized in ACC for HC was totally absent for SZ. By contrast, the trial-by-trial modulation of FMθ (larger power in slower trials) was observed and localized in ACC for both groups, despite a smaller magnitude in SZ, which suggested that FMθ, not N2, might serve as the neural substrate of conflict processing in SZ. Taken together, our results enrich the current neurocognitive models of SZ by revealing dissociable neural responses between N2 and FMθ during conflict processing in SZ., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Negative symptoms are the major challenge in clinical management of schizophrenia. Dorsomedial prefrontal cortex (DMPFC) has been suggested to be highly involved in the mechanisms of negative symptoms of schizophrenia. However, the effect of repetitive Transcranial Magnetic Stimulation (rTMS) over DMPFC has not yet been well studied. In this double-blind, randomized controlled rTMS clinical trial, thirty-three participants (17 in active group and 16 in sham group) were enrolled. This study includes the rTMS treatment phase (lasts for 4 weeks) and a subsequently naturalistic follow-up phase (lasts for another 4 weeks). Schizophrenia patients with prominently negative symptoms were randomly assigned to receive 10 Hz or sham rTMS intervention. The score change in Scale of Negative Symptoms (SANS) was defined as the primary outcome measure. There was a significant decrease in negative symptoms, especially affective flattening and anhedonia in schizophrenia patients after DMPFC-rTMS intervention. Moreover, the negative symptoms improvement could maintain at least another 4 weeks. In addition, no memory impairment or serious adverse reaction of rTMS emerged. Our results suggest that high frequency rTMS over DMPF may represent a safe and effective treatment for negative symptoms in patients with schizophrenia., (Copyright © 2021. Published by Elsevier B.V.)

Purpose/background: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation., Methods/procedures: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2)., Findings/results: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES., Implications/conclusions: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC)., Methods: Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained., Results: CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters., Conclusions: These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To investigate the immediate and lasting effects of transcranial electrical stimulation (tES) on working memory (WM) in schizophrenia. We performed a literature search to identify randomized controlled trials (RCTs) evaluating the ability of tES to ameliorate WM. Twelve studies were included: 215 patients in the active stimulation group and 214 in the sham stimulation group. Meta-analysis demonstrated a significant efficacy of tES on WM in follow up, a summary of one or more assessments weeks after the last tES session (standardized mean difference (SMD) 0.33, 95% confidence interval (CI) 0.04 to 0.62; p = 0.02; n = 190, 4 studies; I 2  = 33%) compared to sham tES, while non-significant results were observed for WM assessed immediately after the last tES session (SMD 0.14, 95% CI -0.12 to 0.41; p = 0.30; n = 417, 11 studies; I 2  = 41%) in schizophrenia. There was no significant difference between the two groups in tolerability and dropouts. Evidence of low quality indicates that effects of tES on WM in schizophrenia may appear a few weeks after the last tES session, but not always be present when tested immediately after the last tES session. Further large-scale RCTs with a parallel-group design, sample size estimation and a longer follow-up period are needed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Auditory P300 oddball and novel components index working memory operations and salience processing, respectively, and are regarded as biomarkers of neurocognitive changes in both chronic and first-episode schizophrenia. Much less is known about whether P300 abnormalities exist in individuals at clinical high risk for psychosis (CHR) and if they are predictors of both transition to psychosis and remission from symptoms. One hundred and four CHR and 69 healthy control individuals (HC) completed P300 oddball paradigm, and 131 CHR and 69 HC subjects completed P300 novel paradigm. All CHR subjects were followed up for one year and stratified into CHR converters (CHRC) and non-converters (CHR-NC), with CHR-NC further stratified into remitted and non-remitted subgroups. Between-group comparisons of P300 oddball and novel amplitude and latency were performed among CHRC, CHR-NC and HC, as well as among CHRC, non-remitted CHR, remitted CHR and HC. CHR converters had lower fronto-central P300 novel amplitude as well as marginally lower P300 oddball amplitude relative to HC. When CHR non-converters were stratified into remitted and non-remitted subgroups, P300 novel amplitude in remitted CHR subjects was comparable to HC, and it was higher than that in CHR subjects who converted to psychosis or who did not remit. Thus, reduced P300 novel amplitude indexing impaired salience processing marked both conversion to psychosis and remission from psychotic symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The disruption of salience network (SN) has been consistently found in patients with schizophrenia and thought to give rise to specific symptoms. However, the functional dysconnectivity pattern of SN remains unclear in first-episode schizophrenia (FES). Sixty-five patients with FES and sixty-six health controls (HC) were enrolled in this study and underwent resting-state functional magnetic resonance imaging (rs-fMRI). The eleven regions of interest (ROIs) within SN were derived from the peaks of the group independent component analysis (gICA). Seed-based whole-brain functional connectivity (FC) analyses were performed with all SN ROIs as the seeds. Both hyper- and hypo-connectivity of SN were found in the FES. Specifically, the increased FC mainly existed between the SN and cortico-cerebellar sub-circuit and prefrontal cortex, while the reduced FC mainly existed within cortico-striatal-thalamic-cortical (CSTC) sub-circuit. Our findings suggest that FES is associated with pronounced dysregulation of SN, characterized prominently by hyperconnectivity of SN-prefrontal cortex and cerebellum, as well as hypoconnectivity of CSTC sub-circuit of the SN.

Schizophrenia has often been viewed as a disorder of connectivity. The single nucleotide polymorphism rs1059004 in the oligodendrocyte lineage transcription factor 2 gene locus has been reported to be associated with schizophrenia. We measured the functional connectivity and functional brain network topology properties in 49 schizophrenic patients and 47 healthy controls. We compared the strength and diversity of the functional connectivity and topological properties of functional networks between different genotypes. The correlations among functional connectivity, topological properties and behavioral performances were also investigated in this study. We found that the connectivity strength of schizophrenic patients carrying the risk A allele was generally decreased whereas connectivity diversity was increased. Regarding topological properties, all groups showed small-world properties, the nodal efficiency showed significant differences in the right precuneus and left middle temporal pole between different genotypes in schizophrenic patients. Moreover, the nodal efficiency in the left middle temporal pole was positively correlated with the neuropsychological assessment battery results of the schizophrenic patients who were homozygous for the C allele. Our results elucidate the contribution of rs1059004 to the functional brain network, and may help enhance the present understanding of the role of risk gene in the functional dysconnectivity of schizophrenia., Competing Interests: Declaration of Competing Interests The authors declare that there are no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The individual heterogeneity is a challenge to the prosperous promises of cutting-edge neuroimaging techniques for better diagnosis and early detection of psychiatric disorders. Individuals with similar clinical manifestations may result from very different pathophysiology. Conventional approaches based on comparing group-averages provide insufficient information to support the individualized diagnosis. Here we present an individualized imaging methodology that combines naturalistic imaging and the normative model. This paradigm adopts video clips with rich cognitive, social, and emotional contents to evoke synchronized brain dynamics of healthy participants and builds a spatiotemporal response norm. By comparing individual brain responses with the response norm, we could recognize patients using machine learning techniques. We applied this methodology to recognize first-episode drug-naïve schizophrenia patients in a dataset containing 72 patients and 54 healthy controls. Some segments of the video evoked more synchronized brain activity in the healthy controls than in the schizophrenia patients. We built a spatiotemporal response norm by averaging the brain responses of the healthy controls in a training set, and trained a classifier to recognize patients based on the differences between individual brain responses and the norm. The performance of the classifier was then evaluated using an independent test set. The mean accuracies from a 5-fold cross-validation were 0.71-0.78 depending on the parameters such as the number of features and the width of the sliding windows. These findings reflected the potential of this methodology towards a clinical tool for individualized diagnosis., Competing Interests: Declaration of competing interest All authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)