Background and Hypothesis Antipsychotics (APs) are often used among individuals with clinical high risk (CHR) for psychosis and affect cortical thickness (CT). Whether clinical and CT changes after initial AP use correlate with long-term clinical outcomes remains largely unknown. Study Design One hundred and thirty-eight CHRs and 65 healthy controls accepted 2 MRI scans at an interval of 2 months. CHRs were categorized as responders (n = 53) and non-responders (n = 69) based on their response to APs after 2-month treatment. According to 2-year outcomes, they were also subdivided into converters (n = 26) and non-converters (n = 96). The relationships among short-term CT changes, AP effects, and long-term outcomes were explored. Study Results At baseline, CHRs had CT reduction in the right inferior temporal cortex with a correlation with clinical symptoms. At 2 month, CHRs showed steeper gray matter loss in bilateral frontotemporal regions than healthy controls. Cortical thickness change rates of the clusters located in bilateral middle temporal and right lateral orbitofrontal cortex were negatively correlated with the cumulative AP dose. Furthermore, 2-year psychosis conversion rate was significantly higher in non-responders than responders (33.3% vs 5.1%). A random forest model based on demographic, clinical, baseline, and longitudinal CT variables predicted 2-year conversion with an AUC of 0.90 (accuracy: 0.83, sensitivity: 0.78, and specificity: 0.89), with model predictive power driven primarily by symptom and CT variables. Conclusions These findings contribute valuable insights into the potential impact of early AP treatment on brain morphology and clinical trajectories and highlight the importance of monitoring the initial treatment responses.

Background and Hypothesis Given that fixation stability is closely linked to cognition, we investigated fixation stability in patients at different stages of schizophrenia, its relationship with cognitive impairments, and its predictive role for conversion to psychosis. Study Design Fixation stability was measured by bivariate contour ellipse area (BCEA), and cognition was assessed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery for 75 patients with first-episode schizophrenia (FES), 75 patients with clinical high-risk (CHR) syndrome, and 75 healthy controls (HCs). After a 1-year longitudinal study, CHR follow-up outcomes were classified as CHR-converters and CHR-nonconverters. Diagnostic model for clinical stages and prediction model for conversion were constructed using logistic regression and Cox regression, respectively. Study Results Patients exhibited fixation instability and cognition impairments compared to HC, with impairments increasing from CHR to FES. In CHR, BCEA negatively correlated with Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery scores, but this correlation was absent in FES. Diagnostic model effectively discriminated HC and FES, with an area under the receiver-operating characteristic curve of 0.914. Among 66 CHR followed up for 1 year, 13 have converted to schizophrenia, with a conversion rate of 19.70%. When divided into large and small BCEA groups (33 each), the conversion rate was 27.27% and 12.12%. Conversion prediction model achieved an area under the receiver-operating characteristic curve of 0.708. Conclusions Our results indicate that fixation instability worsens with schizophrenia progression, which is associated with cognitive impairments. Additionally, BCEA may serve as a biomarker for predicting conversion to psychosis.

BACKGROUND:Clinical high risk for psychosis (CHR) is often managed with antipsychotic medications, but their effects on neurocognitive performance and clinical outcomes remain insufficiently explored. This study investigates the association between aripiprazole and olanzapine use and cognitive and clinical outcomes in CHR individuals, compared to those receiving no antipsychotic treatment. METHODS:A retrospective analysis was conducted on 127 participants from the Shanghai At Risk for Psychosis (SHARP) cohort, categorized into three groups: aripiprazole, olanzapine, and no antipsychotic treatment. Neurocognitive performance was evaluated using the MATRICS Consensus Cognitive Battery (MCCB), while clinical symptoms were assessed through the Structured Interview for Prodromal Syndromes (SIPS) at baseline, 8 weeks, and one year. RESULTS:The non-medicated group demonstrated greater improvements in cognitive performance, clinical symptoms, and functional outcomes compared to the medicated groups. Among the antipsychotic groups, aripiprazole was associated with better visual learning outcomes than olanzapine. Improvements in neurocognition correlated significantly with clinical symptom relief and overall functional gains at follow-up assessments. CONCLUSIONS:These findings suggest potential associations between antipsychotic use and cognitive outcomes in CHR populations while recognizing that observed differences may reflect baseline illness severity rather than medication effects alone. Aripiprazole may offer specific advantages over olanzapine, underscoring the importance of individualized risk-benefit evaluations in treatment planning. Randomized controlled trials are needed to establish causality.

Pattern separation and pattern completion are opposing yet complementary components of mnemonic processing that rely heavily on the hippocampus. It has been shown that processing within the dentate gyrus (DG) subfield promotes pattern separation while operations within the CA3 subfield are important for pattern completion. Schizophrenia has been associated with anatomical and functional hippocampal abnormalities, including within the DG and CA3. We hypothesized that an impairment in hippocampal circuitry in individuals with first-episode schizophrenia leads to deficits in pattern separation (mnemonic discrimination) and pattern completion (recognition memory), that these deficits contribute to delusions and that antipsychotic treatment improves circuit functioning. We measured behavioral and neural responses during the identification of new, repeated and similar stimuli using high-resolution fMRI in 45 medication-free or minimally treated individuals with first-episode schizophrenia (FES) and 49 matched healthy controls (HC). We found recognition memory and pattern separation deficits in FES and a negative association between memory performance and the severity of delusions. Neural analyses revealed deficits in BOLD responses in the hippocampus during mnemonic discrimination in FES compared with HC. Importantly, by investigating the association between trial-level neural activity and behavior before and after treatment, we found that antipsychotics normalized DG activity during pattern separation. Last, trial-level cortical responses during mnemonic discrimination predicted performance in FES at baseline, suggesting a compensatory role. This case-control study provides important insight into the impact of schizophrenia and antipsychotic treatment on memory systems and uncovers systems-level contributions to pattern separation and pattern completion. Dysfunction in the hippocampal circuitry in individuals with first-episode schizophrenia and delusions is linked to deficits in behavioral pattern separation and recognition memory.

Schizophrenia is a severe psychiatric disorder characterized by widespread white matter (WM) alterations, manifesting as neurodevelopmental deficits and dysconnectivity abnormalities. Over the past two decades, studies have focused on the clinical high-risk (CHR) stage of psychosis and have yielded fruitful information on WM abnormalities that exist prior to the full onset of psychosis, shedding light on biological mechanisms underlying psychosis development. This review presents a summary of current findings on cross-sectional and longitudinal WM alterations in individuals with CHR and their links to clinical symptoms and neurocognitive dysfunction. Next, we review the utilization of WM characterization in predicting clinical outcomes. Taken together, the literature suggests the clinical significance of WM characteristics and their great potential in predicting the conversion to psychosis, despite some methodological and conceptual challenges that remain to be addressed in future studies. Future CHR research would greatly benefit from utilizing WM to guide pharmacological and non-pharmacological targeted treatments, optimize clinical prediction models, and enable more accurate clinical care.

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.

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.

Pattern separation and pattern completion are opposing yet complementary components of mnemonic processing that heavily rely on the hippocampus. It has been shown that processing within the dentate gyrus (DG) subfield promotes pattern separation while operations within the CA3 subfield are important for pattern completion. Schizophrenia has been associated with anatomical and functional hippocampal abnormalities, including within the DG and CA3. We hypothesized that an impairment in hippocampal circuitry in individuals with first-episode schizophrenia leads to deficits in pattern separation (mnemonic discrimination) and pattern completion (recognition memory), that these deficits contribute to delusions, and that antipsychotic treatment improves circuit functioning. We measured behavioral and neural responses during the identification of new, repeated, and similar stimuli using high-resolution fMRI in 45 medication-free or minimally-treated patients with first-episode schizophrenia and 49 matched controls. We found recognition memory and pattern separation deficits in patients and a negative association between memory performance and the severity of delusions. Neural analyses revealed deficits in both univariate BOLD responses and multivariate patterns in the hippocampus during mnemonic discrimination in patients compared to controls. Importantly, by investigating the association between trial-level neural activity and behavior before and after treatment, we found that antipsychotics normalized DG activity during pattern separation and CA3 activity during pattern completion. Lastly, trial-level cortical responses during mnemonic discrimination predicted performance in patients at baseline, suggesting a compensatory role. This study provides new insight into the impact of schizophrenia and antipsychotic treatment on memory systems and uncovers systems-level contributions to pattern separation and pattern completion.### Competing Interest StatementThe authors have declared no competing interest.

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.

Error monitoring plays a key role in people's adjustment to social life. This study aimed to examine the direct (DE) and indirect effects (IDE) of error monitoring, as indicated by error-related negativity (ERN), on social functioning in a clinical cohort from high-risk (APS) to first-episode psychosis (FEP). This study recruited 100 outpatients and 49 healthy controls (HC). ERN was recorded during a modified flanker task; social functioning was evaluated using the social scale of global functioning. The path analysis was executed using the "lavaan" package. When controlling for age and education, the clinical cohort had a smaller ERN than the HC group (F1, 145 = 19.58, p < 0.001, partial η2 = 0.12, 95%CI: 0.04-0.22). ERN demonstrated no substantial direct impact on current social functioning; however, it manifested indirect influences on social functioning via the disorganization factor of the Positive and Negative Syndrome Scale, both with (standardized IDE: -0.139, p = 0.009) and without (standardized IDE: -0.087, p = 0.018) accounting for the diagnosis, defined as a dummy variable (FEP = 1 and APS = 0) and included as a covariate. These findings suggest that error monitoring, as indicated by ERN, may serve as a potential prognostic indicator of social functioning in patients with psychosis.

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 naive 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_layer_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.

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.

Background Disrupted white matter (WM) microstructure has been commonly identified in youth at clinical high risk (CHR) for psychosis. Several lines of evidence suggest that fatty acids, especially unsaturated fatty acids (UFAs), might play a crucial role in the WM pathology of early onset psychosis. However, evidence linking UFA and WM microstructure in CHR is quite sparse. Aims We investigated the relationship between the plasma UFA level and WM microstructure in CHR participants and healthy controls (HC). Methods Plasma fatty acids were assessed and diffusion tensor imaging (DTI) data were performed with tract-based spatial statistics (TBSS) analysis for 66 individuals at CHR for psychosis and 70 HC. Results Both the global and regional diffusion measures showed significant between-group differences, with decreased fractional anisotropy (FA) but increased mean diffusivity (MD) and radial diffusivity (RD) found in the CHR group compared with the HC group. On top of that, we found that in the HC group, plasma arachidic acid showed obvious trend-level associations with higher global FA, lower global MD and lower global RD, which regionally spread over the corpus callosum, right anterior and superior corona radiata, bilateral anterior and posterior limb of the internal capsule, and bilateral superior longitudinal fasciculus. However, there were no associations between global WM measures and any UFA in the CHR group. Conversely, we even found negative associations between arachidic acid levels and regional FA values in the right superior longitudinal fasciculus and right retrolenticular part of the internal capsule in the CHR group. Conclusions Compared with the HC group, CHR subjects exhibited a different pattern of association between WM microstructure and plasma UFA, with a neuroprotective effect found in the HC group but not in the CHR group. Such discrepancy could be due to the excessively upregulated UFAs accumulated in the plasma of the CHR group, highlighting the role of balanced plasma-membrane fatty acids homeostasis in WM development.

Poor cognitive insight, including low self-reflectiveness and high self-certainty, contributes to poor clinical insight, which includes awareness of illness, relabelling of specific symptoms, and treatment compliance. However, inconsistent results regarding cognitive insight among individuals at clinical high risk of psychosis (CHR) have been reported. This study investigated the difference in cognitive insight among groups with different severity of positive symptoms and analysed the effect of cognitive insight on clinical insight in each group. All participants, including CHR individuals with 3 or 4 points (L-Pitem, n = 85) and 5 points (H-Pitem, n = 37) on any positive-symptom item of the Scale of Prodromal Syndromes, and patients with first-episode psychosis (FEP, n = 59), were measured cognitive and clinical insight using the Beck Cognitive Insight Scale and the Schedule of Assessment of Insight, respectively. The self-reflectiveness of cognitive insight was highest in the LPitem group and lowest in the FEP group. Self-reflectiveness was positively associated with awareness of illness in the L-Pitem and FEP groups; both self-reflectiveness and self-certainty was positively associated with treatment compliance in the L-Pitem group. Improving self-reflectiveness of cognitive insight may conduce to good clinical insight. Self-certainty may have different implication to individuals with mild prodromal symptoms.

Background: Clinical high risk (CHR) of psychosis is characterized by cognitive impairment in social interaction. However, research investigating the neurobiological underpinnings of social interactions and interpersonal re-lationships in CHR participants is sparse.Methods: 21 CHR and 54 healthy controls (HCs) participated in the study. Dyads were formed between one CHR, one sex-matched HC, and two sex-matched HCs comprising 19 CHR-HC dyads and 19 HC-HC dyads. The con-centration changes of oxyhemoglobin and deoxyhemoglobin were examined during a two-block button-press "cooperation" and "competition" task using functional near-infrared spectroscopy(fNIRS) hyperscanning tech-nology. CHR diagnosis and psychopathological assessments were performed by Structured Interview for Pro-dromal Syndromes (SIPS) and Scale of Prodromal Symptoms (SOPS). Neural synchronizations were compared between CHR-HC dyads and HC-HC dyads. Correlation analyses were performed to identify the relationship between neural synchronization, clinical syndrome and cognition.Results: During the cooperation, but not the competition task, the CHR-HC dyads showed reduced inter-brain neural synchronization (INS) in the right inferior frontal gyrus (IFG) compared to the HC-HC dyads. INS also showed a positive correlation with the average cooperation rate. Moreover, the reduced INS in the CHR-HC group was significantly correlated with symptoms score of suspiciousness/persecutory ideas and movement disorders.Conclusions: The decreased INS in right IFG during cooperation could account for CHR's cognitive impairment of social interaction. Our findings provide evidence that inter-brain neural synchronization potentially represents a biomarker of social interaction deficits of CHR.

Abstract 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.

BackgroundClinical high risk (CHR) of psychosis is a state in which positive symptoms cause the subjects distress but do not approach a severity level that fulfils the criteria for a psychotic episode. CHR exhibits cognitive deficits; however, the underlying neurobiological mechanisms remain unclear. This study aimed to investigate whether brain activation measured by the levels of oxygenated hemoglobin (oxy-Hb) in CHR subjects could be correlated with cognitive deficits.MethodsFifty-eight CHR individuals who fulfilled the criteria for attenuated positive syndrome as specified in the Structured Interview for Prodromal Syndrome (SIPS) and the Scale of Prodromal Syndrome (SOPS) and 58 age- and sex-matched healthy participants were included in the study. All subjects completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) that includes tests measuring attention, verbal memory, verbal fluency, executive function, and general intelligence. Functional near-infrared spectroscopy (fNIRS) was used to measure the level of oxy-Hb in the dorsolateral prefrontal and frontotemporal cortices.ResultsWe observed significantly decreased oxy-Hb levels in channel 32 (located in the right superior temporal gyrus, rSTG)) within the CHR individuals compared with that in the healthy controls (HCs) (t=−3.44, Bonferroni-corrected p=0.002), indicating lower brain activity. A significant positive correlation was observed between task-related β values and working memory in the CHR group (r=0.35, p=0.008).ConclusionsThe brain activation of rSTG is abnormal among subjects at clinicial high risk for psychosis. This abnormality is probably associated with the neural mechanisms of deficits in the working memory during the early stage of psychosis.

PURPOSE:This study investigated temporal dynamics in degree centrality (DC) of the brain functional connectome in first-episode schizophrenia with different short-term treatment responses.METHODS:A total of 127 first-episode patients (FEPs) with schizophrenia and 133 healthy controls (HCs) were recruited in this study. All subjects underwent resting-state functional magnetic resonance imaging. FEPs were scanned at baseline (pretreatment) and at follow-up (posttreatment), while HCs were scanned only at baseline. The patients were exposed to naturalistic antipsychotic treatment for 12 weeks, and classified as schizophrenia responders (SRs) or nonresponders (NRs). Voxel-wise dynamic DC analyses were conducted among the SRs (n=75), NRs (n=52), and HCs (n=133) to assess temporal variability in functional connectivity across the entire neuronal network.RESULTS:The SRs and NRs showed dissimilar dynamic DC at baseline, with differences mainly involving the temporal lobe. Different DC alteration was observed in the left fusiform gyrus, right fusiform gyrus, left middle cingulate cortex, and left superior parietal gyrus in the SRs and NRs pre- and posttreatment. SRs group and NRs presented opposite changing patterns of dynamic DC in particular regions of the brain.CONCLUSION:These findings indicate that dynamic DC abnormalities exist in unmedicated patients with schizophrenia. The NRs differed from the SRs in dynamic DC not only at baseline but in the characteristics of changes before and after treatment as well. Our study may contribute to understanding pathophysiology in schizophrenia with different treatment responses.

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.

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 corticocortical 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.