The neural and genetic underpinnings of different developmental trajectories of Attention-Deficit/Hyperactivity Symptoms in children and adolescents.

BACKGROUND: The trajectory of attention-deficit hyperactivity disorder (ADHD) symptoms in children and adolescents, encompassing descending, stable, and ascending patterns, delineates their ADHD status as remission, persistence or late onset. However, the neural and genetic underpinnings governing the trajectory of ADHD remain inadequately elucidated. METHODS: In this study, we employed neuroimaging techniques, behavioral assessments, and genetic analyses on a cohort of 487 children aged 6-15 from the Children School Functions and Brain Development project at baseline and two follow-up tests for 1 year each (interval 1: 1.14 ± 0.32 years; interval 2: 1.14 ± 0.30 years). We applied a Latent class mixed model (LCMM) to identify the developmental trajectory of ADHD symptoms in children and adolescents, while investigating the neural correlates through gray matter volume (GMV) analysis and exploring the genetic underpinnings using polygenic risk scores (PRS). RESULTS: This study identified three distinct trajectories (ascending-high, stable-low, and descending-medium) of ADHD symptoms from childhood through adolescence. Utilizing the linear mixed-effects (LME) model, we discovered that attention hub regions served as the neural basis for these three developmental trajectories. These regions encompassed the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), responsible for inhibitory control; the right inferior parietal lobule (IPL), which facilitated conscious focus on exogenous stimuli; and the bilateral middle frontal gyrus/precentral gyrus (MFG/PCG), accountable for regulating both dorsal and ventral attention networks while playing a crucial role in flexible modulation of endogenous and extrinsic attention. Furthermore, our findings revealed that individuals in the ascending-high group exhibited the highest PRS for ADHD, followed by those in the descending-medium group, with individuals in the stable-low group displaying the lowest PRS. Notably, both ascending-high and descending-medium groups had significantly higher PRS compared to the stable-low group. CONCLUSIONS: The developmental trajectory of ADHD symptoms in the general population throughout childhood and adolescence can be reliably classified into ascending-high, stable-low, and descending-medium groups. The bilateral MFG/PCG, left ACC/mPFC, and right IPL may serve as crucial brain regions involved in attention processing, potentially determining these trajectories. Furthermore, the ascending-high pattern of ADHD symptoms exhibited the highest PRS for ADHD.

Learning to read may help promote attention by increasing the volume of the left middle frontal gyrus and enhancing its connectivity to the ventral attention network.

Attention and reading are essential skills for successful schooling and in adult life. While previous studies have documented that attention development supports reading acquisition, whether and how learning to read may improve attention among school-age children and the brain structural and functional development that may be involved remain unknown. In this prospective longitudinal study, we examined bidirectional and longitudinal predictions between attention and reading development and the neural mediators of attention and reading development among school-age children using cross-lagged panel modeling. The results showed that better baseline reading performance significantly predicted better attention performance one year later after controlling for baseline attention performance. In contrast, after controlling for baseline reading performance, attention did not significantly predict reading performance one year later, while more attention problems also significantly predicted worse reading performance. Both the increasing gray matter volume of the left middle frontal gyrus and the increasing connectivity between the left middle frontal gyrus and the ventral attention network mediated the above significant longitudinal predictions. This study, directly revealed that reading skills may predict the development of important cognitive functions, such as attention, in school-age children. Therefore, learning to read is not only a challenge for school-age children but is also an important way to optimize attention and brain development.

Development of brain state dynamics involved in working memory.

Human functional brain networks are dynamically organized to enable cognitive and behavioral flexibility to meet ever-changing environmental demands. Frontal-parietal network (FPN) and default mode network (DMN) are recognized to play an essential role in executive functions such as working memory. However, little is known about the developmental differences in the brain-state dynamics of these two networks involved in working memory from childhood to adulthood. Here, we implemented Bayesian switching dynamical systems approach to identify brain states of the FPN and DMN during working memory in 69 school-age children and 51 adults. We identified five brain states with rapid transitions, which are characterized by dynamic configurations among FPN and DMN nodes with active and inactive engagement in different task demands. Compared with adults, children exhibited less frequent brain states with the highest activity in FPN nodes dominant to high demand, and its occupancy rate increased with age. Children preferred to attain inactive brain states with low activity in both FPN and DMN nodes. Moreover, children exhibited lower transition probability from low-to-high demand states and such a transition was positively correlated with working memory performance. Notably, higher transition probability from low-to-high demand states was associated with a stronger structural connectivity across FPN and DMN, but with weaker structure-function coupling of these two networks. These findings extend our understanding of how FPN and DMN nodes are dynamically organized into a set of transient brain states to support moment-to-moment information updating during working memory and suggest immature organization of these functional brain networks in childhood, which is constrained by the structural connectivity.

Default mode network scaffolds immature frontoparietal network in cognitive development.

The default mode network (DMN) is a workspace for convergence of internal and external information. The frontal parietal network (FPN) is indispensable to executive functioning. Yet, how they interplay to support cognitive development remains elusive. Using longitudinal developmental fMRI with an n-back paradigm, we show a heterogeneity of maturational changes in multivoxel activity and network connectivity among DMN and FPN nodes in 528 children and 103 young adults. Compared with adults, children exhibited prominent longitudinal improvement but still inferior behavioral performance, which paired with less pronounced DMN deactivation and weaker FPN activation in children, but stronger DMN coupling with FPN regions. Children's DMN reached an adult-like level earlier than FPN at both multivoxel activity pattern and intranetwork connectivity levels. Intrinsic DMN-FPN internetwork coupling in children mediated the relationship between age and working memory-related functional coupling of these networks, with posterior cingulate cortex (PCC)-dorsolateral prefrontal cortex (DLPFC) coupling emerging as most prominent pathway. Coupling of PCC-DLPFC may further work together with task-invoked activity in PCC to account for longitudinal improvement in behavioral performance in children. Our findings suggest that the DMN provides a scaffolding effect in support of an immature FPN that is critical for the development of executive functions in children.

History of suicidal behavior and clozapine prescribing among people with schizophrenia in China: a cohort study.

BACKGROUND: Clozapine is an off-label drug used in most countries to prevent suicide in individuals with schizophrenia. However, few studies have reported real-world prescription practices. This study aimed to explore the association between a history of suicidal behavior and clozapine prescribing during eight weeks of hospitalization for individuals with early-stage schizophrenia. METHODS: This observational cohort study used routine health data collected from a mental health hospital in Beijing, China. The study included 1057 inpatients who had schizophrenia onset within 3 years. History of suicidal behavior was coded from reviewing medical notes according to the Columbia Suicide Severity Rating Scale. Information on antipsychotic use during hospitalization was extracted from the prescription records. Time to clozapine use was analyzed using Cox regression models adjusted for sociodemographic and clinical covariates. RESULTS: The prevalence rates of self-harm, suicidal behavior, and suicide attempt were 12.3%, 7.5%, and 5.4%, respectively. A history of self-harm history was positively associated with clozapine uses upon admission (4.1% vs. 0.8%, exact p = 0.009). Among those who had not used clozapine and had no clozapine contraindication, A history of suicidal behavior increased the possibility of switch to clozapine within 56 days after admission (Hazard Ratio[95% CI], 6.09[2.08-17.83]) or during hospitalization (4.18[1.62-10.78]). CONCLUSION: The use of clozapine for early-stage schizophrenia was more frequent among those with suicidal behavior than among those without suicidal behavior in China, although the drug instructions do not label its use for suicide risk.

Study Protocol: Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project.

BACKGROUND: Objective and quantifiable markers are crucial for developing novel therapeutics for mental disorders by 1) stratifying clinically similar patients with different underlying neurobiological deficits and 2) objectively tracking disease trajectory and treatment response. Schizophrenia is often confounded with other psychiatric disorders, especially bipolar disorder, if based on cross-sectional symptoms. Awake and sleep EEG have shown promise in identifying neurophysiological differences as biomarkers for schizophrenia. However, most previous studies, while useful, were conducted in European and American populations, had small sample sizes, and utilized varying analytic methods, limiting comprehensive analyses or generalizability to diverse human populations. Furthermore, the extent to which wake and sleep neurophysiology metrics correlate with each other and with symptom severity or cognitive impairment remains unresolved. Moreover, how these neurophysiological markers compare across psychiatric conditions is not well characterized. The utility of biomarkers in clinical trials and practice would be significantly advanced by well-powered transdiagnostic studies. The Global Research Initiative on the Neurophysiology of Schizophrenia (GRINS) project aims to address these questions through a large, multi-center cohort study involving East Asian populations. To promote transparency and reproducibility, we describe the protocol for the GRINS project. METHODS: The research procedure consists of an initial screening interview followed by three subsequent sessions: an introductory interview, an evaluation visit, and an overnight neurophysiological recording session. Data from multiple domains, including demographic and clinical characteristics, behavioral performance (cognitive tasks, motor sequence tasks), and neurophysiological metrics (both awake and sleep electroencephalography), are collected by research groups specialized in each domain. CONCLUSION: Pilot results from the GRINS project demonstrate the feasibility of this study protocol and highlight the importance of such research, as well as its potential to study a broader range of patients with psychiatric conditions. Through GRINS, we are generating a valuable dataset across multiple domains to identify neurophysiological markers of schizophrenia individually and in combination. By applying this protocol to related mental disorders often confounded with each other, we can gather information that offers insight into the neurophysiological characteristics and underlying mechanisms of these severe conditions, informing objective diagnosis, stratification for clinical research, and ultimately, the development of better-targeted treatment matching in the clinic.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Pathological Intraplaque Hemorrhage as the Gold Standard to Assess the Efficacy of Ultrasound in Predicting Vulnerable Carotid Plaque Rupture.

OBJECTIVE: To assess the clinical utility of ultrasound in predicting the risk of carotid vulnerable plaque rupture using pathological intraplaque hemorrhage as the gold standard. METHODS: A total of 118 patients who underwent endarterectomy due to symptomatic carotid artery stenosis were enrolled. Conventional ultrasound assessed the plaque thickness, area stenosis rate, echo, and surface morphology. Neovascularization were assessed by contrast-enhanced ultrasound (CEUS) and tracing intraplaque nonenhanced areas. According to neovascularization grade (0-4), plaques were classified as low-, intermediate-, and high risk. Fresh intraplaque hemorrhage within the pathology was adopted as the gold standard for diagnosing plaque rupture risk. Thus, we divided patients into ruptured risk and nonruptured risk groups to assess the value of crucial factors for plaque rupture risk using ultrasound. RESULTS: Of the 118 patients, hypertension accounted for 71.2%, hyperlipidemia 68.6%, diabetes 52.5%, and statin history 64.4%. In the rupture risk group, diabetes, smoking, and stenosis rate were significantly higher than the nonrupture risk group (P < .001); plaque thickness ≥4 mm (P > .05); and mainly hypoechoic with irregular surface morphology (P < .001), nonenhanced areas in the plaques (P < .001), and neovascularization >grade 2 (P < .001). Compared with the low-risk group, plaque rupture risk was 7.219 times higher in the medium-risk group and 18.333 times higher in the high-risk group. The kappa value of the interobserver consistency of crucial ultrasound parameters was >0.75, and the intraclass correlation coefficient was 0.919 (P < .01). CONCLUSIONS: Both conventional ultrasound and CEUS have significant clinical importance in the prediction of rupture risk in vulnerable carotid plaques, thereby enabling stroke risk stratification and the assessment of plaque rupture risk.

CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages.

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility. METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) (n = 9 ~ 10/group) on anxiety behaviours and microglial biology. RESULTS: FES patients showed higher scores of perceived stress scale (PSS, p < 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein (p < 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR < 0.05) than HCs. In blood RNA-seq, CSF1R-associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS (p < 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as CUS, CSF1Ri enhanced anxiety (both p < 0.001). Genes for brain angiogenesis and intensity of CD31+-blood vessels were dampened after CUS-CSF1Ri treatment. Furthermore, CSF1Ri preferentially diminished juxta-vascular microglia/macrophages and induced microglia/macrophages morphological changes (all p < 0.05). CONCLUSION: Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis.

Subcortical structures associated with childhood trauma and perceived stress in schizophrenia.

BACKGROUND: Childhood trauma influences the clinical features of schizophrenia. In this study, we examined how childhood trauma and perceived stress are associated with clinical manifestations and subcortical gray matter volumes (GMVs) in patients with schizophrenia. METHODS: We recruited 127 patients with schizophrenia and 83 healthy controls for assessment of early childhood trauma, perceived stress, and clinical symptoms. With structural brain imaging, we identified the GMVs of subcortical structures and examined the relationships between childhood trauma, perceived stress, clinical symptoms, and subcortical GMVs. RESULTS: Compared to controls, patients with schizophrenia showed higher levels of childhood trauma and perceived stress. Patients with schizophrenia showed significantly smaller amygdala and hippocampus GMVs as well as total cortical GMVs than age-matched controls. Childhood trauma score was significantly correlated with the severity of clinical symptoms, depression, perceived stress, and amygdala GMVs. Perceived stress was significantly correlated with clinical symptoms, depression, and hippocampus and amygdala GMVs. Further, the association between childhood trauma (emotional neglect) and stress coping ability was mediated by right amygdala GMV in patients with schizophrenia. CONCLUSIONS: Patients with schizophrenia had more exposure to early-life trauma and poorer stress coping. Both childhood trauma and perceived stress were associated with smaller amygdala volumes. The relationship between early-life trauma and perceived stress was mediated by right amygdala GMV in patients with schizophrenia. These findings together suggest the long-term effects of childhood trauma on perceived stress and the subcortical volumetric correlates of the effects in schizophrenia.

History of suicide attempt associated with amygdala and hippocampus changes among individuals with schizophrenia.

Abnormalities in subcortical brain structures may reflect higher suicide risk in mood disorders, but less is known about its associations for schizophrenia. This cross-sectional imaging study aimed to explore whether the history of suicide attempts was associated with subcortical changes among individuals with schizophrenia. We recruited 44 individuals with schizophrenia and a history of suicide attempts (SZ-SA) and 44 individuals with schizophrenia but without a history of suicide attempts (SZ-NSA) and 44 healthy controls. Linear regression showed that SZ-SA had smaller volumes of the hippocampus (Cohen's d = -0.72), the amygdala (Cohen's d = -0.69), and some nuclei of the amygdala (Cohen's d, -0.57 to -0.72) than SZ-NSA after adjusting for age, sex, illness phase, and intracranial volume. There was no difference in the volume of the subfields of the hippocampus. It suggests the history of suicide attempts is associated with subcortical volume alterations in schizophrenia.

Developmental Sex Differences in Negative Emotion Decision-Making Dynamics: Computational Evidence and Amygdala-Prefrontal Pathways.

Sex differences in human emotion and related decision-making behaviors are recognized, which can be traced back early in development. However, our understanding of their underlying neurodevelopmental mechanisms remains elusive. Using developmental functional magnetic resonance imaging and computational approach, we investigated developmental sex differences in latent decision-making dynamics during negative emotion processing and related neurocognitive pathways in 243 school-aged children and 78 young adults. Behaviorally, girls exhibit higher response caution and more effective evidence accumulation, whereas boys show more impulsive response to negative facial expression stimuli. These effects parallel sex differences in emotion-related brain maturity linking to evidence accumulation, along with age-related decrease in emotional response in the basolateral amygdala and medial prefrontal cortex (MPFC) in girls and an increase in the centromedial amygdala (CMA) in boys. Moreover, girls exhibit age-related decreases in BLA-MPFC coupling linked to evidence accumulation, but boys exhibit increases in CMA-insula coupling associated with response caution. Our findings highlight the neurocomputational accounts for developmental sex differences in emotion and emotion-related behaviors and provide important implications into the neurodevelopmental mechanisms of sex differences in latent emotional decision-making dynamics. This informs the emergence of sex differences in typical and atypical neurodevelopment of children's emotion and related functions.

Progressive Stabilization of Brain Network Dynamics during Childhood and Adolescence.

Functional brain networks require dynamic reconfiguration to support flexible cognitive function. However, the developmental principles shaping brain network dynamics remain poorly understood. Here, we report the longitudinal development of large-scale brain network dynamics during childhood and adolescence, and its connection with gene expression profiles. Using a multilayer network model, we show the temporally varying modular architecture of child brain networks, with higher network switching primarily in the association cortex and lower switching in the primary regions. This topographical profile exhibits progressive maturation, which manifests as reduced modular dynamics, particularly in the transmodal (e.g., default-mode and frontoparietal) and sensorimotor regions. These developmental refinements mediate age-related enhancements of global network segregation and are linked with the expression profiles of genes associated with the enrichment of ion transport and nucleobase-containing compound transport. These results highlight a progressive stabilization of brain dynamics, which expand our understanding of the neural mechanisms that underlie cognitive development.

Vocal emotion perception in schizophrenia and its diagnostic significance.

BACKGROUND: Cognitive and emotional impairment are among the core features of schizophrenia; assessment of vocal emotion recognition may facilitate the detection of schizophrenia. We explored the differences between cognitive and social aspects of emotion using vocal emotion recognition and detailed clinical characterization. METHODS: Clinical symptoms and social and cognitive functioning were assessed by trained clinical psychiatrists. A vocal emotion perception test, including an assessment of emotion recognition and emotional intensity, was conducted. One-hundred-six patients with schizophrenia (SCZ) and 230 healthy controls (HCs) were recruited. RESULTS: Considering emotion recognition, scores for all emotion categories were significantly lower in SCZ compared to HC. Considering emotional intensity, scores for anger, calmness, sadness, and surprise were significantly lower in the SCZs. Vocal recognition patterns showed a trend of unification and simplification in SCZs. A direct correlation was confirmed between vocal recognition impairment and cognition. In diagnostic tests, only the total score of vocal emotion recognition was a reliable index for the presence of schizophrenia. CONCLUSIONS: This study shows that patients with schizophrenia are characterized by impaired vocal emotion perception. Furthermore, explicit and implicit vocal emotion perception processing in individuals with schizophrenia are viewed as distinct entities. This study provides a voice recognition tool to facilitate and improve the diagnosis of schizophrenia.

Association of cortical thickness and cognition with schizophrenia treatment resistance.

AIM: Approximately a third of patients with schizophrenia fail to adequately respond to antipsychotic medications, a condition known as treatment resistance (TR). We aimed to assess cognitive and cortical thickness deficits and their relationship to TR in schizophrenia. METHOD: We recruited patients with schizophrenia (n = 127), including patients at treatment initiation (n = 45), treatment-responsive patients (n = 40) and TR patients (n = 42), and healthy controls (n = 83). Clinical symptoms, neurocognitive function, and structural images were assessed. We performed group comparisons, and explored association of cortical thickness and cognition with TR. RESULTS: The TR patients showed significantly more severe clinical symptoms and cognitive impairment relative to the treatment-responsive group. Compared to healthy controls, 56 of 68 brain regions showed significantly reduced cortical thickness in patients with schizophrenia. Reductions in five regions were significantly associated with TR (reduction in TR relative to treatment-responsive patients), i.e. in the right caudal middle frontal gyrus, superior frontal cortex, fusiform gyrus, pars opercularis of the inferior frontal cortex, and supramarginal cortex. Cognition deficits were also significantly correlated with cortical thickness in these five regions in patients with schizophrenia. Cortical thickness of the right caudal middle frontal gyrus, superior frontal cortex and pars opercularis of the inferior frontal cortex also significantly mediated effects of cognitive deficits on TR. CONCLUSION: Treatment resistance in schizophrenia was associated with reduced thickness in the right caudal middle frontal gyrus, superior frontal cortex, fusiform gyrus, pars opercularis of the inferior frontal cortex, and supramarginal cortex. Cortical abnormalities further mediate cognitive deficits known to be associated with TR.

Translating ENIGMA schizophrenia findings using the regional vulnerability index: Association with cognition, symptoms, and disease trajectory.

Patients with schizophrenia have patterns of brain deficits including reduced cortical thickness, subcortical gray matter volumes, and cerebral white matter integrity. We proposed the regional vulnerability index (RVI) to translate the results of Enhancing Neuro Imaging Genetics Meta-Analysis studies to the individual level. We calculated RVIs for cortical, subcortical, and white matter measurements and a multimodality RVI. We evaluated RVI as a measure sensitive to schizophrenia-specific neuroanatomical deficits and symptoms and studied the timeline of deficit formations in: early (≤5 years since diagnosis, N = 45, age = 28.8 ± 8.5); intermediate (6-20 years, N = 30, age 43.3 ± 8.6); and chronic (21+ years, N = 44, age = 52.5 ± 5.2) patients and healthy controls (N = 76, age = 38.6 ± 12.4). All RVIs were significantly elevated in patients compared to controls, with the multimodal RVI showing the largest effect size, followed by cortical, white matter and subcortical RVIs (d = 1.57, 1.23, 1.09, and 0.61, all p < 10-6 ). Multimodal RVI was significantly correlated with multiple cognitive variables including measures of visual learning, working memory and the total score of the MATRICS consensus cognitive battery, and with negative symptoms. The multimodality and white matter RVIs were significantly elevated in the intermediate and chronic versus early diagnosis group, consistent with ongoing progression. Cortical RVI was stable in the three disease-duration groups, suggesting neurodevelopmental origins of cortical deficits. In summary, neuroanatomical deficits in schizophrenia affect the entire brain; the heterochronicity of their appearance indicates both the neurodevelopmental and progressive nature of this illness. These deficit patterns may be useful for early diagnosis and as quantitative targets for more effective treatment strategies aiming to alter these neuroanatomical deficit patterns.

Functional disconnection between subsystems of the default mode network in schizophrenia.

BACKGROUND: A dysfunctional default mode network (DMN) has been reported in patients with schizophrenia. However, the stability of the deficits has not been determined across different stages of the disorder. METHODS: We examined the functional connectivity of the DMN subsystems of 125 patients with first-episode schizophrenia (FES) or recurrent schizophrenia (RES), compared to that of 82 healthy controls. We tested the robustness of the findings in an independent cohort of 158 patients and 39 healthy controls. We performed resting-state functional connectivity analysis, and examined the strength of the connections within and between the three subsystems of the DMN (core, dorsal medial prefrontal cortex [dMPFC], and medial temporal lobe [MTL]). We also analyzed the connectivity correlations to symptoms and illness duration. RESULTS: We found reduced connectivity strength between the core and MTL subsystems in schizophrenia patients compared to controls, with no differences between the FES and RES patient groups; these findings were validated in the second sample. Schizophrenia patients also showed a significant reduction in connectivity within the MTL and between the dMPFC-MTL subsystems, similarly between FES and RES groups. The connectivity strength within the core subsystem was negatively correlated with clinical symptoms in schizophrenia. There was no significant correlation between the DMN subsystem connectivity and illness duration. CONCLUSIONS: DMN subsystem connectivity deficits are present in schizophrenia, and the homochronicity of their appearance indicates the trait-like nature of these alterations. The DMN deficit may be useful for early diagnosis, and MTL dysfunction may be a crucial mechanism underlying schizophrenia.

Elevated salivary kynurenic acid levels related to enlarged choroid plexus and severity of clinical phenotypes in treatment-resistant schizophrenia.

Patients with treatment-resistant schizophrenia (TRS) suffer severe, long-term psychotic symptoms and chronic stress. Salivary kynurenic acid (KYNA) and choroid plexus were evidenced to relate to psychological stress. We hypothesized that TRS patients would have higher salivary KYNA levels than patients who respond to antipsychotics (NTRS) and healthy controls (HC), and increased salivary KYNA levels are associated with clinical phenotypes and choroid plexus volume. A total of 66 HC participants, 53 patients with TRS and 46 with NTRS were enrolled. Salivary KYNA levels were measured by liquid chromatography-tandem mass spectrometry, choroid plexus volume by magnetic resonance imaging, and cognitive functions with the MATRICS Consensus Cognitive Battery. The TRS group had significantly higher salivary KYNA levels than the NTRS group (p = 0.003), who in turn had higher salivary KYNA than HC (p = 0.02). Higher salivary KYNA levels were associated with larger choroid plexus volume (r = 0.48, p = 0.004); lower attention/vigilance (r = -0.44, p = 0.004), verbal learning (r = -0.44, p = 0.004), total MCCB score (r = -0.42, p = 0.005); and a higher total PANSS score (r = 0.48, p = 0.004) in TRS patients. An enlarged choroid plexus also related to worse attention/vigilance (r = -0.39, p = 0.03), verbal learning (r = -0.55, p = 0.001), total MCCB score (r = -0.41, p = 0.02) and clinical symptoms (r = 0.48, p = 0.004) in TRS patients only. We conclude that elevated salivary KYNA levels and associated choroid plexus enlargement are clinically relevant indicators of TRS, with salivary KYNA being particularly valuable as a peripheral marker. Our findings should benefit TRS research and benefit the improvement of personalized treatment.

Childhood trauma and cognitive deficits in patients with schizophrenia: mediation by orbitofrontal cortex H-shaped sulci volume.

BACKGROUND: A line of evidence has shown that childhood trauma and patterns of H-shaped sulci in the orbitofrontal cortex (OFC) are associated with cognitive deficits in patients with schizophrenia. Studies have also suggested that childhood trauma is associated with OFC volumetrics. This study investigated the interrelationship between childhood trauma, OFC H-shaped sulci volume and cognitive function in patients with first-episode schizophrenia. We hypothesized that OFC H-shaped sulci volume would mediate the relationship between childhood trauma and cognitive function in patients with first-episode schizophrenia. METHODS: We recruited patients with first-episode schizophrenia (n = 63) and healthy controls (n = 48), and quantified OFC H-shaped sulci volumes with 3.0 T high-resolution MRI. We assessed cognitive function and childhood trauma experiences using the MATRICS Consensus Cognitive Battery (MCCB) and the Childhood Trauma Questionnaire (CTQ). RESULTS: Patients with first-episode schizophrenia had smaller left OFC H-shaped sulci volumes, more severe childhood trauma experiences and worse cognitive function than healthy controls. CTQ total score and emotional and physical neglect subscores were negatively correlated with left OFC H-shaped sulci volume. CTQ total score and emotional neglect and sexual abuse subscores were negatively correlated with cognitive function in patients with first-episode schizophrenia. Interestingly, the CTQ total score and physical neglect subscore were positively correlated with cognitive function in healthy controls. Left OFC H-shaped sulci volume played a mediating role in CTQ emotional neglect subscore, CTQ total score and MCCB composite score. LIMITATIONS: The small sample size and retrospective design need to be considered. CONCLUSION: Childhood trauma might contribute to cognitive deficits in patients with first-episode schizophrenia by affecting left OFC H-shaped sulci volume. This finding can help in the design of strategies to improve cognitive function in patients with first-episode schizophrenia.

TGF-ß1 is associated with deficits in cognition and cerebral cortical thickness in first-episode schizophrenia.

BACKGROUND: Evidence indicates that cytokines are associated with cognitive deficits in schizophrenia; however, the underlying brain-behaviour mechanisms remain unclear. We hypothesized that aberrations in brain structural connectivity mediate the cytokine effect in schizophrenia. METHODS: In this study, we recruited patients with first-episode schizophrenia (n = 75, average illness duration 12.3 months, average medication period 0.6 days) and healthy controls (n = 44) of both sexes. We first conducted whole-blood RNA sequencing to detect differentially expressed genes. We also explored transcriptomic data on the dorsal lateral prefrontal cortices (dlPFC) retrieved from the CommonMind Consortium for gene functional clustering; we measured plasma transforming growth factor ß1 (TGF-ß1) levels by enzyme-linked immunosorbent assay; we acquired high-resolution T 1-weighted MRI data on cortical thickness MRI; and we assessed cognitive function using the validated Chinese version of the MATRICS Consensus Cognitive Battery. We compared these parameters in patients with schizophrenia and controls, and analyzed their associations. RESULTS: Patients with schizophrenia had higher TGF-ß1 at both the mRNA level (log2 fold change = 0.24; adjusted p = 0.026) and the protein level (12.85 ± 6.01 µg/mL v. 8.46 ± 5.15 µg/mL, adjusted p < 0.001) compared to controls. Genes coexpressed with TGFB1 in the dlPFC were less abundant in patients with schizophrenia compared to healthy controls. In patients with schizophrenia, TGF-ß1 protein levels were inversely correlated with cortical thickness, especially of the lateral occipital cortex (r = -0.47, adjusted p = 0.001), and with the MATRICS Consensus Cognitive Battery visual learning and memory domain (r = -0.50, adjusted p < 0.001). We found a complete mediation effect of the thickness of the lateral occipital cortex on the negative relationship between TGF-ß1 and visual cognition (p < 0.05). LIMITATIONS: We did not explore the effect of other blood cytokines on neurocognitive performance and cortical thickness. Participants from the CommonMind Consortium did not all have first-episode schizophrenia and they were not all antipsychotic-naive, so we could not exclude an effect of antipsychotics on TGF-ß1 signalling in the dlPFC. The sample size and cross-sectional design of our study were additional limitations. CONCLUSION: These findings highlighted an association between upregulated blood levels of TGF-ß1 and impairments in brain structure and function in schizophrenia.