Neurochemical and brain functional changes in the ventromedial prefrontal cortex of first-episode psychosis patients: A combined functional magnetic resonance imaging-proton magnetic resonance spectroscopy study.

OBJECTIVE: Previous studies showed alterations of brain function in the ventromedial prefrontal cortex of schizophrenia patients. Also, neurochemical changes, especially GABA level alteration, have been found in the medial prefrontal cortex of schizophrenia patients. However, the relationship between GABA level in the ventromedial prefrontal cortex and brain functional activity in schizophrenia patients remains unexplored. METHODS: In total, 23 drug-naïve, first-episode psychosis patients and 26 matched healthy controls completed the study. The single voxel proton magnetic resonance spectroscopy data were acquired in ventromedial prefrontal cortex region, which was used as the seed region for resting-state functional connectivity analysis. The proton magnetic resonance spectroscopy data were processed to quantify the concentrations of GABA+, glutamine and glutamate, and N-acetylaspartate in ventromedial prefrontal cortex. Spearman correlation analysis was used to examine the relationship between metabolite concentration, functional connectivity and clinical variables. Pearson correlation analysis was used to examine the relationship between GABA+ concentration and functional connectivity value. RESULTS: In first-episode psychosis patients, GABA+ level in ventromedial prefrontal cortex was higher and was positively correlated with ventromedial prefrontal cortex-left middle orbital frontal cortex functional connectivity. N-acetylaspartate level was positively correlated with positive symptoms, and the functional connectivity between ventromedial prefrontal cortex and left precuneus was negatively associated with negative symptoms of first-episode psychosis patients. CONCLUSION: Our results indicated that ventromedial prefrontal cortex functional connectivity changes were positively correlated with higher local GABA+ level in first-episode psychosis patients. The altered neurochemical concentration and functional connectivity provide insights into the pathology of schizophrenia.

Impaired cue identification and intention retrieval underlie prospective memory deficits in patients with first-episode schizophrenia.

OBJECTIVE: Schizophrenia is associated with impairment in prospective memory, the ability to remember to carry out an intended action in the future. It has been established that cue identification (detection of the cue event signaling that an intended action should be performed) and intention retrieval (retrieval of an intention from long-term memory following the recognition of a prospective cue) are two important processes underlying prospective memory. The purpose of this study was to examine prospective memory deficit and underlying cognitive processes in patients with first-episode schizophrenia. METHODS: This study examined cue identification and intention retrieval components of event-based prospective memory using a dual-task paradigm in 30 patients with first-episode schizophrenia and 30 healthy controls. All participants were also administered a set of tests assessing working memory and retrospective memory. RESULTS: Both cue identification and intention retrieval were impaired in patients with first-episode schizophrenia compared with healthy controls ( ps < 0.05), with a large effect size for cue identification (Cohen's d = 0.98) and a medium effect size for intention retrieval (Cohen's d = 0.62). After controlling for working memory and retrospective memory, the difference in cue identification between patients and healthy controls remained significant. However, the difference in intention retrieval between the two groups was no longer significant. In addition, there was a significant inverse relationship between cue identification and negative symptoms ( r = -0.446, p = 0.013) in the patient group. CONCLUSION: These findings suggest that both cue identification and intention retrieval in event-based prospective memory are impaired in patients with first-episode schizophrenia. Cue identification and intention retrieval could be potentially used as biomarkers for early detection and treatment prognosis of schizophrenia. In addition, addressing cue identification deficit through cognitive enhancement training may potentially improve negative symptoms as well.

Efficacy of Cortical-Hippocampal Target Intermittent Theta Burst Stimulation (iTBS) on Associative Memory of Schizophrenia: A Double-Blind, Randomized Sham-Controlled Trial.

Objective: The objective of our study was to evaluate whether intermittent theta burst stimulation(iTBS) applied to the regions with the strongest cortico-hippocampal connectivity within the lateral parietal cortical (LPC) or dorsolateral prefrontal cortical (DLPFC) areas in individuals with schizophrenia could enhance associative memory. Methods: We randomized 96 participants with schizophrenia to receive either active iTBS applied to the right DLPFC, left LPC or sham iTBS for 20 days. Clinical and cognitive assessments were performed at baseline and at the end of treatment. The primary outcome was change in associative memory. The secondary outcome was change in other cognitive functions and psychiatric symptoms. Results: In comparison to the sham group, iTBS targeting the right DLPFC or left LPC in schizophrenia did not yield significant improvements in auditory-auditory associative memory (F=1.27, p=0.294), auditory-visual associative memory (F=0.49, p=0.617), or visual-visual associative memory (F=1.094, p=0.347). Furthermore, after adjusting for variables such as education, disease duration, and negative symptoms, no significant changes were observed in any of these three memory domains. Conclusion: Although our study suggests that iTBS applied to the cortical-hippocampal did not lead to a significant change in associative memory. However, further investigation combining hippocampal-targeted iTBS with functional magnetic resonance imaging (fMRI) is warranted to elucidate the regulatory effects of iTBS on hippocampal function. Trial Registration: clinicaltrials.gov NCT03608462.

Transcranial ultrasound stimulation modulates the interhemispheric balance of excitability in human motor cortex.

Background. Low-intensity transcranial ultrasound stimulation (TUS) could induce both immediate and long-lasting neuromodulatory effects in human brains. Interhemispheric imbalance at prefrontal or motor cortices generally associates with various cognitive decline in aging and mental disorders. However, whether TUS could modulate the interhemispheric balance of excitability in human brain remains unknown.Objective. This study aims to explore whether repetitive TUS (rTUS) intervention can modulate the interhemispheric balance of excitability between bilateral motor cortex (M1) in healthy subjects.Approach. Motor evoked potentials (MEPs) at bilateral M1 were measured at 15 min and 0 min before a 15 min active or sham rTUS intervention on left M1 and at 0 min, 15 min and 30 min after the intervention, and the Chinese version of brief neurocognitive test battery (C-BCT) was conducted before and after the intervention respectively. Cortical excitability was quantified by MEPs, and the long-lasting changes of MEP amplitude was used as an index of plasticity.Results. In the active rTUS group (n= 20), the ipsilateral MEP amplitude increased significantly compared with baselines and lasted for up to 30 min after intervention, while the contralateral MEP amplitude decreased lasting for 15 min, yielding increased laterality between bilateral MEPs. Furthermore, rTUS intervention induced changes in some C-BCT scores, and the changes of scores correlated with the changes of MEP amplitudes induced by rTUS intervention. The sham rTUS group (n= 20) showed no significant changes in MEPs and C-BCT scores. In addition, no participants reported any adverse effects during and after the rTUS intervention, and no obvious temperature increase appeared in skull or brain tissues in simulation.Significance. rTUS intervention modulated the plasticity of ipsilateral M1 and the interhemispheric balance of M1 excitability in human brain, and improved cognitive performance, suggesting a considerable potential of rTUS in clinical interventions.

Stress-induced red nucleus attenuation induces anxiety-like behavior and lymph node CCL5 secretion.

Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid organs and how they interface with lymphoid organs to produce stress-induced anxiety-like behavior remain elusive. Using stressed human participants and rat models, we show that CCL5 levels are increased in stressed individuals compared to controls. Stress-inducible CCL5 is mainly produced from cervical lymph nodes (CLN). Retrograde tracing from CLN identifies glutamatergic neurons in the red nucleus (RN), the activities of which are tightly correlated with CCL5 levels and anxiety-like behavior in male rats. Ablation or chemogenetic inhibition of RN glutamatergic neurons increases anxiety levels and CCL5 expression in the serum and CLNs, whereas pharmacogenetic activation of these neurons reduces anxiety levels and CCL5 synthesis after restraint stress exposure. Chemogenetic inhibition of the projection from primary motor cortex to RN elicits anxiety-like behavior and CCL5 synthesis. This brain-lymph node axis provides insights into lymph node tissue as a stress-responsive endocrine organ.

Cross-modal associative memory impairment in schizophrenia.

Impaired associative memory function in patients with schizophrenia has received considerable attention. However, previous studies have primarily concentrated on unisensory materials, which limits our understanding of the broader implications of this impairment. In this study, we sought to expand on this knowledge by examining two types of associative memory domains in individuals with schizophrenia, leveraging both visual (Vis) and auditory (Aud) materials. A total of 32 patients with schizophrenia and 29 healthy controls were recruited to participate in the study. Each participant participated in an experiment composed of three paradigms in which different abstract materials (Aud-Aud, Aud-Vis, and Vis-Vis) were presented. Subsequently, the discriminability scores of the two groups were calculated and compared in different modal tasks. Results from the study indicated that individuals with schizophrenia demonstrated varying degrees of associative memory dysfunction in both the same and cross-modalities, with the latter having a significantly lower score than healthy controls (t = 4.120, p < 0.001). Additionally, the cross-modal associative memory function was significantly and negatively correlated with the severity of negative symptoms among individuals diagnosed with schizophrenia (r = -0.362, p = 0.042). This study provides evidence of abnormalities in the processing and memorization of information that integrates multiple sensory modalities in individuals with schizophrenia. This is of great significance for further understanding the cognitive symptoms and pathological mechanisms of schizophrenia, potentially guiding the development of relevant interventions and treatment methods.

Brain functional network changes associated with psychological symptoms in emergency psychological responding professionals after the first wave of COVID-19 pandemic.

Background: Emergency psychological responding professionals are recruited to help deal with psychological issues as the Corona Virus Disease 2019 (COVID-19) continues. We aimed to study the neural correlates of psychological states in these emergency psychological responding professionals after exposure to COVID-19 related trauma at baseline and after 1-year self-adjustment. Methods: Resting-state functional MRI (rs-fMRI) and multiscale network approaches were utilized to evaluate the functional brain activities in emergency psychological professionals after trauma. Temporal (baseline vs. follow-up) and cross-sectional (emergency psychological professionals vs. healthy controls) differences were studied using appropriate t-tests. The brain functional network correlates of psychological symptoms were explored. Results: At either time-point, significant changes in the ventral attention (VEN) and the default mode network (DMN) were associated with psychological symptoms in emergency psychological professionals. In addition, the emergency psychological professionals whose mental states improved after 1 year demonstrated altered intermodular connectivity strength between several modules in the functional network, mainly linking the DMN, VEN, limbic, and frontoparietal control modules. Conclusion: Brain functional network alterations and their longitudinal changes varied across groups of EPRT with distinctive clinical features. Exposure to emergent trauma does cause psychological professionals to produce DMN and VEN network changes related to psychological symptoms. About 65% of them will gradually adjust mental states, and the network tends to be rebalanced after a year.

Neurometabolic and functional changes of default-mode network relate to clinical recovery in first-episode psychosis patients: A longitudinal 1H-MRS and fMRI study.

BACKGROUND: Antipsychotic treatment has improved the disrupted functional connectivity (FC) and neurometabolites levels of the default mode network (DMN) in schizophrenia patients, but a direct relationship between FC change, neurometabolic level alteration, and symptom improvement has not been built. This study examined the association between the alterations in DMN FC, the changes of neurometabolites levels in the medial prefrontal cortex (MPFC), and the improvementsinpsychopathology in a longitudinal study of drug-naïve first-episode psychosis (FEP) patients. METHODS: Thirty-two drug-naïve FEP patients and 30 matched healthy controls underwent repeated assessments with the Positive and Negative Syndrome Scale (PANSS) and 3T proton magnetic resonance spectroscopy as well as resting-state functional magnetic resonance imaging. The levels of γ-aminobutyric acid, glutamate, N-acetyl-aspartate in MPFC, and the FC of DMN were measured. After 8-week antipsychotic treatment, 24 patients were re-examined. RESULTS: After treatment, the changes in γ-aminobutyric acid were correlated with the alterations of FC between the MPFC and DMN, while the changes in N-acetyl-aspartate were associated with the alterations of FC between the posterior cingulate cortex/precuneus and DMN. The FC changes of both regions were correlated with patients PANSS positive score reductions. The structural equation modeling analyses revealed that the changes of DMN FC mediated the relationship between the changes of neurometabolites and the symptom improvements of the patients. CONCLUSIONS: The derived neurometabolic-functional changes underlying the clinical recovery provide insights into the prognosis of FEP patients. It is noteworthy that this is an exploratory study, and future work with larger sample size is needed to validate our findings.

Longitudinal alterations of modular functional-metabolic coupling in first-episode schizophrenia.

Altered network organization and aberrant neurometabolic levels have been associated with schizophrenia. However, modular alterations of functional-neurometabolic coupling in various stages of schizophrenia remain unclear. This longitudinal study enrolled 34 drug-naïve first-episode schizophrenia (FES) patients and 30 healthy controls (HC). The FES patients underwent resting-state functional magnetic resonance imaging (rs-fMRI) and proton magnetic resonance spectroscopy (1H-MRS) at baseline, 2 months, and 6 months of treatment. For 1H-MRS, the concentrations of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA) and glutamate + glutamine in the ventromedial prefrontal cortex region were measured. A graph theoretical approach was applied for functional connectivity-based modular parcellation. We found that intra-default mode network (DMN) connectivity, inter-modular connectivity between the DMN and the hippocampus, and inter-modular connectivity between the DMN and the frontoparietal module were significantly different across 6-month treatment in the FES patients. The inter-module connectivity of the DMN and hippocampus correlated positively with NAA concentration in the HC group, while this correlation was absent in FES patients. This exploratory study suggests an altered modular connectivity in association with neurometabolite concentrations in FES patients and provides insights into multimodal neuroimaging biomarkers in schizophrenia. Future studies with larger sample sizes are needed to consolidate our findings.

Dynamic functional connectivity and its anatomical substrate reveal treatment outcome in first-episode drug-naïve schizophrenia.

Convergent evidence has suggested a significant effect of antipsychotic exposure on brain structure and function in patients with schizophrenia, yet the characteristics of favorable treatment outcome remains largely unknown. In this work, we aimed to examine how large-scale brain networks are modulated by antipsychotic treatment, and whether the longitudinal changes could track the improvements of psychopathologic scores. Thirty-four patients with first-episode drug-naïve schizophrenia and 28 matched healthy controls were recruited at baseline from Shanghai Mental Health Center. After 8 weeks of antipsychotic treatment, 24 patients were re-scanned. Through a systematical dynamic functional connectivity (dFC) analysis, we investigated the schizophrenia-related intrinsic alterations of dFC at baseline, followed by a longitudinal study to examine the influence of antipsychotic treatment on these abnormalities by comparing patients at baseline and follow-up. A structural connectivity (SC) association analysis was further carried out to investigate longitudinal anatomical changes that underpin the alterations of dFC. We found a significant symptomatic improvement-related increase in the occurrence of a dFC state characterized by stronger inter-network integration. Furthermore, symptom reduction was correlated with increased FC variability in a unique connectomic signature, particularly in the connections within the default mode network and between the auditory, cognitive control, and cerebellar network to other networks. Additionally, we observed that the SC between the superior frontal gyrus and medial prefrontal cortex was decreased after treatment, suggesting a relaxation of normal constraints on dFC. Taken together, these findings provide new evidence to extend the dysconnectivity hypothesis in schizophrenia from static to dynamic brain network. Moreover, our identified neuroimaging markers tied to the neurobiology of schizophrenia could be used as potential indicators in predicting the treatment outcome of antipsychotics.

Prolactin levels influenced by antipsychotic drugs in schizophrenia: A systematic review and network meta-analysis.

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.

High frequency repetitive transcranial magnetic stimulation of dorsomedial prefrontal cortex for negative symptoms in patients with schizophrenia: A double-blind, randomized controlled trial.

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.

Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments (SMART-CAT) in first-episode schizophrenia patients: Rationale and trial design.

Accumulated studies have investigated pharmacological interventions for first-episode schizophrenia (FES) patients. However, studies on subsequent treatment steps, which are essential to guide clinicians, are largely missing. This Sequential Multiple-Assignment Randomized Trials comparing Antipsychotic Treatments (SMART-CAT) program intends to evaluate the effectiveness of commonly used antipsychotic drugs in FES patients. The major goals of this study are to examine: 1) what would be the optimal subsequent sequential treatment if the first antipsychotic drug failed; 2) whether clozapine could be used in those first-trial failed and have superior efficacy compared to other atypical antipsychotics. In this article we will report the detail protocol of SMART-CAT. The SMART-CAT is a randomized controlled clinical multicenter trial in which 9 institutions in China will participate. A total of 720 FES patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase; participants who do well on an assigned treatment will remain on that treatment for the duration of the 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment. Phase 1 is a randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Subjects who fail to respond after 8 weeks will enter the phase 2 randomization. Phase 2 is an equipoise-stratified randomization trial, and patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for 8 weeks. Subjects who fail to respond after phase 2 will enter an open label trial (phase 3); patients who receive clozapine in phase 2 and fail to respond will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B). The primary outcome for the treatment phase is the treatment efficacy rate, which is defined as at least 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score. We hypothesize that clozapine is more therapeutically effective than any other SGAs to patients who failed to meet efficacy criteria in Phase 1, and earlier treatment with clozapine can improve the functional outcomes of schizophrenia patients. As for the naturalistic follow-up phase, time to all-cause treatment failure, marked by its discontinuation is selected as the primary outcome, since it reflects both efficacy and side effects. The all-cause discontinuation is defined as discontinuing for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. The results of the SMART-CAT trial will provide evidence for the selection of antipsychotics in FES patients who fail to respond to the first trial of an antipsychotic drug. It will also provide evidence for the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs. The study is based on the combination of sequential therapy and dynamic therapy, which can be more suitable to assess the effectiveness of treatment options in the real-world clinical setting. As a result, we hope that this study can provide guidance for an optimal treatment algorithm in first-episode schizophrenia patients. Trial registration: ID NCT03510325 in ClinicalTrials.gov.

Stress and sleep: a survey based on wearable sleep trackers among medical and nursing staff in Wuhan during the COVID-19 pandemic.

BACKGROUD: COVID-19 pandemic has significantly affected the sleep health of local medical and nursing staff. AIM: We used wearable pulse oximeters to monitor and screen the medical and nursing staff working in hospitals designated for COVID-19 in the Wuhan area. This study aimed to establish a reliable basis to provide sleep intervention for the medical and nursing staff. METHODS: Thirty medical and nursing staff members with symptoms of insomnia were instructed to wear medical ring-shaped pulse oximeters to monitor their sleep overnight. We also used the Insomnia Severity Index (ISI) and the Chinese version of the Self-Reporting Questionnaire (SRQ-20) to evaluate the severity of insomnia and mental health status, respectively, for each participant. RESULTS: Among the 30 participants, only 26 completed the screening. Ten cases (38.5%) demonstrated moderate to severe sleep apnoea-hypopnea syndrome (SAHS) when using an oxygen desaturation index ≥15 times/hour as the cut-off value. Participants with comorbid moderate to severe SAHS had significantly higher ISI and SRQ scores (p values 0.034 and 0.016, respectively) than those in the insomnia group. Correlation analysis revealed that ISI was positively correlated with total sleep time (TST) (r=0.435, p=0.026), and negatively correlated with deep sleep (r=-0.495, p=0.010); furthermore, patient SRQ scores were positively correlated with TST, sleep efficiency (SE) and REM (rapid eyes movement) sleep % (r=0.454 and 0.389, 0.512; p=0.020, 0.050 and 0.008, respectively). Stepwise logistic regression indicated that SRQ-20 and sex were risk factors for insomnia with comorbid SAHS, and their OR values were 1.516 and 11.56 (95% CI 1.053 to 2.180 and 1.037 to 128.9), respectively. CONCLUSION: Medical and nursing staff with insomnia showed clear signs of comorbid sleep apnoea attributable to stress. The wearable pulse oximeters accurately monitored the participants' breathing when asleep.

Individual Perceived Stress Mediates Psychological Distress in Medical Workers During COVID-19 Epidemic Outbreak in Wuhan.

BACKGROUND: Since the novel coronavirus disease (COVID-19) outbreak in Wuhan, thousands of medical workers have been dispatched to support Wuhan against the virus. The purpose of this study was to identify the independent risk factors for psychological distress in order to develop a more effective strategy and precise evidence-based psychological intervention for medical workers. METHODS: This multisite cross-sectional survey recruited doctors and nurses from local and nonlocal medical teams working at 16 hospitals in Wuhan to complete this online survey from February to March, 2020. Psychological status was evaluated through Perceived Stress Scales (PSS), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder Scale (GAD-7) and Acute Stress Disorder Scale (ASDS). RESULTS: Of 966 participants, the prevalence of stress (95.9%), depression (46.0%) and anxiety (39.3%) were high. Local medical workers exhibited even higher scores of PSS, PHQ-9, GAD-7 and ASDS than those from outside Hubei (P<0.001). Females had more severe perceived stress, depression and anxiety than males (P<0.001). Multiple logistic regression showed that perceived stress is associated with increased odds of depression (OR=1.413; 95% CI: 1.338-1.493; P<0.001) and anxiety (OR=1.515; 95% CI: 1.407-1.631; P<0.001). CONCLUSION: Our findings demonstrated a high prevalence of stress, depression, anxiety and acute distress among medical workers on the front-line during the COVID-19 outbreak in Wuhan. The level of psychological impact may be mediated by individual perceptions of stressful events.

Abnormal interhemispheric functional interactions in drug-naïve adult-onset first episode psychosis patients.

Previous neuroimaging studies have shown that the cortical functional dysconnectivity contributed to the etiology of schizophrenia (SCZ). However, the interhemispheric functional interactions in SCZ remain not fully understood. The clinical heterogeneity of SCZ might lead to the variations in the findings and the effect of medication had a profound influence on the patient's functional features. In this study, we were aimed at investigating the interhemispheric functional interactions in drug-naïve adult-onset first episode psychosis (FEP) patients. Using voxel-mirrored homotopic connectivity (VMHC) analysis for functional magnetic resonance imaging (fMRI) data, we found decreased VMHC values in precuneus, posterior cingulate cortex (PCC), pallidum gyrus, inferior temporal gyrus and superior temporal gyrus in FEP patients. Additionally, the peak VMHC value of PCC was negatively correlated with the PANSS depression factor score. And the peak VMHC value of precuneus was positively correlated with the PANSS positive factor score. The results indicated that the disrupted interhemispheric functional connectivity of posterior default mode network (DMN) was related to emotion and consciousness dysregulation in FEP patients.

Modular Functional-Metabolic Coupling Alterations of Frontoparietal Network in Schizophrenia Patients.

Background: Brain functional dysconnectivity, as well as altered network organization, have been demonstrated to occur in schizophrenia. Brain networks are increasingly understood to exhibit modular community structures, which provides advantages in robustness and functional adaptivity. The frontoparietal network (FPN) serves as an important functional module, and metabolic and functional alterations in the FPN are associated with the pathophysiology of schizophrenia. However, how intra-modular biochemical disruptions lead to inter-modular dysfunction of the FPN, remains unclear. In this study, we aim to investigate alterations in the modular functional-metabolic coupling of the FPN, in patients with schizophrenia. Methods: We combined resting-state functional magnetic resonance imaging (rs-fMRI) and magnetic resonance spectroscopy (MRS) technology and acquired multimodal neuroimaging data in 20 patients with schizophrenia and 26 healthy controls. For the MRS, the dorsolateral prefrontal cortex (DLPFC) region within the FPN was explored. Metabolites including gamma aminobutyric acid (GABA), N-aspart-acetyl (NAA) and glutamate + glutamine (Glx) were quantified, using LCModel software. A graph theoretical approach was applied for functional modular parcellation. The relationship between inter/intra-modular connectivity and metabolic concentration was examined using the Pearson correlation analysis. Moreover, correlations with schizophrenia symptomatology were investigated by the Spearman correlation analysis. Results: The functional topological network consisted of six modules in both subject groups, namely, the default mode, frontoparietal, central, hippocampus, occipital, and subcortical modules. Inter-modular connectivity between the frontoparietal and central modules, and the frontoparietal and the hippocampus modules was decreased in the patient group compared to the healthy controls, while the connectivity within the frontoparietal modular increased in the patient group. Moreover, a positive correlation between the frontoparietal and central module functional connectivity and the NAA in the DLPFC was found in the healthy control group (r = 0.614, p = 0.001), but not in the patient group. Significant functional dysconnectivity between the frontoparietal and limbic modules was correlated with the clinical symptoms of patients. Conclusions: This study examined the links between functional connectivity and the neuronal metabolic level in the DLPFC of SCZ. Impaired functional connectivity of the frontoparietal areas in SCZ, may be partially explained by a neurochemical-functional connectivity decoupling effect. This disconnection pattern can further provide useful insights in the cognitive and perceptual impairments of schizophrenia in future studies.

Repetitive transcranial magnetic stimulation as an adjunctive treatment for negative symptoms and cognitive impairment in patients with schizophrenia: a randomized, double-blind, sham-controlled trial.

Purpose: Effective treatment options for negative symptoms and cognitive impairment in patients with schizophrenia are still to be developed. The present study was to examine potential benefits of repetitive transcranial magnetic stimulation (rTMS) to improve negative symptoms and cognition in this patient population. Methods: The study was a 4-week, randomized, double-blind sham-controlled trial. Patients with schizophrenia were treated with adjunctive 20-Hz rTMS for 4 weeks or sham condition to the left dorsolateral prefrontal cortex (DLPFC). Negative symptoms were measured using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative symptom scale (PANSS) negative subscale at baseline and week 4. Cognitive function was measured using the MATRICS Consensus Cognitive Battery (MCCB) at the same two time points. In addition, possible moderators for rTMS treatment efficacy were explored. Results: Sixty patients (33 in the treatment group, 27 in the sham group) completed the study. There was a significant decrease in negative symptoms after 4-week rTMS treatment as measured by the SANS total score and the PANSS negative symptom subscale score. However, there was no significant improvement in cognition with rTMS treatment. Stepwise multiple linear regression analysis suggested that the baseline severity of positive symptoms may predict poorer improvement in negative symptoms at week 4. Conclusion: Twenty-Hz rTMS stimulation over left DLPFC as an adjunctive treatment might be beneficial in improving negative symptoms of schizophrenia. Future studies with a longer treatment duration and a larger sample size are needed. Clinical trial ID: NCT01940939.

Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment.

BACKGROUND: Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent. METHOD: Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons. RESULTS: At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018). CONCLUSIONS: White matter deficits were validated in the present study by a relatively large sample of medication naïve and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.