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Multi-scale analysis of schizophrenia risk genes, brain structure, and clinical symptoms reveals integrative dues for subtyping schizophrenia patients

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Journal of Molecular Cell Biology 2019年第8期11卷 678-687页

作者： Liang Ma Edmund T.Rolls Xiuqin Liu Yuting Liu Zeyu Jiao Yue Wang Weikang Gong Zhiming Ma Fuzhou Gong Lin Wan CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences Beijing 100101 China National Center of Mathematics and Interdisciplinary Sciences Academy of Mathematics and Systems Science Chinese Academy of Sciences Beijing 100190 China Department of Computer Science University of Warwick Coventry CV4 7AL UK Oxford Centre for Computational Neuroscience Oxford 0X2 7JF UK School of Mathematics and Physics University of Science and Technology Beijing Beijing 100083 China School of Science Beijing Jiaotong University Beijing 100044 China Centre for Computational Systems Biology School of Mathematical Sciences Fudan University Shanghai 200433 China CAS-MPG Partner Institute for Computational Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China University of Chinese Academy of Sciences Beijing 100049 China

Analysis Unking directly genomics, neuroimaging phenotypes and clinical measurements is crucial for understanding psychiatric disorders, but remains ***, we describe a multi-scale analysis using genome-wide SNPs, gene expression, grey matter volume (GMV), and the positive and negative syndrome scale scores (PANSS) to explore the etiology of schizophrenia. With 72 drug-naive schizophrenic first episode patients (FEPs) and 73 matched heathy controls, we identified 108 genes, from schizophrenia risk genes, that correlated significantly with GMV, which are highly co-expressed in the brain during development. Among these 108 candidates, 19 distinct genes were found associated with 16 brain regions referred to as hot clusters (HCs), primarily in the frontal cortex, sensory-motor regions and temporal and parietal *** patients were subtyped into three groups with distinguishable PANSS scores by the GMV of the identified HCs. Furthermore, we found that HCs with common GMV among patient groups are related to genes that mostly mapped to pathways relevant to neural signaling, which are associated with the risk for *** results provide an integrated view of how genetic variants may affect brain structures that lead to distinct disease *** method of multi-scale analysis that was described in this research, may help to advance the understanding of the etiology of schizophrenia.

关键词： schizophrenia PANSS multi-scale analysis hot cluster grey matter volume pathway

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Prefrontal dysfunction and a monkey model of schizophrenia

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Neuroscience Bulletin 2015年第2期31卷 235-241页

作者： Ping Mao Ding Cui Xu-Dong Zhao Yuan-Ye Ma Kunming General Hospital of Chengdu Military Command State Key Laboratory of Brain and Cognitive Science Institute of Biophysics Chinese Academy of Sciences Yunnan Key Laboratory of Primate Biomedical Research Kunming Institute of Zoology Chinese Academy of Sciences

The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In addition to the features typical of schizophrenia, patients also present with aspects of cognitive disorders. Based on these relationships, a monkey model mimicking the cognitive symptoms of schizophrenia has been made using treatment with the non-specific competitive N-methyI-D-aspartate receptor antagonist, phencyclidine. The symptoms are ameliorated by atypical antipsychotic drugs such as clozapine. The beneficial effects of clozapine on behavioral .impairment might be a specific indicator of schizophrenia-related cognitive impairment.

关键词： prefrontal cortex schizophrenia monkey model

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Smoking and Serum Lipid Profiles in schizophrenia

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Neuroscience Bulletin 2016年第4期32卷 383-388页

作者： Hui-Mei An Yun-Long Tan Shu-ping Tan Jing Shi Zhi-Ren Wang Fu-De Yang Xu-Feng Huang Jair C.Soars Thomas R.Kosten Xiang-Yang Zhang Beijing Hui Long Guan Hospital Peking University Centre for Translational Neuroscience School of MedicineIllawarra Health and Medical Research InstituteUniversity of Wollongong Department of Psychiatry and Behavioral Sciences The University of Texas Health Science Center at Houston Department of Psychiatry and Behavioral Sciences Baylor College of Medicine

schizophrenia is associated with a high preva- lence of cigarette-smoking and abnormal lipid profiles. The purpose of this study was to determine whether the profiles differ between schizophrenic smokers and non-smokers and whether the lipid profiles are related to psychopathological symptoms. Serum lipid profiles were measured in 130 male inpatients with DSM-IV-defined schizophrenia： 104 smokers and 26 non-smokers. Symptoms were assessed using the Positive and Negative Syndrome Scale （PANSS）. Our results showed that positive PANSS symp- toms were fewer in smokers than in non-smokers, while the negative symptoms were fewer in those who smoked more cigarettes. Total protein and globulin levels were significantly lower in the smokers than in the non-smokers. However, there was no significant difference in total cholesterol, triglycerides, high-density lipoprotein choles terol （HDL-c）, low-density lipoprotein cholesterol, apolipoprotein A1, or apolipoprotein B between the smokers and non-smokers. However, the PANSS positive subscale had a significant negative correlation with the HDL-c levels （a protective factor） in the smokers but not in the non-smokers. Our findings suggest that schizophrenic patients who smoke have fewer psychotic symptoms, but contrary to expectation, smoking does not alter lipid profile levels.

关键词： schizophrenia Nicotine Cigarettesmoking Lipid profiles Symptoms

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Developments in Biological Mechanisms and Treatments for Negative Symptoms and Cognitive Dysfunction of schizophrenia

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Neuroscience Bulletin 2021年第11期37卷 1609-1624页

作者： Qiongqiong Wu Xiaoyi Wang Ying Wang Yu-Jun Long Jing-Ping Zhao Ren-Rong Wu National Clinical Research Center for Mental Disorders Department of PsychiatryThe Second Xiangya Hospital of Central South UniversityChangsha 410011China Shanghai Institutes for Biological Sciences Chinese Academy of SciencesShanghai 200031China

The causal mechanisms and treatment for the negative symptoms and cognitive dysfunction in schizophrenia are the main issues attracting the attention of psychiatrists over the last *** first part of this review summarizes the pathogenesis of schizophrenia,especially the negative symptoms and cognitive dysfunction from the perspectives of genetics and *** second part describes the novel medications and several advanced physical therapies(e.g.,transcranial magnetic stimulation and transcranial direct current stimulation)for the negative symptoms and cognitive dysfunction that will optimize the therapeutic strategy for patients with schizophrenia in future.

关键词： schizophrenia Genetics Epigenetics Negative symptoms Cognitive dysfunction Physical therapy

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Proton magnetic resonance spectroscopy of the anterior cingulate gyrus and caudate nucleus in schizophrenia patients versus healthy controls

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Neural Regeneration Research 2011年第6期6卷 467-473页

作者： Lutfi Incesu Meral Baydin Kerim Aslan Baris Diren Huseyin Sahin Omer Boke Senol Dane Department of Radiology Medical FacultyOndokuz Mayis University Department of Radiology Gazi State Hospital Department of Radiology Ataturk State Hospital Department of Radiology Medicana International Hospital Department of Psychiatry Medical FacultyOndokuz Mayis University Department of Physiology Medical FacultyFatih University

Proton magnetic resonance spectroscopy （^1 H-MRS） permits the assessment of cerebral neurometabolites, such as N-acetylaspartate, choline, and creatine, in vivo and has been used to study schizophrenia. The present study used ^1H-MRS to compare the spectroscopy change of N-acetylaspartate, creatine, and choline metabolite levels in the anterior cingulate and caudate nucleus of both schizophrenia patients and healthy controls, as well as between the left and right cerebral hemispheres in the schizophrenia patients. Results showed that N-acetylaspartate and creatine metabolite levels in the left anterior cingulate gyrus were significantly lower in the schizophrenia patients than in the healthy controls, indicating hypometabolism. In addition, choline concentration in the left caudate nucleus of schizophrenia patients was significantly lower than in the right caudate nucleus, indicating that it is necessary to study the cerebral lateralization of ^1H-MRS in schizophrenia patients.

关键词： schizophrenia magnetic resonance spectroscopy anterior cingulate gyrus caudate nucleus neurocognitive test

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Impaired prepulse inhibition of acoustic startle in Chinese patients with first-episode, medication-naive schizophrenia

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Chinese Medical Journal 2013年第3期126卷 526-531页

作者： WANG Zhi-ren TAN Yun-long YANG Fu-de ZHANG Wu-fang ZOU Yi-zhuang TAN Shu-ping SONG Chong-sheng LI Ying-li ZHANG Wei-hua ZHOU Dong-feng Institute of Mental Health Peking University Key Laboratory of Mental Health Ministry of Health (Peking University) Beijing 100191 China Beijing Hui-Long-Guan Hospital Beijing 100096 China

Background Patients with schizophrenia have prominent abnormality in information processing that can be observed by measures of prepulse inhibition （PPI） of acoustic startle reflex and PPI deficits have been considered as a candidate endophenotypic marker of schizophrenia. However, there has been little information on PPI and related measures in Chinese patients with schizophrenia. The research was to explore the deficits of acoustic startle reflex that might exist in Chinese patients with schizophrenia. Methods Startle response to acoustic stimuli, habituation, and PPI were examined in 31 Chinese patients with first-episode, medication-naive schizophrenia and 30 age-and sex-matched healthy Chinese controls. At the same day of startle testing, psychopathological symptoms of the patients were assessed with the Positive and Negative Syndrome Scale （PANSS）. Results Compared with healthy controls, patients exhibited the significant reduction in startle response and PPI deficits at 60 milliseconds （ms） intervals （PP160, P 〈0.05） but not at 30 or 120 ms intervals. Furthermore, there was a relatively strong correlation between PPI60 （P 〈0.05） and scores of positive scale of PANSS in patients with schizophrenia. Conclusion Our findings confirmed impaired PPI in Chinese patients with schizophrenia and suggested that a relationship between sensorimotor gating deficits and clinical symptoms of patients with schizophrenia might exist.

关键词： acoustic startle prepulse inhibition schizophrenia

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Effects of Repetitive Transcranial Magnetic Stimulation Treatment on Event-Related Potentials in schizophrenia

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Chinese Medical Journal 2018年第3期131卷 301-306页

作者： Xiao-Dong Lin Xing-Shi Chen Ce Chen Li-Jun Zhang Zuo-Liang Xie Zi-Ye Huang Guang-Dong Chen Wan-Tao Ding Zhi-Guang Lin Ming-Dao Zhang Chong Chen Rong-Qin Wu Department of Psychiatry Wenzhou Seventh People's Hospital Wenzhou Zhejiang 325005 China Department of Electrophysiology Shanghai Mental Health Center Shanghai Jiao Tong University School of Medicine Shanghai 200030 China Department of Function Shanghai Jing'an District Mental Health Center Shanghai 200030 China

Background：Repetitive transcranial magnetic stimulation （rTMS） and event-related potentials （ERPs） are a noninvasive technique that widely used in neurophysiological *** rTMS has shown clinical utility for a number of neurological conditions,Recently,there was little understanding of the the efficacy ofrYMS on schizophrenia（SZ） and the change of ERP between before and after rTMS *** objective of this study was to investigate the characteristics of N400,mismatch negativity （MMN）,and P300 before and after treatment with rTMS in ***：One hundred and twenty-seven SZ patients hospitalized in Shanghai Mental Health Center from March 2015 to July 2017,divided into two groups （85 patients were recruited as rTMS group and 42 were recruited as sham rTMS [ShrTMS] group） and 76 normal controls （NCs） who were the staff and refresher staff in our hospital were recruited at the same time.A Chinese-made rTMS and a Runjie W J-1 ERPs instrument were used in the present experiment.N400 was elicited by congruent and noncongruent Chinese *** rTMS treatment,N400,P300,and MMN characteristics were compared with those before treatment and NC ***：Compared with NC,the SZ patients exhibited delays in N400,P300,and MMN latency and decreased N400,P300,and MMN amplitudes in their frontal area （P 〈 0.05）.After 25 rTMS treatments,N400 amplitudes in the frontal area （elicited by idioms with same phonic and different shape and meaning and with different phonic,shape,and meaning） were increased in the SZ patients （P 〈 0.05）.However,there was no significant change in N400 before and after treatment with ShrTMS in SZ patients （P 〉 0.05）.Amplitudes for MMN and target P300 also increased in SZ patients after rTMS treatment （P 〈 0.05）.Conclusions：Based on our preliminary findings,we believe that the combined usage of N400,MMN,and P300 could be a valuable index and an electrophysiological reference in evaluating the effects ofrTMS treatment in SZ patients.

关键词： Frontal Area Repetitive Transcranial Magnetic Stimulation Mismatch Negativity N400 P300 schizophrenia

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Correlation Between Brain Activation Changes and Cognitive Improvement Following Cognitive Remediation Therapy in schizophrenia： An Activation Likelihood Estimation Meta-analysis

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Chinese Medical Journal 2016年第5期129卷 578-585页

作者： Yan-Yan Wei Ji-Jun Wang Chao Yan Zi-Qiang Li Xiao Pan Yi Cui Tong Su Tao-Shenn Liu Yun-Xiang Tang Department of Medical Psychology Faculty of Mental Health Second Military Medical University Shanghai 200433 China Department of EEG Source Imaging Shanghai MentaIHealth Center Shanghai Jiao Tong University School of Medicine Shanghai 200030 China Key Laboratory of Brain Functional Genomics Ministry of Education Shanghai Key Laboratoiy of Brain Functional Genomics East C hina Normal University Shanghai 200062 China Department of Psychiatry Faculty of Mental Health Second Military Medical University Shanghai 200433 China

Background：Several studies using functional magnetic resonance imaging （fMRI） and positron emission tomography （PET） have indicated that cognitive remediation therapy （CRT） might improve cognitive function by changing brain activations in patients with ***,the results were not consistent in these changed brain areas in different *** present activation likelihood estimation （ALE） meta-analysis was conducted to investigate whether cognitive function change was accompanied by the brain activation changes,and where the main areas most related to these changes were in schizophrenia patients after *** of whole-brain studies and whole-brain ＋ region of interest （ROI） studies were compared to explore the effect of the different methodologies on the ***：A computerized systematic search was conducted to collect fMRI and PET studies on brain activation changes in schizophrenia patients from pre-to *** studies using fMRI techniques were included in the *** ALE 2.3.1 was used to perform meta-analysis across these imaging ***：The main areas with increased brain activation were in frontal and parietal lobe,including left medial frontal gyrus,left inferior frontal gyrus,right middle frontal gyrus,right postcentral gyrus,and inferior parietal lobule in patients after CRT,yet no decreased brain activation was *** similar increased activation brain areas were identified in ALE with or without ROI studies,analysis including ROI studies had a higher ALE ***：The current findings suggest that CRT might improve the cognition of schizophrenia patients by increasing activations of the frontal and parietal *** addition,it might provide more evidence to confirm results by including ROI studies in ALE meta-analysis.

关键词： Activation Likelihood Estimation Cognitive Remediation Therapy Meta-analysis schizophrenia

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A Systematic Characterization of Structural Brain Changes in schizophrenia

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Neuroscience Bulletin 2020年第10期36卷 1107-1122页

作者： Wasana Ediri Arachchi Yanmin Peng Xi Zhang Wen Qin Chuanjun Zhuo Chunshui Yu Meng Liang School of Medical Imaging and Tianjin Key Laboratory of Functional Imaging Tianjin Medical UniversityTianjin 300203China Department of Radiography and Radiotherapy Faculty of Allied Health SciencesGeneral Sir John Kotelawala Defence UniversityRatmalana 10390Sri Lanka Department of Radiology and Tianjin Key Laboratory of Functional Imaging Tianjin Medical University General HospitalTianjin 300052China Department of Psychiatric-Neuroimaging-Genetics and Comorbidity Laboratory Tianjin Mental Health CenterTianjin Anding HospitalTianjin 300222China CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China

A systematic characterization of the similarities and differences among different methods for detecting structural brain abnormalities in schizophrenia,such as voxel-based morphometry(VBM),tensor-based morphometry(TBM),and projection-based thickness(PBT),is important for understanding the brain pathology in schizophrenia and for developing effective biomarkers for a diagnosis of ***,such studies are still ***,we performed VBM,TBM,and PBT analyses on T1-weighted brain MR images acquired from 116 patients with schizophrenia and 116 healthy *** found that,although all methods detected wide-spread structural changes,different methods captured different information-only 10.35%of the grey matter changes in cortex were detected by all three methods,and VBM only detected 11.36%of the white matter changes detected by ***,pattern classification between patients and controls revealed that combining different measures improved the classification accuracy(81.9%),indicating that fusion of different structural measures serves as a better neuroimaging marker for the objective diagnosis of schizophrenia.

关键词： Voxel-based morphometry Tensor-based morphometry Deformation-based morphometry Cortical thickness Multivariate pattern analysis Structural MRI schizophrenia

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Progressive Grey Matter Volume Changes in Patients with schizophrenia over 6 Weeks of Antipsychotic Treatment and Their Relationship to Clinical Improvement

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Neuroscience Bulletin 2018年第5期34卷 816-826页

作者： Xiao Zhang Yuyanan Zhang Jinmin Liao Sisi Jiang Jun Yan Weihua Yue Dai Zhang Hao Yan Peking University Sixth Hospital/Institute of Mental Health Beijing 100191 China Key Laboratory of Mental Health Ministry of Health (Peking University) and National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital) Beijing 100191 China Peking-Tsinghua Joint Center for Life Sciences and PKU IDG/McGovern Institute for Brain Research Peking University Beijing 100871 China

Cross-sectional and longitudinal studies have identified widespread and progressive grey matter volume （GMV） reductions in schizophrenia, especially in the frontal lobe. In this study, we found a progressive GMV decrease in the rostral medial frontal cortex （rMFC, including the anterior cingulate cortex） in the patient group during a 6-week follow-up of 40 patients with schizophrenia and 31 healthy controls well-matched for age, gender, and education. The higher baseline GMV in the rMFC predicted better improvement in the positive score on the Positive and Negative Syndrome Scale （PANSS）, and this might be related to the improved reality-monitoring. Besides, a higher baseline GMV in the posterior rMFC predicted better remission of general symptoms, and a lesser GMV reduction in this region was correlated with better remission of negative symptoms, probably associated with ameliorated self-referential pro- cessing and social cognition. Besides, a shorter disease course and higher educational level contributed to better improvement in the general psychopathological PANSS score, and a family history was negatively associated with improvement of the negative and total PANSS scores. These phenomena might be important for understanding the neuropathological mechanisms underlying the symp- toms of schizophrenia and for making clinical decisions.

关键词： schizophrenia Grey matter volume Rostral medial frontal cortex Treatment response Biomarker

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