缺陷型精神分裂症脑连接组学与谷氨酸系统关联研究

Deficit schizophrenia (DS), characterized by the presence of primary and enduring negative symptoms, has been demonstrated as severe social function decline and poor treatment response, which suggested DS representing a homogeneous disease entity. However, its neurobiological mechanisms is still unclear. Glutamatergic hypofunction hypothesis is one of the best mechanism for negative symptoms of schizophrenia, which provide the important clues for the reserach on the etiology of deficit schizophrenia. Based on our preliminary researches of DS, the present study will further investigate the effect of genetic polymorphisms of glutamate system pathways on brain connectome in the DS patients. The DS, non-deficit schizophrenia (NDS) patients and healthy control subjects will be recruited and matched on age and gender. The psychotic symptom, social function and neurocognition will be evaluated at time of recruitment. The subjects will be scanned to collect the multi-modality neuroimaging data using 3.0T MRI. Technology of imaging connectomics will be performed to analyze the brain structural and functinal topological characteristics in the subjects. The second generation sequencing technology will be used to detect the single nucleotide polymorphism in glutamate system pathways. Furthermore, we would investigate the association between genetic variation of glutamate system pathways and the changes of brain connectomics in the DS patients. We expect that these studies will contribute to our understanding of the etiopathological mechanism of schizophrenia and improve the future study for clinical medication of schizophrenia.

缺陷型精神分裂症（DS）以原发性、持久性阴性症状为基本临床特征，临床疗效差且持续衰退，可能是一种独立疾病亚型，其神经生物学机制至今不明。谷氨酸系统功能低下假说是目前对精神分裂症（SCH）阴性症状解释最为完善的病因机制，为探讨DS病理机制提供了重要线索。本研究将基于缺陷型SCH前期研究基础，利用遗传影像策略探讨谷氨酸通路遗传变异对DS患者脑连接组学的特征性影响。在中国汉族人群募集缺陷型和非缺陷性SCH患者，匹配正常对照组，进行多维度神经认知和社会功能评估；利用脑连接组学分析方法研究缺陷型SCH患者脑结构与功能拓扑学特征；以二代测序技术分析谷氨酸系统候选基因SNP位点，从通路层面上探讨谷氨酸系统与缺陷型SCH患者脑连接组学特征性关联，为阐明缺陷型SCH这一高度同质性的疾病亚型神经病理机制提供理论依据，期望能最终有利于推进精神分裂症的有效临床治疗。

缺陷型精神分裂症（DS）以原发性、持久性阴性症状为基本临床特征，其药物治疗疗效差且持续衰退，可能是一种独立疾病亚型，对其研究可提高同质性、有助于阐明DS临床不良结局的生物学特征。本课题探讨了DS患者神经认知和社会认知特征、脑连接组学、谷氨酸通路与神经影像交互作用等。本课题组国内外首次发现DS和NDS患者不同核心认知损害领域，以及不同的面部表情识别和述情障碍特征。本课题组脑连接组学研究部分国内外首先报道DS和NDS患者全脑静息态拓扑学网络共性和差异性，DS具有特征性颞叶功能连接异常模式。DS患者左侧颞顶联合区皮层厚度显著薄于NDS患者，可能参与其原发性阴性症状病理机制。DS患者小脑左侧Crus II区神经活性下降，并可能通过大脑-小脑神经环路代偿。DS患者默认网络特异性损害脑区与其低认知水平相关。本研究发现精神分裂症与谷氨酸基因通路交互作用影响的脑区存在于皮质-皮下核团神经环路中；DS患者左侧丘脑的度中心指标下降并与阴性症状相关，可能是多NMDA受体基因集聚效应的关键脑区，提示DS可能为精神分裂症独立疾病亚型，为慢性缺陷型精神分裂症临床不良结局相关的神经认知和遗传影像学特征提供了初步研究证据。