【作者】 谢敏；

【导师】 李涛； 王强；

【作者基本信息】 四川大学 ， 精神病与精神卫生学， 2022， 博士

【摘要】 目的:精神分裂症是一种重性的精神障碍,多起病于青少年晚期和成年早期,病程迁延,致残率高。既往研究显示精神分裂谱系障碍患者遭受过儿童期创伤比例较高,且儿童期创伤与认知功能损害及症状持续存在有关。大脑白质微结构损害导致的大脑广泛连接障碍是精神分裂症神经病理基础。遗传是精神分裂症脑白质微结构损害的重要病因。近期研究发现环境因素(如儿童期创伤)在脑白质微结构异常中也起着重要作用。大量脑形态学研究发现经历儿童期创伤的健康受试者和精神分裂症大脑均存在广泛的白质结构异常。目前关于儿童期创伤累及精神分裂症的脑白质微结构特征的研究很少,且仅有证据表明儿童期创伤会增加精神分裂症的患病风险,神经发育异常个体更易暴露于儿童期创伤,以及儿童期创伤与基因的交互作用对认知和部分大脑结构存在影响,但精神分裂症儿童期创伤与基因的交互作用对大脑白质微结构的影响尚不清楚。因此本研究的目的是为了探讨:1、儿童期创伤和脑白质微结构异常与精神分裂症的关系;2、精神分裂症多基因风险分数(Polygenic Risk Score,PRS)与脑白质微结构的关系;3、儿童期创伤与PRS的交互作用对精神分裂症脑白质微结构的影响。材料与方法:本研究共纳入601名受试者,其中首发精神分裂症(First Episode schizophrenia,FES)182例,正常对照(Healthy Controls,HCs)419例。其中328名受试者有弥散张量磁共振(Diffusion Tensor Imaging,DTI)和儿童期创伤问卷评估数据,469名被试有微阵列芯片数据,163名受试者同时有DTI、T1结构相和遗传数据。通过独立样本T检验比较两样本的儿童期创伤及亚型创伤分数。对FES和HCs行基于纤维束示踪的空间统计(Tract Based Spatial Statistics,TBSS)的双样本T检验,以年龄和性别为协变量。通过Pearson相关分析差异脑区平均各项异性分数(Fractional Anisotropy,FA)与儿童期创伤分数、临床症状量表的相关性。采用中介分析探索儿童期创伤、大脑白质微结构异常以及疾病的关系。使用Pearson相关分析PRS和大脑白质微结构、创伤及临床症状的相关关系。采用多元线性回归:分析PRS与诊断的交互作用对精神分裂症脑白质微结构的影响;建立PRS与儿童期创伤的交乘项,分析二者交互作用对脑白质微结构的影响;模型中以年龄和性别为协变量。结果:1、FES患者儿童期创伤总分、情感虐待、躯体虐待、性虐待、情感忽视和躯体忽视分数显著高于HCs(P<0.05)。与HCs相比,精神分裂症患者在左侧丘脑前辐射、左侧额枕下束、胼胝体辐射前部及枕部FA值降低(P<0.05,TFCE和FWE校正)。中介分析显示儿童期创伤部分中介了大脑白质结构异常与FES的关系(中介效应百分比为25%)。2、精神分裂症患者PRS与脑桥横束(r=0.256,P=0.038)的FA值呈正相关,与胼胝体压部(r=-0.270,P=0.028)和左侧毯(r=-0.263,P=0.033)的FA值呈负相关。校正年龄和性别后,PRS与诊断对于胼胝体体部(β=-0.316,P=0.048)、胼胝体压部(β=-0.351,P=0.029)和左侧大脑脚(β=-0.356,P=0.029)存在交互作用。3、校正年龄和性别后,精神分裂症患者儿童期创伤与PRS对左侧扣带(β=-0.287,P=0.011)、右侧扣带(海马)(β=-0.331,P=0.004)和左侧毯(β=-0.217,P=0.033)的交互效应显著;情感虐待与PRS对脑桥横束(β=0.206,P=0.032)、左侧扣带(β=-0.198,P=0.031)、右侧扣带(β=-0.215,P=0.033)和左侧毯(β=-0.184,P=0.040)的交互效应显著;躯体虐待与PRS交互作用对胼胝体压部(β=-0.234,P=0.022)、右侧后放射冠(β=-0.282,P=0.028)和左侧后放射冠(β=-0.355,P=0.003)存在影响;躯体忽视和PRS对右侧扣带(海马)(β=-0.363,P=0.002)存在交互作用。结论:精神分裂症患者遭受了更多的儿童期创伤,且儿童期创伤、大脑白质微结构异常与遗传均可能参与精神分裂症的病理生理机制。本研究发现儿童期创伤中介了脑白质微结构异常对精神分裂症的影响。此外,精神分裂症患者儿童期创伤与遗传对特定的大脑白质区域存在交互作用,儿童期创伤分数越高和PRS得分越高者FA值越低。因此,在进行临床治疗时,精神科医生不仅应考虑症状的严重程度,还应考虑个体家族史、儿童期创伤和神经发育轨迹。更多还原

【Abstract】 Objectives:Schizophrenia is a severe prolonged mental disorder,with a high disability rate,which most occurred in in late adolescence and early adult.Previous studies found that patients with schizophrenia spectrum disorder have a higher rate of childhood trauma,which has been linked to cognitive impairment and persistent symptoms.Widespread brain connectivity disorder caused by impairment of white matter microstructure is the neuropathological basis of schizophrenia.Previous studies confirmed that genetics are the main cause of white matter alterations in patients with schizophrenia.However,recent studies have found that environmental factors(such as childhood trauma)also play an important role in the abnormality of white matter microstructure.A great body of brain morphological studies revealed that the widespread white matter abnormalities were also observed in healthy adults and schizophrenia with childhood trauma history.There are few studies about childhood trauma and microstructure deficits of white matter in schizophrenia.Only the evidence suggests that childhood trauma may increase the risk of schizophrenia,individuals with developmental abnormalities are prone to experience childhood trauma,and there was observed that interaction effect between childhood trauma and gene on cognitive and brain structure.However,the interaction effects of childhood trauma and gene on brain white matter microstructure are not clear.Therefore,our study aimed to explore: 1.the relationships among childhood trauma,white matter microstructure deficits and schizophrenia;2.the relationship between schizophrenic polygenic scores(PRS)and white matter microstructure;3.the interaction effects of childhood trauma and PRS on the microstructure of white matter.Materials and Methods:A total of 601 subjects were included in this study,including 182 First Episode schizophrenia(FES)and 419 Healthy Controls(HCs).328 subjects were evaluated by Childhood Trauma questionnaire(CTQ)and collected Diffusion Tensor Imaging(DTI)data,469 subjects had microarray data and only 163 subjects had DTI,T1 and genetic data.Total childhood trauma and subtype scores of two samples and were compared by independent sample T test.Tract Based Spatial Statistics(TBSS)double-sample T test was performed on FES and HCs group,with age and gender as covariables.The correlation between fractional anisotropy(FA)and childhood trauma scores,clinical symptom scale was analyzed through Pearson correlation analysis.The Mediation analysis was used to explore the relationship among childhood trauma,white matter microstructure alterations and schizophrenia.The relationships between PRS and white matter microstructure,childhood trauma and clinical symptoms was analyzed using Pearson correlation.After adjustment for age and gender variables,multiple linear regression was used to analyze the interaction effects between PRS and diagnosis on white matter.The multiplication of PRS and childhood trauma was established to analyze the effect of their interaction on the microstructure of white matter.Results:1.Total childhood trauma score,subtype scores of emotional abuse,physical abuse,sex abuse,emotional neglect and physical neglect in FES were significantly higher than HCs(P < 0.05).Compared with HCs,the FA values of forceps major,forceps minor,left anterior thalamic radiation and inferior fronto-occipital fasciculus(IFOF)were decreased in FES(P < 0.05,TFCE and FWE correction).And mediation analysis showed that the association between white matter deficits and FES was partly mediated via childhood trauma(the proportion of mediation 25%).2.PRS was positively correlated with FA values of pontine crossing tract(r =0.256,P = 0.038),and negatively correlated with FA values in splenium of corpus callosum(r =-0.270,P = 0.028)and left tapetum(r =-0.263,P = 0.033)in patients with schizophrenia.After adjusting for age and sex,the interaction between PRS and diagnosis was observed in body of corpus callosum(β =-0.316,P = 0.048),splenium of corpus callosum(β =-0.351,P = 0.029)and left cerebral peduncle(β =-0.356,P= 0.029).3.After adjusting for age and sex,the interaction effects of total scores of childhood trauma and PRS on left cingulum(β =-0.287,P = 0.011),right cingulum(hippocampus)(β =-0.331,P = 0.004)and left tapetum(β =-0.217,P = 0.033)were significant in schizophrenia.The interaction between emotional abuse and PRS on pontine crossing tract(β = 0.206,P = 0.032),left cingulum(β =-0.198,P = 0.031),right cingulum(β =-0.215,P = 0.033)and left tapetum(β =-0.184,P = 0.040)were significant in patients with schizophrenia.The interactions between physical abuse and PRS were observed in the splenium of corpus callosum(β =-0.234,P = 0.022),right posterior corona radiata(β =-0.282,P = 0.028)and left posterior corona radiata(β =-0.355,P = 0.003).There was also an interaction between physical neglect and PRS on the right cingulum(hippocampus)(β =-0.363,P = 0.002).Conclusion:Patients with schizophrenia were suffered from more childhood trauma.And childhood trauma,deficits of white matter microstructure and genetic may involve in the pathophysiology of schizophrenia.Moreover,our study found that childhood trauma could partly explain the relationship between white matter microstructure abnormality and schizophrenia.In addition,the interactions between childhood trauma and genetic were observed in specific white matter brain regions in schizophrenia,indicating that individuals with higher childhood trauma score and PRS score were more likely with lower FA value in specific tracts.Therefore,in the clinical treatment,a psychiatrist should not only consider the severity of symptoms,but the family history,childhood trauma and neural development trajectory of the individual should also be taken into account.更多还原