N-back任务功能性磁共振成像探讨亚甲基四氢叶酸还原酶基因 C677 T多态性对精神分裂症患者工作记忆的影响研究

摘要

目的：应用N-back任务功能性磁共振成像探讨亚甲基四氢叶酸还原酶（ MTHFR）基因C677T多态性对精神分裂症患者工作记忆相关脑区功能的影响。方法选取2007年2月—2008年8月北京大学第六医院住院或门诊汉族精神分裂症患者33例为病例组，另同时期从社区招募健康志愿者30例为对照组，均接受颅脑功能性磁共振成像检测，功能性磁共振成像扫描时完成N-back工作记忆任务。同时采集受试者静脉血，采用DNA测序方法检测MTHFR基因C677T位点基因型。经过头动校正及空间标准化质控，最终病例组纳入20例，对照组纳入27例。使用统计参数图（ SPM8）软件进行全因子分析，比较诊断（对照组、病例组）及MTHFR基因型对工作记忆相关脑区激活的作用。结果对照组与病例组性别、年龄、 MTHFR基因型、2-back正确反应率比较，差异均无统计学意义（ P＞0.05）。病例组受教育时间较对照组缩短（ P＜0.05）。全因子分析结果显示，右侧岛叶、右侧角回、左侧额中回、左侧岛盖的激活存在诊断主效应；事后分析显示，病例组右侧岛叶、左侧额中回、左侧岛盖的激活均较对照组增强（ P＜0.001）。病例组和对照组右侧尾状核、左侧角回和左侧壳核的激活存在MTHFR基因型主效应；事后分析显示， MTHFR基因CT和CC基因型携带者上述工作记忆相关脑区的激活均较 TT基因型携带者增强（P＜0.001）。病例组MTHFR基因CT和CC基因型携带者右侧尾状核、左侧角回、左侧苍白球的激活较TT基因型携带者增强（ P＜0.001）。未发现工作记忆相关脑区激活诊断和MTHFR基因型存在交互作用。结论工作记忆任务中，与健康者相比，精神分裂症患者多个脑区存在“低效”的激活增加。精神分裂症患者MTHFR基因C677T多态性可能影响双侧基底核区、左侧顶下小叶在工作记忆任务中的激活。%Objective To explore the effect of MTHFR C677T polymorphism on brain activations in regions associated with working memory in patients with schizophrenia using N-back task related functional magnetic resonance image ( fMRI). Methods Recruited 33 schizophrenic patients of Han ethnic group who received hospitalized or outpatient treatment in the Sixth Hospital of Peking University from February 2007 to August 2008 as the case group.And another 27 healthy volunteers enrolled from communities were assigned into the control group .All subjects underwent MRI scans during the N-back working memory task.Venous blood was sampled from the subjects , and the MTHFR C677T polymorphism was tested by DNA sequencing .After quality control of head motion and spacial normalization , 20 patients and 27 healthy controls were included the final statistical analysis.Using statistical parametric mapping ( SPM8 ) software, full factorial analysis was conducted to analyze the effect of diagnosis and MTHFR genotypes on brain activations in regions related to working memory .Results The control group and the case group were not significantly different (P>0.05) in gender, age, MTHFR genotype and the correct rate of 2-back.The case group was shorter (P<0.05) than control group in education time.The full factorial analysis showed that the activations in right insula , right angular gyrus , left middle frontal gyrus and left insula opercula had significant main effect of diagnosis ( P<0.001); the postmortem analysis showed that the case group was stronger in the activations in right insula , left middle frontal gyrus and left insula operula than the control group ( P<0.001 ) .The main effect of MTHFR genotype was found in the right caudate nucleus, left angular gyrus and left pallidum (P<0.001); the postmortem analysis showed that MTHFR CC/CT carriers were stronger ( P<0.001 ) than MTHFR TT carriers in the activations in those regions related with working memory .In case group, MTHFR CC/CT carriers were stronger ( P<0.001) than MTHFR TT carriers in the activations in right caudate nucleus , left angular gyrus and left pallidum .No interaction effect was found between the diagnosis and MTHFR genotype in activations in regions related with working memory .Conclusion During working memory task , schizophrenia patients showed "inefficient"hyper activation in several brain regions compared to healthy control .In the case group, MTHFR gene C677T polymorphism may affect the activation of bilateral basal ganglia region , left inferior parietal lobule in working memory tasks .