正常脑老化中静息态功能磁共振成像功能连接的研究进展

【摘要】静息态功能磁共振成像（fMRI）作为一种不需要任务刺激就能呈现功能脑影像的技术手段,在临床上被广泛应 用。基于静息态fMRI的静息态功能连接（RSFC）,作为一种重要的计算机辅助分析法,能够度量不同脑区的脑功能连接 强度,对脑老化相关的神经科学领域的研究具有重要意义。本文介绍了功能连接的基本概念,总结了近年来脑老化相关 的人脑功能连接的研究成果,最后提出了该研究领域存在的问题及未来的研究方向。     

抑郁症的静息态脑功能磁共振研究

本研究的目的是研究抑郁症患者与健康人静息态脑功能的差别。对符合DSM-IV诊断标准的53例抑郁症患者和38例正常对照进行静息态功能磁共振扫描,采用局部一致性(regional homogeneity,ReHo)的方法分析数据,然后进行基于体素的组间比较,分析其静息态脑功能的差异。结果显示与正常组相比,抑郁组在双侧前扣带皮质(anterior cingulate cortex,ACC)、左侧内侧前额叶皮质、左侧颞中回均有ReHo值降低。ACC位置ReHo值显著降低提示抑郁症患者在前扣带皮质及其相邻部位自发神经活动异常。     

连枷臂综合征患者静息态功能磁共振局部一致性研究

目的采用静息态功能磁共振成像(RS-fMRI)技术观察连枷臂综合征(flailarm syndrome,FAS)患者脑区局部一致性(ReHo)的变化特点。方法选取10名确诊的连枷臂综合征患者组成病例组,另选择10名健康志愿者组成健康对照组;病例组符合2000年修订版EI-Escorial标准临床确诊的诊断标准;对病例组及健康对照组进行RS-fMRI扫描,并进行图像数据预处理,以ReHo值作为观测指标,分析并比较两组受试者的差异。结果静息态下,与健康对照组相比,FAS组患者在双侧楔前叶、左侧后扣带回、左侧楔叶的ReHo值增高,双侧中央盖沟、左侧中央前回、左侧中央后回、双侧内侧及旁扣带脑回、右侧岛叶ReHo值减低(AlphaSim矫正,P0.05,voxels20)。结论 FAS患者ReHo异常变化的脑区包括运动区及非运动系统,RSfMRI为进一步理解FAS患者的神经病理学机制提供了依据。     

作曲家大脑的静息态脑功能网络研究

音乐家大脑是认识大脑可塑性机制的天然模型,也是脑影像科学关注的重点研究对象之一。但是,目前针对音乐家的研究,包括对音乐创作方面的脑机制研究,仍以钢琴演奏家为主要研究对象。鉴于创作与表演是两个不同阶段且存在巨大差异,仅以钢琴演奏家作为研究对象对音乐家脑机制的研究是不完整的。专业作曲家是一类特殊的音乐家,他们经历过长期的音乐训练,能够在创造性思维的引领下,结合情感等要素来进行音乐素材的组织。用功能磁共振(fMRI)采集29名作曲家在作曲任务前后的大脑静息态影像,利用独立成分分析方法分离出其脑功能网络中常见的13个成分。采用配对t检验,对比分析作曲前后这些成分的变化。结果发现,在完成作曲任务后,以下脑功能网络连接显著减弱,包括听觉网络(AN)与右侧额顶网络(RFPN)、感觉运动网络(SMN)与突显网络(SN);同时也发现在完成作曲任务后,以下脑功能网络连接显著增强,包括自我参照网络(SRN)与视觉I区网络(VN1)、自我参照网络(SRN)与视觉II区网络(VN2)、默认模式网络(DMN)与视觉I区网络(VN1)。这些结果证明,感觉、认知加工等与视觉区域的协调整合在作曲过程中的重要性,对推动音乐家大脑可塑性的认识和音乐创作的脑机制研究均十分有意义。     

基于静息态功能磁共振图像的动态功能连接特征的智商预测

目的近年来越来越多的研究表明大脑不同脑区间的功能连接的动态波动具有生理意义,但关于智商(intelligence quotient,IQ)的相关研究较少。本文基于动态功能连接(dynamic functional connectivity,DFC)提取动态特征对智商进行评估,为智商预测探索新的特征参数和预测模型。方法基于97个儿童静息态功能磁共振图像(resting state functional magnetic resonance image,RS-fMRI),采用滑动窗相关计算方法构建DFC。基于DFC提取相应时域、频域特征,通过弹性网(elastic-net,E-Net)和最小角回归(least angle regression,LAR)算法建立智商回归模型进行个体智商预测,并通过置换检验验证其显著性。结果基于动态功能连接的特定频段(0.075~0.1 Hz)频域特征和波动均值特征,可以实现对智商的基本预测,且频域特征的表现优于时域特征。另外,基于LAR算法构建的预测模型的表现优于E-Net算法。结论个体脑功能连接随时间的动态波动足以预测个体智商,且特定频段的频域特征和LAR算法能够提高预测准确率,这可为个体智商评估研究和动态功能连接的应用提供新的思路。     

一氧化二氮中毒青年患者静息态功能磁共振局部一致性

目的应用静息态功能磁共振成像(BOLD-fMRI)技术研究一氧化二氮(N_2O)中毒的青年患者脑区局部一致性(ReHo)的变化特点,探究滥用N_2O所致神经毒性的机制。方法选取9名N_2O中毒后的青年患者组成病例组,另招募相匹配的12名健康青年志愿者组成健康对照组。对病例组及健康对照组均进行RS-fMRI扫描,并进行图像数据预处理,以ReHo值作为观测指标,分析并比较两组受试者间的差异。结果静息态下,与健康对照组相比较,N_2O中毒患者在双侧眶部额上回、双侧嗅皮质、右侧尾状核、右侧中央前回、右侧中央后回、右侧额中回、左侧中央旁小叶ReHo值减低(AlphaSim矫正,P0.05,voxels54),差异具有统计学意义。未发现有ReHo增高的脑区。结论 N_2O中毒患者出现了ReHo减低的脑区,表明N_2O中毒影响了神经兴奋的敏感性。RS-fMRI为进一步理解过量N_2O产生的神经毒性的病理学机制提供了依据。     

吸烟成瘾者戒烟前后的静息态功能磁共振研究

为了发现吸烟成瘾者在戒烟前后的脑功能特征改变,探索戒烟过程的神经生理理论基础,14名吸烟成瘾者同意戒烟并完成了试验,另外11名健康不吸烟的志愿者参与了对照试验。采取两因素混合实验设计方法,以静息态功能磁共振影像技术为技术手段,利用区域一致性算法来研究吸烟成瘾者在戒烟前后的神经活动及其与正常人之间的差异,并对这些差异进行组内与组间交互分析。戒烟两周后,在补充运动区、中央旁小叶、距状裂周围皮层、楔叶和舌回等区域的Re Ho值明显上升,意味着在这些脑区的神经活动同步性增强,而在楔前叶和后扣带回脑区同步性降低。在补充运动区、中央旁小叶、中央前回、中央后回、眶部额上回等脑区存在组间交叉效应。本研究结果显示吸烟成瘾者戒烟2周后在补充运动区的功能显著增强。     

探索大脑网络连接的几种方式——基于静息态功能磁共振数据

目的:在研究脑网络连接过程中,存在不同的连接方式。本文的目的在于探索不同连接方式之间的区别和特点。方法:利用3T磁共振设备,实验当中采集22个健康人静息态功能磁共振数据,依据运动控制过程当中的活动脑区,提取出前额叶皮层、运动联合皮层、基底节、初级运动皮层、初级感觉皮层、小脑中部及小脑侧面区域的时间序列。然后,分别利用Pearson相关、偏相关、偏最小二乘算法、格兰杰因果方程建模、结构方程建模方法来构建上述七个脑区之间的连接。最后,把由五种连接方法建立的结构图与运动控制过程当中的信号传递图做比较,以比较五种不同的连接方法。结果:实验结果表明在无向连接图里面,偏相关显示了较好的结果。在有向连接图里面,格兰杰因果方程建模与模板匹配更好。结论:在脑网络研究当中,不同的连接方法会对实验结果造成不同的影响。实际研究当中,应该结合实际的实验条件和目的,选择合理的连接方法。     

阴性颞叶癫痫患者静息态脑功能连接网络特征融合策略的分析

静息态功能磁共振成像(rfMRI)的功能连接(FC)可为阴性颞叶癫痫提供脑功能异常指标,但冗余特征影响了精准性。为此,本研究提出结合特异性指数模型与判别相关分析(DCA)的特征融合策略以改善识别效果。将20位患者与20位健康人的rfMRI数据预处理后,以健康人为对照组,构建两类特异性指数模型以量化FC和脑网络FC;采用最小冗余最大相关(mRMR)及独立样本t检验去除冗余特征,应用DCA融合2类FC特异性指标;将融合特征分别输入到K近邻、支持向量机和逻辑回归分类器中,并以嵌套10次10折交叉验证与嵌套10次5折分层交叉验证的平均分类精度来评估算法有效性。结果表明,融合特征识别率达到了91.25%～92.50%,高于非融合方案的识别水平。所提出的特征融合策略可有效地处理冗余信息,增强特征判别能力,为精准识别阴性颞叶癫痫提供了新思路。     

颞叶癫痫致痫侧静息态脑功能网络拓扑的特异性研究

癫痫是世界常见的典型脑内异常神经放电导致中枢认知功能网络失调的神经疾病.作为当今先进技术的静息态功能磁共振成像(rfMRI),其功能连接(fMRI-FC)可为评估脑功能提供科学的检测指标.在此提出参照健康人的癫痫脑功能网络多节点指标融合的特异性模型,提取致痫侧脑功能网络拓扑属性,试图在高阶计算fMRI-FC,以提高其检...     

蛋氨酸合酶基因A275 6G位点多态性与非综合征型唇腭裂的关联性研究

目的 研究蛋氨酸合酶基因(methionine synthase,MS)A2756G位点多态性与非综合征型唇腭裂(nonsyndromic cleft lip with or without cleft palate,NSCL/P)的关联性.方法 采用PCR-限制性片段长度多态性技术检测97个NSCL/P病例组核心家庭和104个对照家庭的MS基因A2756G位点的多态性;用人群关联研究分析、病例组核心家庭的传递不平衡检测(transmission disequilibrium test,TDT)、单体型的相对危险度分析(haplotype-based haplotype relative risk,HHRR)、家庭为基础的关联研究(family-based association tests,FBAT)等统计分析.结果 子代、父亲、母亲病例组和对照组之间基因型和等位基因的分布差异均无统计学意义(P>0.05);本研究中在子代和母亲组中未检出GG基因型,AG基因型相对于AA基因型的比值比OR和95%CI分别为子代1.78(0.74～4.34)、父亲0.80(0.36～1.79)、母亲1.26(0.54～2.93),G相对于A基因的OR和95%CI分别为子代1.70(0.78～3.73)、父亲0.88(0.49～1.75)、母亲1.23(0.59～2.60),携带有突变基因G并不能增加患NSCL/P的危险.病例组核心家庭分析,TDT分析χ2=0.034,P>0.05;HHRR分析χ2=0.03,P>0.05;FBAT分析Z=0.186,P>0.05.结论 结果未显示出MS基因A2756G位点多态性和NSCL/P发生的相关性,还待进一步研究.     

MSX1基因微卫星多态性与非综合征性唇腭裂的相关性研究

目的探讨肌肉片段同源盒1基因（muscle segment homeobox1,MSX1）与湖南汉族非综合征性唇腭裂（nonsydromic cleft lip and patate,NSCLP）的相关性。方法以MSX1基因内含子区的（CA）n微卫星作为遗传标记,对湖南汉族129例NSCLP患儿和108名正常儿童采用聚合酶链反应-变性聚丙烯酰胺凝胶基因分型技术进行基因分型,并经测序确定片段长度,应用病例对照研究进行相关性分析。结果湖南汉族人群MSX1基因（CA）n等位基因分布符合Hardy-Weinberg平衡,杂合率及多态信息量均为0.50;CA4等位基因频率在唇裂伴或不伴腭裂组及单纯性腭裂组高于对照组,CA4,4基因型频率在唇裂伴或不伴腭裂组和单纯性腭裂组高于对照组,差异均有统计学意义（均P〈0.05）。结论MSX1基因内（CA）n微卫星是多态性较好的遗传标记;MSX1基因可能与湖南汉族人群NSCLP发病相关。     

Interactions between superoxide dismutase and paraoxonase polymorphic variants in nonsyndromic cleft lip with or without cleft palate in the Brazilian population

During development, oxidative stress is hypothesized to mediate embryotoxicity, which may be intensified by exposition to environmental factors and by genetic variations in the enzymes involved in protecting cells from these damaging effects, including superoxide dismutase (SOD) and paraoxonase (PON). The aim of this study was to evaluate the influence of single-nucleotide polymorphisms (SNP) in genes associated with the neutralization of oxidative stress (SOD and PON family members) in the risk of nonsyndromic oral cleft in the Brazilian population. Initially, we tested for association between 28 SNP in SOD1, SOD2, SOD3, PON1, PON2, and PON3 among 325 nonsyndromic cleft lip with or without cleft palate (NSCL±P) case-parent trios. Multiple logistic regression analyses were used to explore gene, GxG and GxE, involving factors that induce oxidative stress accumulation during pregnancy. Signals still significant after both Bonferroni correction and in permutation test were subsequently confirmed in an ancestry-structured case–control analysis with 722 NSCL±P and 866 controls from the same population. In the trio sample, transmission disequilibrium test (TDT) (allele and haplotype) and GxE analysis showed no significant associations, but multiple pairwise GxG interactions involving 10 SNP in PON1, PON2, and PON3 were detected and further examined in the case–control sample. The PON1 rs2237583 and PON2 rs17166879 yielded significant evidence of SNP-SNP interactions after adjustment for multiple tests (both Bonferroni correction and 10,000 permutation test). The C allele and the CT genotype of PON1 rs2237583 were associated with significant protective effects against NSCL±P, while rs3917490 showed a significant association only in the sample composed of patients displaying high African ancestry. Our results reveal associations between rs2237583 and rs3917490 in PON1 and GxG interactions containing rs2237583 and rs17166879 with the susceptibility of NSCL±P in the Brazilian population. Furthermore, this study underlines the recent tendency of taking into account potential GxG interactions to clarify the underlying mechanisms associated with the etiology of this common malformation. Environ. Mol. Mutagen. 60: 185–196, 2019. © 2018 Wiley Periodicals, Inc.     

唇腭裂相关基因研究进展

唇腭裂是一种常见的先天性畸形,其病因非常复杂,目前倾向认为是由多种基因和环境因素共同作用的结果。常见的引起唇腭裂相关的基因有TGFA,TGFβ3, BCL3, F13A等;环境因素在唇腭裂发生中的遗传修饰作用也很重要,主要的环境激发因素包括致畸因子（如烟草、酒精、糖皮质激素等）、感染和营养缺乏。基于基因打靶技术建立的鼠基因敲除模型很好地模拟了人类疾病的表现型,成为研究唇腭裂的一种强有力手段。     

Rs2262251 in lncRNA RP11‐462G12.2 is associated with nonsyndromic cleft lip with/without cleft palate

Nonsyndromic cleft lip with/without cleft palate (NSCL/P) is one of the most common human congenital defects. Rs2262251 (G>C) in long noncoding RNA (lncRNA) RP11‐462G12.2 is in high linkage disequilibrium with rs8049367, which was identified in our previous genome‐wide association study on NSCL/P, and is a potential causative single‐nucleotide polymorphism (SNP) for NSCL/P. To test these hypotheses, rs2262251 was evaluated in another cohort of 1,314 cases and 1,259 controls. Rs2262251 was associated with NSCL/P risk (p = .003). However, no association was detected for cleft palate only. SNP rs2262251 affected the structure and expression of lncRNA RP11‐462G12.2 in HEK293 and HEPM cells and in lip tissues from patients with NSCL/P. Overexpression of the rs2262251 G allele contributed to reducing the number of cells in the G0/G1 phase, inhibiting cell apoptosis, and promoting cell proliferation in vitro. The rs2262251 C allele regulated the expression of miR‐744‐5p and its target gene IQSEC2, both of which were expressed in human lip tissues, and showed reverse correlation during mouse lip development. Taken together, these findings suggest that rs2262251 is associated with the risk of NSCL/P and participates in a lncRNA–miRNA–mRNA regulatory axis in which miR‐744‐5p and IQSEC2 combine to control NSCL/P development.     

基于体素的形态学分析唇腭裂患儿脑结构特征

目的 采用基于体素的形态学分析(VBM)方法探讨唇腭裂患儿脑结构特征.方法 在1.5 T磁共振扫描仪上采集数据,运用优化VBM方法比较10例唇腭裂患儿及10例正常对照婴幼儿的脑结构.对2组婴幼儿的灰白质密度和体积进行基于体素的双样本t检验,对比结果采用国际通用的统计参数图(SPM)表示,分析唇腭裂患儿大脑灰质密度及体积异常区域分布特征及其临床意义.结果 唇腭裂组的灰质体积在属于额上回的双侧前额叶内侧显著低于正常对照组(差异团簇体积体素个数:5220、4871,团簇水平校正后P值均小于0.05),灰质密度在左侧颞上回显著高于正常对照组(体素水平校正后P值小于0.05),脑白质密度和体积均无显著性的差异.结论 唇腭裂患儿与听觉及认知有关的皮层可能异于正常婴幼儿,应对此类患儿进行中枢听觉处理功能及认知功能的早期检查和早期干预.     

Maternal MTHFR variant forms increase the risk in offspring of isolated nonsyndromic cleft lip with or without cleft palate

The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investigated 110 sporadic CL/P patients, their parents and 289 unrelated controls for c.665C>T (commonly known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala) polymorphism in the MTHFR gene. Transmission disequilibrium test (TDT) showed no distortion in allele transmission. Nevertheless, association studies revealed significant differences in allele frequencies between mothers of CL/P patients and controls. This work supports the hypothesis that a lower MTHFR enzyme activity in pregnant women, mostly related to the c.665C>T variant form, is responsible for a higher risk of having CL/P affected offspring.     

2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population

The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL±P). Here, we investigated 5 reported genome‐wide loci for NSCL±P in an ancestry‐structured case‐control study containing 1697 Brazilian participants (831 NSCL±P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13.11 were genotyped using TaqMan allelic discrimination assays and genomic ancestry was estimated using a panel of 40 biallelic short insertion/deletion polymorphic markers informative of the Brazilian population. Logistic regression analysis of the single‐markers revealed rs7552 in 2p24.2 as a susceptibility risk marker for NSCL±P, yielding an odds ratio (OR) of 1.71 (95% confidence interval (CI): 1.31‐2.24, P = 9 × 10^?6) in the homozygous state. Several SNP‐SNP interactions containing rs7552 reached significance after adjustment for multiple tests (both Bonferroni assumption and 1000 permutation test), with the most significant interaction involving the 3‐loci among rs7552, rs9891446 and rs73039426 (P = 6.1 × 10^?9 and p_{1000 permutation} = 0.001). Our study is the first to support the association of rs7552 in 2p24.2 with NSCL±P in the highly admixed Brazilian population.