精神分裂症患者同胞对脑白质的磁共振研究
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摘要
目的:针对精神分裂症的结构失连接假说,利用精神分裂症患者的健康同胞和正常人作为对照,探索与精神分裂症有关的固有的生物学特征。
方法:共收集38对精神分裂症患者及其健康同胞和35名正常人。所有入组的研究对象都接受了适于精神疾病诊断和统计手册第四版(Diagnostic and Statistic Manual versionⅣ,DSM-Ⅳ)的结构式临床访谈(structural clinical interview for DSM-Ⅳ,SCID),使用SCID患者版筛查以确定精神分裂症患者符合DSM-Ⅳ精神分裂症的诊断标准。采用阳性和阴性综合征量表(Positive and Negative Syndrome Scale,PANSS)评估临床症状。采用连线测验(Trail Making Test,TMT)、威斯康星卡片分类测验(Wisconsin Card Sorting Test,WCST)、言语流畅性测验(Verbal fluence Test,VFT)和色词干扰任务(StroopColor-Word Task,SCWT)评估患者的精神运动性、执行功能、语言能力和注意力。以上所有评定和评估都由一名精神科主治医生实施。所有研究对象在评定当天进行了磁共振扫描,包括弥散张量成像(diffusion tensor imaging,DTI)和三维结构磁共振成像(three-dimensional structure magnetic resonance imaging,3D-MRI)。
MRI扫描后,排除头动等因素导致有质量问题的数据:
1).在SPM2(statistic parameters mapping2)上用基于像素的分析方法(voxel-based analysis,VBA)对34对精神分裂症患者(男20女14)及其健康同胞(男20女14)和32名正常人(男19女13)的各向异性(fractional anisotropy,FA)进行单因素方差分析,确定有显著性差异的白质区域;计算出每个研究对象有显著性差异区域的FA绝对值,在SPSS12.0上进行单因素方差分析及验后检验,明确任意两组间的差异。
2).用基于像素的形态学方法(voxel-based morphometry,VBM)比较30对精神分裂症患者(男16女14)及其健康同胞(男19女11)和30名正常对照(男18女12)的白质密度,确定有显著性差异的区域并计算出密度值;用有显著性差异的白质密度区域做感兴趣区,进行纤维追踪,计算追踪出的纤维束的弥散张量指数,在SPSS12.0上分析三组之间弥散张量指数的差异,以及该指数与认知功能和精神残灾⒆雌婪值南喙匦浴?
结果:
1.三组FA值的比较结果
单因素方差分析显示三组的左侧前额叶、左侧海马和左侧前扣带FA值有显著的组主效应。在左侧前额叶和海马白质区,验后检验显示精神分裂症患者及其健康同胞的脑白质FA值显著低于正常对照,患者的FA值小于其健康同胞但差异无显著性。在左侧前扣带区,验后检验显示精神分裂症患者脑白质FA值显著低于其健康同胞和正常对照,健康同胞的FA值大于正常对照但差异无显著性。
2.三组脑白质密度和弥散张量指数的比较
单因素方差分析显示三组的左侧前额叶和胼胝体膝部脑白质密度有显著的组主效应。验后检验显示精神分裂症患者及其健康同胞这两个脑区的脑白质密度显著低于正常对照,患者与健康同胞之间的差异无显著性。
单因素方差分析显示穿过左侧前额叶和胼胝体膝部感兴趣区的神经纤维束弥散张量指数在三组之间有显著的组主效应。验后检验显示精神分裂症患者及其健康同胞这两个区域的弥散张量指数显著小于正常对照,患者和健康同胞之间的差异无显著性。
相关分析发现,在健康同胞组,穿过胼胝体膝部感兴趣区的白质纤维束弥散张量指数与完成连线测验的耗时数呈显著性正相关;在患者组,该指标与完成色词干扰任务的耗时数呈显著正相关。穿过胼胝体膝部和左侧前额叶感兴趣区的白质纤维束弥散张量指数都与患者的PANSS评定的阳性症状分量表分呈显著性正相关。
结论:
1.左侧前额叶、海马脑白质完整性降低可能意味着精神分裂症的患病风险,而左侧前扣带的脑白质完整性降低则可能是由高风险状态向该病转换的决定因素。
2.左侧前额叶及其连接的胼胝体膝部白质结构失连接可能与精神分裂症的患病风险有关,且该结构失连接可能是精神分裂症阳性症状和注意力、精神运动等认知功能障碍的病理基础。
Objective: Investigation of inherent biological characteristics related to schizophrenia in schizophrenia patients, their healthy siblings and healthy controls, and this may provide evidence for the hypothesis of distributed connectivity.
Methods: We recruited 38 pairs of schizophrenia patients (met DSM-Ⅳdiagnostic criteria for schizophrenia) and their healthy siblings, and 35 healthy controls. All subjects were screened by Structural Clinical Interview for DSM-Ⅳ(SCID), with SCID-P for patients and SCID-NP for siblings and controls. One trained psychiatrists performed the assessment for psychotic symptoms using Positive and Negative Syndrome Scale (PANSS). Meanwhile, all subjects were assessed by a series of cognitive tests including Trail Making Test (TMT), Wisconsin Card Sorting Test (WCST), Verbal Fluence Test (VFT) and Stroop Color-Word Task (SCWT). Then all subjects were scanned in 1.5T GE scanner, including diffusion tensor imaging (DTI) and three-dimensional structural magnetic resonance imaging (3D-MRI).
Unqualified data due to head motion and other factors were ruled out after scan. 1) FA maps from 34 pairs of schizophrenia patients and their healthy sibling and 32 healthy controls were analyzed using a voxel-wise one-way analysis of variance (ANOVA) for identifying regions with significant difference; and then mean FA values were calculated in each identified region for all subjects and were analyzed by one-way ANOVA.
2) To compare white matter density among three groups for identifying regions with significant difference by a voxel-wise one-way ANOVA, and then mean white matter values were calculated in each identified region for all subjects and were analyzed by one-way ANOVA; to use the identified regions as ROI for fiber tracking and to reconstruct the fiber tracts transversing two ROIs; to calculate and analyze diffusional measure of reconstructed tracts among three groups; to correlate diffusional measure with cognitive and clinical measures in each group.
Results:
1. Comparison of FA values among three groups
Comparison of FA among the three groups, one-way ANOVA revealed a significant group main effect in the left prefrontal cortex (PFC), hippocampus and anterior cingulate cortex (ACC). In the left PFC and hippocampus, post hoc tests indicated that FA values in both schizophrenia patients and healthy siblings were lower than those in healthy controls, without significant difference between patients and siblings. In marked contrast, only schizophrenia patients exhibited reduced FA in the left ACC as compared with either siblings or controls, without significant difference between siblings and controls.
2. Comparison of white matter density and diffusional measures
Comparison of white matter density and diffusional measures among the three groups, one-way ANOVA revealed a significant group main effect in the left PFC and genu of corpus callosum. Post hoc tests indicated that healthy siblings shared reduced white matter density and diffusional measures with schizophrenia patients as compared with healthy controls in both regions; and diffusional measures were significantly positive correlation with cognitive measures and clinical measures.
Conclusions:
1. Reduction of white matter integrity in the left PFC and hippocampus may be related to the higher risk of healthy siblings to develop schizophrenia, which may be eventually attributed to additional reduced white matter integrity in the left ACC.
2. Structural disconnectivity in the left PFC and genu of corpus callosum may be related to genetic risk for schizophrenia. And the disconnectivity may be pathophysiological substrate of positive symptoms and cognitive impairment such as attention and psychomotor function in schizophrenia.
方法:共收集38对精神分裂症患者及其健康同胞和35名正常人。所有入组的研究对象都接受了适于精神疾病诊断和统计手册第四版(Diagnostic and Statistic Manual versionⅣ,DSM-Ⅳ)的结构式临床访谈(structural clinical interview for DSM-Ⅳ,SCID),使用SCID患者版筛查以确定精神分裂症患者符合DSM-Ⅳ精神分裂症的诊断标准。采用阳性和阴性综合征量表(Positive and Negative Syndrome Scale,PANSS)评估临床症状。采用连线测验(Trail Making Test,TMT)、威斯康星卡片分类测验(Wisconsin Card Sorting Test,WCST)、言语流畅性测验(Verbal fluence Test,VFT)和色词干扰任务(StroopColor-Word Task,SCWT)评估患者的精神运动性、执行功能、语言能力和注意力。以上所有评定和评估都由一名精神科主治医生实施。所有研究对象在评定当天进行了磁共振扫描,包括弥散张量成像(diffusion tensor imaging,DTI)和三维结构磁共振成像(three-dimensional structure magnetic resonance imaging,3D-MRI)。
MRI扫描后,排除头动等因素导致有质量问题的数据:
1).在SPM2(statistic parameters mapping2)上用基于像素的分析方法(voxel-based analysis,VBA)对34对精神分裂症患者(男20女14)及其健康同胞(男20女14)和32名正常人(男19女13)的各向异性(fractional anisotropy,FA)进行单因素方差分析,确定有显著性差异的白质区域;计算出每个研究对象有显著性差异区域的FA绝对值,在SPSS12.0上进行单因素方差分析及验后检验,明确任意两组间的差异。
2).用基于像素的形态学方法(voxel-based morphometry,VBM)比较30对精神分裂症患者(男16女14)及其健康同胞(男19女11)和30名正常对照(男18女12)的白质密度,确定有显著性差异的区域并计算出密度值;用有显著性差异的白质密度区域做感兴趣区,进行纤维追踪,计算追踪出的纤维束的弥散张量指数,在SPSS12.0上分析三组之间弥散张量指数的差异,以及该指数与认知功能和精神残灾⒆雌婪值南喙匦浴?
结果:
1.三组FA值的比较结果
单因素方差分析显示三组的左侧前额叶、左侧海马和左侧前扣带FA值有显著的组主效应。在左侧前额叶和海马白质区,验后检验显示精神分裂症患者及其健康同胞的脑白质FA值显著低于正常对照,患者的FA值小于其健康同胞但差异无显著性。在左侧前扣带区,验后检验显示精神分裂症患者脑白质FA值显著低于其健康同胞和正常对照,健康同胞的FA值大于正常对照但差异无显著性。
2.三组脑白质密度和弥散张量指数的比较
单因素方差分析显示三组的左侧前额叶和胼胝体膝部脑白质密度有显著的组主效应。验后检验显示精神分裂症患者及其健康同胞这两个脑区的脑白质密度显著低于正常对照,患者与健康同胞之间的差异无显著性。
单因素方差分析显示穿过左侧前额叶和胼胝体膝部感兴趣区的神经纤维束弥散张量指数在三组之间有显著的组主效应。验后检验显示精神分裂症患者及其健康同胞这两个区域的弥散张量指数显著小于正常对照,患者和健康同胞之间的差异无显著性。
相关分析发现,在健康同胞组,穿过胼胝体膝部感兴趣区的白质纤维束弥散张量指数与完成连线测验的耗时数呈显著性正相关;在患者组,该指标与完成色词干扰任务的耗时数呈显著正相关。穿过胼胝体膝部和左侧前额叶感兴趣区的白质纤维束弥散张量指数都与患者的PANSS评定的阳性症状分量表分呈显著性正相关。
结论:
1.左侧前额叶、海马脑白质完整性降低可能意味着精神分裂症的患病风险,而左侧前扣带的脑白质完整性降低则可能是由高风险状态向该病转换的决定因素。
2.左侧前额叶及其连接的胼胝体膝部白质结构失连接可能与精神分裂症的患病风险有关,且该结构失连接可能是精神分裂症阳性症状和注意力、精神运动等认知功能障碍的病理基础。
Objective: Investigation of inherent biological characteristics related to schizophrenia in schizophrenia patients, their healthy siblings and healthy controls, and this may provide evidence for the hypothesis of distributed connectivity.
Methods: We recruited 38 pairs of schizophrenia patients (met DSM-Ⅳdiagnostic criteria for schizophrenia) and their healthy siblings, and 35 healthy controls. All subjects were screened by Structural Clinical Interview for DSM-Ⅳ(SCID), with SCID-P for patients and SCID-NP for siblings and controls. One trained psychiatrists performed the assessment for psychotic symptoms using Positive and Negative Syndrome Scale (PANSS). Meanwhile, all subjects were assessed by a series of cognitive tests including Trail Making Test (TMT), Wisconsin Card Sorting Test (WCST), Verbal Fluence Test (VFT) and Stroop Color-Word Task (SCWT). Then all subjects were scanned in 1.5T GE scanner, including diffusion tensor imaging (DTI) and three-dimensional structural magnetic resonance imaging (3D-MRI).
Unqualified data due to head motion and other factors were ruled out after scan. 1) FA maps from 34 pairs of schizophrenia patients and their healthy sibling and 32 healthy controls were analyzed using a voxel-wise one-way analysis of variance (ANOVA) for identifying regions with significant difference; and then mean FA values were calculated in each identified region for all subjects and were analyzed by one-way ANOVA.
2) To compare white matter density among three groups for identifying regions with significant difference by a voxel-wise one-way ANOVA, and then mean white matter values were calculated in each identified region for all subjects and were analyzed by one-way ANOVA; to use the identified regions as ROI for fiber tracking and to reconstruct the fiber tracts transversing two ROIs; to calculate and analyze diffusional measure of reconstructed tracts among three groups; to correlate diffusional measure with cognitive and clinical measures in each group.
Results:
1. Comparison of FA values among three groups
Comparison of FA among the three groups, one-way ANOVA revealed a significant group main effect in the left prefrontal cortex (PFC), hippocampus and anterior cingulate cortex (ACC). In the left PFC and hippocampus, post hoc tests indicated that FA values in both schizophrenia patients and healthy siblings were lower than those in healthy controls, without significant difference between patients and siblings. In marked contrast, only schizophrenia patients exhibited reduced FA in the left ACC as compared with either siblings or controls, without significant difference between siblings and controls.
2. Comparison of white matter density and diffusional measures
Comparison of white matter density and diffusional measures among the three groups, one-way ANOVA revealed a significant group main effect in the left PFC and genu of corpus callosum. Post hoc tests indicated that healthy siblings shared reduced white matter density and diffusional measures with schizophrenia patients as compared with healthy controls in both regions; and diffusional measures were significantly positive correlation with cognitive measures and clinical measures.
Conclusions:
1. Reduction of white matter integrity in the left PFC and hippocampus may be related to the higher risk of healthy siblings to develop schizophrenia, which may be eventually attributed to additional reduced white matter integrity in the left ACC.
2. Structural disconnectivity in the left PFC and genu of corpus callosum may be related to genetic risk for schizophrenia. And the disconnectivity may be pathophysiological substrate of positive symptoms and cognitive impairment such as attention and psychomotor function in schizophrenia.
引文
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