静息态fMRI显示DMD脑异常功能区及其与认知障碍的相关关系
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摘要
目的:杜兴型肌营养不良症(Duchenne muscular dystrophy,DMD)是一组X染色体连锁隐性遗传病,患病率为活产男婴的1/3500,是人类第二常见隐性遗传病。此疾病主要表现是儿童期起病的进行性肌无力、肌萎缩,并且常伴有认知障碍等中枢神经系统合并症。DMD是抗肌萎缩基因(dystrophin gene)突变的结果,导致其表达的抗肌萎缩蛋白异常。抗肌萎缩蛋白在许多组织中有表达,主要位于骨骼肌肌纤维膜的内表面,在中枢神经系统如大脑皮层的锥状神经元、海马及小脑的Purkinje细胞有表达。而关于mdx模型(缺乏dystrophin或dystrophin处于非功能状态的小鼠模型)的皮质脊髓系统的组织结构研究显示感觉运动皮层的神经元数量和密度均少于对照组。迄今为止,很少有关于DMD患者的大脑的影像学研究,先前的DMD患者及mdx模型的头颅MRI研究肉眼未见明显的大脑结构异常。关于10例DMD患儿及17例成人对照组的PET研究显示右侧感觉运动皮层葡萄糖代谢减低。经颅磁刺激研究显示,DMD患者左侧运动皮层的兴奋性减低。与PET相比,功能磁共振(fMRI)对身体无放射性更适用于儿童研究。静息态fMRI的低频振荡信号能够反映出大脑的自发性活动。静息态fMRI不需要任何认知任务在儿童研究中很容易实现。本研究主要应用静息fMRI技术局部一致性分析方法分析DMD患者的颅内低频振荡信号以及其是否与认知之间存在相关关系。
方法:采用德国西门子1.5T MRI扫描机采集了28例DMD患儿(5.2~13.9岁)及34例相应年龄正常对照组(5.2~14.2岁)头颅静息fMRI的BOLD数据,扫描参数为TR/TE 2000/40 ms,共20层,轴面,层厚5.0mm,层间距1.0mm,FOV 220mm×220mm,翻转角90o ,矩阵64×64,扫描时间390 s(195个时间点)。然后用SPM5(Statistical Parametric Mapping,http://www.fil.ion.ucl.ac.uk/spm/)软件进行数据预处理,包括层面时间校正,头动校正,空间标准化(最小体素大小为3mm×3mm×3mm)。选择头动参数平动小于2mm,旋动小于2度的研究对象继续分析。用静息态fMRI软件包进行去线型趋势和低通滤波后,对预处理后数据计算全脑ReHo值,每个个体体素ReHo值除以个体大脑脑内均值得到ReHo图,然后进行高斯核(Gaussian kernel)的全宽半高(FWHM)为8mm的空间平滑以减低空间噪声。做双样本t检验比较两组脑内ReHo的差异,然后做校正来去除假阳性结果;最后将DMD患者ReHo减低的区域与智商之间做相关。
结果:结果显示23例DMD患者(8.4±2.1岁)与23例正常对照组(8.3±2.1岁)相比,进行两样本t检验结果显示,在多重比较校正前双侧感觉运动皮层、双侧额中回、双侧颞中回、双侧颞下回、扣带前后回、双侧角回、双侧尾状核头、右侧海马以及小脑内部的低频振荡信号的局部一致性活较对照组减低;在p<0.05, t>2.011,最小体积大于1971mm3校正后显示右侧额中回、右侧颞中回内部的低频振荡信号的局部一致性活动减低。相关分析结果显示DMD患儿右侧额中回ReHo值降低的脑区与操作智商中的填图存在相关关系(p=0.012 r=0.579),DMD患儿右侧颞中回ReHo值降低的脑区与语言智商中的知识及算术存在相关关系(p=0.047 r=0.353 p=0.035 r=0.499)。
结论:本研究将fMRI应用于DMD研究,分析静息状态下DMD患儿的脑内自发低频振荡信号特点。校正前双侧感觉运动皮层、双侧额中回、双侧颞中回、双侧颞下回、扣带前后回、双侧角回、双侧尾状核头、右侧海马以及小脑内部的低频振荡信号的局部一致性活较对照组减低;校正后DMD组右侧额中回及颞中回内ReHo值较正常对照组减低,此结果提示DMD患者右侧额中回及颞中回的大脑自发的低频振荡信号的同步一致性减低,也就是说DMD患者右侧额中回及颞中回静息状态下的兴奋性减低;并且这种兴奋性减低与认知存在相关关系。
Objective: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease affecting one in 3500 males born and is the second most commonly occurring genetically inherited disease in humans. DMD is characterized by the well-known progressive skeletal muscle weakness and different extent of cognitive impairment. DMD is lack of dystrophin protein which is normally localized in brain to cortical pyramidal neurons, hippocampus and cerebellar Pukinje cells, besides to skeletal muscle. Studies on the mdx model (an animal model of Duchenne muscular dystrophy), found the absolute number and the cell packing density of labeled cortico-spinal neurons were lower in mdx than in controls. To date, there have been only a few in vivo brain imaging studies on DMD patients. Previous brain magnetic resonance imaging (MRI) studies on DMD patients and mdx model did not find prominent structural abnormality in DMD subjects. A PET study on ten boys with DMD and 17 normal adults demonstrated decreased glucose metabolism in children with DMD in the right sensorimotor cortex. Abnormal brain activity was also supported by transcranial magnetic stimulation study, in which the DMD patient revealed decreased excitability in the primary motor cortex. Compared to PET, functional MRI (fMRI) has no radioactivity and is therefore more suitable for children studies. However, it has never been used to study the brain function of DMD patients. Low frequency (0.01-0.08 Hz) fluctuation (LFF) of the resting-state functional MRI signal may reflect the spontaneous brain activity. Resting-state fMRI study does not need cognitive tasks and is very easy to be implemented for children study. We have proposed a regional homogeneity (ReHo) approach to measure the synchronization of the LFF of resting-state fMRI signal in brain cortex in DMD patients and the correlation between it and intelligence.
Methods: In this study, 28 boys with DMD (age range, 5.2~13.9years) and 34 age-matched normal boys (age range, 5.2~14.2years) were included in this study. The imaging studies were done using a Siemens 1.5-Tesla scanner (Siemens, Germany). The rest-stating fMRI BOLD images were acquired axially using the following parameters: 2000/40 ms (TR/TE), 20 slices, 5.0/1.0 mm (thickness/gap), 220 mm×220 mm (FOV), 64×64 (resolution), 90o (flip angle). The resting-fMRI scanning session lasted for 390 s. MRI image preprocessing was conducted with Statistical Parametric Mapping (SPM5, (http://www.fil.ion.ucl.ac.uk/spm/), including slice-timing, motion correction, spatial normalization and resampling(3mm×3mm×3mm). Subjects with head motion larger than 2 mm maximum displacement in x, y, or z and 2oof any angular motion during the fMRI scan were excluded from further analysis. Then, linear trend was removed, and band-pass filter (0.01–0.08Hz) was computed to reduce low-frequency drift and high-frequency noise by using in-house software Resting-State fMRI Data Analysis Toolkit (REST, http://resting-fmri.sourceforge.net). ReHo analysis was performed for each participant and the ReHo of each voxel was divided by the individual global mean of ReHo within a brain-mask. Subsequently, the functional scans were spatially smoothed with a 8mm×8mm×8mm full width at half maximum Gaussian kernel to decrease spatial noise. The second-level random-effect two-sample t-tests were performed on the individual ReHo in a voxel-by-voxel manner in brain. Then do the correction to the brain which decreased ReHo in DMD patients compared to controls for exclude the false positive ones. The correlation analysis was computed between the area of the decreased ReHo and the intelligence in DMD patients.
Result: Compared with normal controls (8.4±2.1 years), boys with DMD (8.3±2.1 years) showed decreased ReHo in the bilateral sensorimotor cortex, bilateral middle frontal gyrus, bilateral middle temporal gyrus, bilateral inferior gyrus, anterior cingulate,posterior cingulate,bilateral angular gyrus, bilateral head of caudate nucleus, right hippocampus and bilateral cerebellum before multiple comparison correction, indicating decreased intra-regional synchronization of spontaneous activity. Clusters with a threshold at P<0.05, t>2.011 and cluster size more than 1971mm3 were considered as significant difference between the two groups after multiple comparison correction, such as right middle frontal gyrus and the right middle temporal gyrus. The correlation analysis showed correlate between the decreased ReHo of right middle frontal gyrus in the DMD patients and picture completion of performance intelligence (P-value=0.012 r=0.579); the correlation between the decreased ReHo of the right middle temporal gyrus and information and arithmetic of verbal intelligence (P-value=0.047 r=0.353, P-value=0.035 r=0.499).
Conclusion: This study was to analyze the intra- and inter-regional synchronization of spontaneous activity in DMD patients by using resting state fMRI. In this study, we found decreased intra- and inter-regional synchronization in the bilateral sensorimotor cortex, bilateral middle frontal gyrus, bilateral middle temporal gyrus, bilateral inferior gyrus, anterior cingulate,posterior cingulate,bilateral angular gyrus, bilateral head of caudate nucleus, right hippocampus and bilateral cerebellum before multiple comparison correction. After multiple comparison correction, we found decreased ReHo in the right middle frontal gyrus and the right middle temporal gyrus in DMD patients comparing to controls. The results are similar to previous findings of decreased ReHo in bilateral sensorimotor areas in DMD patients. The results may be related to the changes of architectural and functional in bilateral sensorimotor cortex in DMD patients. The previous study about mdx showed decreased number and the cell packing density of labeled cortico-spinal neurons. The decreased intra-regional and inter-regional synchronization in the right middle frontal gyrus and the right middle temporal gyrus of DMD patients in the current results may be promoted the relationship with the decreased spontaneous activities of the central nervous system and intelligence in the patients. We believe that the future fMRI studies could help us to further understand the pathophysiology in the central nervous system of DMD patients.
方法:采用德国西门子1.5T MRI扫描机采集了28例DMD患儿(5.2~13.9岁)及34例相应年龄正常对照组(5.2~14.2岁)头颅静息fMRI的BOLD数据,扫描参数为TR/TE 2000/40 ms,共20层,轴面,层厚5.0mm,层间距1.0mm,FOV 220mm×220mm,翻转角90o ,矩阵64×64,扫描时间390 s(195个时间点)。然后用SPM5(Statistical Parametric Mapping,http://www.fil.ion.ucl.ac.uk/spm/)软件进行数据预处理,包括层面时间校正,头动校正,空间标准化(最小体素大小为3mm×3mm×3mm)。选择头动参数平动小于2mm,旋动小于2度的研究对象继续分析。用静息态fMRI软件包进行去线型趋势和低通滤波后,对预处理后数据计算全脑ReHo值,每个个体体素ReHo值除以个体大脑脑内均值得到ReHo图,然后进行高斯核(Gaussian kernel)的全宽半高(FWHM)为8mm的空间平滑以减低空间噪声。做双样本t检验比较两组脑内ReHo的差异,然后做校正来去除假阳性结果;最后将DMD患者ReHo减低的区域与智商之间做相关。
结果:结果显示23例DMD患者(8.4±2.1岁)与23例正常对照组(8.3±2.1岁)相比,进行两样本t检验结果显示,在多重比较校正前双侧感觉运动皮层、双侧额中回、双侧颞中回、双侧颞下回、扣带前后回、双侧角回、双侧尾状核头、右侧海马以及小脑内部的低频振荡信号的局部一致性活较对照组减低;在p<0.05, t>2.011,最小体积大于1971mm3校正后显示右侧额中回、右侧颞中回内部的低频振荡信号的局部一致性活动减低。相关分析结果显示DMD患儿右侧额中回ReHo值降低的脑区与操作智商中的填图存在相关关系(p=0.012 r=0.579),DMD患儿右侧颞中回ReHo值降低的脑区与语言智商中的知识及算术存在相关关系(p=0.047 r=0.353 p=0.035 r=0.499)。
结论:本研究将fMRI应用于DMD研究,分析静息状态下DMD患儿的脑内自发低频振荡信号特点。校正前双侧感觉运动皮层、双侧额中回、双侧颞中回、双侧颞下回、扣带前后回、双侧角回、双侧尾状核头、右侧海马以及小脑内部的低频振荡信号的局部一致性活较对照组减低;校正后DMD组右侧额中回及颞中回内ReHo值较正常对照组减低,此结果提示DMD患者右侧额中回及颞中回的大脑自发的低频振荡信号的同步一致性减低,也就是说DMD患者右侧额中回及颞中回静息状态下的兴奋性减低;并且这种兴奋性减低与认知存在相关关系。
Objective: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease affecting one in 3500 males born and is the second most commonly occurring genetically inherited disease in humans. DMD is characterized by the well-known progressive skeletal muscle weakness and different extent of cognitive impairment. DMD is lack of dystrophin protein which is normally localized in brain to cortical pyramidal neurons, hippocampus and cerebellar Pukinje cells, besides to skeletal muscle. Studies on the mdx model (an animal model of Duchenne muscular dystrophy), found the absolute number and the cell packing density of labeled cortico-spinal neurons were lower in mdx than in controls. To date, there have been only a few in vivo brain imaging studies on DMD patients. Previous brain magnetic resonance imaging (MRI) studies on DMD patients and mdx model did not find prominent structural abnormality in DMD subjects. A PET study on ten boys with DMD and 17 normal adults demonstrated decreased glucose metabolism in children with DMD in the right sensorimotor cortex. Abnormal brain activity was also supported by transcranial magnetic stimulation study, in which the DMD patient revealed decreased excitability in the primary motor cortex. Compared to PET, functional MRI (fMRI) has no radioactivity and is therefore more suitable for children studies. However, it has never been used to study the brain function of DMD patients. Low frequency (0.01-0.08 Hz) fluctuation (LFF) of the resting-state functional MRI signal may reflect the spontaneous brain activity. Resting-state fMRI study does not need cognitive tasks and is very easy to be implemented for children study. We have proposed a regional homogeneity (ReHo) approach to measure the synchronization of the LFF of resting-state fMRI signal in brain cortex in DMD patients and the correlation between it and intelligence.
Methods: In this study, 28 boys with DMD (age range, 5.2~13.9years) and 34 age-matched normal boys (age range, 5.2~14.2years) were included in this study. The imaging studies were done using a Siemens 1.5-Tesla scanner (Siemens, Germany). The rest-stating fMRI BOLD images were acquired axially using the following parameters: 2000/40 ms (TR/TE), 20 slices, 5.0/1.0 mm (thickness/gap), 220 mm×220 mm (FOV), 64×64 (resolution), 90o (flip angle). The resting-fMRI scanning session lasted for 390 s. MRI image preprocessing was conducted with Statistical Parametric Mapping (SPM5, (http://www.fil.ion.ucl.ac.uk/spm/), including slice-timing, motion correction, spatial normalization and resampling(3mm×3mm×3mm). Subjects with head motion larger than 2 mm maximum displacement in x, y, or z and 2oof any angular motion during the fMRI scan were excluded from further analysis. Then, linear trend was removed, and band-pass filter (0.01–0.08Hz) was computed to reduce low-frequency drift and high-frequency noise by using in-house software Resting-State fMRI Data Analysis Toolkit (REST, http://resting-fmri.sourceforge.net). ReHo analysis was performed for each participant and the ReHo of each voxel was divided by the individual global mean of ReHo within a brain-mask. Subsequently, the functional scans were spatially smoothed with a 8mm×8mm×8mm full width at half maximum Gaussian kernel to decrease spatial noise. The second-level random-effect two-sample t-tests were performed on the individual ReHo in a voxel-by-voxel manner in brain. Then do the correction to the brain which decreased ReHo in DMD patients compared to controls for exclude the false positive ones. The correlation analysis was computed between the area of the decreased ReHo and the intelligence in DMD patients.
Result: Compared with normal controls (8.4±2.1 years), boys with DMD (8.3±2.1 years) showed decreased ReHo in the bilateral sensorimotor cortex, bilateral middle frontal gyrus, bilateral middle temporal gyrus, bilateral inferior gyrus, anterior cingulate,posterior cingulate,bilateral angular gyrus, bilateral head of caudate nucleus, right hippocampus and bilateral cerebellum before multiple comparison correction, indicating decreased intra-regional synchronization of spontaneous activity. Clusters with a threshold at P<0.05, t>2.011 and cluster size more than 1971mm3 were considered as significant difference between the two groups after multiple comparison correction, such as right middle frontal gyrus and the right middle temporal gyrus. The correlation analysis showed correlate between the decreased ReHo of right middle frontal gyrus in the DMD patients and picture completion of performance intelligence (P-value=0.012 r=0.579); the correlation between the decreased ReHo of the right middle temporal gyrus and information and arithmetic of verbal intelligence (P-value=0.047 r=0.353, P-value=0.035 r=0.499).
Conclusion: This study was to analyze the intra- and inter-regional synchronization of spontaneous activity in DMD patients by using resting state fMRI. In this study, we found decreased intra- and inter-regional synchronization in the bilateral sensorimotor cortex, bilateral middle frontal gyrus, bilateral middle temporal gyrus, bilateral inferior gyrus, anterior cingulate,posterior cingulate,bilateral angular gyrus, bilateral head of caudate nucleus, right hippocampus and bilateral cerebellum before multiple comparison correction. After multiple comparison correction, we found decreased ReHo in the right middle frontal gyrus and the right middle temporal gyrus in DMD patients comparing to controls. The results are similar to previous findings of decreased ReHo in bilateral sensorimotor areas in DMD patients. The results may be related to the changes of architectural and functional in bilateral sensorimotor cortex in DMD patients. The previous study about mdx showed decreased number and the cell packing density of labeled cortico-spinal neurons. The decreased intra-regional and inter-regional synchronization in the right middle frontal gyrus and the right middle temporal gyrus of DMD patients in the current results may be promoted the relationship with the decreased spontaneous activities of the central nervous system and intelligence in the patients. We believe that the future fMRI studies could help us to further understand the pathophysiology in the central nervous system of DMD patients.
引文
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44 Brian D. Gonsalves,Itamar Kahn,Tim Curran,et al. Memory Strength and Repetition Suppression: Multimodal Imaging of Medial Temporal Cortical. Neuron, 2005, 47:751–76
1 Mehler MF. Brain dystrophin, neurogenetics and mental retardation. Brain Res Brain Res Rev, 2000, 32:277–307
2 Bresolin N, Castelli E, Comi GP, et al. Cognitive impairment in Duchenne muscular dystrophy. Neuromusc. Disord., 1994, 4(4):359–369
3 Lee JS, Pfund Z, Juhász C,et al. Altered regional brain glucose metabolism in Duchenne muscular dystrophy: a pet study. Muscle Nerve, 2002, 26: 506–512
4 Jueptner M, Weiller C. Does measurement of regional cerebral blood flow reflect synaptic activity? Implications for PET and fMRI. Neuroimage, 1995, 2:148–156
5 Tracey I, Scott RB, Thompson CH, et al. Brain abnormalities in Duchenne muscular dystrophy: phosphorus-31 magnetic resonance spectroscopy and neuropsychological study. Lancet, 1995, 345:1260–1264
6 Rae C, Scott B, Thompson CH, et al. Brain biochemistry in Duchenne muscular dystrophy: a 1H magnetic resonance and neuropsychological study. J Neurol Sci, 1998, 160:148–157
7 Anderson JL, Head SI, Rae C, et al. Brain function in Duchenne muscular dystrophy. Brain, 2002, 125:4–13
8 Prosser EJ, Murphy EG, Thompson MW. Intelligence and the gene or Duchenne muscular dystrophy. Arch Dis Child 1969, 44:221–30
9 Hinton VJ, Fee RJ, Goldstein EM, et al. Verbal and memory skills in maleswith Duchenne muscular dystrophy. Dev Med Child Neurol, 2007, 49(2): 123–128
10 Hinton VJ, De Vivo DC, Fee R, et al. Investigation of poor academic achievement in children with Duchenne muscular dystrophy. Learn Disabil Res Pract, 2004, 19(3):146–154
11 Hinton VJ, De Vivo DC,Nereo NE, et al. Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy. J Int Neuropsychol Soc, 2001, 7(1):45–54
12 Wicksell RK, Kihlgren M, Melin L, er al. Specific cognitive deficits are common in children with Duchenne muscular dystrophy. Child neurology, 2004, 46:154–159
13 Coletta MVD, Scola RH, Wiemes GRM, et al. Event-Related Potentials(P300) and neupopsychological aeeessment in boys exhibiting Duchenne muscular dystrophy. Arq Neuropsiquiatr, 2007, 65(1):59–62
14 Cotton SM, Voudouris NJ, Greenwood KM. Association between intellectual functioning and age in children and young adults with Duchenne muscular dystrophy: further results from a meta-analysis. Dev Med Child Neurol, 2005, 47:257–265
15 Marsh GG, Munsat TL. Evidence for early impairment of verbal intelligence in Duchenne muscular dystrophy. Archives of Disease in Childhood, 1974, 49:118
16 Billard C, Gillet P, Barthez MA, et al. Reading ability and processing in Duchenne muscular dystrophy and spinal muscular atrophy. Child neurology, 1998, 40:12–20