原发全面强直阵挛性癫痫脑结构损伤网络机制研究

发布时间：2018-06-01 06:01

本文选题：皮层厚度 + 丘脑　；参考：《南方医科大学》2015年硕士论文

【摘要】：[目的]以往研究表明原发全面强直阵挛性癫痫(idiopathic generalized epilepsy with generalized tonic colonic seizure, IGE-GTCS)存在丘脑及额叶皮层等灰质结构的萎缩,结构协变分析发现丘脑及皮层间的灰质形态学改变存在密切相关关系,认为癫痫丘脑-皮层网络是结构协变网络(structural covariance network, SCN)的基础,但目前缺乏直接的解剖学证据。本研究采用联合结构形态学的皮层厚度分析及弥散张量成像(diffusion tensor imaging,DTI)技术对IGE-GTCS患者大脑皮层形态学改变的网络组织模式进行研究,构建对应丘脑-皮层灰质SCN的白质纤维网络基础,探究IGE-GTCS脑结构形态学协同改变的病理生理机制。[材料和方法]66例IGE-GTCS患者和66例年龄、性别匹配的健康志愿者作为正常对照(healthy control, HC)纳入本研究。使用德国西门子Magnetom Trio 3.0T磁共振采集高分辨率T1结构数据及DTI数据。采用连接组计算机系统对高分辨率T1结构数据进行处理,通过图像降噪、颅骨剥离、皮层重建、图像配准得到受试者大脑皮层数据,平滑处理后供下一步使用。计算大脑平均皮层厚度,并利用丘脑模板分割得到每名受试者丘脑体积。采用两样本t检验比较IGE-GTCS组及HC组丘脑体积及个体平均皮层厚度差异。利用Surfstat软件,采用两样本t检验比较IGE-GTCS组及正常对照组皮层厚度脑图差异；采用相关分析分别构建患者及正常人的丘脑-皮层灰质SCN,并比较两组间差异,提取患者、正常人SCN及组间差异所涉及皮层脑区作为感兴趣区(region of interest, ROI)。利用PANDA软件包,对所有受试者DTI数据进行处理,采用确定性追踪的方法,追踪丘脑至前一步所提取的所有ROI间的白质纤维束,纤维数量(fibernumber, FN)大于1则认为两个节点间存在白质纤维连接,计算该纤维束平均各向异性分数(Fractional anisotropy, FA)。采用两样本t检验比较组间组间FN及FA值差异,及丘脑-皮层厚度相关脑区与丘脑-皮层白质纤维构成比差异。[结果]IGE-GTCS组丘脑体积(14793.68±1467.82mm3)明显小于HC组(15794.79±1500.38,P0.05)。IGE-GTCS组全脑平均皮层厚度(2.45±0.09mm)与HC组(2.47±0.09)差异无统计学意义(P=0.226)。两组间皮层厚度脑图比较结果：IGE-GTCS组较HC组双侧前扣带回、中央前回、眶额部皮层、颞极,及右侧中央后回等脑区皮层厚度下降；双侧后扣带回、楔前叶及枕中回皮层厚度增加。IGE-GTCS组中,大脑皮层厚度与丘脑体积呈正相关关系的脑区大体位于双侧颞中回、梭状回以及海马区；呈负相关相关的脑区大体位于双侧前扣带回、额中回及中央后回。在HC组中,大脑皮层厚度与丘脑体积呈正相关关系的脑区大体位于双侧颞上回及颞下回,左侧中央后回,右侧前扣带回、内侧额上回；呈负相关关系的脑区主要位于左侧楔叶、楔前叶,右侧枕中回、顶下小叶,双侧海马及海马旁回。IGE-GTCS患者相较于正常人,丘脑体积-皮层厚度相关趋势上升的脑区主要位于左侧舌回、楔叶、楔前叶、颞下回,右侧颞上回、中央前回、中央后回、海马及海马旁回。相关趋势下降的脑区主要位于双侧内侧前额叶及背外侧前额叶。丘脑-皮层IGE-GTCS组平均FA值降低的纤维束共有4束,分别由丘脑连至左侧海马及海马旁回,右侧海马及海马旁回,右侧岛叶,左侧边缘叶及舌叶；其中IGE-GTCS组丘脑理解左侧边缘叶及舌叶纤维束FN值较HC组降低。[结论]IGE-GTCS患者在疾病状态长期影响下,发生了丘脑-皮层灰质SCN重塑,表现为丘脑及以额叶为主的大脑皮层萎缩,以顶、枕叶为主大脑皮层厚度增加,并且额叶与丘脑的相关趋势降低。而白质纤维网络作为解剖学基础,在一定程度上介导了IGE-GTCS灰质SCN的重塑。IGE-GTCS患者部分纤维束传导性下降,则进一步提示丘脑-皮层白质纤维网络损伤可能具有特异性,说明癫痫疾病导致的脑网络病理生理改变可能存在更复杂的生物学机制。[目的]：IGE-GTCS丘脑-皮层SCN分析发现,患者丘脑-皮层灰质形态学萎缩存在密切相关关系,提示癫痫疾病状态影响下特异脑区灰质结构的塑形。但是,这种脑区间灰质结构改变的因果关系,以及其与癫痫疾病进程之间的关系尚不明确。本研究引入Granger因果网络分析技术,观察随着癫痫疾病的进展,丘脑癫痫源区灰质萎缩对其他脑区结构改变的影响。[材料和方法]101名IGE-GTCS患者被纳入本研究,另外纳入了101名年龄、性别匹配的健康志愿者作为HC。使用德国西门子Magnetom Trio 3.0T磁共振采集高分辨率T1结构数据。采用DPARSF软件对高分辨率T1结构数据进行预处理,通过计算机算法进行配准、分割、调制及平滑处理后得到每名受试者的灰质结构脑图。采用两样本t检验对预处理后的灰质图像进行组间比较。并对IGE-GTCS组受试者全脑灰质与病程进行基于体素的相关分析。根据组间两样本t检验的结果,提取IGE-GTCS组特异性脑损伤区域为ROI。将IGE-GTCS组所有被试按病程由短到长排序,病程相同的患者则按发作频率由低到高排序。以上一步提取特异性脑损伤区域为ROI,以病程为时间序列,采用基于系数的Granger分析方法,将ROI时间序列作为x(n),全脑每一个体素的时间序列作为y(n),计算Fx-y,最终得到ROI到全脑的Granger因果效应图。[结果]与HC组比较,IGE-GTCS组出现以右侧丘脑、岛叶,双侧内侧前额叶、眶额部皮层及小脑半球为主的灰质体积下降,未发现灰质体积增加脑区。IGE-GTCS患者中与病程呈负相关关系的脑区主要有双侧丘脑、海马及海马旁回、岛叶、中央旁小叶、补充运动区及小脑半球,未发现正相关关系脑区。根据两样本t检验结果,以双侧丘脑为ROI, Granger因果效应分析结果显示,IGE-GTCS患者丘脑主要正向驱动双侧前扣带回、眶额部皮层、楔前叶、顶下小叶、舌回、岛叶、颞下回、尾状核、小脑半球；主要负向驱动双侧额叶、顶叶及颞叶的部分背外侧皮层及右侧小脑后叶。[结论]IGE-GTCS患者存在丘脑、额叶为主的脑结构损伤,表现为灰质体积下降,并随着病程的延长,丘脑-皮层环路脑结构的损伤趋于严重。这种丘脑与额叶之间特殊的丘脑-皮层环路异常,可能导致了IGE-GTCS患者的意识损害。而额叶等脑区的损伤继发于丘脑损伤之后,提示IGE脑损害首先作用于丘脑。IGE-GTCS患者特定脑结构的损伤,及相关连接效应的异常,将帮助我们更进一步理解IGE-GTCS的起源及进展机制,有望对IGE的靶向治疗研究提供形态学证据。[目的]:IGE-GTCS患者常规影像学检查无法发现明显局灶性结构异常,缺乏手术指征,以长期口服抗癫痫药物(antiepileptic drugs, AEDs)治疗为主。长期乃至终身服用AEDs,易造成耐药及肝肾功能损伤。另一方面,AEDs在抑制神经元异常放电的同时,可能造成意识损伤。本研究采用基于体素的形态学分析方法,对口服丙戊酸(valproic acid, VPA)的IGE-GTCS患者进行研究,探究VPA对脑灰质结构的影响,为其药理作用的生物学机制提供神经影像学证据。[材料和方法]19名服用VPA治疗的IGE-GTCS患者,19名未服药患者被纳入本研究及19名健康志愿者纳入本研究。使用德国西门子Magnetom Trio 3.0T磁共振采集高分辨率T1结构数据。采用DPARSF软件对高分辨率T1结构数据进行预处理,通过计算机算法进行配准、分割、调制及平滑处理后得到每名受试者的灰质结构脑图。采用方差分析对预处理后的灰质图像进行比较。针对服药组患者,将服药时间与全脑灰质体积进行体素依赖的相关分析,将性别、年龄纳为协变量,排除对结果干扰。考虑到病程可能是一个混淆因素,可能影响相关分析结果,将性别、年龄及病程均纳为协变量进行回归,再次将服药时间与全脑灰质体积进行体素依赖的相关分析。[结果]两组患者双侧额叶体积较正常对照组下降。服药组患者脑灰质体积增加的区域大致呈对称性分布,以双侧背外侧额叶、尾状核及小脑半球为主,同时双侧中央后回灰质体积萎缩。当只将性别、年龄纳为协变量时,双侧丘脑、壳核与服药时间呈正相关关系,双侧小脑后叶与病程呈负相关关系。当将病程、性别、年龄均纳为协变量时,双侧丘脑、壳核、岛叶与服药时间呈正相关关系,双侧小脑前叶与病程呈负相关关系。[结论]采用VBM的方法发现服用VPA的GTCS病人较未服药病人,出现以双侧背外侧额叶、尾状核及小脑半球为主的脑区灰质体积增加,并且随着服药时间的延长,双侧壳核、丘脑体积增加,而这些脑区跟意识控制及运动控制等密切相关,也是VPA的重要作用靶区,提示可能由于以VPA为主的AEDs抑制了痫样放电或者癫痫临床发作,从而延缓了相应脑区的亚临床损伤。
[Abstract]:[Objective] the previous study showed that the idiopathic generalized epilepsy with generalized tonic colonic seizure, IGE-GTCS existed in the gray matter structure of the thalamus and frontal cortex. The structural covariant analysis found that there was a close correlation between the gray matter morphologic changes between the thalamus and the cortex. The brain cortical network is the basis of the structural covariance network (SCN), but it lacks direct anatomical evidence at present. This study uses the cortical thickness analysis of the joint structural morphology and the diffusion tensor imaging (DTI) technique to organize the morphological changes of the cerebral cortex of the patients with IGE-GTCS. The basis of the white matter fiber network corresponding to the thalamus cortical gray matter SCN was constructed to explore the pathophysiological mechanism of the IGE-GTCS brain structure morphological synergetic change. [materials and methods]66 cases IGE-GTCS patients and 66 age, sex matched healthy volunteers as normal controls (healthy control, HC) were included in this study. The high resolution T1 structure data and DTI data were collected by the Magnetom Trio 3.0T magnetic resonance. The high resolution T1 structure data were processed by the connection group computer system. The brain cortical data of the subjects were obtained by image denoising, skull peeling, cortical reconstruction and image registration, and then used for the next step after smoothing treatment. The average cerebral cortex thickness was calculated. The volume of thalamus was obtained by dividing the thalamus template. The difference of thalamus volume and average cortical thickness between group IGE-GTCS and HC group was compared by two sample t test. Using Surfstat software, two samples of t test were used to compare the difference of cerebral cortex thickness between the IGE-GTCS group and the normal control group, and the patients were constructed by correlation analysis. And the normal human thalamocortical gray matter SCN, and compare the differences between the two groups, the extraction patients, the normal people SCN and the difference between the groups involved in the cortex brain region as the region of interest (region of interest, ROI). Using PANDA software package, all subjects DTI data processing, using the method of true qualitative tracking, tracking the thalamus to the previous step extraction of the extraction The white matter fiber bundles and the number of fibers (fibernumber, FN) were greater than 1 between the ROI and the white matter fiber connections between the two nodes. The average anisotropy fraction of the fiber bundles was calculated (Fractional anisotropy, FA). The difference between the FN and FA values among the groups was compared with the two sample t test, and the thalamic cortex thickness related brain area and the thalamus cortical white matter fiber were compared. [results of group]IGE-GTCS, the volume of thalamus (14793.68 + 1467.82mm3) was significantly smaller than that of group HC (15794.79 + 1500.38, P0.05), the average cortical thickness of group.IGE-GTCS (2.45 + 0.09mm) and HC group (2.47 + 0.09) had no statistical significance (P=0.226). The comparison between the two groups of the mesothelial thickness of the mesothelial layer of the two group: the IGE-GTCS group was compared with the HC group bilateral anterior cingulate gyrus, In the precentral gyrus, the cortical thickness of the orbital frontal cortex, the temporal pole, and the right posterior central gyrus decreased, and the thickness of the posterior cingulate gyrus, the anterior cineus and the middle occipital gyrus increased in the.IGE-GTCS group. The cerebral cortex, which had a positive correlation with the volume of the thalamus, was generally located in the middle temporal gyrus, fusiform gyrus, and the hippocampus. In the HC group, the cerebral cortex, which has a positive correlation with the volume of the thalamus, is generally located in the bilateral superior temporal and inferior temporal gyrus, the left posterior central gyrus, the right anterior cingulate gyrus, the medial frontal gyrus, and the negative correlation of the brain area in the left cuneate, the anterior wedge, the right side, and the right side. Occipital gyrus, inferior parietal lobule, bilateral hippocampal and paraphippocampal.IGE-GTCS patients were compared to normal people. The brain areas of the thalamus volume cortical thickness increased mainly in the left lingual gyrus, wedge, pretemporal gyrus, right temporal gyrus, the anterior central gyrus, the posterior central gyrus, the hippocampus and the parahippocampal gyrus. The average FA value of the medial prefrontal lobe and the dorsolateral prefrontal lobe in the thalamus IGE-GTCS group had 4 bundles, including the thalamus to the left hippocampus and the parahippocampal gyrus, the right hippocampus and the parahippocampal gyrus, the right Island leaf, the left edge leaf and the tongue leaf, and the IGE-GTCS group thalamus understood that the FN value of the left marginal lobe and the ligule fiber bundle was lower than that of the HC group. [Conclusion: [Conclusion]]IGE-GTCS patients have the thalamocortical gray matter SCN remodeling under the long-term influence of the disease, showing the atrophy of the thalamus and the frontal cortex. The thickness of the cerebral cortex increases with the top and the occipital lobe, and the correlation between the frontal lobe and the thalamus is reduced. The decrease of partial fibrous conduction in the reshaped.IGE-GTCS patients with IGE-GTCS gray matter SCN may further suggest that the damage of the thalamic cortex white matter fiber network may be specific, indicating that the pathophysiological changes in the brain network caused by epilepsy may have more complex biological mechanisms. [Objective]:IGE-GTCS thalamic - cortical SCN analysis found that There is a close correlation between the morphological atrophy of the thalamus cortical gray matter in the patient, which suggests that the state of the epileptic state affects the shape of the gray matter structure in the specific brain region. However, the causal relationship between the change of the gray matter structure and the relationship with the process of epilepsy is not clear. This study introduced the Granger causality network analysis technique to observe. With the progress of epilepsy, the effect of gray matter in the source area of the thalamus on the structural changes in other brain regions. [materials and methods]101 IGE-GTCS patients were included in this study, and 101 age, sex matched healthy volunteers were used as HC. to collect high resolution T1 structure data using German SIEMENS Magnetom Trio 3.0T MRI. The DPARSF software is used to preprocess the high resolution T1 structure data. The gray matter structure of each person is obtained after registration, segmentation, modulation and smoothing by computer algorithm. Two sample t tests are used to compare the pre processed gray matter images. The whole brain gray matter and the course of disease in the IGE-GTCS group are based on the basis of comparison. The correlation analysis of voxel. According to the results of the two sample t test among the groups, the specific brain damage area of group IGE-GTCS was extracted by ROI.. All the subjects in group IGE-GTCS were sorted from short to long in the course of disease. The patients with the same course of disease were sorted from low to high according to the frequency of attack, and the specific brain injury area was ROI, and the course of disease was time series, Using the Granger analysis method based on coefficient, the time series of ROI was used as X (n) and the time series of each individual element in the whole brain was used as y (n), and Fx-y was calculated. Finally, the Granger causality effect of ROI to the whole brain was obtained. [results] the IGE-GTCS group appeared in the right thalamus, the insula, the bilateral medial prefrontal lobe, the orbital frontal cortex and the cerebellar hemisphere. The volume of gray matter decreased, and there was no increase in the volume of gray matter in the brain area of.IGE-GTCS patients with negative correlation with the course of the disease. There were bilateral thalamus, hippocampus and parahippocampal gyrus, insula, paracentral lobule, supplemental motor area and cerebellar hemisphere, and no positive correlation was found in the brain region. The root of the two samples was t test, and bilateral thalamus was ROI, Granger The results of causal effect analysis showed that the main positive drive of the thalamus in IGE-GTCS patients was bilateral anterior cingulate gyrus, orbital frontal cortex, anterior lobe, lower lobule, lingual gyrus, insula, inferior temporal gyrus, caudate nucleus, cerebellar hemisphere; main negative lateral frontal cortex, partial dorsolateral cortex of the parietal and temporal lobe and right posterior lobe of the cerebellum. [conclusion]IGE-GTCS patients have hillock. Brain, frontal lobe, mainly brain structural damage, manifested as gray matter volume, and as the duration of the disease prolonged, the damage to the brain structure of the thalamus cortical loop tends to be serious. This special thalamus cortical loop between the thalamus and frontal lobes may lead to the impairment of consciousness in IGE-GTCS patients. It is suggested that IGE brain damage first acts on the damage of specific brain structure in the.IGE-GTCS patients of thalamus and the abnormal connection effect, which will help us to further understand the origin and mechanism of IGE-GTCS and provide morphological evidence for the study of target therapy for IGE. [Objective]: the routine imaging examination of IGE-GTCS patients can not find the obvious Bureau. The focal structural abnormalities, lack of operation indications, are mainly treated with long-term oral antiepileptic drugs (antiepileptic drugs, AEDs). Long-term and lifelong use of AEDs may cause resistance and liver and kidney function damage. On the other hand, AEDs may cause conscious damage while inhibiting abnormal discharge of neurons. This study uses Morphin based morphological credits. Analysis method, study the IGE-GTCS patients with valproic acid (VPA), explore the effect of VPA on the structure of brain gray matter, and provide neuroimaging evidence for the biological mechanism of its pharmacological action. [materials and methods,]19 names of IGE-GTCS patients who were treated with VPA, were included in this study and 19 healthy volunteers. In this study, high resolution T1 structure data are collected using the German SIEMENS Magnetom Trio 3.0T magnetic resonance. DPARSF software is used to preprocess the high resolution T1 structure data, and the gray structure brain maps of each person are obtained after registration, segmentation, modulation and smoothing by computer algorithm. To compare the gray matter images. According to the correlation analysis between the time of taking medicine and the volume of total gray matter in the whole brain, the sex and age are considered as covariate, and the interference of the results is excluded. In the two groups, the volume of bilateral frontal lobe was lower than that of the normal control group. The area of the increased volume of cerebral gray matter in the patients of the drug group was roughly symmetrical, with bilateral dorsolateral frontal lobes, caudate nucleus and cerebellar hemisphere dominated, and bilateral posterior central back ash. The bilateral thalamus and the putamen were positively correlated with the time of taking medicine, and the posterior lobe of bilateral cerebellum had a negative correlation with the course of the disease. The bilateral thalamus, the putamen, the island leaf were positively correlated with the time of taking medicine, and the bilateral anterior lobe of the cerebellum was negatively correlated with the course of the disease. [Conclusion] [Conclusion] the VBM method was used to find that the volume of gray matter in the brain region of the GTCS patients taking VPA was increased in bilateral dorsolateral frontal lobes, caudate nucleus and cerebellar hemisphere, and the volume of bilateral putamen and thalamus increased with the time of taking medicine, and these brain areas were closely related to consciousness control and exercise control. It is also an important target area for VPA, suggesting that VPA based AEDs may inhibit epileptiform discharge or epileptic clinical seizures, which may delay subclinical injury in the corresponding brain regions.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R742.1

【共引文献】