發(fā)布時(shí)間：2018-04-05 15:06

  本文選題：腦皮層厚度　切入點(diǎn)：血流灌注　出處：《第四軍醫(yī)大學(xué)》2012年博士論文

【摘要】：創(chuàng)傷后應(yīng)激障礙(Post-traumatic Stress Disorder, PTSD)指由突發(fā)性、威脅性或?yàn)?zāi)難性事件引起人體延遲出現(xiàn)并長期持續(xù)存在的精神障礙。常常表現(xiàn)為再度體驗(yàn)創(chuàng)傷，易激惹和回避行為，并常伴有睡眠障礙、注意力難以集中、警覺性過高、過度驚嚇反應(yīng)等癥狀。大部分人在創(chuàng)傷后數(shù)天至六個(gè)月內(nèi)發(fā)病，經(jīng)過一段時(shí)間調(diào)整后都可以恢復(fù)正常。據(jù)報(bào)道，在美國，約有3.6%的人曾患有PTSD，而其中7.8%的患者終身患病。引發(fā)創(chuàng)傷的事件包括戰(zhàn)爭、暴力犯罪、性侵害、交通事故、失業(yè)、離婚、自然災(zāi)害等，PTSD患者多為直接或間接接觸創(chuàng)傷事件的幸存者、目擊者和救援者。有研究表明，不同類型的創(chuàng)傷可能影響PTSD嚴(yán)重程度和癥狀表現(xiàn)。目前，PTSD已成為流行病學(xué)、心理學(xué)、社會(huì)醫(yī)學(xué)等多個(gè)學(xué)科的研究熱點(diǎn)。尤其是，近年來，礦難、地震、海嘯、恐怖襲擊頻發(fā)，這些突發(fā)的災(zāi)難性事件所引起的PTSD越來越受到人們的關(guān)注。 目前，各國科學(xué)家已通過遺傳、神經(jīng)、生化、內(nèi)分泌、心理及社會(huì)等多方面的研究，對(duì)PTSD病理、病因?qū)W機(jī)制進(jìn)行了探討，但具體機(jī)制仍不甚明晰。同時(shí)，由于對(duì)介導(dǎo)PTSD癥狀的大腦環(huán)路缺乏清晰的認(rèn)識(shí)，目前仍未有針對(duì)PTSD的有效治療方法。 近年來，影像醫(yī)學(xué)的發(fā)展為腦部疾病的研究提供了新的手段。特別是磁共振成像(Magnetic Resonance Imaging, MRI)已逐漸從結(jié)構(gòu)成像擴(kuò)展到功能成像，從單模態(tài)成像發(fā)展到多模態(tài)成像。從多方面來分析患者的結(jié)構(gòu)變化、血流灌注、功能代謝和功能連接等信息，將MRI的多種模態(tài)相結(jié)合，并應(yīng)用到腦部疾病的診斷和評(píng)價(jià)，是目前的研究熱點(diǎn)和難點(diǎn)�，F(xiàn)已有研究通過影像手段，初步發(fā)現(xiàn)了PTSD患者在腦部結(jié)構(gòu)和功能方面不同程度的病理性損害。 對(duì)于精神類疾病，在疾病引發(fā)實(shí)質(zhì)性病變之前，往往會(huì)先出現(xiàn)功能代謝、血流灌注和功能區(qū)形狀(如腦皮層厚度)的改變。因此，對(duì)腦皮層厚度和腦血流的分析往往可以檢測出疾病發(fā)生早期對(duì)人體結(jié)構(gòu)和功能的影響。各向異性分?jǐn)?shù)(fractional anisotropy，F(xiàn)A)和表面彌散系數(shù)(apparent diffusion coefficient,ADC)可以有效反映微結(jié)構(gòu)及分子水平的病理、生理學(xué)改變，能夠檢測早期的病變引起的腦損傷。但目前，尚未見基于MRI影像，對(duì)礦難創(chuàng)傷后PTSD所引起腦皮層厚度、血流及DTI指標(biāo)變化的研究。 本研究針對(duì)上述問題，利用礦難幸存者的MRI結(jié)構(gòu)、灌注和彌散張量成像(Diffusion Tensor Imaging, DTI)數(shù)據(jù)，進(jìn)行腦皮層厚度、腦血流及DTI指標(biāo)分析，檢測礦難創(chuàng)傷后早期PTSD(MRI掃描時(shí)間為事故發(fā)生后6個(gè)月)對(duì)腦部結(jié)構(gòu)和功能的影響；并進(jìn)一步研究這些結(jié)構(gòu)和功能的變化與PTSD癥狀的嚴(yán)重程度的相關(guān)關(guān)系及相關(guān)程度。 本研究被試者為2007年河南省三門峽市東風(fēng)井，因河床水通過采空區(qū)涌入井下，而被困1400米深地下72小時(shí)的幸存者。參加本研究的20名幸存者中10人滿足DSM-IV中描述的PTSD指標(biāo)，為PTSD組；另外10人不滿足，為非PTSD組。PTSD病情的嚴(yán)重程度通過創(chuàng)傷后應(yīng)激障礙量表(Clinician-administered PTSD Scale, CAPS)進(jìn)行評(píng)價(jià)。 本研究主要包含以下研究內(nèi)容： 1、腦皮層厚度的準(zhǔn)確測量及分析 在已有研究的基礎(chǔ)上，本文構(gòu)建了基于拉普拉斯方程的腦皮層三維厚度檢測流程和方法，提高了計(jì)算速度和測量的準(zhǔn)確性。首先考慮到DARTEL標(biāo)準(zhǔn)化算法對(duì)腦部細(xì)微結(jié)構(gòu)進(jìn)行配準(zhǔn)具有更高的準(zhǔn)確性，檢測細(xì)微結(jié)構(gòu)的異常變化具有更高的敏感性，本研究中利用VBM-DARTEL工具包對(duì)MRI的T1序列圖像進(jìn)行預(yù)處理，得到分割后的腦灰質(zhì)、白質(zhì)和腦脊液數(shù)據(jù)。并在預(yù)處理結(jié)果的基礎(chǔ)上，采用改進(jìn)的基于拉普拉斯偏微分方程的三維厚度測量方法測量腦皮層厚度，該方法通過在腦皮層內(nèi)部構(gòu)建勢能場，并利用垂直等勢面場線的長度來定義皮層厚度，使內(nèi)、外表面具有唯一可逆對(duì)應(yīng)點(diǎn)，避免了最短歐氏距離引起的測量誤差，是目前腦皮層厚度測量最準(zhǔn)確、有效的測量方法之一。但由于大腦腦溝區(qū)域的復(fù)雜形態(tài)變化和數(shù)據(jù)采集過程中各種因素的影響，容易造成分割誤差。因此，在測量腦皮層三維厚度之后，采用腦溝厚度校正方法對(duì)可能存在誤分割的腦溝區(qū)域進(jìn)行校正，并根據(jù)校正后的灰質(zhì)圖像，重新測量腦皮層厚度，從而得到更準(zhǔn)確的三維厚度值，并構(gòu)建三維腦皮層厚度圖像。 在構(gòu)建腦皮層結(jié)構(gòu)和三維厚度圖像的基礎(chǔ)上，利用SPM對(duì)兩組間的體積及皮層厚度進(jìn)行統(tǒng)計(jì)學(xué)分析。由于在人口學(xué)特征分析中，兩組除年齡外，其他特征都不存在統(tǒng)計(jì)學(xué)差異，因此，本研究以年齡作為協(xié)變量，通過兩樣本t檢驗(yàn)進(jìn)行分析，未發(fā)現(xiàn)兩組的體積存在統(tǒng)計(jì)學(xué)差異的區(qū)域。但對(duì)腦皮層厚度的統(tǒng)計(jì)分析表明，較非PTSD組，PTSD組在左腦頂葉、右腦額下回和右腦海馬旁回區(qū)域腦皮層厚度明顯變薄。 為了探索PTSD嚴(yán)重程度與腦皮層厚度間的相關(guān)關(guān)系，本研究采用穿過厚度變薄區(qū)域的場線上的所有體素，作為感興趣區(qū)域(Regional of Interest,ROI)。通過ROI分析發(fā)現(xiàn)，PTSD組的10名被試者的右腦額下回的平均厚度與PTSD癥狀的嚴(yán)重程度(CAPS值)明顯負(fù)相關(guān)。 2、腦血流(Cerebral Blood Flow, CBF)的準(zhǔn)確測量及分析 通過灌注成像掃描序列的篩選，本研究使用無創(chuàng)、標(biāo)記效率高的脈沖式動(dòng)脈自旋標(biāo)記(Pulsed Artery Spin Labeling, PASL)掃描序列來分析礦難后早期PTSD患者的CBF變化。為此，，本研究在已有研究的基礎(chǔ)上，構(gòu)建了PASL序列CBF準(zhǔn)確測量方法。 首先，由于PASL序列圖像成像速度快，圖像分辨率較低，本研究利用SPM分別對(duì)PASL序列圖像和T1序列結(jié)構(gòu)圖像進(jìn)行預(yù)處理，并將結(jié)構(gòu)像信息應(yīng)用到功能像當(dāng)中，提高標(biāo)準(zhǔn)化的準(zhǔn)確性和功能圖像的分辨率。經(jīng)過預(yù)處理后，圖像分辨率有所提高，但仍受到部分容積效應(yīng)(Partial Volume Effect,PVE)的嚴(yán)重影響。為此，本研究首次利用PASL序列的時(shí)間信息，構(gòu)建了PASL時(shí)間序列，并使用MAP-EM算法分析時(shí)間序列中每個(gè)體素點(diǎn)中的混合組織參數(shù)，并結(jié)合CBF的測量方法，在對(duì)圖像進(jìn)行部分容積校正的基礎(chǔ)上，獲得更準(zhǔn)確的CBF分布圖。 獲得CBF分布圖后，通過分析，未發(fā)現(xiàn)兩組的平均CBF統(tǒng)計(jì)學(xué)差異。但考慮到年齡對(duì)CBF的影響，本研究以年齡作為協(xié)變量，采用SPM進(jìn)行兩樣本t檢驗(yàn)，發(fā)現(xiàn)PTSD組，較非PTSD組，在右腦額葉區(qū)域CBF明顯增高。但通過ROI分析，未發(fā)現(xiàn)PTSD組在該區(qū)域的平均CBF值與PTSD癥狀嚴(yán)重程度(CAPS值)存在相關(guān)關(guān)系。 3、DTI數(shù)據(jù)分析 本研究使用DTI Studio和SPM聯(lián)合分析了礦難幸存者的DTI序列數(shù)據(jù)，發(fā)現(xiàn)PTSD組，較非PTSD組，在右腦側(cè)腦室、右腦梭狀回、右腦顳上回和右腦顳中回區(qū)域FA值明顯降低，在右腦顳上回和右腦胼胝體區(qū)域ADC值明顯增高。但通過ROI分析，未發(fā)現(xiàn)PTSD組在這些區(qū)域的平均FA值或ADC值與PTSD癥狀嚴(yán)重程度(CAPS值)存在相關(guān)關(guān)系。這可能是由于PTSD早期引起的結(jié)構(gòu)及功能變化不明顯，F(xiàn)A和ADC指標(biāo)尚無顯著變化所導(dǎo)致的。 4、小結(jié) 本研究首先構(gòu)建了基于拉普拉斯方程的腦皮層厚度檢測流程和方法，提高了計(jì)算速度和測量的準(zhǔn)確性；考慮到灌注成像的分辨率低及PVE對(duì)CBF測量的影響，將基于MAP-EM算法的部分容積校正理論與CBF測量方法相結(jié)合，得到更準(zhǔn)確的CBF分布圖，上述方法為研究神經(jīng)系統(tǒng)或腦部疾病引起的腦皮層厚度和血流變化提供了有效的手段。 基于提出的方法，本研究對(duì)經(jīng)歷礦難的20名幸存者構(gòu)成的PTSD組和對(duì)照組的腦皮層厚度和CBF分布進(jìn)行了統(tǒng)計(jì)分析，發(fā)現(xiàn)了多個(gè)厚度或CBF存在差異的的區(qū)域。同時(shí)，使用DTI Studio和SPM聯(lián)合分析了DTI序列數(shù)據(jù)，發(fā)現(xiàn)了多個(gè)FA和ADC值異常的腦區(qū)。以上結(jié)果一方面可為進(jìn)一步理解PTSD病理、病因?qū)W機(jī)制奠定基礎(chǔ)，另一方面，提出的區(qū)域或指標(biāo)，有望進(jìn)一步成為早期PTSD臨床診斷和評(píng)價(jià)的依據(jù)。
[Abstract]:Posttraumatic stress disorder (Post-traumatic Stress, Disorder, PTSD) refers to a sudden, threatening or catastrophic events caused by human mental disorders in delayed and long-term existence. Is often re experience the trauma, irritability and avoidance behavior, and often accompanied by sleep disorders, difficulty concentrating, high alertness, excessive shock the reaction and other symptoms. Most of the people in a few days to six months after trauma in the onset, after a period of time after the adjustment can be restored to normal. It is reported that in the United States, about 3.6% of people who suffer from PTSD, of which 7.8% of the patients. The lifetime risk for incident triggered trauma including war, violence, sexual assault, traffic accident, unemployment, divorce, natural disasters, PTSD patients are direct or indirect contact with trauma survivors, witnesses and rescuers. Studies have shown that different types of trauma may influence the severity of PTSD And symptomatic performance. At present, PTSD has become a research hotspot in many disciplines such as epidemiology, psychology, social medicine and so on. Especially in recent years, PTSD caused by disasters, earthquakes, tsunamis and terrorist attacks has been more and more concerned.
At present, many scientists have been using genetic, biochemical, neural, endocrine, research on psychological and social aspects of PTSD pathology, etiology, mechanism is discussed, but the mechanism is not very clear. At the same time, because of the symptoms of PTSD mediated brain circuits lack a clear understanding, at present there is no effective treatment for PTSD.
In recent years, the development of medical imaging provides a new tool for the study of brain diseases. Especially, magnetic resonance imaging (Magnetic Resonance, Imaging, MRI) has gradually changed from structure imaging is extended to functional imaging, from single modality imaging to multi modality imaging. To analyze the structure changes of patients with blood perfusion function from several aspects. The metabolic and functional connectivity information, combine multi modality of MRI, and applied to the diagnosis and evaluation of brain diseases, is a research hotspot and difficulty at present. We have studied by imaging techniques, preliminary findings in patients with PTSD in brain structure and function of different degree of pathological damage.
For mental illness, before causing substantive changes in the disease, often appear before the function of metabolism, shape perfusion and functional areas (such as cortical thickness) change. Therefore, the analysis of the thickness and blood flow to the brain cortex can often be detected early influence to the human body structure and function of the anisotropic disease. Score (fractional anisotropy, FA) and apparent diffusion coefficient (apparent diffusion, coefficient, ADC) can effectively reflect the pathological microstructure and molecular level, physiological changes, can cause brain damage, early detection of the lesions. But at present, has not yet been based on MRI image, the thickness of the mine caused by cerebral cortex PTSD after trauma. Study on the changes of blood flow and DTI index.
Based on the above problems, the use of MRI structure mining survivors, perfusion and diffusion tensor imaging (Diffusion Tensor, Imaging, DTI) data of cortical thickness analysis, cerebral blood flow and DTI index, early detection of PTSD mine after trauma (MRI scan time was 6 months after the accident) effects on brain structure and function the degree of correlation; and the severity of changes and further study of these structures and functions with PTSD symptoms.
The research subjects for Dongfeng well Sanmenxia city of Henan province in 2007, because the river water through the mined out area into the underground, trapped 1400 meters deep underground for 72 hours. The survivors of the 20 survivors of 10 people participated in this study meet the PTSD criteria described in DSM-IV and PTSD group; the other 10 were not satisfied the PTSD severity for non PTSD group.PTSD severity scale (Clinician-administered PTSD Scale, CAPS) were evaluated.
The main contents of this study are as follows:
1, accurate measurement and analysis of cerebral cortex thickness
On the basis of the existing research, this paper constructs the 3D cortical thickness detection method and process based on the Laplasse equation, the computation speed and improves the accuracy of measurement. Firstly, considering the DARTEL standard algorithm has a higher accuracy on the fine structure of the brain registration, detection of abnormal changes in the fine structure has higher sensitivity, T1 image sequence of MRI pretreated by VBM-DARTEL kit in this study, obtained after segmentation of brain gray matter, white matter and cerebrospinal fluid data. And based on the pretreatment result, the improved thickness measurement method based on 3D Laplasse partial differential equation of cortical thickness measurement, the method by constructing the potential field in the cerebral cortex inside, and the vertical equipotential surface field line length to define the cortical thickness, the inner, outer surface has only reversible corresponding points and avoid the shortest Euclidean distance The measurement error caused by the cortical thickness measurement is the most accurate, one of the effective measures. But due to the influence of various brain sulcal regions complex morphological changes and factors in the process of data collection, easy to cause the segmentation error. Therefore, after measuring the cortical thickness of three-dimensional, by sulcus thickness correction method for possible correction of sulcal regions segmentation error, and according to the gray image after correction, re measurement of cortical thickness, so as to obtain more accurate values of 3D thickness, cortical thickness and the construction of three-dimensional images.
In the foundation of the structure of the cortex thickness and three-dimensional image, the statistical analysis on the volume and cortical thickness between the two groups using SPM. The analysis on the demographic characteristics of the two groups except for age, other characteristics have no significant differences, therefore, in this study, age as a covariate, through the analysis of two samples t test, no significant differences between the two groups of the volume of the region found. But the statistics of cortical thickness analysis showed that compared with non PTSD group, PTSD group in the left parietal lobe, right inferior frontal gyrus and right parahippocampal gyrus regional cortical thickness was significantly thinner.
In order to explore the relationship between PTSD and the severity of cortical thickness, this study used across the thickness of the field line all voxels as region of interest (Regional of, Interest, ROI). The ROI analysis showed that the severity of the average thickness of the PTSD group of 10 subjects of right frontal gyrus the symptoms of PTSD (CAPS) was significantly negative correlation.
2, accurate measurement and analysis of cerebral blood flow (Cerebral Blood Flow, CBF)
By screening the perfusion imaging scanning sequence, this study using noninvasive, pulsed arterial spin labeling labeling efficiency high (Pulsed Artery Spin Labeling, PASL CBF) changes in patients with early PTSD scan sequence analysis after the accident. Therefore, the study on the basis of existing research, construct the accurate measurement method of PASL sequence CBF.
First, the imaging speed of PASL image sequence, image resolution is low, the research on PASL sequence structure image and T1 image sequences are processed by SPM, and will be applied to function like structures like information, improve the standardization and accuracy of image resolution. After preprocessing, image resolution improved, but is still subject to partial volume effect (Partial Volume, Effect, PVE) is seriously affected. Therefore, this study is the first to use the time information of PASL sequences, constructed the PASL time series, hybrid organization parameters using MAP-EM algorithm and analysis of time series in each voxel point, combined with the method of CBF. Based on the partial volume correction of the image, get the CBF distribution more accurately.
CBF map, through the analysis, the average CBF was not different between two groups. But considering the influence of age on CBF, based on the age as a covariate, using SPM two sample t test group PTSD, compared with non PTSD group, in the right frontal lobe area increased obviously. But by CBF the analysis of ROI, not PTSD group in the region average CBF value and the PTSD symptom severity was found (CAPS) correlated.
3, DTI data analysis
This study used DTI Studio and SPM combined analysis of DTI sequence data mining accident survivors, PTSD group, compared with non PTSD group, in the right side of the right ventricle, fusiform gyrus, lower back area FA value of right temporal gyrus and right middle temporal, right superior temporal gyrus and right brain in the corpus callosum area ADC value was significantly higher. But through the analysis of ROI, PTSD group in the average FA in these regions or ADC values and the severity of PTSD symptoms was found (CAPS) correlated. This may be due to early PTSD caused by the change of structure and function is not obvious, caused by the FA and ADC index had no significant change.
4, a summary
This study first constructs the cortical thickness of the Laplasse equation and the detection process based method, improves the accuracy and computation speed measurement; considering the influence of low resolution and PVE perfusion imaging on CBF measurement, the partial volume correction algorithm of MAP-EM theory and CBF measurement method based on the combination of figure CBF distribution more accurately the changes of cerebral cortex thickness and blood flow, the method for the study of nervous system and brain diseases caused by providing effective means.
The proposed method based on the study of 20 survivors experience mine consisting of PTSD group and control group in cerebral cortex thickness and the distribution of CBF was analyzed, found a number of regional differences in the thickness or CBF. At the same time, the use of DTI Studio and SPM combined analysis of DTI sequence data, found a number of FA and ADC value of brain abnormalities. The above results on the one hand to further understand the etiology of PTSD pathology, lay the foundation of mechanism, on the other hand, regional or index is put forward, is expected to become the early clinical diagnosis of PTSD and evaluation basis.

【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R749.5

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1 金睿;鄭成強(qiáng);張虹;;針灸治療創(chuàng)傷后應(yīng)激障礙的相關(guān)研究與心身醫(yī)學(xué)[A];第四屆中國中西醫(yī)結(jié)合學(xué)會(huì)心身醫(yī)學(xué)專業(yè)委員會(huì)換屆大會(huì)暨第七屆全國中西醫(yī)結(jié)合心身醫(yī)學(xué)學(xué)術(shù)交流會(huì)論文匯編[C];2013年

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1 楊莎;電針干預(yù)創(chuàng)傷后應(yīng)激障礙患者腦功能改變的靜息態(tài)磁共振影像研究[D];成都中醫(yī)藥大學(xué);2013年

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