7 Tesla磁共振功能成像对癫痫大鼠脑损伤的长期跟踪研究
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摘要
背景与目的：癫痫是一种常见的脑部疾病，颞叶癫痫是癫痫发作的常见类型，通常起源于内侧颞叶结构，并累及脑内多个部位。然而，目前关于癫痫动物脑损伤的长期动态研究还相对较少。本研究应用磁共振T2mapping技术、体积测量技术和DTI技术检测毛果芸香碱诱导的大鼠癫痫模型在癫痫后急性期、潜伏期和慢性期脑组织的的动态改变，并评估抗癫痫药地西泮和苯巴比妥的神经保护效果。
材料和方法：本研究得到了当地动物使用和动物保护制度委员会的批准。实验选取20只成年雌性Sprague Dawley大鼠（荷兰)进行实验，在应用锂剂24小时后，14只大鼠通过使用多次腹腔低剂量注射毛果芸香碱成功地诱发为癫痫发作持续状态。癫痫持续发作l小时后，一组大鼠（7只）采用地西泮终止癫痫，命名为KO组，另一组大鼠（7只）采用苯巴比妥联合地西泮终止癫痫，命名为PB组。然后用7Tesla动物专用磁共振扫描仪在癫痫前及癫痫发作终止后的不同时间点：24小时、48小时、1周、6周、3个月和6个月对以上2组大鼠进行T2mapping检查和DTI检查。本研究采用Image J软件分别在T2mapping序列和DTI序列上测量大鼠顶叶皮层、颞叶皮层、梨状皮层、杏仁核、海马背侧、海马腹侧上部、海马腹侧下部、海马后部、丘脑背侧、丘脑腹侧、黑质、胼胝体的T2弛豫时间和FA值及ADC值，采用ITK-SNAP2.1软件在T2mapping序列上测量脑体积、海马体积、脑脊液体积和颅腔体积。然后用SPSS13.0统计学软件对所测值行独立样本t检验，比较不同感兴趣区T2弛豫时间、FA值和ADC值在两侧大脑半球间、不同时间点及两组之间是否存在显著性差异，P <0.05为差异有显著性。
结果：T2弛豫时间、海马体积、FA值和ADC值在两半球间均未见明显统计学差异。KO组和PB组大鼠所有兴趣区的T2弛豫时间、FA值及海马体积、脑体积、脑脊液体积和颅腔体积随时随时间变化规律相似，但KO组均较PB组改变明显。各兴趣区ADC值在两组间变化规律不同。
结论：癫痫后的脑组织改变是一个长期的过程，磁共振T2mapping技术、体积测量技术和DTI技术可以用来监测癫痫过程中的脑改变，苯巴比妥联合地西泮确实有明显的神经保护作用。
Backgroud and obiecte: Status epilepticus (SE) is a common brain insult thatmay lead to development of temporal lobe epilepsy (TLE) which is frequentlycharacterized by hippocampal sclerosis, and other areas can also be involved.However, relatively limited information is available for dynamic changes aboutbrain during disease progresssion. The present study aims to estimate thesechanges in acute, latent and chronic phases of epileptogenesis by using a longterm (until6months) MR imaging follow up in the rat pilocarpine model thatmimics most clinical and neuropathological features of TLE, and to evaluatepossible neuroprotective effect of the drugs diazepam (DZP) andPhenobarbital(PB).
Materials and Methods: The study was approved by the local Animal WelfareCommittee.20female Sprague Dawley rats were studied. Status epileticus (SE)was successfully induced in14rats by administration of pilocarpine. SE wasinterrupted with either DZP and PB (n=7, group PB) or DZP alone (n=7, groupKO). MR scans were performed before (baseline), and24h,48h,1week,6weeks,3months, and6months after SE onset, to include acute and chronic phasesof epileptogenesis. MR examinations were carried out on a7Tesla animalscanner. Image J software were adapt to measure the T2relaxation time, FA value and ADC value, the region of interest(ROI) including retrosplenialparital cortex, retrosplenial temporal cortex, amygdale, piriform andenthorinal cortex, dorsal hippocampus, ventral hippocampus, posteriorhippocampus, dorsal thalamus, ventral thalamus, substantial nigra and corpuscallosum. Volumes of the hippocampus, CSF (cerebrospinal fluid) andintracranial vault were measured manually by using the free software ITK-SNAP.SPSS13.0was performed to do the Statistical analysis. The T2relaxation time,FA value and ADC value and hippocampal volume between cerebral hemispheres,different time points, and different groups were compared by using thetwo-tailed t-test.
Resules: There was no significant difference in T2relaxation time, FA valueand ADC value and hippocampal volume between cerebral hemispheres. The T2relaxation time, FA value and volumes of the hippocampus, CSF and intracranialvault time dependence in different ROI showed similar in KO and PB group.However, the values of KO group changed more predominance than PB group. TheADC value time dependence appeared different between two groups.
Conclusions: SE-induced neurodegeneration is a very long lasting process,which could be detected by MR T2mapping sequence, volume measurement and DTI.The combination of DZP and PB seems to have neuroprotective effects concerningbrain injury.
材料和方法：本研究得到了当地动物使用和动物保护制度委员会的批准。实验选取20只成年雌性Sprague Dawley大鼠（荷兰)进行实验，在应用锂剂24小时后，14只大鼠通过使用多次腹腔低剂量注射毛果芸香碱成功地诱发为癫痫发作持续状态。癫痫持续发作l小时后，一组大鼠（7只）采用地西泮终止癫痫，命名为KO组，另一组大鼠（7只）采用苯巴比妥联合地西泮终止癫痫，命名为PB组。然后用7Tesla动物专用磁共振扫描仪在癫痫前及癫痫发作终止后的不同时间点：24小时、48小时、1周、6周、3个月和6个月对以上2组大鼠进行T2mapping检查和DTI检查。本研究采用Image J软件分别在T2mapping序列和DTI序列上测量大鼠顶叶皮层、颞叶皮层、梨状皮层、杏仁核、海马背侧、海马腹侧上部、海马腹侧下部、海马后部、丘脑背侧、丘脑腹侧、黑质、胼胝体的T2弛豫时间和FA值及ADC值，采用ITK-SNAP2.1软件在T2mapping序列上测量脑体积、海马体积、脑脊液体积和颅腔体积。然后用SPSS13.0统计学软件对所测值行独立样本t检验，比较不同感兴趣区T2弛豫时间、FA值和ADC值在两侧大脑半球间、不同时间点及两组之间是否存在显著性差异，P <0.05为差异有显著性。
结果：T2弛豫时间、海马体积、FA值和ADC值在两半球间均未见明显统计学差异。KO组和PB组大鼠所有兴趣区的T2弛豫时间、FA值及海马体积、脑体积、脑脊液体积和颅腔体积随时随时间变化规律相似，但KO组均较PB组改变明显。各兴趣区ADC值在两组间变化规律不同。
结论：癫痫后的脑组织改变是一个长期的过程，磁共振T2mapping技术、体积测量技术和DTI技术可以用来监测癫痫过程中的脑改变，苯巴比妥联合地西泮确实有明显的神经保护作用。
Backgroud and obiecte: Status epilepticus (SE) is a common brain insult thatmay lead to development of temporal lobe epilepsy (TLE) which is frequentlycharacterized by hippocampal sclerosis, and other areas can also be involved.However, relatively limited information is available for dynamic changes aboutbrain during disease progresssion. The present study aims to estimate thesechanges in acute, latent and chronic phases of epileptogenesis by using a longterm (until6months) MR imaging follow up in the rat pilocarpine model thatmimics most clinical and neuropathological features of TLE, and to evaluatepossible neuroprotective effect of the drugs diazepam (DZP) andPhenobarbital(PB).
Materials and Methods: The study was approved by the local Animal WelfareCommittee.20female Sprague Dawley rats were studied. Status epileticus (SE)was successfully induced in14rats by administration of pilocarpine. SE wasinterrupted with either DZP and PB (n=7, group PB) or DZP alone (n=7, groupKO). MR scans were performed before (baseline), and24h,48h,1week,6weeks,3months, and6months after SE onset, to include acute and chronic phasesof epileptogenesis. MR examinations were carried out on a7Tesla animalscanner. Image J software were adapt to measure the T2relaxation time, FA value and ADC value, the region of interest(ROI) including retrosplenialparital cortex, retrosplenial temporal cortex, amygdale, piriform andenthorinal cortex, dorsal hippocampus, ventral hippocampus, posteriorhippocampus, dorsal thalamus, ventral thalamus, substantial nigra and corpuscallosum. Volumes of the hippocampus, CSF (cerebrospinal fluid) andintracranial vault were measured manually by using the free software ITK-SNAP.SPSS13.0was performed to do the Statistical analysis. The T2relaxation time,FA value and ADC value and hippocampal volume between cerebral hemispheres,different time points, and different groups were compared by using thetwo-tailed t-test.
Resules: There was no significant difference in T2relaxation time, FA valueand ADC value and hippocampal volume between cerebral hemispheres. The T2relaxation time, FA value and volumes of the hippocampus, CSF and intracranialvault time dependence in different ROI showed similar in KO and PB group.However, the values of KO group changed more predominance than PB group. TheADC value time dependence appeared different between two groups.
Conclusions: SE-induced neurodegeneration is a very long lasting process,which could be detected by MR T2mapping sequence, volume measurement and DTI.The combination of DZP and PB seems to have neuroprotective effects concerningbrain injury.
引文
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1. Chang BS, Lowenstein DH. Epilepsy. N. Engl. J. Med.2003,349(13):1257–1266.
2. Fisher R, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J. Epilepticseizures and epilepsy: definitions proposed by the International League AgainstEpilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia2005,46(4):470–472.
3. Epilepsy. World Health Organization，2009.
4. Brodie MJ, Elder AT, Kwan P, et al. Epilepsy in later life. Lancet neurology2009,8(11):1019–30.
5. Elaine Wyllie, Gregory D, Cascino Barry E, et al. Wyllie's Treatment of Epilepsy:Principles and Practice, Wolters Kluwer Health,2010,601-609.
6. RegestaG, Tanganelli P, Clinical aspects and biological bases of drug-resistantepilepsies, Epilepsy Res,1999,34:109–122.
7. Jutila L, Ylinen A, Partanen K. MR volumetry of the entorhinal, perirhinal, andtemporopolar cortices in drug-refractory temporal lobe epilepsy, American Journal ofNeuroradiology,2001,22:1490-1501.
8. Schwarcz R, Witter MP. Memory impairment in temporal lobe epilepsy: the role ofentorhinal lesions. Epilepsy Research,2002(50):161-177.
9.张瑞华,王玉平。癫病点燃模型的研究进展,脑与神经疾病杂志,2006,14(3):235-236.
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