帕金森病猴苍白球神经元放电序列的时间模式研究
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摘要
目前对帕金森病苍白球神经元放电特性的研究都是从频率编码的角度进行的,虽对其神经元放电形式有所涉及但仅仅停留在区分是峰放电还是爆发放电以及放电数量的多少上,这样无法判断苍白球神经元如何携带帕金森病的确定性信息。已经有迹象表明:苍白球内侧部神经元放电频率在帕金森病患者中无明显变化而爆发式放电变化明显,并且与病情和多巴胺能神经元减少程度成正相关,但是无震颤的帕金森病患者亦能记录到低频爆发式放电。与频率编码不同,时间编码考虑到了放电脉冲在时间上的相关性,而目前普遍认为时间编码包含更多的信息,是神经信息编码的基础。所以,从时间编码的角度使用非线性动力学方法,结合现代医学信息学理论和现代信号处理技术对帕金森病恒河猴猴苍白球神经元放电特征进行深入的研究与分析,有望揭示帕金森病猴模型苍白球神经元放电信号中所包含的特征性信息,对于深入了解苍白球在帕金森病发病中的作用,进一步揭示帕金森病的发病机理,均有重大意义。
目的
在原发性帕金森病苍白球神经元电生理活动中,其放电频率与症状之间无明显相关性。但研究其相邻动作电位的时间间隔的特性时发现其混钝结构发生了特异性变化,它与患者的强直、运动迟缓呈负相关。这说明了内侧苍白球和外侧苍白球神经元表现的帕金森病的信息不是简单的通过放电的多少来携带,而是可能将携带的信息蕴藏在特定的放电模式之中。本实验的目的就在于从时间编码角度利用非线性理论方法提取并分析恒河猴在生理及病理状态下苍白球神经元放电信号中所包含的与帕金森病相关的特征性信息,进一步丰富PD的发病机理。
方法
1、采用血管内介入方法,将MPTP直接注入恒河猴一侧颈内动脉,制作偏侧帕金森病猴模型。
2、使用在体胞外记录的方法,分别在建模前后不同时间段内,多次采集猴苍白球不用亚区神经元的放电信号。
3、对采集到的电信号进行鉴别筛选,保留符合条件的电信号并建立相应的峰峰间期(ISIs)序列数据库。
4、计算各亚区神经元放电频率,观察阿朴吗啡对其放电频率的影响。
5、采用非线性研究方法对各亚区ISIs序列进行放电模式、小波熵、非稳定周期轨道等研究。
6、比较上述各项检测指标在生理及病理状态下的变化,提取与帕金森病密切相关的信息。
结果
1、采用血管内介入的方法将MPTP直接注入恒河猴颈内动脉,可以成功制作出偏侧帕金森病猴模型,该方法安全、简单,给药剂量准确,手术操作时间短,对动物损伤小,术后恢复快,出现帕金森症状稳定,一次制作成功率高。
2、病理状态下GPi平均放电频率大幅升高,由10.3±2.7Hz升高至29.1±15.1Hz,其放电模式由建模前的不规则变为相对规则,爆发式放电所占比例明显增加,在皮下注射阿朴吗啡后放电频率降低。病理状态下GPe平均放电频率有较明显降低,由32.6±9.9Hz降至25.9±14.1Hz,其放电模式无明显变化。
3、GPi神经元放电的峰峰间期序列分布模式的变化:生理状态下不规则放电占多数,呈正态不对称分布;病理状态下规则放电所占比例大,呈正偏态分布,存在1～3Hz的低频慢波振荡。而GPe在生理及病理情况下2种放电模式所占比例无明显变化。
4、病理状态下的GPi放电信号可检测到非稳定周期1,2,3轨道,而生理状态下不存在周期3轨道;并且病理状态下周期2轨道比正常状态下明显增多。
5、经过MPTP处理后,猴GPi神经元放电信号复杂性升高,表现为小波熵数值升高,且可随病情波动。
结论
苍白球可被看作是一个非线性系统,从时间编码角度使用非线性动力学方法去进行电生理研究,可以获得更多帕金森病相关信息。与外侧苍白球相比,内侧苍白球在帕金森病的发病中起着更为关键的作用。
Parkinson’s disease (PD) is the most common movement disorder in the elderly. Its main manifestations are tremor, akinsia, rigidity, and postural instability. The underlying pathology of PD and MPTP-induced parkinsonism is a loss of midbrain dopaminergic neurons. Previous work revealed changes in the activity of globus pallidus (GP) neurons of MPTP-treated monkeys as compared with healthy ones, and the only finding was that the firing rates of GPi increased, whereas GPe cells displayed decreased firing rates. No more information about PD was shown. Many physiologists believe that the mode of the neural code is mean rate code which has been proved by many researches. However, this mode has many limitations such as too simple, low efficiency, less information et al. The frequence code theory has shown its limitation while the nonlinear theory and time code are popular and play a great role in neuroscience research in nowdays. In this essay we will use a new way to analysis the electrophysiological character of neuron of globus pallidus in monkeys.. Objective
Analysis ISIs of different parts of globus pallidus in monkeys before and after treated by MPTP by methods derived from nonlinear dynamics and open out the relationship between PD and the electrophysiological character of neuron of globus pallidus.
Methods
(1)MPTP were injected directly into arteria carotis interna of the monkeys by means of endovascular to make PD models.
(2)Record the discharges of GPi and GPe neurons (before and after surgery) for at least 180s, and the data is stored in hard disk.
(3)Identify and select the single-unit discharge based on the amplitude, frequency and pattern. Only the single-unit discharge neurons would be studied. The neurons are located by identifying the typical neuron discharge of Gpe, Gpi and lamina between Gpe and Gpi and compared with the standard atlas.
(4) Demarcate the spikes after operation and set up trains of Interspike Intervals. Calculate the firing rates before and after apomorphine was injected.
(5) Calculate the UPO, Wavelet Entropy and the distribution mode of the ISIs of the GPi by nonlinear methods.
(6) Compare the nonlinear index in (5) between healthy and PD monkeys and extract information which have relation with PD.
Results
(1) Making Parkinsonism monkeys by means of endovascular is a more safe, and simple method. An precise dose of MPTP can be injected into monkey painlessly and the monkey may recover in a short time.
(2) The firing rates of GPi increased, whereas GPe cells displayed decreased firing rates when the monkey were treated by MPTP. The firing rates decrease when monkey were treated with apomorphine.
(3) The charge mode was more regular in Parkinsonism monkey’s GPi neurons than healthy ones, while no changes were found in ISIs of GPe neuron. An oscillation about 1~3Hz was found in the ISIs of GPi neuron.
(4) ISIs of GPi neuron can be detected UPOs 1,2,3 orbit.
(5) Wavelet Entropy of GPi ISIs increase after monkeys were treated with MPTP, which show high diversity in Parkinsonism monkeys.
Conclusion
The results above demonstrate that the ISIs of globus pallidus in parkinson’s disease are chaotic. Many nonlinear research methods can be used to study the electrophysiology of Parkinsonism basal ganglia. Gpi is more close to the mechanism of PD compared with GPe.
目的
在原发性帕金森病苍白球神经元电生理活动中,其放电频率与症状之间无明显相关性。但研究其相邻动作电位的时间间隔的特性时发现其混钝结构发生了特异性变化,它与患者的强直、运动迟缓呈负相关。这说明了内侧苍白球和外侧苍白球神经元表现的帕金森病的信息不是简单的通过放电的多少来携带,而是可能将携带的信息蕴藏在特定的放电模式之中。本实验的目的就在于从时间编码角度利用非线性理论方法提取并分析恒河猴在生理及病理状态下苍白球神经元放电信号中所包含的与帕金森病相关的特征性信息,进一步丰富PD的发病机理。
方法
1、采用血管内介入方法,将MPTP直接注入恒河猴一侧颈内动脉,制作偏侧帕金森病猴模型。
2、使用在体胞外记录的方法,分别在建模前后不同时间段内,多次采集猴苍白球不用亚区神经元的放电信号。
3、对采集到的电信号进行鉴别筛选,保留符合条件的电信号并建立相应的峰峰间期(ISIs)序列数据库。
4、计算各亚区神经元放电频率,观察阿朴吗啡对其放电频率的影响。
5、采用非线性研究方法对各亚区ISIs序列进行放电模式、小波熵、非稳定周期轨道等研究。
6、比较上述各项检测指标在生理及病理状态下的变化,提取与帕金森病密切相关的信息。
结果
1、采用血管内介入的方法将MPTP直接注入恒河猴颈内动脉,可以成功制作出偏侧帕金森病猴模型,该方法安全、简单,给药剂量准确,手术操作时间短,对动物损伤小,术后恢复快,出现帕金森症状稳定,一次制作成功率高。
2、病理状态下GPi平均放电频率大幅升高,由10.3±2.7Hz升高至29.1±15.1Hz,其放电模式由建模前的不规则变为相对规则,爆发式放电所占比例明显增加,在皮下注射阿朴吗啡后放电频率降低。病理状态下GPe平均放电频率有较明显降低,由32.6±9.9Hz降至25.9±14.1Hz,其放电模式无明显变化。
3、GPi神经元放电的峰峰间期序列分布模式的变化:生理状态下不规则放电占多数,呈正态不对称分布;病理状态下规则放电所占比例大,呈正偏态分布,存在1～3Hz的低频慢波振荡。而GPe在生理及病理情况下2种放电模式所占比例无明显变化。
4、病理状态下的GPi放电信号可检测到非稳定周期1,2,3轨道,而生理状态下不存在周期3轨道;并且病理状态下周期2轨道比正常状态下明显增多。
5、经过MPTP处理后,猴GPi神经元放电信号复杂性升高,表现为小波熵数值升高,且可随病情波动。
结论
苍白球可被看作是一个非线性系统,从时间编码角度使用非线性动力学方法去进行电生理研究,可以获得更多帕金森病相关信息。与外侧苍白球相比,内侧苍白球在帕金森病的发病中起着更为关键的作用。
Parkinson’s disease (PD) is the most common movement disorder in the elderly. Its main manifestations are tremor, akinsia, rigidity, and postural instability. The underlying pathology of PD and MPTP-induced parkinsonism is a loss of midbrain dopaminergic neurons. Previous work revealed changes in the activity of globus pallidus (GP) neurons of MPTP-treated monkeys as compared with healthy ones, and the only finding was that the firing rates of GPi increased, whereas GPe cells displayed decreased firing rates. No more information about PD was shown. Many physiologists believe that the mode of the neural code is mean rate code which has been proved by many researches. However, this mode has many limitations such as too simple, low efficiency, less information et al. The frequence code theory has shown its limitation while the nonlinear theory and time code are popular and play a great role in neuroscience research in nowdays. In this essay we will use a new way to analysis the electrophysiological character of neuron of globus pallidus in monkeys.. Objective
Analysis ISIs of different parts of globus pallidus in monkeys before and after treated by MPTP by methods derived from nonlinear dynamics and open out the relationship between PD and the electrophysiological character of neuron of globus pallidus.
Methods
(1)MPTP were injected directly into arteria carotis interna of the monkeys by means of endovascular to make PD models.
(2)Record the discharges of GPi and GPe neurons (before and after surgery) for at least 180s, and the data is stored in hard disk.
(3)Identify and select the single-unit discharge based on the amplitude, frequency and pattern. Only the single-unit discharge neurons would be studied. The neurons are located by identifying the typical neuron discharge of Gpe, Gpi and lamina between Gpe and Gpi and compared with the standard atlas.
(4) Demarcate the spikes after operation and set up trains of Interspike Intervals. Calculate the firing rates before and after apomorphine was injected.
(5) Calculate the UPO, Wavelet Entropy and the distribution mode of the ISIs of the GPi by nonlinear methods.
(6) Compare the nonlinear index in (5) between healthy and PD monkeys and extract information which have relation with PD.
Results
(1) Making Parkinsonism monkeys by means of endovascular is a more safe, and simple method. An precise dose of MPTP can be injected into monkey painlessly and the monkey may recover in a short time.
(2) The firing rates of GPi increased, whereas GPe cells displayed decreased firing rates when the monkey were treated by MPTP. The firing rates decrease when monkey were treated with apomorphine.
(3) The charge mode was more regular in Parkinsonism monkey’s GPi neurons than healthy ones, while no changes were found in ISIs of GPe neuron. An oscillation about 1~3Hz was found in the ISIs of GPi neuron.
(4) ISIs of GPi neuron can be detected UPOs 1,2,3 orbit.
(5) Wavelet Entropy of GPi ISIs increase after monkeys were treated with MPTP, which show high diversity in Parkinsonism monkeys.
Conclusion
The results above demonstrate that the ISIs of globus pallidus in parkinson’s disease are chaotic. Many nonlinear research methods can be used to study the electrophysiology of Parkinsonism basal ganglia. Gpi is more close to the mechanism of PD compared with GPe.
引文
[1] Jacques D,Eagle. K,Kopyov V. Use of posteroventral pallidotomy for treatment of Parkinson's Disease:Is pallidotomy still an experimental procedure. stereotact Funct Neurosurg. 1998,70:19-31
[2] Jamal M,Jacques F,Kim J. Infrequent types of pallidal discharges during pallidotomy. stereotact Funct Neurosurg. 1997,69:231-235
[3] Laitinen L,Bergenheim A,Hariz M. Leksell's posteroventral pallidotomy in the treatment of parkinson's disease. J Neurosurg, 1992,76:63-61
[4] Philip A,Jerrold L,Roy A. Ablative surgery and deep Brain Stimulation for parkinson's disease.Neurosurg.1998,3;989-1013
[5] Ring HA and Serra-Mestres J. Neuropsychiatry of the basal anglia. Journal of Neurology, Neurosurgery & Psychiatry. 72(1):12-21, January 2002.
[6] Beardelli A, Rothwell JC. Thompson PD and et al. Pathophysiology of bradykinesia in Parkinson's disease. Brain,2001; 124(11):2131-2146
[7] Lauwereyns J, Watanabe K, Coe B, Hikosaka O.A neural correlate of response bias in monkey caudate nucleus.Nature 2002 ,418(6896):413-7
[8] suda I.Toward an interpretation of dynamic neural activity in terms of chaotic dynamical systems.Behav Brain Sci. 2001 24(5):793-810
[9] Lozano AM, Hutchison WD. Microelectrode recordings in the pallidum. Mov Disord 2002,17 Suppl 3:S150-155
[10] Benert M., Bennay M., Fedrowitz M and et al. Altered Discharge Pattern of Basal Ganglia Output Neurons in an Animal Model of Idiopathic Dystonia. J. Neurosci. 2002 22(4): 7244-7253
[11] 11 高国栋主编. 帕金森病诊疗关键.南京:江苏科学技术出版社,2003.167-179
[12] 高国栋,张华,张宝国等.微电极记录技术在手术治疗帕金森病中的作用.中华神经外科杂志.1998,14:202-5
[13] Roach, ES. Both postsynaptic and presynaptic dysfunction contribute to Parkinson disease: any mechanism will not do. Arch Neurol. 2007 Jan;64(1):137-40
[14] Lee JI, Verhagen M, Lenz FA, et al. Internal pallidal neuronal activity during mild drug-related dyskinesias in Parkinson's Disease: decreased firing rates and altered firing patterns. J Neurophysiol. 2007 Jan 10;79(2):209-215
[15] 高国栋,赵亚群, 王学廉等. CT 定位微电极引导选择性丘脑腹中间核毁损术治疗震颤型帕金森病(附 33 例报告). 中国神经精神疾病杂志.2000,(6):37-38
[16] Fine J, Duff J, Chen R, et al. Long-term follow-up of unilateral pallidotomy in advanced Parkinson's disease. N Engl J Med. 2000 Jun 8;342(23):1708-14
[17] Loher TJ, Burgunder JM, Pohle T, et al. Long-term pallidal deep brain stimulation in patients with advanced Parkinson disease: 1-year follow-up study. J Neurosurg. 2002 May;96(5):844-53
[18] Hua Z, Guodong G, Qinchuan L, Yaqun Z, Qinfen W, Xuelian W. Analysis of complications of radiofrequency pallidotomy. Neurosurgery, 2003;52(1):89-101
[19] Sanghera MK, Grossman RG, Kalhorn CG . Basal ganglia neuronal discharge in primary and secondary dystonia in patients undergoing pallidotomy. Neurosurgery. 2003 Jun;52(6):1358-70
[20] Hutchison WD, Lang AE, Lozano AM. Pallidal neuronal activity: implications for models of dystonia. Ann Neurol. 2003 Apr;53(4):480-8
[21] Gernert M, Bennay M, Fedrowitz M , et al. Altered Discharge Pattern ofBasal Ganglia Output Neurons in an Animal Model of Idiopathic Dystonia. J. Neurosci. 2002 22(4): 7244-7253
[22] 赵亚群.硕士论文.帕金森病患者苍白球神经元放电的离线分析.第四军医大学;2001,11:61-63
[23] 李维新, 高国栋.苍白球神经元放电模式的非线性动力学研究. 第四军医大学博士毕业论文,2005:61-80
[24] 王举磊,高国栋,菅忠.帕金森病苍白球神经元放电的非线性特征.中国临床康复,2005;9(17): 16-18
[25] 胡三觉等.神经元自发放电的时间模式.<<复杂性科学探索>>,民主建设出版社;1999:166-187
[26] Duan Jian-Hong, Xing Jun-Ling, Yang Jing, et al. Different firing patterns induced by veratridine and aconitine in injured dorsal root ganglion neurons. Acta Physiologica Sinca. 2005, 57(2): 169-174.
[27] 建红,段玉斌,胡三觉. 藜芦碱引起神经元放电峰峰间期慢波振荡. 生物物理学报. 2002,(1):50-53
[28] Ji-Hong Zheng, Zhong Jian, Jun Chen. Detection of Deterministic Behavior Within the Tissue Injury-Induced Persistent Firing of Nociceptive Neurons in the Dorsal Horn of the Rat Spinal Cord. Journal of Computational Neuroscience 2002,13,23-34
[29] Wichmann T, Soares J. Neuronal firing before and after burst discharges in the monkey basal ganglia is predictably patterned in the normal state and altered in parkinsonism. J Neurophysiol. 2006 Apr;95(4):2120-33
[30] Soares J, Kliem MA, Betarbet R, et al. Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J Neurosci. 2004 Jul 21;24(29):6417-26.
[31] DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007 Jan;64(1):20-4
[32] Deadwyler SA , Hampson RE. Ensemble activity and behavior : Whats the code .Science,1995,270∶ 1 316～1318.
[33] RhoadesBK,WeilJC,KowalskiJM,etal. Distri2 bution2free graphical and statistical analysis of serial dependence in neuronal spike trains. J Neurosci Methods,1996,64∶ 2 5～37
[34] Szucs A. Application of the spike density function in analysis of neuronal firing patterns. J neurosci Methods,1998,81:159～167
[35] 张建树.混沌生物学.西安:陕西科学技术出版社,1998.27—68
[36] Class L. Synchronization and rhythmic processes in physiology. Nature,2001,410:277～284
[37] 杨红军,胡三觉 . 混沌在神经系统中的作用 . 生理科学进展,2002,33(3):259-261
[38] Rabinovich MI , Abarbanel DI. The role of chaos in neural systems. Neuroscience,1998,87:5～14
[39] Reinagel P, Reid RC. Temporal coding of visual information in the thalamus. J Neurosci.2000,20:5392～5400
[40] ZhangXS,RoyRJ,JensenEW. EEG complexity as a measure of depth of anesthesia for patients. IEEE Trans Biomed Eng, 2001, 48:1424～1433
[41] Molnar M , Skinner J E , Csepe V , et al. Correlation dimension changes accompanying the occurrence of the mismatch negativity and the P3 event2related potential component. Electroencephalogr Clin Neurophysiol , 1995 ,95:118～126
[42] Kobayashi T, Madokoro S, Wada Y, et al. Human sleep EEG analysis using the correlation dimension. Clin Electroencephalogr , 2001 , 32:112～118
[43] Stam CJ,Jelles B,Achtereekte HA , et al. Diagnostic usefulness of linear and nonlinear quantitative EEG analysis in Alzheimer’s disease. Clin Electroencephal,1996,27:69-77
[44] Lehnertz K, Andrzejak RG, Arnhold J , et al. Nonlinear EEGanalysisinepilepsy: its possible use for interictal focus localization,seizure anticipation,and prevention. J Clin Neurophysiol,2001,18:209～222
[45] Sarbadhikari SN , Chakrabarty K. Chaos in the brain: a short review alluding to epilepsy , depression , exercise and lateralization. Med Eng Phys,2001,23:445～455
[46] Schiff SJ , Jerger K, Duong DH, et al. Controlling chaos in the brain. Nature,1994,370:615～620
[47] Understedt U.6-Hydroxydopamine induced degeneration of central monoamine neurons. Eur J Pharmcol,1968,5(1):107-110
[48] Lee CS,Sauer H, Bjorklund A,et al. Dopaminnergic neuronal degeneration and motor impairments following lesions by intrastriatal 6-OHDA in the rat. Neuroscience,1996,72(3):641-644
[49] Perese DA, Ulman J, Viola J,et al. A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res,1989,494(2):285-293
[50] Paxinos G, Watson C. The Rat brain in stereotaxic coordinates. 5rd ed. San Diego, CA: Academic Press; 2005.
[51] Barneoud P, Parmentier S, Mazadier M, et al. Effects of complete and partial leisons of the dopaminergic mesctelencephalic system on skilled forelimb use in the rat. Neuroscience,1995,67(4):837-848
[52] Hefi F, Melamed E,Wurtman RJ. Partial lesions of the dopaminergic nigrostriatal system in rat brain:biochemical characterization. Brain Res,1980,195:123-137
[53] Ahn TB, Kim JM, Kwon KM,et al. Survival and migration of transplanted neural stem cell-derived dopamine cells in the brain of parkinsonian rat. Int J Neurosci,2004,114(5):575-585
[54] Yasuhara T, Shingo T, Muraoka K,et al. Early transplantation of an encapsulated glial cell line-derived neurotrophic factor-producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease. J Neurosurg,2005,102(1):80-89
[55] Chiueh CC, Buns RS, Marker SP,et al.Primate model of parkinsonism selective lesion of nigrostrialtal neurons by MPTP produces an extrapyamidal syndrome in rhesus monkeys. Life Sci,1986,39:7-10
[56] Sundstrom E, Samuelsson EB. Comparison of key steps in MPTP neurotoxity in rodents. Pharmacol Toxicol,1997,81:226-231
[57] Hamre K, Tharp, Poon K, et al. Differential strain susceptibility following MPTP administration acts in an autosomal sominant fashion: quantitative analysis in seven strains of musculus. Brain Res,1999,828:91-103
[58] Jakowec MW, Petzinger GM. MPTP-lesioned model of parkinson’s disease, with emphasis on mice and nonhuman primates. Comp Med, 2004,54(5):497-513
[59] Burns RS, Chiueh CC, Markey SP,et al. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by MPTP. Proc Natl Acad Sci USA, 1983, 80(14):4546-4550
[60] 张进禄,刘玉军,鲁强,等。单侧境内动脉注入 MPTP 建立偏侧帕金森病灵长类模型的研究。首都医科大学学报,1998,19:1-3
[61] 刘晟,王维,于小平,等。MPTP 诱导猴偏侧帕金森病模型的制作。中国医学影像学技术,2006,22(3):353-356
[62] 王伟,姜晓丹,徐如祥,等。颈内动脉注射 MPTP 制作偏侧恒河猴帕金森病模型研究。中国微侵袭神经外科杂志,2005,10(3):129-132
[63] Suwelsck D, Hurtado-Lorenzo A, Millan E, et al. Neuronal expression of the transcription factor Gli1 using the Talpha1 alpha-tubulin promoter is neuronprotective in an experimental model of Parkinson’s disease. Gene Ther,2004,11(24):1742-1752
[64] Takagi Y, Takahashi J,Saiki H, et al. Dopaminergic neurons generated from monkey embryonic stem cells fuction in a Parkinson primate model. J Clin Invest,2005,115(1):102-109
[65] Muramatsu Y, Kurosaki R, Watanabe H, et al. Cerebral alterations in a MPTP-mouse model of Parkinson’s disease- an immunocytochemical study. J Neural Transm,2003,10(10):1129-1144
[66] Anden NE. Effects of reserpine and a tyrosine hydroxylase inhibitor on the monoamine levels in different regions of the central nervous system. Eur J Pharmacol,1967,1:1-15
[67] Lapchak PA, Beck KD, Araujo DM, et al. Chronic intranigral administration of brain-derived neurontropic factor produces striatal dopaminergic hypodunction in unlesioned adult rats and fails to attenuate the decline of striatal dopaminergic function following medial forebrain bundle transaction. Neuroscience,1993,53:639-650
[68] Brecknell JE, Dunnett SB, Fawcett JWA. Wuantitative study of cell death in the substantia nigra following a mechanical lesion of the medical forebrain bundle. Neuroscience,1995,64:210-227
[69] 梁希彬,罗涌,卢峻,等。线刀毁损大鼠内侧前脑束建立部分损伤的帕金森病模型。神经解剖学杂志,2001,17(3):199-204
[70] Ben-Shachar Youdim MBH. Intranigral iron injection induces behavioraland biochemical “Parkinsonism” in rats. J Neurochem,1991,57:2133-2135
[71] Scherzer CR, Jensen RV, Gullans SR, et al. Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson’s disease. Hum Mol Genet,2003,12(19):2457-2466
[72] Legare ME, Hanneman WH. Genetic, biochemical, and characterization of neurological mutant 3, a new mouse model for Parkinson’s disease. Genet Mol Res,2002,2(3):288-294
[73] Kirik D, Annett LE, Burger C, et al. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA,2003,100(5):2884-2889
[74] Lindsten K, Menendez-Benito V, Masucci MG, et al. A transgenic mouse model of the ubiquitin/proteasome system, Nat Bioteacnol, 2003, 21(8):897-902
[75] Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Nati Acad Sci USA,2005,102(6):2174-2179
[76] Vingerhoets FJG, Snow BJ, Tetrud JW, et al. Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions. Ann Neurol,1994,36(5):765-770
[77] 马羽,王运杰。脑深部电刺激术治疗帕金森病的疗效及机制研究。中国医科大学博士论文,2005:22-25
[78] Clarkc CE, Boycc S, Robterson RG, et al. Drug-induced dyskinesia in primates rendered hemiparkinsonism by intracarotid administration of MPTP. J Ncurol Sci,1989,90(3):307-314
[79] Bankiewicz KS, Oldfield EH, Chiueh CC, et al. Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of MPTP. Life Sci,1986,39(1):7-16
[80] Meissner W, Prunier C, Guilloteau D, et al. Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson’s disease. Mol Neurobiol,2003,28(3):209-218
[81] Castagnoli N Jr, Petzer JP, Steyn S, et al. Monoamine oxidase B inhibition and neuronprotection: studys on selective adenosine A2A receptor antagonists. Neurology,2003,61(11):S62-68
[82] Hill MP, Bezard E, McGuire SG, et al. Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset. Mov Disord,2003,18(11):1301-1305
[83] 汤克俭,徐德隆,余慧贞,等.自制 MPTP 制备恒河猴帕金森病模型评价.中国神经精神疾病杂志,1991,17(2):162-163
[84] Elsworth JD,Taylor JR,Sladek JR, et al.Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates one year after MPTP treatment. Neuroscience,2000,95(4):399-408
[85] Filion M, Trembiay L. Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res, 1991,547:142-151
[86] Filion M, Trembiay L, Bedard PJ. Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res,1991,547:151-161
[87] 何正友,蔡玉梅,钱清泉.小波熵理论及其在电力系统故障检测中的应用研究[J]中国电机工程学报,2005,25(5):38-43.
[88] 杨建平,阮文.基于小波包变换的图像消噪方法[J]井冈山师范学院学报,2005,26(3):17-19
[2] Jamal M,Jacques F,Kim J. Infrequent types of pallidal discharges during pallidotomy. stereotact Funct Neurosurg. 1997,69:231-235
[3] Laitinen L,Bergenheim A,Hariz M. Leksell's posteroventral pallidotomy in the treatment of parkinson's disease. J Neurosurg, 1992,76:63-61
[4] Philip A,Jerrold L,Roy A. Ablative surgery and deep Brain Stimulation for parkinson's disease.Neurosurg.1998,3;989-1013
[5] Ring HA and Serra-Mestres J. Neuropsychiatry of the basal anglia. Journal of Neurology, Neurosurgery & Psychiatry. 72(1):12-21, January 2002.
[6] Beardelli A, Rothwell JC. Thompson PD and et al. Pathophysiology of bradykinesia in Parkinson's disease. Brain,2001; 124(11):2131-2146
[7] Lauwereyns J, Watanabe K, Coe B, Hikosaka O.A neural correlate of response bias in monkey caudate nucleus.Nature 2002 ,418(6896):413-7
[8] suda I.Toward an interpretation of dynamic neural activity in terms of chaotic dynamical systems.Behav Brain Sci. 2001 24(5):793-810
[9] Lozano AM, Hutchison WD. Microelectrode recordings in the pallidum. Mov Disord 2002,17 Suppl 3:S150-155
[10] Benert M., Bennay M., Fedrowitz M and et al. Altered Discharge Pattern of Basal Ganglia Output Neurons in an Animal Model of Idiopathic Dystonia. J. Neurosci. 2002 22(4): 7244-7253
[11] 11 高国栋主编. 帕金森病诊疗关键.南京:江苏科学技术出版社,2003.167-179
[12] 高国栋,张华,张宝国等.微电极记录技术在手术治疗帕金森病中的作用.中华神经外科杂志.1998,14:202-5
[13] Roach, ES. Both postsynaptic and presynaptic dysfunction contribute to Parkinson disease: any mechanism will not do. Arch Neurol. 2007 Jan;64(1):137-40
[14] Lee JI, Verhagen M, Lenz FA, et al. Internal pallidal neuronal activity during mild drug-related dyskinesias in Parkinson's Disease: decreased firing rates and altered firing patterns. J Neurophysiol. 2007 Jan 10;79(2):209-215
[15] 高国栋,赵亚群, 王学廉等. CT 定位微电极引导选择性丘脑腹中间核毁损术治疗震颤型帕金森病(附 33 例报告). 中国神经精神疾病杂志.2000,(6):37-38
[16] Fine J, Duff J, Chen R, et al. Long-term follow-up of unilateral pallidotomy in advanced Parkinson's disease. N Engl J Med. 2000 Jun 8;342(23):1708-14
[17] Loher TJ, Burgunder JM, Pohle T, et al. Long-term pallidal deep brain stimulation in patients with advanced Parkinson disease: 1-year follow-up study. J Neurosurg. 2002 May;96(5):844-53
[18] Hua Z, Guodong G, Qinchuan L, Yaqun Z, Qinfen W, Xuelian W. Analysis of complications of radiofrequency pallidotomy. Neurosurgery, 2003;52(1):89-101
[19] Sanghera MK, Grossman RG, Kalhorn CG . Basal ganglia neuronal discharge in primary and secondary dystonia in patients undergoing pallidotomy. Neurosurgery. 2003 Jun;52(6):1358-70
[20] Hutchison WD, Lang AE, Lozano AM. Pallidal neuronal activity: implications for models of dystonia. Ann Neurol. 2003 Apr;53(4):480-8
[21] Gernert M, Bennay M, Fedrowitz M , et al. Altered Discharge Pattern ofBasal Ganglia Output Neurons in an Animal Model of Idiopathic Dystonia. J. Neurosci. 2002 22(4): 7244-7253
[22] 赵亚群.硕士论文.帕金森病患者苍白球神经元放电的离线分析.第四军医大学;2001,11:61-63
[23] 李维新, 高国栋.苍白球神经元放电模式的非线性动力学研究. 第四军医大学博士毕业论文,2005:61-80
[24] 王举磊,高国栋,菅忠.帕金森病苍白球神经元放电的非线性特征.中国临床康复,2005;9(17): 16-18
[25] 胡三觉等.神经元自发放电的时间模式.<<复杂性科学探索>>,民主建设出版社;1999:166-187
[26] Duan Jian-Hong, Xing Jun-Ling, Yang Jing, et al. Different firing patterns induced by veratridine and aconitine in injured dorsal root ganglion neurons. Acta Physiologica Sinca. 2005, 57(2): 169-174.
[27] 建红,段玉斌,胡三觉. 藜芦碱引起神经元放电峰峰间期慢波振荡. 生物物理学报. 2002,(1):50-53
[28] Ji-Hong Zheng, Zhong Jian, Jun Chen. Detection of Deterministic Behavior Within the Tissue Injury-Induced Persistent Firing of Nociceptive Neurons in the Dorsal Horn of the Rat Spinal Cord. Journal of Computational Neuroscience 2002,13,23-34
[29] Wichmann T, Soares J. Neuronal firing before and after burst discharges in the monkey basal ganglia is predictably patterned in the normal state and altered in parkinsonism. J Neurophysiol. 2006 Apr;95(4):2120-33
[30] Soares J, Kliem MA, Betarbet R, et al. Role of external pallidal segment in primate parkinsonism: comparison of the effects of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism and lesions of the external pallidal segment. J Neurosci. 2004 Jul 21;24(29):6417-26.
[31] DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol. 2007 Jan;64(1):20-4
[32] Deadwyler SA , Hampson RE. Ensemble activity and behavior : Whats the code .Science,1995,270∶ 1 316～1318.
[33] RhoadesBK,WeilJC,KowalskiJM,etal. Distri2 bution2free graphical and statistical analysis of serial dependence in neuronal spike trains. J Neurosci Methods,1996,64∶ 2 5～37
[34] Szucs A. Application of the spike density function in analysis of neuronal firing patterns. J neurosci Methods,1998,81:159～167
[35] 张建树.混沌生物学.西安:陕西科学技术出版社,1998.27—68
[36] Class L. Synchronization and rhythmic processes in physiology. Nature,2001,410:277～284
[37] 杨红军,胡三觉 . 混沌在神经系统中的作用 . 生理科学进展,2002,33(3):259-261
[38] Rabinovich MI , Abarbanel DI. The role of chaos in neural systems. Neuroscience,1998,87:5～14
[39] Reinagel P, Reid RC. Temporal coding of visual information in the thalamus. J Neurosci.2000,20:5392～5400
[40] ZhangXS,RoyRJ,JensenEW. EEG complexity as a measure of depth of anesthesia for patients. IEEE Trans Biomed Eng, 2001, 48:1424～1433
[41] Molnar M , Skinner J E , Csepe V , et al. Correlation dimension changes accompanying the occurrence of the mismatch negativity and the P3 event2related potential component. Electroencephalogr Clin Neurophysiol , 1995 ,95:118～126
[42] Kobayashi T, Madokoro S, Wada Y, et al. Human sleep EEG analysis using the correlation dimension. Clin Electroencephalogr , 2001 , 32:112～118
[43] Stam CJ,Jelles B,Achtereekte HA , et al. Diagnostic usefulness of linear and nonlinear quantitative EEG analysis in Alzheimer’s disease. Clin Electroencephal,1996,27:69-77
[44] Lehnertz K, Andrzejak RG, Arnhold J , et al. Nonlinear EEGanalysisinepilepsy: its possible use for interictal focus localization,seizure anticipation,and prevention. J Clin Neurophysiol,2001,18:209～222
[45] Sarbadhikari SN , Chakrabarty K. Chaos in the brain: a short review alluding to epilepsy , depression , exercise and lateralization. Med Eng Phys,2001,23:445～455
[46] Schiff SJ , Jerger K, Duong DH, et al. Controlling chaos in the brain. Nature,1994,370:615～620
[47] Understedt U.6-Hydroxydopamine induced degeneration of central monoamine neurons. Eur J Pharmcol,1968,5(1):107-110
[48] Lee CS,Sauer H, Bjorklund A,et al. Dopaminnergic neuronal degeneration and motor impairments following lesions by intrastriatal 6-OHDA in the rat. Neuroscience,1996,72(3):641-644
[49] Perese DA, Ulman J, Viola J,et al. A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain Res,1989,494(2):285-293
[50] Paxinos G, Watson C. The Rat brain in stereotaxic coordinates. 5rd ed. San Diego, CA: Academic Press; 2005.
[51] Barneoud P, Parmentier S, Mazadier M, et al. Effects of complete and partial leisons of the dopaminergic mesctelencephalic system on skilled forelimb use in the rat. Neuroscience,1995,67(4):837-848
[52] Hefi F, Melamed E,Wurtman RJ. Partial lesions of the dopaminergic nigrostriatal system in rat brain:biochemical characterization. Brain Res,1980,195:123-137
[53] Ahn TB, Kim JM, Kwon KM,et al. Survival and migration of transplanted neural stem cell-derived dopamine cells in the brain of parkinsonian rat. Int J Neurosci,2004,114(5):575-585
[54] Yasuhara T, Shingo T, Muraoka K,et al. Early transplantation of an encapsulated glial cell line-derived neurotrophic factor-producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease. J Neurosurg,2005,102(1):80-89
[55] Chiueh CC, Buns RS, Marker SP,et al.Primate model of parkinsonism selective lesion of nigrostrialtal neurons by MPTP produces an extrapyamidal syndrome in rhesus monkeys. Life Sci,1986,39:7-10
[56] Sundstrom E, Samuelsson EB. Comparison of key steps in MPTP neurotoxity in rodents. Pharmacol Toxicol,1997,81:226-231
[57] Hamre K, Tharp, Poon K, et al. Differential strain susceptibility following MPTP administration acts in an autosomal sominant fashion: quantitative analysis in seven strains of musculus. Brain Res,1999,828:91-103
[58] Jakowec MW, Petzinger GM. MPTP-lesioned model of parkinson’s disease, with emphasis on mice and nonhuman primates. Comp Med, 2004,54(5):497-513
[59] Burns RS, Chiueh CC, Markey SP,et al. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by MPTP. Proc Natl Acad Sci USA, 1983, 80(14):4546-4550
[60] 张进禄,刘玉军,鲁强,等。单侧境内动脉注入 MPTP 建立偏侧帕金森病灵长类模型的研究。首都医科大学学报,1998,19:1-3
[61] 刘晟,王维,于小平,等。MPTP 诱导猴偏侧帕金森病模型的制作。中国医学影像学技术,2006,22(3):353-356
[62] 王伟,姜晓丹,徐如祥,等。颈内动脉注射 MPTP 制作偏侧恒河猴帕金森病模型研究。中国微侵袭神经外科杂志,2005,10(3):129-132
[63] Suwelsck D, Hurtado-Lorenzo A, Millan E, et al. Neuronal expression of the transcription factor Gli1 using the Talpha1 alpha-tubulin promoter is neuronprotective in an experimental model of Parkinson’s disease. Gene Ther,2004,11(24):1742-1752
[64] Takagi Y, Takahashi J,Saiki H, et al. Dopaminergic neurons generated from monkey embryonic stem cells fuction in a Parkinson primate model. J Clin Invest,2005,115(1):102-109
[65] Muramatsu Y, Kurosaki R, Watanabe H, et al. Cerebral alterations in a MPTP-mouse model of Parkinson’s disease- an immunocytochemical study. J Neural Transm,2003,10(10):1129-1144
[66] Anden NE. Effects of reserpine and a tyrosine hydroxylase inhibitor on the monoamine levels in different regions of the central nervous system. Eur J Pharmacol,1967,1:1-15
[67] Lapchak PA, Beck KD, Araujo DM, et al. Chronic intranigral administration of brain-derived neurontropic factor produces striatal dopaminergic hypodunction in unlesioned adult rats and fails to attenuate the decline of striatal dopaminergic function following medial forebrain bundle transaction. Neuroscience,1993,53:639-650
[68] Brecknell JE, Dunnett SB, Fawcett JWA. Wuantitative study of cell death in the substantia nigra following a mechanical lesion of the medical forebrain bundle. Neuroscience,1995,64:210-227
[69] 梁希彬,罗涌,卢峻,等。线刀毁损大鼠内侧前脑束建立部分损伤的帕金森病模型。神经解剖学杂志,2001,17(3):199-204
[70] Ben-Shachar Youdim MBH. Intranigral iron injection induces behavioraland biochemical “Parkinsonism” in rats. J Neurochem,1991,57:2133-2135
[71] Scherzer CR, Jensen RV, Gullans SR, et al. Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson’s disease. Hum Mol Genet,2003,12(19):2457-2466
[72] Legare ME, Hanneman WH. Genetic, biochemical, and characterization of neurological mutant 3, a new mouse model for Parkinson’s disease. Genet Mol Res,2002,2(3):288-294
[73] Kirik D, Annett LE, Burger C, et al. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci USA,2003,100(5):2884-2889
[74] Lindsten K, Menendez-Benito V, Masucci MG, et al. A transgenic mouse model of the ubiquitin/proteasome system, Nat Bioteacnol, 2003, 21(8):897-902
[75] Perez FA, Palmiter RD. Parkin-deficient mice are not a robust model of parkinsonism. Proc Nati Acad Sci USA,2005,102(6):2174-2179
[76] Vingerhoets FJG, Snow BJ, Tetrud JW, et al. Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions. Ann Neurol,1994,36(5):765-770
[77] 马羽,王运杰。脑深部电刺激术治疗帕金森病的疗效及机制研究。中国医科大学博士论文,2005:22-25
[78] Clarkc CE, Boycc S, Robterson RG, et al. Drug-induced dyskinesia in primates rendered hemiparkinsonism by intracarotid administration of MPTP. J Ncurol Sci,1989,90(3):307-314
[79] Bankiewicz KS, Oldfield EH, Chiueh CC, et al. Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of MPTP. Life Sci,1986,39(1):7-16
[80] Meissner W, Prunier C, Guilloteau D, et al. Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson’s disease. Mol Neurobiol,2003,28(3):209-218
[81] Castagnoli N Jr, Petzer JP, Steyn S, et al. Monoamine oxidase B inhibition and neuronprotection: studys on selective adenosine A2A receptor antagonists. Neurology,2003,61(11):S62-68
[82] Hill MP, Bezard E, McGuire SG, et al. Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset. Mov Disord,2003,18(11):1301-1305
[83] 汤克俭,徐德隆,余慧贞,等.自制 MPTP 制备恒河猴帕金森病模型评价.中国神经精神疾病杂志,1991,17(2):162-163
[84] Elsworth JD,Taylor JR,Sladek JR, et al.Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates one year after MPTP treatment. Neuroscience,2000,95(4):399-408
[85] Filion M, Trembiay L. Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res, 1991,547:142-151
[86] Filion M, Trembiay L, Bedard PJ. Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res,1991,547:151-161
[87] 何正友,蔡玉梅,钱清泉.小波熵理论及其在电力系统故障检测中的应用研究[J]中国电机工程学报,2005,25(5):38-43.
[88] 杨建平,阮文.基于小波包变换的图像消噪方法[J]井冈山师范学院学报,2005,26(3):17-19