【作者】 王举磊；

【导师】 高国栋； 胡三觉； 陈军； 王学廉；

【作者基本信息】 第四军医大学 ， 外科学， 2008， 博士

【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。更多还原

【Abstract】 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.. ObjectiveAnalysis 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.ConclusionThe 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.更多还原