帕金森病患者的运动症状与基底节神经元振荡活动相关性研究

Degeneration of nigral dopaminergic neurons is associated with motor signs of Parkinson's disease (PD) which include bradykinesia, rigidity and tremor. Changes in the firing rate of basal ganglia neurons are believed to result in PD symptoms. Contrary to the rate-based hypothesis, the pathophysiology of PD is often correlated with abnormal burst firing and oscillatory activity in the basal ganglia. Single multi-units activity and local field potential (LPFs) recorded from parkinsonian animals and patients have shown that oscillatory activity and neuronal synchronization in the globus pallidus internus (GPi) and the subthalamic nucleus (STN) include two major frequency bands: the "tremor frequency" 3-8 Hz band and the higher "8-30 Hz" beta band. However, the exact role of neuronal oscillations in the basal ganglia in relation to PD symptoms remains unclear. Our previous studies found that beta oscillations in the STN were associated with bradykinesia and rigidity; tremor frequency oscillations were associated with tremor. Stimulation or lesioning resulted in abolishing the parkinsonian motor symptoms, respectively. Thus, we predict that the oscillations in the basal ganglia nucleus such as STN or GPi might directly involve in the pathophysiology of bradykinesia, rigidity. The oscillations in the motor thalamus might mainly involve in tremor genesis. The interactions affecting both neuronal oscillation and firing rate in the basal ganglia play a critical role in the development of parkinsonian motor signs. We take advantage of a series patients with PD who undergo surgery either deep brain stimulation or lesioning for the treatment by investigating the relationship between the oscillatory activity in the basal ganglia and pakinsonian motor signs. The present study will focus on study of the neuronal oscillations in the BG in relation to parkinsonian motor signs. The motor thalamus will be used as a comparison. The first goal of the project is to identify characteristics of neuronal oscillatory activity in the basal ganglia. The second goal is to explore the relationship between neuronal oscillations in the basal ganglia in relation to parkinsonian motor signs. In particular, we should answer questions that whether the beta oscillation is associated with bradykinesia and rigidity or not. We believe that findings of the project will provide more detailed information to understand the role of neuronal oscillations and firing rate as well in the basal ganglia in relation to parkinsonia motor signs. We also believe that the results will be useful for the development of therapeutic treatment for PD.

揭示基底节异常电活动与帕金森病（PD）症状的关系是研究热点。频率假说提出多巴胺缺失导致基底节神经元放电频率的改变与PD症状相关，而振荡活动假说则认为同步化振荡活动起到重要作用，至今尚未得到证实。我们认为基底节神经元放电频率的改变与同步化振荡活动的相互效应起到关键作用。我们发现β频谱振荡活动与运动迟缓僵直相关，α频谱振荡活动与震颤相关，振荡活动神经元的放电频率高于非振荡活动神经元，手术干预振荡活动神经元的位置改善PD，这些发现对于揭示基底节异常活动与PD症状的关系有重要意义。本项目拟利用手术治疗PD患者的优势，应用微电极和肌电同步化记录技术，围绕僵直迟缓型、僵直迟缓伴震颤型和震颤型患者，以基底节核团STN 和GPi为研究对象，拟阐明基底节:(1)振荡活动神经元特点;(2)与PD症状的关系;(3)是否主要参与迟缓、僵直;(4)是否参与震颤，以期揭示PD运动症状的病理生理，为临床治疗提供依据。

依据帕金森病（PD）基底节病理生理假说，黑质多巴胺缺失导致基底节神经元的异常改变（包括频率、振荡活动）参与PD运动症状。本研究围绕不同类型PD患者基底节异常振荡活动神经元放电特点进行研究, 拟阐明与PD运动症状的关系。依照研究计划，本研究以基底节核团STN 和GPi为研究对象，Vop（GPi投射区）/Vim（小脑投射区）为对照。通过峰间隔、功率谱及其相干性等分析方法研究发现: .1. STN 和GPi及其Vop/Vim 存在不同类型的振荡活动神经元，包括震颤节律；β节律和无振荡活动神经元;.2. STNβ振荡活动神经元与僵直迟缓型PD的肢体肌电相关，提示β振荡活动直接参与PD的僵直迟缓; 另外，与混合型PD相比，僵直迟缓型患者存在大量的β振荡活动神经元,提示不同类型的异常振荡活动神经元的数量在PD症状起到重要作用；.3. 发现STN 振荡活动神经元频率和模式比例的增加与PD症状进展相关：与早期患者STN相比，进展期PD患者的STN神经元放电频率增加29.6%； 振荡活动神经元增加36.8%，β振荡活动神经元增加77.8%，而震颤节律振荡活动神经元减少33.0%, 表明放电频率和β振荡活动神经元在进展型寄到重要作用； .4. 发现STN, GPi振荡活动神经元放电频率和比例与Vop和Vim不同， 结果发现： 1) GPi神经元放电频率的增加而Vop放电频率的显著减低支持PD病理生理假说； 2) STN和GPi β振荡活动神经元比例显著高于Vop/Vim，支持假说纹状体多巴胺的缺失导致基底节β振荡活动神经元增加；3) 基底节和Vop/Vim都存在与震颤相关振荡活动神经元提示基底节环路和小脑环路共同参与PD震颤；而与基底节相比，Vim存在与震颤相关的振荡活动神经元显著高于基底节核团，支持假说小脑环路可能在震颤发生发展起到关键作用。.5. 在80例患者行STN DBS治疗的4.9年随访研究中发现: 1) PD僵直、震颤和混合型患者对STN长期刺激反应不同，STNDBS对僵直迟缓型显示最佳疗效； 2) STN DBS在药物“开合关”状态显示对震颤的持续效应，提示震颤与多巴胺缺失并不直接相关。该结果提示PD僵直迟缓型与基底节-丘脑皮层环路相关而震颤型可能与小脑-丘脑-皮层环路相关。