Neurophysiological mechanisms underlying parkinsonian motor signs

描述（由申请人提供）：本研究的目的是确定基底神经节丘脑网络中特定的神经生理变化，这些变化是帕金森病（PD）的三个主要运动体征——运动迟缓、强直和震颤的发展和严重程度的基础。这将通过使用连续低剂量的神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），比较同一只猴子在正常、轻度、中度和重度帕金森症状时的单个神经元活动来完成。将被检查的结构包括苍白球的内部和外部节（分别为GPi和GPe）、丘脑下核（STN）和运动丘脑，包括前腹肌、口部腹侧肌和口部腹后侧肌。具体目标1和2将确定基底神经节网络中这些节点的神经元活动特征，这些节点是运动迟缓、强直和震颤发展的基础，并表征随着这些运动体征严重程度的增加而发生的神经元活动变化的演变。具体目标2还将确定每个丘脑亚核纤维保留病变对个体运动体征的相对影响。具体目标3将评估在具体目标1和2中发现的神经生理活动的特定变化的因果作用。这将通过在正常猴子的STN和GPi中复制这些神经生理变化，并在轻度帕金森猴子的这些节点上使用外部编程植入的刺激器来增强这些变化来实现。通过检查PD不同阶段发生的神经生理变化，并将其与个体运动症状的发生和严重程度联系起来，我们将能够阐明PD相关运动症状发展和严重程度的神经元基础。这将反过来为有前途的新疗法的发展提供理论基础，如深部脑刺激和基因疗法，这些疗法旨在调节基底神经节丘脑回路中的神经元活动。本研究的目的是确定导致帕金森病（PD）运动问题的基底节区脑细胞活动的具体变化。帕金森氏症患者在运动方面有特殊的问题，表现为运动迟缓（运动迟缓）、僵硬（僵硬）以及四肢和面部无法控制的节律运动（震颤）。这项研究将确定导致每种运动症状的大脑活动的具体变化，并确定它们与每种症状的严重程度增加之间的关系。这项研究的结果将为改进当前和未来治疗方法的发展提供必要的理解，例如，深部脑刺激和基因治疗，旨在调节与PD运动症状发展有关的基底神经节丘脑回路中的神经元活动。

DESCRIPTION (provided by applicant): The goal of this study is to identify the specific neurophysiological changes in the basal ganglia thalamic network that underlie the development and severity of bradykinesia, rigidity and tremor, the three cardinal motor signs of Parkinson's disease (PD). This will be done by comparing single neuron activity during normal, mild, moderate and severe parkinsonian symptoms in the same monkeys using sequential low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Structures that will be examined include the internal and external segments of the globus pallidus (GPi and GPe, respectively), the subthalamic nucleus (STN), and the motor thalamus including ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis. Specific aims 1 and 2 will determine the characteristics of neuronal activity at these nodal points within the basal ganglia network that underlie the development of bradykinesia, rigidity and tremor and characterize the evolution of changes in neuronal activity that occur with increasing severity of these motor signs. Specific aim 2 will also determine the relative effect of fiber sparing lesions of each thalamic subnucleus on individual motor signs. Specific aim 3 will assess the causal role of the particular changes in neurophysiological activity found to occur in specific aims 1 and 2. This will be done by reproducing these neurophysiological changes in the STN and GPi in normal monkeys and augmenting them in mildly parkinsonian monkeys using externally programmed implanted stimulators at these nodal points. By examining the neurophysiological changes that occur at different stages of PD and relating them to the occurrence and severity of individual motor symptoms, we will be able to clarify the neuronal basis underlying the development and severity of motor signs associated with PD. This will in turn provide the rationale from which to base the development of promising new therapies such as deep brain stimulation and gene therapy that are directed at modulating neuronal activity in the basal ganglia thalamic circuit. The goal of this study is to identify the specific changes in the activity of brain cells in the basal ganglia that cause the movement problems in Parkinson's disease (PD). People with PD develop specific problems with movement manifested as slowness (bradykinesia), stiffness (rigidity), and uncontrollable rhythmic movements in the extremities and face (tremor). This study will identify the specific changes in brain activity that cause each motor symptom and determine how they are related to increasing severity of each symptom. The results of this study will provide the understanding necessary for the refinement of current and development of future therapies, e.g., deep brain stimulation and gene therapy, directed at modulating the neuronal activity in the basal ganglia thalamic circuit responsible for the development of PD motor symptoms.