Neurophysiological mechanisms underlying parkinsonian motor signs

帕金森运动体征背后的神经生理机制

• 批准号: 7365022
• 负责人: Gary S. Russo
• 金额: $ 51.54万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365022
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Affect; Animals; Anterior; Area; Basal Ganglia; Bradykinesia; Brain; Cell Nucleus; Characteristics; Deep Brain Stimulation; Development; Dose; Electric Stimulation; Evolution; Face; Fiber; Frequencies; Future; Globus Pallidus; Goals; Implant; Incidence; Individual; Intervention; Lesion; Limb structure; Mediating; Modeling; Monkeys; Motor; Motor Cortex; Movement; Movement Disorders; Muscle Rigidity; Nerve Degeneration; Neurons; Neurotoxins; Nodal; Numbers; Operative Surgical Procedures; Parkinson Disease; Parkinsonian Disorders; Pattern; Process; Property; Range; Rate; Relative (related person); Reporting; Role; Severities; Signal Transduction; Specificity; Staging; Structure; Structure of subthalamic nucleus; Symptoms; Testing; Thalamic structure; Tremor; base; brain cell; gene therapy; improved; neurophysiology; programs; receptive field; relating to nervous system; response

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.

描述（由申请人提供）：这项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，这些变化是帕金森氏病（PD）的三个基本电动机迹象，这是Bradykinesia，僵化和震颤的发展和严重性。这将通过在同一猴子中使用顺序的低剂量神经毒素1-甲基-4-苯基-4-苯基-1,2,3,6-四氢吡啶（MPTP）在同一猴子中的正常，轻度，中和重度症状中进行单个神经元活性来完成。将要检查的结构包括plobus pallidus（GPI和GPE）的内部和外部段，丘脑下核（STN）以及运动丘脑，包括前腹侧前，腹侧腹侧侧侧侧侧pars pars Oralis和腹侧腹侧后期。具体目的1和2将确定基底神经节网络中这些淋巴结点上神经元活性的特征，这是Bradykinesia，僵硬和震颤的发展，并表征了这些运动迹象严重程度增加的神经元活动变化的演变。具体的目标2还将确定每个丘脑亚核对单个运动标志的纤维保留病变的相对影响。具体目标3将评估在特定目标1和2中发现的神经生理活性特定变化的因果作用。这将通过在正常猴子中繁殖STN和GPI的这些神经生理学变化来完成，并在这些Nodal点使用外部编程的植入式刺激器在Parkinsonian猴子中增强它们。通过检查在PD不同阶段发生的神经生理变化，并将其与单个运动症状的发生和严重程度有关，我们将能够阐明与PD相关的运动符号的发育和严重性的神经元基础。反过来，这将提供基于有希望的新疗法（例如深脑刺激和基因疗法）的基本原理，这些疗法旨在调节基底神经节丘脑回路中的神经元活性。这项研究的目的是确定引起帕金森氏病（PD）运动问题的脑细胞活性的特定变化。患有PD的人会出现特定的问题，其运动表现为缓慢（Bradykinesia），僵硬（刚度）和四肢和面部（震颤）中无法控制的节奏运动。这项研究将确定导致每种运动症状的大脑活动的特定变化，并确定它们与每种症状的严重程度的增加有关。这项研究的结果将提供对当前和未来疗法发展的必要理解，例如深脑刺激和基因疗法，旨在调节负责PD运动症状发展的基底神经节丘脑回路中的神经元活性。