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: 8029519
• 负责人: KENNETH B BAKER
• 金额: $ 59.33万
• 依托单位: UNIVERSITY OF MINNESOTA
• 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/8029519
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Affect; Animals; Anterior; Area; Basal Ganglia; Bradykinesia; Brain; Cell Nucleus; Characteristics; Data; Deep Brain Stimulation; Development; Dose; Evolution; Face; Fiber; Frequencies; Future; Globus Pallidus; Goals; Implant; Incidence; Individual; Intervention; Lesion; Limb structure; Mediating; Modeling; Monkeys; Motor; Motor Cortex; Movement; Movement Disorders; Nerve Degeneration; Neurons; Neurotoxins; Nodal; Parkinson Disease; Parkinsonian Disorders; Pattern; Physiological; Principal Investigator; Process; Property; Relative (related person); Reporting; Research Personnel; Role; Severities; Specificity; Staging; Structure; Structure of subthalamic nucleus; Symptoms; Testing; Thalamic structure; Time; Tremor; base; brain cell; gene therapy; improved; neuron development; 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）：本研究的目的是确定丘脑基底节网络中特定的神经生理学变化，这些变化是运动迟缓、强直和震颤（帕金森病（PD）的三个主要运动体征）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) 比较同一只猴子的正常、轻度、中度和重度帕金森病症状期间的单个神经元活动来完成。将检查的结构包括苍白球的内部和外部部分（分别为 GPi 和 GPe）、丘脑底核 (STN) 和运动丘脑，包括前腹肌、口外侧腹肌和口外侧腹肌。具体目标 1 和 2 将确定基底神经节网络内这些节点处神经元活动的特征，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的纤维保留损伤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特定变化的因果作用。这将通过在正常猴子中重现 STN 和 GPi 中的这些神经生理变化并使用以下方法在轻度帕金森猴中增强它们来完成在这些节点处植入外部编程的刺激器。通过检查帕金森病不同阶段发生的神经生理学变化，并将其与个体运动症状的发生和严重程度联系起来，我们将能够阐明与帕金森病相关的运动体征的发展和严重程度的神经元基础。这反过来将为开发有前景的新疗法（例如旨在调节基底节丘脑回路中的神经元活动的深部脑刺激和基因疗法）提供基础。本研究的目的是确定导致帕金森病 (PD) 运动问题的基底神经节脑细胞活动的具体变化。帕金森病患者会出现特定的运动问题，表现为四肢和面部的缓慢（运动迟缓）、僵硬（僵硬）以及无法控制的节律性运动（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严重程度的增加之间的关系。这项研究的结果将为完善当前和未来疗法的发展提供必要的理解，例如深部脑刺激和基因疗法，旨在调节负责 PD 运动症状发展的基底节丘脑回路中的神经元活动。