Pallidal Physiology in Human and Primate Dystonia

描述（由申请人提供：肌张力障碍是一种运动障碍，定义为持续肌肉收缩综合征，导致扭曲和重复运动以及异常姿势。它往往是毁灭性的，其病理生理学知之甚少。最近，人们试图从涉及皮层、基底神经节和丘脑的环路改变的角度来理解运动障碍。苍白球内（GPi）在这个回路中占据关键位置，因为它是基底神经节的主要输出结构。另一种运动障碍，帕金森病（PD），已被发现与过度和异常模式的GPi活动。这一发现导致通过苍白球失活改善PD的手术治疗。 相反，PD，更好地了解肌张力障碍已受到阻碍，缺乏数据的生理基础神经节在这种情况下，并缺乏一个良好的特点非人灵长类动物模型的肌张力障碍。这两个问题都在这项正在进行的研究中得到解决。在最初的三年里，我们记录并分析了14例肌张力障碍患者的283个苍白球单位，正常恒河猴的74个单位和4例帕金森病患者的75个单位。人类患者接受电生理标测作为苍白球手术治疗运动障碍的常规部分。我们发现，与正常猕猴相比，肌张力障碍与GPi中的神经元活动减少有关，在大多数情况下，但不是所有情况下，GPi中的爆裂活动增加，以及外部苍白球中的活动略有减少。这些数据支持肌张力障碍的模型，其中基底神经节的直接和间接通路都过度活跃。然而，有些病例在放电率或放电模式上几乎没有异常，这促使人们继续寻找肌张力障碍的“标志性”异常。此外，我们开始在恒河猴中开发局灶性臂肌张力障碍模型，其中肌张力障碍是由熟练运动任务的重复执行产生的。 在拟议的延续，自发和运动相关的放电GPi将在10个额外的肌张力障碍患者进行研究，新的重点是神经元的感觉反馈和交叉相关的同时记录的细胞。在肌张力障碍的猕猴模型中，将分析毁损苍白球对运动性能的影响。 实验测试了以下假设：1）人类的特发性肌张力障碍与GPi中异常的神经元同步性和对体感检查的异常反应有关。2)在非人类灵长类动物中，由重复手臂运动任务诱导的肌张力障碍可以通过GPi的病变来改善，从而建立了该模型与人类特发性肌张力障碍的相关性。 这些实验应该允许完善现有的肌张力障碍的病理生理学的理论，并提供了一个更好的理由苍白球手术的肌张力障碍。在大型非人类灵长类动物中开发动物模型将为进一步详细研究肌张力障碍中的基底神经节生理学提供可能性，超出人类手术期间可能的研究范围。

DESCRIPTION (provided by applicant: Dystonia is a movement disorder defined as a syndrome of sustained muscle contractions, causing twisting and repetitive movements, and abnormal postures. It is often devastating and its pathophysiology is poorly understood. Recently, attempts have been made to understand movement disorders in terms of alterations in a loop circuit involving the cortex, basal ganglia and thalamus. The globus pallidus internus (GPi) occupies a critical position in this circuit since it is the major output structure of the basal ganglia. Another movement disorder, Parkinson's disease (PD), has been found to be associated with excessive and abnormally patterned GPi activity. This finding has led to improved surgical treatments for PD by pallidal inactivation. In contrast to PD, a better understanding of dystonia has been hampered by a lack of data on the physiology of the basal ganglia in this condition, and by the lack of a well-characterized nonhuman primate model of dystonia. Both problems are addressed in this ongoing study. In the initial three years, we recorded and analyzed 283 pallidal units in 14 patients with dystonia, 74 units in a normal Rhesus macaque, and 75 units from four patients with Parkinson's disease. Human patients undergo electrophysiologic mapping as a routine part of pallidal surgery for movement disorders. We showed that, in comparison with normal macaque, dystonia is associated with reduced neuronal activity in the GPi in most but not all cases, increased bursting activity in GPi, and a slight reduction in activity in the external pallidum. These data lend support to a model of dystonia in which both direct and indirect pathways of the basal ganglia are overactive. However, some cases show little abnormality in discharge rate or pattern, motivating a continued search for a "signature" abnormality in dystonia. In addition, we began development of a model of focal arm dystonia in the Rhesus macaque, in which dystonia is generated by repetitive performance of a skilled motor task. In the proposed continuation, spontaneous and movement-related discharge in GPi will be studied in ten additional dystonia patients, with a new emphasis on neuronal responses to sensory feedback and cross correlation of simultaneously recorded cells. In the macaque model of dystonia, the effect on motor performance of lesioning the globus pallidus will be analyzed. The experiments test the following hypotheses: 1) Idiopathic dystonia in humans is associated with abnormal neuronal synchrony and abnormal responses to somatosensory examination in the GPi. 2) In non-human primates, dystonia induced by a repetitive arm movement task can be ameliorated by lesions of the GPi, establishing the relevance of this model to human idiopathic dystonias. These experiments should allow refinement of existing theories of the pathophysiology of dystonia, and provide a better rationale for pallidal surgery in dystonia. Development of an animal model in a large nonhuman primate will open the possibility for further detailed investigations of basal ganglia physiology in dystonia, beyond those which are possible during human surgery.