Pallidal Physiology in Human and Primate Dystonia

描述(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的综合征，导致扭曲和重复的运动，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，人们试图从涉及皮质、基底节和丘脑的环路改变的角度来理解运动障碍。苍白球内侧核(GPI)是基底节的主要输出结构，在该回路中占有重要地位。另一种运动障碍，帕金森氏病(PD)，已被发现与过度和异常的GPI活动有关。这一发现通过苍白球失活改进了帕金森病的外科治疗。 与帕金森病不同的是，对肌张力障碍的更好理解一直受到缺乏关于这种情况下基底节生理学的数据的阻碍，以及缺乏具有良好特征的非人类灵长类动物肌张力障碍的模型。这两个问题都在这项正在进行的研究中得到了解决。在最初的三年里，我们记录和分析了14名肌张力障碍患者的283个苍白球单位，74个正常猕猴的单位，以及4个帕金森病患者的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，肌张力障碍在大多数情况下(但不是所有情况下)与GPI中的神经元活性降低、GPI中的爆发性活动增加以及外部苍白球中的活动轻微减少有关。这些数据支持一种肌张力障碍的模型，在该模型中，基底神经节的直接和间接通路都过度活跃。然而，一些病例在放电频率或模式方面几乎没有异常，这促使人们继续寻找肌张力障碍的“标志性”异常。此外，我们开始在猕猴身上建立局灶性手臂肌张力障碍的模型，其中肌张力障碍是通过重复执行熟练的运动任务而产生的。 在建议的继续研究中，将在另外10名肌张力障碍患者中研究GPI的自发和运动相关放电，新的重点是神经元对感觉反馈的反应和同时记录的细胞的相互关联。在肌张力障碍猕猴模型中，将分析损毁苍白球对运动能力的影响。 实验验证了以下假设：1)人类特发性肌张力障碍与GPI中神经元的异常同步性和对躯体感觉检查的异常反应有关。2)在非人类灵长类动物中，由重复的手臂运动任务引起的肌张力障碍可以通过损伤GPI来改善，这建立了这个模型与人类特发性肌张力障碍的相关性。 这些实验应该可以完善现有的肌张力障碍的病理生理学理论，并为苍白球手术治疗肌张力障碍提供更好的理论基础。在大型非人灵长类动物中建立动物模型将为进一步详细研究肌张力障碍的基底节生理学提供可能，而不是人类手术中可能的研究。

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.