Deep Brain Stimulation in Parkinson's Models

描述(由申请人提供)： 虽然苍白球或丘脑底核的高频深部脑刺激(HF-DBS)已成为治疗帕金森病耐药症状的常用技术，但HF-DBS发挥作用的机制尚不清楚。在拟议的研究中，长期服用杀虫剂鱼藤酮的能力将首先在猴子身上进行测试，以产生帕金森氏症的动物模型。使用现已在华盛顿大学区域灵长类研究中心提供的PET成像，将使用多巴胺能神经末梢中存在的单胺囊状转运体的标记来测量服用鱼藤酮后多巴胺神经支配的变化。随着时间的推移，这些变化将与行为的变化以及丘脑基底神经节接受区神经元放电速度和模式的电生理变化相关。 然后，这个模型将被用来将HF-DBS的电生理效应与刺激诱导的皮质和丘脑区域新陈代谢的变化联系起来。HF-DBS可以从丘脑的基底神经节接收神经元记录到。带有代谢标记物[8-F]氟代脱氧葡萄糖(FDG)的PET成像将用于测量新陈代谢。这项技术通常显示帕金森氏症患者苍白球和丘脑的代谢相对较高，而额叶皮质的代谢相对较低。然而，据报道，HF-DBS引起的变化好坏参半。电生理学和代谢成像的结合将使我们能够解决与人类文献中的一些差异。 将特别关注用鱼藤酮处理的猴子丘脑中爆发行为的异常模式的发展，以及HF-DBS对爆发行为的影响。这将检验这样一种假设，即帕金森病的一些症状，以及使用HF-DBS缓解帕金森病，是基底节-丘脑-皮质环路活动异常模式的结果。

DESCRIPTION (provided by applicant): Although high-frequency deep brain stimulation (HF-DBS) in the globus pallidus or subthalamic nucleus has become a common technique used to treat drug-resistant symptoms of Parkinson's disease, the mechanisms by which HF-DBS exerts its effects are unknown. In the proposed studies, the ability of chronic administration of the insecticide rotenone, to produce an animal model of Parkinson's disease will first be tested in monkeys. Using PET imaging now available in the University of Washington Regional Primate Research Center, changes in dopamine innervation after administration of rotenone will be measured using a marker of the monoamine vescicular transporter that is present in dopaminergic nerve terminals. These changes will then be correlated, over time, with changes in behavior and with electrophysiological changes in the rate and pattern of discharge of neurons in basal ganglia-receiving areas of the thalamus. This model will then be used to couple the electrophysiological effects of HF-DBS, which can be recorded from basal ganglia-receiving neurons of the thalamus, to the stimulation-induced changes in regional metabolism in the cortex and thalamus. PET imaging with the metabolic marker, [8-F] flurodeoxyglucose (FDG), will be used to measure metabolism. This technique has generally shown a relative hypermetabolism in the globus pallidus and thalamus of humans with Parkinson's disease and a relative hypometabolism in areas of the frontal cortex. Changes reported to be induced by HF-DBS have been mixed however. The combination of electrophysiology and metabolic imaging will allow us to address some of the discrepancies from the human literature. Special attention will be paid to the development of abnormal patterns of bursting behavior in the thalamus of monkeys treated with rotenone, as well as the effect of HF-DBS on burst behavior. This will test the hypothesis that some of the symptomatology of Parkinson's disease, and its relief using HF-DBS, is a consequence of abnormal patterns of activity in basal ganglia-thalamic-cortical circuits.