Deep Brain Stimulation in Parkinson's Models

帕金森病模型中的深部脑刺激

• 批准号: 6630512
• 负责人: MARJORIE E ANDERSON
• 金额: $ 39.67万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630512
• 关键词: Macaca fascicularis; Parkinson's disease; basal ganglia; behavior test; brain electrical activity; brain imaging /visualization /scanning; disease /disorder model; dopamine; electrical measurement; electrophysiology; frontal lobe /cortex; histochemistry /cytochemistry; magnetic resonance imaging; neural transmission; neurons; pesticide biological effect; positron emission tomography; thalamus

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.

描述（由申请人提供）： 虽然苍白球或丘脑底核的高频脑深部电刺激（HF-DBS）已成为治疗帕金森病耐药症状的常用技术，但HF-DBS发挥其作用的机制尚不清楚。在拟议的研究中，将首先在猴子中测试长期施用杀虫剂鱼藤酮以产生帕金森病动物模型的能力。使用华盛顿大学区域灵长类动物研究中心现有的PET成像，使用多巴胺能神经末梢中存在的单胺囊泡转运蛋白标记物测量鱼藤酮给药后多巴胺神经支配的变化。随着时间的推移，这些变化将与行为变化以及丘脑基底节接收区神经元放电速率和模式的电生理变化相关。 然后，该模型将用于耦合HF-DBS的电生理效应，其可以从丘脑的基底神经节接收神经元记录，以刺激诱导的皮质和丘脑区域代谢的变化。将使用代谢标记物[8-F]氟脱氧葡萄糖（FDG）的PET成像来测量代谢。该技术通常显示帕金森病患者的苍白球和丘脑中的相对高代谢，以及额叶皮质区域中的相对低代谢。然而，报告的HF-DBS引起的变化喜忧参半。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的一些差异。 特别注意的是，在用鱼藤酮处理的猴子的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。这将测试的假设，帕金森氏病的一些神经病学，其缓解使用高频DBS，是一个结果的异常模式的活动在基底神经节-丘脑-皮质电路。