Effects of DBS on sensorimotor processes

描述(由申请人提供) 帕金森病(Parkinson‘s Disease，PD)是最常见的神经退行性疾病之一。反应时任务(RTT)是一种测量感觉运动反应的行为测试，在帕金森氏症患者中存在损害。在帕金森病动物模型中也发现了RTT的损害。损毁STN能够恢复被黑质纹状体多巴胺损毁的大鼠的反应时反应。近十年来，丘脑底核(STN)脑深部电刺激(DBS)治疗帕金森综合征(PS)的临床应用日益广泛。缺乏用于DBS研究的大鼠行为模型，阻碍了理解DBS治疗作用的神经机制的努力。这项建议将结合先进的慢性、多通道、单单位记录技术和大鼠独特的DBS方法来研究黑质纹状体多巴胺损毁大鼠进行RTT的神经反应。目标将是使用DBS来恢复RT表现，作为自愿运动的测试。64个记录电极植入运动皮质、苍白球、STN和黑质网状部(SNR)，4对刺激电极植入STN和SNR。在RTT期间，将同时记录细胞外的尖峰活动。对照结束后，双侧纹状体内注射6-羟多巴胺，损毁黑质纹状体多巴胺系统。将多巴胺损毁后的行为和电生理结果与对照条件下的结果进行比较，以揭示多巴胺耗竭的影响。然后在RTT期间对STN和SNR进行高频刺激(HFS)，以抵消多巴胺耗竭对RTT的不利影响。本研究将阐明帕金森病病理生理发展过程中调节RTT不同方面的神经反应。STN和SNR的DBS将恢复基底节丘脑皮质环路的正常神经处理的假设将通过分析行为有效DBS期间的单个和整体神经反应来检验。这项建议的目的是了解DBS对帕金森病影响的基本神经机制。将DBS纳入众所周知的病理生理基底节-丘脑皮质网络模型，从而能够恢复正常的网络功能来治疗帕金森病是本研究的最终目的。这项研究将主要在北京大学中国进行，作为美国国立卫生研究院R01-NS43441号拨款的延伸。

DESCRIPTION (provided by applicant) Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorders. Reaction time task (RTt), a behavioral test measuring the sensorimotor reaction, is impaired in Parkinsonian patients. Impairment of RTt was also found in the animal model of PD. Lesion of the STN is able to restore the reaction time response that is disrupted by nigrostriatal dopamine lesion in the rat. Deep brain stimulation (DBS) of subthalamic nucleus (STN) has been used increasingly in the clinic to alleviate Parkinsonian syndromes (PS) during the past decade. Lack of behavioral model of rats for DBS research has hampered efforts to understand the neural mechanisms underlying the therapeutic effects of DBS. This proposal will combine advanced chronic, multiple-channel, single unit recording technique with unique DBS methods in the rat to study the neural responses in nigrostriatal dopamine lesioned rats performing RTt. An aim will be to use DBS to restore RT performance as a test of voluntary movement. Sixty-four recording electrodes will be implanted into the motor cortex, the globus pallidus, the STN, and the substantia nigra pars reticulata (SNr) and 4 pair of stimulation electrodes into the STN and SNr. Extracellular spike activity will be recorded simultaneously during RTt. After control sessions are completed, lesion of nigrostriatal dopamine system will be made by injection of 6-OHDA into both sides of striatum. The behavioral and electrophysiologic results after dopamine lesion will be compared with that obtained from the control condition to reveal the effects of dopamine depletion. High frequency stimulation (HFS) of STN and SNr will then be applied during RTt to counteract the adverse effects of dopamine depletion on RTt. This study will illustrate the neural responses mediating different aspects of RTt during the pathophysiological development of PD. The hypothesis that DBS of STN and SNr will restore normal neural processing in the basal ganglia thalamocortical circuit will be tested by analyzing the single and ensemble neural responses during behaviorally effective DBS. The aim of this proposal is to understand the fundamental neural mechanisms underlying the effects of DBS on PD. Incorporating the DBS into the well understood pathophysiological basal ganglia-thalamocortical network model and thus being able to restore normal network function to treat PD is the ultimate goal of this study. This research will be done primarily at Peking University in China as an extension of NIH grant R01-NS43441.