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。反应时间任务（RTt），一种测量感觉运动反应的行为测试，在帕金森病患者中受损。在PD动物模型中也发现RTt受损。损毁的丘脑能够恢复反应时间的反应，是破坏黑质纹状体多巴胺损伤的大鼠。在过去的十年中，丘脑底核（subthalamic nucleus，DBS）的脑深部电刺激（Deep brain stimulation，DBS）越来越多地用于临床以减轻帕金森综合征（Parkinsonian syndrome，PS）。由于缺乏用于DBS研究的大鼠行为模型，阻碍了对DBS治疗作用的神经机制的理解。本研究将联合收割机结合先进的慢性、多通道、单单位记录技术和独特的大鼠DBS方法，研究黑质纹状体多巴胺损伤大鼠进行RT的神经反应。目的是使用DBS恢复RT性能作为自愿运动的测试。将64个记录电极植入运动皮层、苍白球、丘脑和黑质网状部（SNr），将4对刺激电极植入丘脑和SNr。将在RTt期间同时记录细胞外尖峰活性。对照组结束后，双侧纹状体注射6-OHDA，造成黑质纹状体多巴胺系统的损伤。将多巴胺损伤后的行为和电生理结果与对照条件下获得的结果进行比较，以揭示多巴胺耗竭的影响。然后在RTt期间施加多巴胺和SNr的高频刺激（HFS）以抵消多巴胺耗竭对RTt的不利影响。本研究将阐明在PD的病理生理发展过程中，神经反应介导的RTt的不同方面。将通过分析行为有效DBS期间的单个和集合神经反应来测试DBS的DBS和SNr将恢复基底神经节丘脑皮质回路中的正常神经处理的假设。该建议的目的是了解DBS对PD影响的基本神经机制。本研究的最终目标是将DBS植入到已被充分理解的病理生理学基底节-丘脑皮质网络模型中，从而能够恢复正常的网络功能来治疗PD。这项研究将主要在中国北京大学进行，作为NIH资助R 01-NS 43441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.