Dorsal Column Stimulation as a New Therapy for Motor Disorders

背柱刺激作为运动障碍的新疗法

• 批准号: 8284352
• 负责人: Miguel A. L. Nicolelis
• 金额: $ 76.34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284352
• 关键词: Acute; Address; Adult; Age; Agonist; Alternative Therapies; Animal Model; Area; Basal Ganglia; Body Weight; Brain; Catalepsy; Chest; Chronic; Clinical; Competence; Corpus striatum structure; Deep Brain Stimulation; Diagnosis; Disease Management; Dopamine; Dorsal; Electric Stimulation; Electrical Stimulation of the Brain; Electrodes; Epilepsy; Exploratory Behavior; Feeding behaviors; Frequencies; Future; Genetic; Globus Pallidus; Human; Implant; Laboratories; Lead; Lesion; Levodopa; Life; Link; Locomotion; Long-Term Effects; Longevity; Macaca mulatta; Modeling; Monkeys; Motor; Motor Cortex; Mus; Nerve Degeneration; Neurons; Neurostimulation procedures of spinal cord tissue; Night Monkey; Northern Night Monkey; Outcome; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Patients; Peripheral Nerves; Population; Primates; Procedures; Property; Protocols documentation; Quality of life; Rattus; Resort; Risk; Rodent; Rodent Model; Seizures; Spinal Cord; Staging; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Surface; Symptoms; Testing; Thalamic structure; Therapeutic; Therapeutic Effect; Translating; Trigeminal nerve structure; Work; clinical application; design; dopaminergic neuron; dorsal column; drinking behavior; efficacy testing; flexibility; grasp; minimally invasive; mitochondrial dysfunction; motor control; motor disorder; motor impairment; neurological pathology; neuromechanism; neurophysiology; nonhuman primate; novel; novel therapeutics; pars compacta; programs; relating to nervous system; retinal rods; sensory cortex; treatment strategy

DESCRIPTION (provided by applicant): In Parkinson's disease (PD), degeneration of dopaminergic neurons enervating the striatum causes progressive impairment of motor function. Treatment strategies involve repetitive administration of dopaminergic precursors or agonists. Although very effective, these strategies decline in efficacy in the long- term. The electrical stimulation of subcortical areas of the brain (deep brain stimulation - DBS) is an effective alternative option, which is rather restricted due to its invasiveness and associated risks. Epidural electrical stimulation of the dorsal spinal cord (dorsal column stimulation - DCS) at the upper thoracic level can lead to a dramatic and instantaneous improvement of locomotion in acute and chronic rodent models of PD. This finding has the potential to translate into a minimally invasive, easy to perform, and inexpensive new treatment for PD, available to a broader group of patients. We propose a comprehensive study addressing the mechanisms and efficacy of DCS using different animal models of PD. Our first specific aim is to study the neuronal mechanisms through which DCS achieves its therapeutic effects; we will use Parkinsonian 6-hydroxydopamine striatal lesioned rats implanted with multi-electrode arrays in eight brain areas, including striatum, subthalamic nucleus, globus pallidus, motor and sensory cortices, thalamus, and substantia nigra pars compacta. The effect of DCS on brain activity will be analyzed in terms of neuronal firing rate and oscillatory and synchrony properties of neuronal populations. In the second specific aim, we will evaluate the long term efficacy of DCS. Mice with a genetic mitochondrial dysfunction, which develop progressive dopaminergic neurodegeneration and severe motor impairment through adult life, will be treated daily with DCS from age 8 weeks until the end of their lives (on average about 28 weeks). Open field activity, catalepsy tests and rotating rod tests will be used to evaluate their motor function and compare it to a sham treated group and a levodopa treated group. Other parameters, like lifespan and body weight will also be used as indicators of the long term efficacy of DCS. The third specific aim is to evaluate DCS in two nonhuman primate species, owl monkeys (Aotus trivirgatus) and rhesus macaques (Macaca mulatta), treated with 6-hydroxydopamine. Rhesus monkeys will provide unique information about the effects of DCS on fine motor bimanual reaching/grasping. Owl monkeys will be used to evaluate the effects of DCS and a DCS/L-dopa combination on general mobility and feeding and drinking behavior. Using the analysis of the electrophysiological recordings obtained from both primate species in cortical and subcortical brain areas related to motor control, we will study the neuronal mechanisms of DCS effects. Our laboratory has a unique expertise in multi-electrode electrophysiological recordings in rodents and primates; this expertise, in combination with our competence in dorsal column stimulation, will allow a comprehensive analysis of both the potential mechanisms through which DCS exerts its effects and whether DCS has potential as a viable future treatment for PD patients.

描述（由申请人提供）：在帕金森病（PD）中，使纹状体衰弱的多巴胺能神经元变性导致运动功能进行性损伤。治疗策略包括重复施用多巴胺能前体或激动剂。尽管非常有效，但从长远来看，这些策略的功效会下降。大脑皮层下区域的电刺激（深部脑刺激 - DBS）是一种有效的替代选择，但由于其侵入性和相关风险而受到相当限制。在上胸椎水平对背侧脊髓进行硬膜外电刺激（背柱刺激 - DCS）可以使急性和慢性 PD 啮齿动物模型的运动能力立即得到显着改善。这一发现有可能转化为一种微创、易于执行且廉价的帕金森病新疗法，可供更广泛的患者群体使用。我们提出一项综合研究，使用不同的 PD 动物模型来探讨 DCS 的机制和功效。我们的第一个具体目标是研究 DCS 实现治疗效果的神经机制；我们将使用帕金森病6-羟基多巴胺纹状体损伤大鼠，在八个脑区植入多电极阵列，包括纹状体、丘脑底核、苍白球、运动和感觉皮质、丘脑和黑质致密部。 DCS 对大脑活动的影响将从神经元放电率以及神经元群的振荡和同步特性方面进行分析。在第二个具体目标中，我们将评估 DCS 的长期疗效。患有遗传性线粒体功能障碍的小鼠在成年后会出现进行性多巴胺能神经变性和严重的运动障碍，从 8 周大到生命结束（平均约 28 周）每天都会接受 DCS 治疗。旷场活动、僵住测试和旋转杆测试将用于评估他们的运动功能，并将其与假治疗组和左旋多巴治疗组进行比较。其他参数，如寿命和体重也将用作 DCS 长期疗效的指标。第三个具体目标是评估两种非人类灵长类动物——猫头鹰猴（Aotus trivirgatus）和恒河猴（Macaca mulatta）在接受 6-羟基多巴胺治疗后的 DCS。恒河猴将提供有关 DCS 对精细运动双手伸手/抓握的影响的独特信息。猫头鹰猴将用于评估 DCS 和 DCS/L-多巴组合对一般活动能力以及进食和饮水行为的影响。通过对从灵长类动物中与运动控制相关的皮质和皮质下大脑区域获得的电生理记录进行分析，我们将研究 DCS 效应的神经元机制。我们的实验室在啮齿动物和灵长类动物的多电极电生理记录方面拥有独特的专业知识；这些专业知识与我们在背柱刺激方面的能力相结合，将能够全面分析 DCS 发挥其作用的潜在机制，以及 DCS 是否有潜力成为 PD 患者未来可行的治疗方法。