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: 8150902
• 负责人: Miguel A. L. Nicolelis
• 金额: $ 76.37万
• 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/8150902
• 关键词: Acute; Address; Adult; Age; Agonist; Animal Model; Area; Body Weight; Brain; Catalepsy; Chest; Chronic; Competence; Corpus striatum structure; Deep Brain Stimulation; Dorsal; Electric Stimulation; Electrodes; Feeding behaviors; Future; Genetic; Globus Pallidus; Implant; Laboratories; Lead; Lesion; Levodopa; Life; 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; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Patients; Population; Primates; Property; Rattus; Risk; Rodent; Rodent Model; Spinal Cord; Staging; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Testing; Thalamic structure; Therapeutic Effect; Translating; dopaminergic neuron; dorsal column; drinking behavior; efficacy testing; grasp; minimally invasive; mitochondrial dysfunction; motor control; motor disorder; motor impairment; nonhuman primate; pars compacta; programs; public health relevance; 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. PUBLIC HEALTH RELEVANCE: We propose a comprehensive three-stage study to evaluate electrical stimulation of the spinal cord as a treatment for Parkinson's disease. In the first stage, we will perform a mechanistic study using Parkinsonian rats to examine the effect of spinal cord stimulation on the activity of multiple brain areas; in the second stage, mice genetically programmed to develop Parkinsonian symptoms will be used to evaluate the long-term effect of stimulation on motor function; and in the third stage, the concept will be translated to a primate model, where monkeys will be used to test the efficacy of spinal cord stimulation to alleviate Parkinsonian symptoms.

描述（由申请人提供）：在帕金森病（PD）中，使纹状体失神经的多巴胺能神经元变性导致运动功能进行性损害。治疗策略涉及重复施用多巴胺能前体或激动剂。虽然这些策略非常有效，但从长远来看，其功效会下降.大脑皮层下区域的电刺激（脑深部电刺激- DBS）是一种有效的替代选择，由于其侵入性和相关风险而受到相当大的限制。在上胸水平处的背侧脊髓的硬膜外电刺激（背柱刺激- DCS）可以导致急性和慢性PD啮齿动物模型中的运动的显著和瞬时的改善。这一发现有可能转化为一种微创、易于执行且廉价的PD新治疗方法，可供更广泛的患者群体使用。我们提出了一个全面的研究，解决DCS的机制和疗效，使用不同的PD动物模型。我们的第一个具体目标是研究DCS实现其治疗效果的神经元机制;我们将使用帕金森病6-羟基多巴胺纹状体损伤大鼠，在8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，丘脑和黑质部丘脑。DCS对大脑活动的影响将在神经元放电率和神经元群体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。具有遗传性线粒体功能障碍的小鼠，其在成年后发展为进行性多巴胺能神经变性和严重的运动障碍，将从8周龄开始每天用DCS治疗，直到其生命结束（平均约28周）。将使用旷场活动、僵硬症测试和旋转杆测试来评价它们的运动功能，并将其与假处理组和左旋多巴处理组进行比较。其他参数，如寿命和体重，也将被用作DCS长期疗效的指标。第三个具体目标是评估DCS在两个非人灵长类动物物种，猫头鹰猴（Aotus trivirgatus）和恒河猴（猕猴），6-羟基多巴胺治疗。恒河猴将提供关于DCS对精细运动双手伸手/抓握的影响的独特信息。将使用猫头鹰猴评价DCS和DCS/L-多巴组合对一般活动性以及进食和饮水行为的影响。使用从两种灵长类动物的大脑皮层和皮层下区域的运动控制相关的电生理记录的分析，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;这种专业知识与我们在背柱刺激方面的能力相结合，将允许全面分析DCS发挥作用的潜在机制以及DCS是否有潜力作为PD患者的可行未来治疗。 公共卫生相关性：我们提出了一个全面的三阶段研究，以评估电刺激脊髓作为帕金森氏病的治疗。在第一阶段，我们将使用帕金森大鼠进行机制研究，以检查脊髓刺激对多个脑区活动的影响;在第二阶段，将使用遗传编程产生帕金森症状的小鼠来评估刺激对运动功能的长期影响;在第三阶段，这一概念将转化为灵长类动物模型，猴子将被用来测试脊髓刺激缓解帕金森病症状的功效。