Dorsal Column Stimulation as a New Therapy for Motor Disorders

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害。治疗策略包括重复使用多巴胺能前体或激动剂。虽然这些策略非常有效，但长期来看效果会下降。脑皮层下电刺激（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。在急性和慢性PD啮齿动物模型中，硬膜外电刺激脊背脊髓（背柱刺激- DCS）在上胸水平可以导致运动的急剧和瞬时改善。这一发现有可能转化为一种微创、易于实施和廉价的PD新治疗方法，可用于更广泛的患者群体。我们建议采用不同的PD动物模型对DCS的机制和功效进行全面的研究。我们的第一个具体目标是研究通过DCS实现其治疗效果的神经元机制；我们将在帕金森病6-羟多巴胺纹状体损伤大鼠的8个脑区植入多电极阵列，包括纹状体、丘脑下核、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和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的长期功效。患有遗传性线粒体功能障碍的小鼠在成年后会发展为进行性多巴胺能神经变性和严重的运动障碍，从8周龄开始每天接受DCS治疗，直到它们的生命结束（平均约28周龄）。野外活动、麻痹试验和旋转棒试验将用于评估他们的运动功能，并将其与假药治疗组和左旋多巴治疗组进行比较。其他参数，如寿命和体重也将被用作DCS长期疗效的指标。第三个具体目标是评估两种非人灵长类动物，猫头鹰猴（Aotus trivirgatus）和恒河猴（Macaca mulatta），在6-羟多巴胺治疗下的DCS。恒河猴将提供关于DCS对精细运动双手到达/抓取的影响的独特信息。猫头鹰猴将被用来评估DCS和DCS/左旋多巴组合对一般活动能力和摄食行为的影响。通过对两种灵长类动物皮层和皮层下脑区与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具有独特的专业知识；这种专业知识，结合我们在背柱刺激方面的能力，将使我们能够全面分析DCS发挥其作用的潜在机制，以及DCS是否有可能成为PD患者未来可行的治疗方法。

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.