Dorsal Column Stimulation as a New Therapy for Motor Disorders

描述(申请人提供)：在帕金森氏病(PD)中，纹状体多巴胺能神经元的退化会导致运动功能的进行性损害。治疗策略包括重复给药多巴胺能前体或激动剂。虽然非常有效，但从长远来看，这些策略的有效性会下降。电刺激大脑皮质下区域(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大的限制。硬膜外上胸水平电刺激脊髓背部可显著改善急、慢性帕金森病啮齿动物模型的运动能力。这一发现有可能转化为一种微创、易于操作、价格低廉的帕金森病新疗法，可供更广泛的患者使用。我们建议使用不同的帕金森病动物模型进行一项全面的研究，以探讨DCSs的机制和疗效。我们的第一个具体目标是研究DCs达到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、丘脑和黑质致密部等八个脑区植入多电极阵列。将从神经元的放电率和神经元群体的振荡和同步特性来分析dcs对大脑活动的影响。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退化和严重的运动障碍，从出生8周到生命结束(平均约28周)，每天都要接受dcs治疗。开阔场地活动、惊厥测试和转杆测试将被用来评估他们的运动功能，并将其与假手术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分布式控制系统长期疗效的指标。第三个具体目标是评估两个非人类灵长类物种，猫头猴(Aotus Trivirgatus)和恒河猴(Macaca Mulatta)用6-羟基多巴胺处理后的DC。恒河猴将提供独一无二的信息，说明dcs对精细运动双手伸展/抓取的影响。OWL猴子将被用来评估分布式控制系统和分布式控制系统/L-多巴组合对一般活动能力以及摄食和饮水行为的影响。通过对两种灵长类动物与运动控制相关的皮质和皮质下脑区的电生理记录的分析，我们将研究dcs效应的神经机制。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，将使我们能够全面分析DCs发挥作用的潜在机制，以及DCs是否有潜力作为未来可行的PD患者的治疗方法。 公共卫生相关性：我们提出了一项综合的三阶段研究，以评估脊髓电刺激作为帕金森氏病的治疗方法。在第一阶段，我们将利用帕金森病大鼠进行机制研究，以检查脊髓刺激对多个脑区活动的影响；在第二阶段，将使用遗传编程为出现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，将把这一概念转化为灵长类动物模型，在那里将用猴子测试脊髓刺激对缓解帕金森症状的效果。

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.