Motor Control Deficits in Parkinson's Disease

描述（由申请人提供）：了解帕金森病（PD）的功能障碍范围，以及它们通过药物或电生理治疗可逆的程度，既可以增加我们对PD治疗的理解，也有助于阐明控制运动的基底神经节-皮层回路的关键功能。我们之前的研究结果使我们假设帕金森病（PD）患者的主要困难是组装和使用新的感觉运动映射或协调。这些过程在持续的运动表现和新技能的习得中都起着重要作用，并且，初步数据表明，多巴胺（DA）替代疗法不能使其正常化。本研究提出了七个实验，旨在证实和扩展这一假设，并研究丘脑下核深部脑刺激（STN DBS）和DA替代疗法在多大程度上能够弥补感觉运动控制、协调和学习方面的缺陷。为了对比这些治疗方法在同一患者中的效果，PD患者将在手术植入电极之前进行ON和OFF DA替代测试，并在手术后再次进行ON和OFF深部脑刺激（和OFF药物）测试。前4个实验检查了视觉和本体感觉信息的整合，这可能在PD中特别缺乏。在不同的视觉反馈条件下，受试者将通过机械臂到达视觉或动作呈现的三维目标。下一个实验要求受试者学习在虚拟环境中移动，这是建立准确目标获取所需的新感觉运动协调的先决条件。受试者被要求掌握扭曲，这些扭曲会造成他们手臂的明显（虚拟）和真实（本体感觉信号）位置之间的差异。通过将运动与正常的感觉对应分离，受试者重新配置感觉运动协调的能力将受到挑战。最后两个实验通过要求受试者将不同的运动动作整合到一个复杂的运动序列中，并能够在这样的动作中补偿机械扰动来挑战受试者。通过检查全方位的行为，需要协调的运动行为，利用可变的感觉信息来指导行为，以及学习新的感觉运动对应关系，可以更系统地评估PD的运动控制及其治疗效果。使用诸如3D沉浸式虚拟现实和机器人引导的3D触摸等当代技术来检查医疗与手术治疗可以改善PD功能障碍的程度的方法是独特的。公共卫生相关性：帕金森病治疗的一个主要问题是不同的治疗方法能在多大程度上改善由该疾病引起的一系列功能障碍。手术植入深部脑刺激器，特别是那些针对丘脑下核的，是帕金森病治疗和恢复功能和生活质量的一种越来越重要的方式。拟议的研究将比较感觉运动控制和学习深度脑刺激疗法与多巴胺能替代疗法的哪些缺陷可以逆转，哪些不能逆转，因此应该填补文献中的一个重要空白，可以为治疗决策提供信息。

DESCRIPTION (provided by applicant): Understanding the range of dysfunctions in Parkinson's disease (PD), and the degrees to which they are reversible by pharmacological or electrophysiological treatments, can both increase our understanding of PD therapies and help illuminate critical functions of basal ganglia-cortical circuits in the control of movement. Our previous findings have led us to hypothesize that a major difficulty for patients with Parkinson disease (PD) is in assembling and using new sensorimotor mappings or coordinations. These processes play a major role both in ongoing motor performance and in the acquisition of new skills, and, preliminary data indicate, are not normalized with dopamine (DA) replacement therapy. The present proposal presents seven experiments that are designed to confirm and extend this hypothesis and to investigate the degrees to which deep brain stimulation to the subthalamic nucleus (STN DBS) and DA replacement therapy are able to remediate deficits in sensorimotor control, coordination, and learning. To contrast the effects of these therapies in the same patients, PD patients will be tested ON versus OFF DA replacement prior to their having surgically implanted electrodes, and again after surgery ON and OFF deep brain stimulation (and off medications). The first 4 experiments examine the integration of visual and proprioceptive information, which may be particularly deficient in PD. Subjects will reach to 3D targets presented either visually or kinesthetically with a robot arm under various conditions of visual feedback. The next experiment introduces the requirement that subjects learn to move within a virtual environment as a prerequisite to establishing the new sensorimotor coordinations necessary for accurate target acquisition. Subjects are required to master distortions that create discrepancies between the apparent (virtual) and real (proprioceptively signaled) location of their arms. By dissociating movements from their normal sensory correspondences, subjects' abilities to reconfigure their sensorimotor coordinations will be challenged. The final 2 experiments challenge subjects by requiring them to integrate different motor acts into a complex motor sequence and to be able to compensate for a mechanical perturbation during such an action. By examining a full range of behaviors, and requiring coordinated motor acts, utilization of variable sensory information to guide behavior, and the learning new sensorimotor correspondences, a more systematic assessment of motor control in PD and its benefit by treatment can be obtained. The proposed approach of using such contemporary technologies as 3D immersive virtual realities and robot-guided 3D reaching in examining the degree to which medical versus surgical therapies can ameliorate dysfunctions in PD is unique. PUBLIC HEALTH RELEVANCE: A major question in the treatment of Parkinson's disease is the degree to which different therapies can ameliorate the range of dysfunctions that are a product of the disorder. Surgical implantation of deep brain stimulators, especially those targeted to the subthalamic nucleus, is an increasingly important modality for treatment and restoring function and quality of life in Parkinson's disease. The proposed studies will compare which deficits in sensorimotor control and learning deep brain stimulation therapy versus dopaminergic replacement therapy can reverse and which they cannot, and thus should fill an important gap in the literature that can inform treatment decisions.