Motor Control Deficits in Parkinson's Disease

描述（由申请人提供）：了解帕金森病（PD）中功能障碍的范围，以及通过药理学或电生理学治疗可逆转的程度，可以增加我们对PD治疗的理解，并有助于阐明基底节-皮质回路在运动控制中的关键功能。我们以前的研究结果使我们假设，帕金森病（PD）患者的一个主要困难是在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获得新技能方面都起着重要作用，并且初步数据表明，多巴胺（DA）替代疗法不能正常化。本提案提出了七个实验，旨在确认和扩展这一假设，并调查在何种程度上脑深部刺激丘脑底核（DBS）和DA替代疗法能够弥补缺陷的感觉运动控制，协调和学习。为了对比这些治疗在相同患者中的效果，PD患者将在手术植入电极之前测试DA置换的ON与OFF，并在手术后再次测试脑深部电刺激的ON和OFF（以及药物）。前4个实验检查视觉和本体感受信息的整合，这可能在PD中特别缺乏。受试者将达到3D目标，无论是视觉或动觉与机器人手臂在各种条件下的视觉反馈。下一个实验介绍了一个要求，即受试者学习在虚拟环境中移动，作为建立准确目标获取所需的新感觉运动协调的先决条件。受试者需要掌握扭曲，造成他们的手臂的明显（虚拟的）和真实的（本体感觉信号）位置之间的差异。通过将运动与他们正常的感觉对应分离，受试者重新配置他们的感觉运动协调的能力将受到挑战。最后2个实验通过要求受试者将不同的运动动作整合成复杂的运动序列来挑战受试者，并且能够补偿在这样的动作期间的机械扰动。通过检查全方位的行为，并要求协调的运动行为，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，可以获得对PD运动控制及其治疗益处的更系统的评估。使用诸如3D沉浸式虚拟现实和机器人引导的3D到达等当代技术来检查药物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：帕金森氏病治疗中的一个主要问题是不同疗法可以在多大程度上改善作为该疾病产物的一系列功能障碍。脑深部刺激器的手术植入，特别是针对丘脑底核的那些，是治疗和恢复帕金森病的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脑深部电刺激疗法与多巴胺能替代疗法中哪些缺陷可以逆转，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.