Multiscale models of proprioceptive encoding to reveal mechanisms of impaired sensorimotor control

项目总结 我们的长期目标是确定神经机制和感觉运动信号在健康中的功能作用 和疾病，以指导机械定向的诊断、评估和治疗 神经运动障碍。在这里，我们解决了理解和治疗 广泛的运动障碍症状，最近被定义为关节高度抵抗，包括 中风、脊髓损伤或脑瘫的痉挛；帕金森氏症的僵硬和高张力。的目标是 这项跨学科的协作性建议旨在确定高抵抗性和分离性的神经机制。 它们在异常运动中的相对作用。我们将专注于两个临床上潜在的神经机制- 明确的神经对高抵抗的贡献：非速度依赖的非自愿背景激活和 速度依赖性伸展反射亢进。我们假设，许多患者的脊髓兴奋性增加 神经功能障碍导致非自主的背景激活和速度依赖的伸展反射亢进 通过三种可分离的神经机制：1)对梭外肌纤维的阿尔法驱动增加背景 肌肉张力，2)肌梭感觉器官中专门的梭内肌纤维的伽马驱动， 增加他们对肌肉拉伸的敏感性，以及3)脊髓变形的感觉运动增益 单突触感觉输入到运动输出。我们提出的对这一假说的检验将促进我们对 这些神经机制对高抵抗力的重要但仍未解决的相对贡献。 基于我们在前一个资助期取得的神经机械和多尺度建模进展，在目标1中，我们将 发展一个多尺度的电子神经肌肉回路模型来预测阿尔法-α-肌动蛋白的独立性变化。 驱动、伽玛驱动和感觉运动增益不同地影响临床相关的运动，如肌腱 分接和摆动试验。在目标2中，我们将描述阿尔法驱动、伽马驱动、 在活体生物中通过临床相关的脊髓兴奋性水平和感觉运动增益 在体内使用去大脑大鼠的准备神经肌肉回路。在目标3中，我们将确定与临床相关的 一种新型生物混合机器人系统中跨越脊髓兴奋性水平的运动异常 活的神经肌肉回路(在活体内)到虚拟的生物力学肢体(在硅胶中)。机器人控制器将强制执行 动态变化的惯性和引力的物理学，允许运动从 体内神经肌肉回路和虚拟肢体之间的因果相互作用。通过密切协调 在这些目标中，我们将建立一个计算和实验框架，以解决临床障碍(1) 确定神经机制和肢体惯性特性的变化如何纠正运动 异常，(2)提供如何通过不同的临床识别这些机制的洞察 评估情景，以及(3)比较不同治疗目标的相对效果。拟议中的工作 可能会对临床相关的人类感觉运动研究和基础感觉运动神经科学产生影响。

PROJECT SUMMARY Our long-term goal is to identify neural mechanisms and the functional roles of sensorimotor signals in health and disease as needed to guide mechanistically targeted diagnoses, assessments, and treatments for neurological movement disorders. Here we address the scientific barriers to understanding and treating a broad class of movement disorder symptoms recently defined as joint hyper-resistance, which encompass spasticity in stroke, spinal cord injury, or cerebral palsy; parkinsonian rigidity, and hypertonia. The objective of this collaborative, interdisciplinary proposal is to identify neural mechanisms of hyper-resistance and dissociate their relative roles in abnormal movement. We will focus on the neural mechanisms underlying two clinically- defined neural contributions to hyper-resistance: non-velocity dependent involuntary background activation and velocity-dependent stretch hyper-reflexia. We hypothesize that increased spinal excitability in many neurological disorders causes involuntary background activation and velocity-dependent stretch hyper-reflexia via three dissociable neural mechanisms: 1) alpha-drive to extrafusal muscle fibers increasing background muscle tension, 2) gamma-drive to specialized intrafusal muscle fibers in muscle spindles sensory organs, increasing their sensitivity to muscle stretch, and 3) sensorimotor gain of the spinal transformation of monosynaptic sensory input into motor output. Our proposed tests of this hypothesis will advance understanding of the important, yet still unresolved relative contributions made by these neural mechanisms to hyper-resistance. Based on our neuromechanical and multiscale modeling advances in the prior funding period, in Aim 1 we will develop a multiscale in silico neuromuscular circuit model to predict how independent changes in alpha- drive, gamma-drive, and sensorimotor gain differentially affect clinically-relevant movements such as the tendon tap and pendulum test. In Aim 2, we will characterize the relative increases in alpha-drive, gamma-drive, and sensorimotor gain across clinically-relevant spinal excitability levels in a living biological neuromuscular circuit in vivo using a decerebrate rat preparation. In Aim 3 we will identify clinically-relevant movement abnormalities across spinal excitability levels in a novel biohybrid robotic system coupling the living neuromuscular circuit (in vivo) to a virtual biomechanical limb (in silico). A robotic controller will enforce the physics of dynamically changing inertial and gravitational forces, allowing movement to emerge from the causal interaction between the in vivo neuromuscular circuit and the virtual limb. Through the close coordination of these Aims, we will establish a computational and experimental framework to address clinical barriers (1) to determine how changes in neural mechanisms and the inertial properties of the limb could correct movement abnormalities, (2) to provide insight into how these mechanisms could be identified through different clinical assessment scenarios, and (3) to compare the relative effects of different treatment targets. The proposed work will likely impact both clinically-relevant human sensorimotor research and basic sensorimotor neuroscience.