Force Feedback Redistribution & Eccentric-Focused Rehab post-SCI

腿部的伸肌积极参与重量支撑和行走活动。这些肌肉 通过抑制性、双向、力依赖性途径广泛连接，这些途径有助于成功地 一系列功能行为的执行，包括运动。这些反射途径被认为是 从高尔基体肌腱器官，并被认为是调节肢体僵硬和促进关节间的协调， 动作任何两块肌肉之间在两个方向上的这些联系的相对大小都是不同的 在对照去大脑动物之间，当静止时，但服从主要从近端到远端的梯度 在跑步机上行走。这一发现表明，这些反射通路的强度和分布 以任务依赖的方式进行调节。我们的初步数据表明胸脊髓 横向半切立即并持续改变了正常分布和一个占主导地位的远端到 出现近端抑制梯度。有这种病变的动物不表现出折刀抑制， 这种现象已知由高尔基体腱器官以外的受体介导，并且由双侧 脊髓背侧损伤力反馈的强度和分布的变化， 我们已经观察到，在运动过程中， 任务-这两个都是具有挑战性的问题，在人类脊髓损伤。这些发现 为损伤后导致运动功能中断的潜在机制提供了新的见解， 确定一个新的、潜在的康复策略。我们的指导假设是SCI引起的力反馈 调节异常导致对近端肌肉的强烈抑制，导致不充分的 在运动的重量支撑阶段期间的肢体僵硬，并且可以使用偏心- 集中训练。目前的应用已经从协作工作发展而来，使用大型动物模型， 在两个成熟的实验室，汇集了脊髓损伤，可塑性，力反馈 和电机控制。拟议的研究分为两组实验。第一组将仔细 描述下胸半切术在抑制步态运动的亚阶段对步态运动学的影响， 力反馈被认为是最活跃的（目标1a）。这些阶段通常与协调的 偏心活动和/或重量接受/支撑。将比较SCI前后的数据。在 同样的动物，一个全面的图片力反馈组织后，SCI将开发 在两个慢性时间点的终末去大脑研究期间（目标1b）。无论是站立还是行走 准备，结合机械方法，将用于测试任务特异性， 异源力反馈反应在特定的肌肉组合。在第二组实验中， 基本的实验设计是相同的，除了离心集中训练将在术后2周引入， SCI.这使得目标1a和1b中使用的动物可用作目标2a和2b的对照。偏心 训练将使用不同的“下坡”步态任务，以更强烈地激活力反馈电路。步态 运动学将在选定的子阶段进行仔细评估，以测试不同平坦和平坦阶段的训练效果， 下坡任务（目标2a）和去大脑，机械研究用于表征训练对 在特定肌肉组合水平上的力依赖组织。将完成所有患者的组织学检查 动物以验证病变特征。在拟议的工作中产生的数据将与现有的 实验室数据库，包含来自对照去大脑制剂的力反馈结果，以减少 使用的动物数量。总的来说，这些研究将为循证医学提供重要信息。 通过理解破坏力反馈的步态相关影响来康复运动技能（目标1a）， SCI（目标1b）后这种体内控制系统的破坏程度，以及改变这种情况的可能性 使用体能训练方法，中断自主步态（目标2a）和基本反射水平（2b）。

Extensor muscles of the leg are actively involved in weight support and walking activities. These muscles are extensively linked by inhibitory, bidirectional, force dependent pathways that contribute to the successful execution of a range of functional behaviors, including locomotion. These reflex pathways are thought to arise from Golgi tendon organs and are believed to regulate limb stiffness and promote inter-joint coordination during movements. The relative magnitudes of these linkages in the two directions between any two muscles vary across control decerebrate animals when quiescent, but obey a predominantly proximal to distal gradient during stepping on a treadmill. This finding indicates that the strength and distribution of these reflex pathways are subject to modulation in a task-dependent manner. Our preliminary data suggest that thoracic spinal cord lateral hemisection immediately and persistently alters the normal distribution and a dominant distal-to- proximal inhibitory gradient emerges. Animals with this lesion do not exhibit clasp-knife inhibition, a phenomenon known to be mediated by receptors other than Golgi tendon organs and that results from bilateral injury to the dorsal half of the spinal cord. The change in the strength and distribution of force feedback that we have observed is correlated with diminished limb stiffness and poor weight acceptance during locomotor tasks – both of which are challenging problems seen in humans with spinal cord injuries. These findings provide new insight into potential mechanisms contributing to disruption of motor function following injury and identify a new, potential rehabilitation strategy. Our guiding hypothesis is that SCI-induced force-feedback dysregulation results in strong inhibition directed toward proximal muscles, contributes to inadequate limb stiffness during weight support phases of movement, and can be reversed using eccentric- focused training. The current application has evolved from collaborative work, using a large animal model, across two established laboratories, bringing together expertise in spinal cord injury, plasticity, force feedback and motor control. The proposed studies are divided into two sets of experiments. The first set will carefully characterize the impact of a low thoracic hemisection on gait kinematics during subphases where inhibitory force feedback is thought to be most active (Aim 1a). These phases typically are associated with coordinated eccentric activity and/or weight acceptance/support. Pre- and post-SCI data, across time, will be compared. In the same animals, a comprehensive picture of force-feedback organization following SCI will be developed during terminal decerebrate studies at two chronic time points (Aim 1b). Both standing and walking preparations, in combination with mechanographic approaches, will be used to test task-specificity of heterogenic force feedback responses in specific muscle combinations. In the second set of experiments, the basic experimental design is the same except that eccentric-focused training will be introduced at 2 wks post- SCI. This allows animals used in Aims 1a and 1b to serve as the controls for Aims 2a and 2b. Eccentric training will use different ‘downslope’ gait tasks to more strongly activate force feedback circuitry. Gait kinematics will be carefully assessed during select subphases to test for training effects during different flat and downslope tasks (Aim 2a) and decerebrate, mechanographic studies used to characterize training effects on force dependent organization at the level of specific muscle combinations. Histology will be completed in all animals to verify lesion characteristics. Data generated in the proposed work will be compared with an existing laboratory database containing force feedback findings from control decerebrate preparations, to reduce the number of animals used. Collectively, these studies will provide important information for evidence-based rehabilitation of motor skills by understanding the gait-associated impact of disrupting force feedback (Aim 1a), the extent of the disruption of this intralimb control system following SCI (Aim 1b), and the potential to alter this disruption at the voluntary gait (Aim 2a) and basic reflex levels (2b) using a physical training approach.