Influence of alpha-2 agonists on reflex pathways and limb stiffness

描述（由申请人提供）：脊髓损伤后康复的目标是恢复活动能力并减轻常见后遗症，如痉挛。脊髓中的神经回路可以在没有脊髓上控制的情况下功能性地协调肌肉，这一事实促使旨在促进剩余回路可塑性的干预措施。然而，活动能力的提高仍然有限，用于治疗痉挛的药物通常会减少痉挛，但不会改善行走。此外，痉挛的临床测试评估个别关节，但痉挛和用于治疗它的药物会影响整个肢体。因此，重要的是要确定反射通路的分布和强度，并确定反射通路是如何在运动任务中自然调节的，以及在功能背景下通过药物调节。我们建议使用多功能力学技术，系统地确定分布，强度和时间过程中的肌间反射网络连接主要后肢肌肉群（目的1）。由于已知自然刺激（如髋关节姿势）会影响肌间神经网络，但调节影响存在争议，因此将使用力学方法来阐明髋关节姿势是否会影响可能促进体重支撑和步态转换的神经通路（目标2）。最后，检查反射通路的系统方法将与α-2激动剂（替扎尼定和可乐定）联合使用，以更好地了解其解痉作用机制（目的3a）和对全肢功能的影响（目的3b）。目前认为其解痉作用是通过抑制兴奋性自生神经元群而实现的 二路。已知II组通路分布广泛，因此肌间通路也可能有助于解痉挛作用和不良行走结局。这一目标将服务于双重目的，即对介导解痉作用的本体感受通路进行分类，同时也将研究结果置于功能背景中。利用机器人技术测量肢体僵硬度，评价肢体整体功能。僵硬度是痉挛状态的一个相关变量，它将肢体的机械特性和神经回路与运动功能联系起来。肢体僵硬度的测量可能是一种创新的方法，以非侵入性评估痉挛的严重程度和在整个肢体水平的抗痉挛药物的影响。总之，这些实验将加强旨在恢复脊髓损伤后的独立活动能力的康复策略，并将加强痉挛的医疗管理。

DESCRIPTION (provided by applicant): A goal of rehabilitation after spinal cord injury is to restore mobility and mitigate common sequalae such as spasticity. The fact that neural circuitry in the spinal cord can functionally coordinate muscles without supraspinal control has prompted interventions intended to promote plasticity of remaining circuitry. Gains in mobility remain limited, however, and medications used to treat spasticity generally reduce spasms but do not improve walking. In addition, clinical tests for spasticity assess individual joints, yet spasticit and the drugs used to treat it affect the whole limb. It is important therefore to identify the distribution and strength of reflex pathways, and determine how reflex pathways are naturally modulated during motor tasks and by medications in a functional context. We propose to use the versatile mechanographic technique to systematically identify the distribution, strength, and time course of intermuscular reflex networks linking major hindlimb muscle groups (Aim 1). Because natural stimuli such as hip posture are known to influence intermuscular neural networks but the modulatory influence is controversial, the mechanographic approach will be used to clarify whether hip posture affects neural pathways that could promote weight support and gait transitions (Aim 2). Lastly, the systematic approach for examining reflex pathways will be used in combination with alpha-2 agonists (tizanidine and clonidine) to better understand their antispasticity mechanisms of action (Aim 3a) and influence on whole limb function (Aim 3b). Currently, the antispastic effects are attributed to suppression of excitatory autogenic group II pathways. Group II pathways are known to be widely distributed and therefore intermuscular pathways could also contribute to the antispastic effect, and the poor walking outcomes. This aim will serve the dual purpose of classifying the proprioceptive pathways that mediate the antispastic effect while also placing the findings in a functional context. Whole limb function wil be evaluated by the measurement of limb stiffness using robotic technology. Stiffness is a relevant variable for spasticity that links mechanical properties of the limb and neural circuits t motor function. The measurement of limb stiffness could be an innovative way to noninvasively assess spasticity severity and the influence of antispastic medications at the whole limb level. Taken together, these experiments will enhance rehabilitation strategies intended to restore independent mobility after spinal cord injury and will enhance the medical management for spasticity.