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和减轻常见的后遗症，如痉挛。脊髓中的神经回路可以在没有脊柱上控制的情况下协调肌肉，这一事实促使干预措施旨在促进剩余回路的可塑性。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，但不能改善行走。此外，痉挛的临床测试评估单个关节，但痉挛和用于治疗它的药物影响整个肢体。因此，确定反射通路的分布和强度，并确定反射通路在运动任务和功能环境下如何通过药物自然调节是很重要的。我们建议使用多功能力学技术系统地识别连接后肢主要肌群的肌间反射网络的分布、强度和时间过程（目的1）。由于已知髋关节姿势等自然刺激会影响肌间神经网络，但其调节作用存在争议，因此将使用机械方法来阐明髋关节姿势是否会影响神经通路，从而促进体重支撑和步态转变（目的2）。最后，检查反射通路的系统方法将与α -2激动剂（tizanidine和clonidine）联合使用，以更好地了解它们的抗痉挛作用机制（Aim 3a）和对整个肢体功能的影响（Aim 3b）。目前认为其抗痉挛作用主要是抑制兴奋性自生群

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.