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

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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.