Multisite Electrode Arrays to Optimize Epidural Stimulation for Spasticity Following Spinal Cord Injury - Project Summary/Abstract After spinal cord injury (SCI), spasticity occurs in approximately 80% of patients. Spasticity involves involuntary muscle movements, co-contraction of muscles, and hyperreflexia. These severe symptoms of spasticity can make daily activities, such as sitting or sleeping, nearly impossible. Current pharmacological treatments for spasticity, such as GABA agonists, have severe side effects such as seizures and dizziness, and depress spinal reflex excitability and muscle activity, which further impedes motor recovery. Therefore, there is a pressing need for new treatment options that will reduce spasticity in SCI patients without decreasing motor output. Epidural stimulation (ES) studies have mainly focused on locomotor recovery, however a decrease in spasticity has been reported, but not heavily explored. The efficacy of ES on functional improvements can vary based on the optimization of the electrode configuration used, necessitating the need to elucidate specific configurations tailored to the treatment of spasticity. Our preliminary results have shown improvement in the frequency dependent depression of the H-reflex in SCI rats following a single session of ES, suggesting a decrease in spasticity. However, this effect is based on how the electrode configuration is optimized. Moreover, the differences in ES-induced evoked potentials between configurations within the same animal can elicit depression or facilitation, providing insight into what configurations might be ideal for the treatment of spasticity. Aim 1 will determine an optimal electrode configuration for epidural stimulation to decrease spasticity and hyperreflexia after SCI. We hypothesize that ES will be optimal for treating spasticity with the usage of configurations that favor depression and that motor output will not be reduced. Spasticity and hyperreflexia mostly manifest from a downregulation of KCC2, a chloride transporter, which largely determines the intracellular chloride concentration of neurons. Therefore, KCC2 is essential in the maintenance of normal inhibition within the adult spinal cord. Activity based therapies, such as locomotor training, decrease spasticity by increasing motoneuronal KCC2 expression. Aim 2 will determine if the restoration of chloride homeostasis contributes to ES effects on spasticity. We hypothesize that ES reduces spasticity through KCC2-mediated mechanisms and that blocking KCC2 activity during treatment will diminish ES-induced changes in spasticity. The proposed project will further elucidate the mechanisms responsible for reducing spasticity with ES and aid in optimizing treatments for spasticity. This ES protocol will provide a valuable resource to pursue translational ES treatments with and without the use of pharmacological intervention.
