Coapplication of noisy patterned electrical stimuli and NMDA plus serotonin facilitates fictive locomotion in the rat spinal cord

Abstract

A new stimulating protocol [fictive locomotion-induced stimulation (FL istim)], consisting of intrinsically variable weak waveforms applied to a single dorsal root is very effective (though not optimal as it eventually wanes away) in activating the locomotor program of the isolated rat spinal cord. The present study explored whether combination of FL istim with low doses of pharmacological agents that raise network excitability might further improve the functional outcome, using this in vitro model. FL istim was applied together with N-methyl-d-aspartate (NMDA) + serotonin, while fictive locomotion (FL) was electrophysiologically recorded from lumbar ventral roots. Superimposing FL istim on FL evoked by these neurochemicals persistently accelerated locomotor-like cycles to a set periodicity and modulated cycle amplitude depending on FL istim rate. Trains of stereotyped rectangular pulses failed to replicate this phenomenon. The GABAB agonist baclofen dose dependently inhibited, in a reversible fashion, FL evoked by either FL istim or square pulses. Sustained episodes of FL emerged when FL istim was delivered, at an intensity subthreshold for FL, in conjunction with subthreshold pharmacological stimulation. Such an effect was, however, not found when high potassium solution instead of NMDA + serotonin was used. These results suggest that the combined action of subthreshold FL istim (e.g., via epidural stimulation) and neurochemicals should be tested in vivo to improve locomotor rehabilitation after injury. In fact, reactivation of spinal locomotor circuits by conventional electrical stimulation of afferent fibers is difficult, while pharmacological activation of spinal networks is clinically impracticable due to concurrent unwanted effects. We speculate that associating subthreshold chemical and electrical inputs might decrease side effects when attempting to evoke human locomotor patterns.