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In intact and spinal-injured anesthetized animals, stimulation levels that did not induce any visible muscle twitches were used to elicit motor evoked potentials (MEPs) of varying amplitude, reflecting the temporal and amplitude dynamics of the background excitability of spinal networks. To characterize the physiological excitability states of neuronal networks driving movement, we designed five experiments in awake rats chronically implanted with an epidural stimulating interface, with and without a spinal cord injury (SCI). First, an uninjured rat at rest underwent a series of single electrical pulses at sub-motor threshold intensity, which generated responses that were continuously recorded from flexor and extensor hindlimb muscles, showing an intrinsic patterned modulation of MEPs. Responses were recruited by increasing strengths of stimulation, and the amplitudes were moderately correlated between flexors and extensors. Next, after SCI, four awake rats at rest showed electrically induced MEPs, varying largely in amplitude, of both flexors and extensors that were mainly synchronously modulated. After full anesthesia, MEP amplitudes were largely reduced, although stimulation still generated random baseline changes, unveiling an intrinsic stochastic modulation. The present five cases demonstrate a methodology that can be feasibly replicated in a broader group of awake and behaving rats to further define experimental treatments involving neuroplasticity. Besides validating a new technology for a neural stimulating interface, the present data support the broader message that there is intrinsic patterned and stochastic modulation of baseline excitability reflecting the dynamics of physiological states of spinal networks. NEW & NOTEWORTHY Chronic implants of a new epidural stimulating interface trace dynamics of spinal excitability in awake rats, before and after injury. Motor evoked potentials induced by trains of pulses at sub-motor threshold intensity were continuously modulated in amplitude. Oscillatory patterns of amplitude modulation reduced with increasing strengths of stimulation and were replaced by an intrinsic stochastic tone under anesthesia. Variability of baseline excitability is a fundamental feature of spinal networks, affecting their responses to external input.

A new stimulating protocol [fictive locomotion-induced stimulation (FListim)], 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 FListim with low doses of pharmacological agents that raise network excitability might further improve the functional outcome, using this in vitro model. FListim was applied together with N-methyl-d-aspartate (NMDA) + serotonin, while fictive locomotion (FL) was electrophysiologically recorded from lumbar ventral roots. Superimposing FListim on FL evoked by these neurochemicals persistently accelerated locomotor-like cycles to a set periodicity and modulated cycle amplitude depending on FListim rate. Trains of stereotyped rectangular pulses failed to replicate this phenomenon. The GABA(B) agonist baclofen dose dependently inhibited, in a reversible fashion, FL evoked by either FListim or square pulses. Sustained episodes of FL emerged when FListim 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 FListim (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.

The spinal cord contains an intrinsic locomotor program driven by a central pattern generator that rhythmically activates flexor and extensor limb motor pools. Although long-lasting locomotor activity can be generated pharmacologically, trains of afferent stimuli trigger only few locomotor cycles. The present study investigated whether a new electrical stimulation protocol (termed FListim) could elicit long-lasting fictive locomotion (FL) in the rat spinal cord in vitro. Thus, after first inducing FL by bath application of N-methyl-d-aspartate and serotonin, the recorded waveform obtained from a lumbar ventral root was digitized and then applied to either a lumbar dorsal root or the cauda equina following washout of pharmacological agents. Two FListim cycles were the threshold input to evoke an episode of FL from ventral roots. Longer cycles (up to 1 min) induced sustained FL (up to 1 min) with stereotyped periodicity (2.2 ± 0.5 s), despite changing frequency (2-4 s) or cycle amplitude of FListim. Gradual filtering out of the noise from FListim trace concomitantly decreased the efficiency of FL so that stimulation with equivalent pure sinusoids produced asynchronous, irregular discharges only that could not be converted to FL by adding spontaneous basal activity. This study is the first demonstration that epochs of rhythmic locomotor-like oscillations applied to a dorsal root represent an efficient stimulus to evoke FL as long as they contain the electrophysiological noise produced within FL cycles. These observations suggest novel strategies to improve the efficiency of electrical stimulation delivered by clinical devices for neurorehabilitation after spinal injury.