Title: Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human

25 The objectives of this study were to probe the contribution of spinal neuron persistent sodium 26 conductances to reflex hyper-excitability in human chronic spinal cord injury. The intrinsic 27 excitability of spinal neurons provides a novel target for medical intervention. Studies in animal 28 models have shown that persistent inward currents, such as persistent sodium currents, 29 profoundly influence neuronal excitability, and recovery of persistent inward currents in spinal 30 neurons of animals with spinal cord injury routinely coincides with the appearance of spastic 31 reflexes. Pharmacologically, this neuronal excitability can be decreased by agents that reduce 32 persistent inward currents, such as the selective persistent sodium current inhibitor riluzole. We 33 were able to recruit seven subjects with chronic incomplete spinal cord injury who were not 34 concurrently taking antispasticity medications into the study. Reflex responses (flexion35 withdrawal and H-reflexes) and volitional strength (isometric maximum voluntary contractions) 36 were tested at the ankle before and after placebo-controlled, double-blinded oral administration 37 of 50mg riluzole. Riluzole significantly decreased the peak ankle dorsiflexion torque component 38 of the flexion-withdrawal reflex. Peak maximum voluntary torque in both dorsiand plantar39 flexion directions was not significantly changed. Average dorsiflexion torque sustained during 40 the five-second isometric maximum voluntary contraction, however, increased significantly. 41 There was no effect, however, on the monosynaptic plantarand dorsi-flexor H-reflex responses. 42 Overall, these results demonstrate a contribution of persistent sodium conductances to 43 polysynaptic reflex excitability in human chronic spinal cord injury without a significant role in 44 maximum strength production. These results suggest that intrinsic spinal cellular excitability 45 could be a target for managing chronic spinal cord injury hyperreflexia impairments without 46 causing a significant loss in volitional strength. 47 48