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Key points Epidural electrical stimulation (ES) of the spinal cord restores/improves locomotion in patients. ES-evoked locomotor movements differ to some extent from the normal ones. Operation of the locomotor network during ES is unknown. We compared the activity of individual spinal neurons during locomotion initiated by signals from the brainstem and by ES. We demonstrated that the spinal network generating locomotion under each of the two conditions is formed by the same neurons. A part of this network operates similarly under the two conditions, suggesting that it is essential for generation of locomotion under both conditions. Another part of this network operates differently under the two conditions, suggesting that it is responsible for differences in the movement kinematics observed under the two conditions. Abstract Locomotion is a vital motor function for both animals and humans. Epidural electrical stimulation (ES) of the spinal cord is used to restore/improve locomotor movements in patients. However, operation of locomotor networks during ES has never been studied. Here we compared the activity of individual spinal neurons recorded in decerebrate cats of either sex during locomotion initiated by supraspinal commands (caused by stimulation of the mesencephalic locomotor region, MLR) and by ES. We found that under both conditions, the same neurons had modulation of their activity related to the locomotor rhythm, suggesting that the network generating locomotion under the two conditions is formed by the same neurons. About 40% of these neurons had stable modulation (i.e. small dispersion of their activity phase in sequential cycles), as well as a similar phase and shape of activity burst in MLR- and ES-evoked locomotor cycles. We suggest that these neurons form a part of the locomotor network that operates similarly under the two conditions, and are critical for generation of locomotion. About 23% of the modulated neurons had stable modulation only during MLR-evoked locomotion. We suggest that these neurons are responsible for some differences in kinematics of MLR- and ES-evoked locomotor movements. Finally, 25% of the modulated neurons had unstable modulation during both MLR- and ES-evoked locomotion. One can assume that these neurons contribute to maintenance of the excitability level of locomotor networks necessary for generation of stepping, or belong to postural networks, activated simultaneously with locomotor networks by both MLR stimulation and ES.

The present experiments were designed to gain additionally insight into how the spinal networks process direct spinal stimulation and peripheral sensory inputs to control posture and locomotor movements. We have developed a plantar pressure stimulation system that can deliver naturalistic postural and gait-related patterns of pressure to the soles of the feet to simulate standing and walking, thereby activating and/or modulating the automated spinal circuitry responsible for standing and locomotion. In the present study we compare the patterns of activation among selected motor pools and the kinematic consequences of these activation patterns in response to patterned heel-to-toe mechanical stimulation of the soles of the feet, and/or transcutaneous electrical spinal stimulation, for postural and locomotion regulation. The studies were performed in healthy individuals (n = 12) as well as in subjects (n = 2) with motor complete spinal cord injury. We found that plantar pressure stimulation and/or spinal stimulation can effectively facilitate locomotor output in the subjects placed with their legs in gravity neutral position. We have shown synergistic effects of combining sensory and spinal cord stimulation, suggesting that the two networks are different, but complementary. Also we provide evidence that plantar stimulation could serve as a novel neuro-rehabilitation tool alone or as part of a multi-modal approach to restoring motor function after complete paralysis due to SCI.

Graphical abstract, Preclinical and clinical neurophysiological and neurorehabilitation research has generated rather surprising levels of recovery of volitional sensory-motor function in persons with chronic motor paralysis following a spinal cord injury. The key factor in this recovery is largely activity-dependent plasticity of spinal and supraspinal networks. This key factor can be triggered by neuromodulation of these networks with electrical and pharmacological interventions. This review addresses some of the systems-level physiological mechanisms that might explain the effects of electrical modulation and how repetitive training facilitates the recovery of volitional motor control. In particular, we substantiate the hypotheses that: (1) in the majority of spinal lesions, a critical number and type of neurons in the region of the injury survive, but cannot conduct action potentials, and thus are electrically non-responsive; (2) these neuronal networks within the lesioned area can be neuromodulated to a transformed state of electrical competency; (3) these two factors enable the potential for extensive activity-dependent reorganization of neuronal networks in the spinal cord and brain, and (4) propriospinal networks play a critical role in driving this activity-dependent reorganization after injury. Real-time proprioceptive input to spinal networks provides the template for reorganization of spinal networks that play a leading role in the level of coordination of motor pools required to perform a given functional task. Repetitive exposure of multi-segmental sensory-motor networks to the dynamics of task-specific sensory input as occurs with repetitive training can functionally reshape spinal and supraspinal connectivity thus re-enabling one to perform complex motor tasks, even years post injury.

The neurotransmitter systems mediating spinal locomotion in response to epidural spinal cord stimulation (ES) have not been identified. Here, we examine the role of the serotonergic system in regulating locomotor behavior of decerebrated cats during ES at L4–L5. ES elicited coordinated, weight-bearing, hindlimb stepping with plantar foot placement on a moving treadmill belt. Ketanserin [a 5-hydroxytryptamine (serotonin) (5-HT)2/7receptor antagonist] depressed this locomotor activity: only weak rhythmic movements without plantar foot placement and depressed EMG activity were observed. Cyproheptadine, a nonselective 5-HT blocker, prevented facilitation of stepping by epidural stimulation. These data demonstrate an important role of the serotonergic system in facilitating locomotion in the presence of epidural stimulation. In the presence of ketanserin, passive movements of one forelimb in a step-like manner immediately induced stepping of both hindlimbs with EMG patterns similar to those observed with ES without ketanserin. Thus, a non-5-HT-dependent spinal circuitry projecting from the cervical to the lumbar region of the spinal cord can facilitate stepping. The specific neurotransmitters responsible for this forelimb-facilitated stepping of the hindlimbs are unknown. These data suggest that a 5-HT2/7receptor-dependent pathway that processes hindlimb locomotor-like proprioception to facilitate hindlimb stepping can be complemented with proprioceptive afferents from the forelimbs via a non-5-HT2/7receptor neurotransmitter system. Thus, different neurotransmitter receptor systems can be used to mediate the same type of sensory event, i.e., locomotor-like proprioception to facilitate the same motor task, i.e., hindlimb stepping.

We investigated the role of afferent information during recovery of coordinated rhythmic activity of the hindlimbs in rats with a complete spinal cord section (approximately T8) and unilateral deafferentation (T12–S2) to answer the following questions: (1) Can bilateral stepping be generated with only afferent projections intact on one side? (2) Can the sensory input from the non-deafferented side compensate for the loss of the afferent input from the deafferented side through the crossed connections within the lumbosacral spinal cord? (3) Which afferent projections to the spinal cord from the non-deafferented side predominantly mediate the effect of epidural stimulation to facilitate stepping? Recovery of stepping ability was tested under the facilitating influence of epidural stimulation at the S1 spinal segment, or epidural stimulation plus quipazine, a 5-HT agonist. All chronic spinal rats were able to generate stepping-like patterns on a moving treadmill on the non-deafferented, but not deafferented, side from 3 to 7 weeks after surgery when facilitated by epidural stimulation. Adaptation to the loss of unilateral afferent input was evident at 7 weeks after surgery, when some movements occurred on the deafferented side. Spinal-cord-evoked potentials were observed on both sides, although middle (monosynaptic) and late (long latency) responses were more prominent on the non-deafferented side. The afferent information arising from the non-deafferented side, however, eventually could mediate limited restoration of hindlimb movements on the deafferented side. These data suggest that facilitation of stepping with epidural stimulation is mediated primarily through ipsilateral afferents that project to the locomotor networks.

Motor responses evoked by stimulating the spinal cord percutaneously between the T11 and T12 spinous processes were studied in eight human subjects during walking and running. Stimulation elicited responses bilaterally in the biceps femoris, vastus lateralis, rectus femoris, medial gastrocnemius, soleus, tibialis anterior, extensor digitorum brevis and flexor digitorum brevis. The evoked responses were consistent with activation of Ia afferent fibres through monosynaptic neural circuits since they were inhibited when a prior stimulus was given and during tendon vibration. Furthermore, the soleus motor responses were inhibited during the swing phase of walking as observed for the soleus H-reflex elicited by tibial nerve stimulation. Due to the anatomical site and the fibre composition of the peripheral nerves it is difficult to elicit H-reflex in leg muscles other than the soleus, especially during movement. In turn, the multisegmental monosynaptic responses (MMR) technique provides the opportunity to study modulation of monosynaptic reflexes for multiple muscles simultaneously. Phase-dependent modulation of the MMR amplitude throughout the duration of the gait cycle period was observed in all muscles studied. The MMR amplitude was large when the muscle was activated whereas it was generally reduced, or even suppressed, when the muscle was quiescent. However, during running, there was a systematic anticipatory increase in the amplitude of the MMR at the end of swing in all proximal and distal extensor muscles. The present findings therefore suggest that there is a general control scheme by which the transmission in the monosynaptic neural circuits is modulated in all leg muscles during stepping so as to meet the requirement of the motor task.

We review some basic and highly relevant concepts in the effort to develop improved rehabilitative interventions for subjects with spinal cord injury (SCI). Interventions that are likely to contribute to improved sensorimotor function include (1) practice of the specific motor task that needs to be improved; and (2) combining the training with one or more interventions--such as pharmacological modulation of the excitability of spinal neural networks, implantation of selected cell types such as olfactory ensheathing glia (OEG), and/or modulation of the excitability of the spinal cord via epidural stimulation. Upon improvement of the neural control of the musculature following SCI, it will always be prudent to maximize the torque output from these activation patterns by assuring that muscle mass is maintained. Therefore, it seems quite feasible that considerable improvement in locomotor performance can be achieved by improved coordination of motor pools, as well as effective recovery of muscle mass, which will assist in the potential generation of normal forces among agonistic and antagonistic muscle groups.

An increasing number of studies supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes functional recovery in humans with spinal cord injury (SCI). However, the neural mechanisms contributing to these effects remain poorly understood. Here we examined motor-evoked potentials in arm muscles elicited by cortical and subcortical stimulation of corticospinal axons before and after 20 min of TESS (30 Hz pulses with a 5 kHz carrier frequency) and sham-TESS applied between C5 and C6 spinous processes in males and females with and without chronic incomplete cervical SCI. The amplitude of subcortical, but not cortical, motor-evoked potentials increased in proximal and distal arm muscles for 75 min after TESS, but not sham-TESS, in control subjects and SCI participants, suggesting a subcortical origin for these effects. Intracortical inhibition, elicited by paired stimuli, increased after TESS in both groups. When TESS was applied without the 5 kHz carrier frequency both subcortical and cortical motor-evoked potentials were facilitated without changing intracortical inhibition, suggesting that the 5 kHz carrier frequency contributed to the cortical inhibitory effects. Hand and arm function improved largely when TESS was used with, compared with without, the 5 kHz carrier frequency. These novel observations demonstrate that TESS influences cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. We hypothesized that these parallel effects contribute to further the recovery of limb function following SCI.SIGNIFICANCE STATEMENTAccumulating evidence supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes recovery of function in humans with spinal cord injury (SCI). Here, we show that a single session of TESS over the cervical spinal cord in individuals with incomplete chronic cervical SCI influenced in parallel the excitability cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. Importantly, these parallel physiological effects had an impact on the magnitude of improvements in voluntary motor output.