Integration of sensory, spinal, and volitional descending inputs in regulation of human locomotion.

We reported previously that both transcutaneous electrical spinal cord stimulation and direct pressure stimulation of the plantar surfaces of the feet can elicit rhythmic involuntary step-like movements in noninjured subjects with their legs in a gravity-neutral apparatus. The present experiments investigated the convergence of spinal and plantar pressure stimulation and voluntary effort in the activation of locomotor movements in uninjured subjects under full body weight support in a vertical position. For all conditions, leg movements were analyzed using electromyographic (EMG) recordings and optical motion capture of joint kinematics. Spinal cord stimulation elicited rhythmic hip and knee flexion movements accompanied by EMG bursting activity in the hamstrings of 6/6 subjects. Similarly, plantar stimulation induced bursting EMG activity in the ankle flexor and extensor muscles in 5/6 subjects. Moreover, the combination of spinal and plantar stimulation exhibited a synergistic effect in all six subjects, eliciting greater motor responses than either modality alone. While the motor responses to spinal vs. plantar stimulation seems to activate distinct but overlapping spinal neural networks, when engaged simultaneously, the stepping responses were functionally complementary. As observed during induced (involuntary) stepping, the most significant modulation of voluntary stepping occurred in response to the combination of spinal and plantar stimulation. In light of the known automaticity and plasticity of spinal networks in absence of supraspinal input, these findings support the hypothesis that spinal and plantar stimulation may be effective tools for enhancing the recovery of motor control in individuals with neurological injuries and disorders.

Initiation and modulation of locomotor circuitry output with multisite transcutaneous electrical stimulation of the spinal cord in noninjured humans.

The mammalian lumbar spinal cord has the capability to generate locomotor activity in the absence of input from the brain. Previously, we reported that transcutaneous electrical stimulation of the spinal cord at vertebral level T11 can activate the locomotor circuitry in noninjured subjects when their legs are placed in a gravity-neutral position (Gorodnichev RM, Pivovarova EA, Pukhov A, Moiseev SA, Savokhin AA, Moshonkina TR, Shcherbakova NA, Kilimnik VA, Selionov VA, Kozlovskaia IB, Edgerton VR, Gerasimenko IU. Fiziol Cheloveka 38: 46-56, 2012). In the present study we hypothesized that stimulating multiple spinal sites and therefore unique combinations of networks converging on postural and locomotor lumbosacral networks would be more effective in inducing more robust locomotor behavior and more selective control than stimulation of more restricted networks. We demonstrate that simultaneous stimulation at the cervical, thoracic, and lumbar levels induced coordinated stepping movements with a greater range of motion at multiple joints in five of six noninjured subjects. We show that the addition of stimulation at L1 and/or at C5 to stimulation at T11 immediately resulted in enhancing the kinematics and interlimb coordination as well as the EMG patterns in proximal and distal leg muscles. Sequential cessation of stimulation at C5 and then at L1 resulted in a progressive degradation of the stepping pattern. The synergistic and interactive effects of transcutaneous stimulation suggest a multisegmental convergence of descending and ascending, and most likely propriospinal, influences on the spinal neuronal circuitries associated with locomotor activity. The potential impact of using multisite spinal cord stimulation as a strategy to neuromodulate the spinal circuitry has significant implications in furthering our understanding of the mechanisms controlling posture and locomotion and for regaining significant sensorimotor function even after a severe spinal cord injury.

Transcutaneous Spinal Cord Stimulation Facilitates Respiratory Functional Performance in Patients with Post-Acute COVID-19.

BACKGROUND: A growing number of studies have reported Coronavirus disease (COVID-19) related to both respiratory and central nervous system dysfunctions. This study evaluates the neuromodulatory effects of spinal cord transcutaneous stimulation (scTS) on the respiratory functional state in healthy controls and patients with post-COVID-19 respiratory deficits as a step toward the development of a rehabilitation strategy for these patients. METHODS: In this before-after, interventional, case-controlled clinical study, ten individuals with post-acute COVID-19 respiratory deficits and eight healthy controls received a single twenty-minute-long session of modulated monophasic scTS delivered over the T5 and T10 spinal cord segments. Forced vital capacity (FVC), peak forced inspiratory flow (PIF), peak expiratory flow (PEF), time-to-peak of inspiratory flow (tPIF), and time-to-peak of expiratory flow (tPEF), as indirect measures of spinal motor network activity, were assessed before and after the intervention. RESULTS: In the COVID-19 group, the scTS intervention led to significantly increased PIF (p = 0.040) and PEF (p = 0.049) in association with significantly decreased tPIF (p = 0.035) and tPEF (p = 0.013). In the control group, the exposure to scTS also resulted in significantly increased PIF (p = 0.010) and significantly decreased tPIF (p = 0.031). Unlike the results in the COVID-19 group, the control group had significantly decreased PEF (p = 0.028) associated with significantly increased tPEF (p = 0.036). There were no changes for FVC after scTS in both groups (p = 0.67 and p = 0.503). CONCLUSIONS: In post-COVID-19 patients, scTS facilitates excitation of both inspiratory and expiratory spinal neural networks leading to an immediate improvement of respiratory functional performance. This neuromodulation approach could be utilized in rehabilitation programs for patients with COVID-19 respiratory deficits.

Novel and direct access to the human locomotor spinal circuitry.

The degree of automaticity of locomotion in primates compared with other mammals remains unclear. Here, we examine the possibility for activation of the spinal locomotor circuitry in noninjured humans by spinal electromagnetic stimulation (SEMS). SEMS (3 Hz and 1.3-1.82 tesla) at the T11-T12 vertebrae induced involuntary bilateral locomotor-like movements in the legs of individuals placed in a gravity-neutral position. The formation of locomotor-like activity during SEMS started with a latency of 0.68 +/- 0.1 s after delivering the first stimulus, unlike continuous vibration of muscles, which requires several seconds. The first EMG burst in response to SEMS was observed most often in a proximal flexor muscle. We speculate that SEMS directly activates the circuitry intrinsic to the spinal cord, as suggested by the immediate response and the electrophysiological observations demonstrating an absence of strictly time-linked responses within the EMG burst associated with individual stimuli during SEMS. SEMS in the presence of vibration of the leg muscles was more effective in facilitating locomotor-like activity than SEMS alone. The present results suggest that SEMS could be an effective noninvasive clinical tool to determine the potential of an individual to recover locomotion after a spinal cord injury, as well as being an effective rehabilitation tool itself.

Electrical Spinal Stimulation, and Imagining of Lower Limb Movements to Modulate Brain-Spinal Connectomes That Control Locomotor-Like Behavior.

Neuronal control of stepping movement in healthy human is based on integration between brain, spinal neuronal networks, and sensory signals. It is generally recognized that there are continuously occurring adjustments in the physiological states of supraspinal centers during all routines movements. For example, visual as well as all other sources of information regarding the subject's environment. These multimodal inputs to the brain normally play an important role in providing a feedforward source of control. We propose that the brain routinely uses these continuously updated assessments of the environment to provide additional feedforward messages to the spinal networks, which provides a synergistic feedforwardness for the brain and spinal cord. We tested this hypothesis in 8 non-injured individuals placed in gravity neutral position with the lower limbs extended beyond the edge of the table, but supported vertically, to facilitate rhythmic stepping. The experiment was performed while visualizing on the monitor a stick figure mimicking bilateral stepping or being motionless. Non-invasive electrical stimulation was used to neuromodulate a wide range of excitabilities of the lumbosacral spinal segments that would trigger rhythmic stepping movements. We observed that at the same intensity level of transcutaneous electrical spinal cord stimulation (tSCS), the presence or absence of visualizing a stepping-like movement of a stick figure immediately initiated or terminated the tSCS-induced rhythmic stepping motion, respectively. We also demonstrated that during both voluntary and imagined stepping, the motor potentials in leg muscles were facilitated when evoked cortically, using transcranial magnetic stimulation (TMS), and inhibited when evoked spinally, using tSCS. These data suggest that the ongoing assessment of the environment within the supraspinal centers that play a role in planning a movement can routinely modulate the physiological state of spinal networks that further facilitates a synergistic neuromodulation of the brain and spinal cord in preparing for movements.

Transcutaneous electrical spinal-cord stimulation in humans.

Locomotor behavior is controlled by specific neural circuits called central pattern generators primarily located at the lumbosacral spinal cord. These locomotor-related neuronal circuits have a high level of automaticity; that is, they can produce a "stepping" movement pattern also seen on electromyography (EMG) in the absence of supraspinal and/or peripheral afferent inputs. These circuits can be modulated by epidural spinal-cord stimulation and/or pharmacological intervention. Such interventions have been used to neuromodulate the neuronal circuits in patients with motor-complete spinal-cord injury (SCI) to facilitate postural and locomotor adjustments and to regain voluntary motor control. Here, we describe a novel non-invasive stimulation strategy of painless transcutaneous electrical enabling motor control (pcEmc) to neuromodulate the physiological state of the spinal cord. The technique can facilitate a stepping performance in non-injured subjects with legs placed in a gravity-neutral position. The stepping movements were induced more effectively with multi-site than single-site spinal-cord stimulation. From these results, a multielectrode surface array technology was developed. Our preliminary data indicate that use of the multielectrode surface array can fine-tune the control of the locomotor behavior. As well, the pcEmc strategy combined with exoskeleton technology is effective for improving motor function in paralyzed patients with SCI. The potential impact of using pcEmc to neuromodulate the spinal circuitry has significant implications for furthering our understanding of the mechanisms controlling locomotion and for rehabilitating sensorimotor function even after severe SCI.

Effects of paired transcutaneous electrical stimulation delivered at single and dual sites over lumbosacral spinal cord.

It was demonstrated previously that transcutaneous electrical stimulation of multiple sites over the spinal cord is more effective in inducing robust locomotor behavior as compared to the stimulation of single sites alone in both animal and human models. To explore the effects and mechanisms of interactions during multi-site spinal cord stimulation we delivered transcutaneous electrical stimulation to the single or dual locations over the spinal cord corresponding to approximately L2 and S1 segments. Spinally evoked motor potentials in the leg muscles were investigated using single and paired pulses of 1ms duration with conditioning-test intervals (CTIs) of 5 and 50ms. We observed considerable post-stimulation modulatory effects which depended on CTIs, as well as on whether the paired stimuli were delivered at a single or dual locations, the rostro-caudal relation between the conditioning and test stimuli, and on the muscle studied. At CTI-5, the paired stimulation delivered at single locations (L2 or S1) provided strong inhibitory effects, evidenced by the attenuation of the compound responses as compared with responses from either single site. In contrast, during L2-S1 paradigm, the compound responses were potentiated. At CTI-50, the magnitude of inhibition did not differ among paired stimulation paradigms. Our results suggest that electrical stimuli delivered to dual sites over the lumbosacral enlargement in rostral-to-caudal order, may recruit different populations of motor neurons initially through projecting sensory and intraspinal connections and then directly, resulting in potentiation of the compound spinally evoked motor potentials. The interactive and synergistic effects indicate multi-segmental convergence of descending and ascending influences on the neuronal circuitries during electrical spinal cord stimulation.