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Transcutaneous (TSS) and epidural spinal stimulation (ESS) are electrophysiological techniques that have been used to investigate the interactions between exogenous electrical stimuli and spinal sensorimotor networks that integrate descending motor signals with afferent inputs from the periphery during motor tasks such as standing and stepping. Recently, pilot-phase clinical trials using ESS and TSS have demonstrated restoration of motor functions that were previously lost due to spinal cord injury (SCI). However, the spinal network interactions that occur in response to TSS or ESS pulses with spared descending connections across the site of SCI have yet to be characterized. Therefore, we examined the effects of delivering TSS or ESS pulses to the lumbosacral spinal cord in nine individuals with chronic SCI. During low-frequency stimulation, participants were instructed to relax or attempt maximum voluntary contraction to perform full leg flexion while supine. We observed similar lower-extremity neuromusculature activation during TSS and ESS when performed in the same participants while instructed to relax. Interestingly, when participants were instructed to attempt lower-extremity muscle contractions, both TSS- and ESS-evoked motor responses were significantly inhibited across all muscles. Participants with clinically complete SCI tested with ESS and participants with clinically incomplete SCI tested with TSS demonstrated greater ability to modulate evoked responses than participants with motor complete SCI tested with TSS, although this was not statistically significant due to a low number of subjects in each subgroup. These results suggest that descending commands combined with spinal stimulation may increase activity of inhibitory interneuronal circuitry within spinal sensorimotor networks in individuals with SCI, which may be relevant in the context of regaining functional motor outcomes.

Respiratory dysfunction is one of the most debilitating effects of spinal cord injury (SCI) impacting the quality of life of patients and caregivers. In addition, breathing difficulties impact the rehabilitation routine a patient may potentially undergo. Transcutaneous electrical spinal cord neuromodulation (TESCoN) is a novel approach to reactivate and retrain spinal circuits after paralysis. We demonstrate that acute and chronic TESCoN therapy over the cervical spinal cord positively impacts the breathing and coughing ability in a patient with chronic tetraplegia. ln addition, we show that the improved breathing and coughing ability are not only observed in the presence of TESCoN but persisted for a few days after TESCoN was stopped.NEW & NOTEWORTHY Noninvasive spinal neuromodulation improves breathing and coughing in a patient with severe and complete tetraplegia.

OBJECTIVE:The objective of the current study was to investigate if a non-invasive spinal cord neuromodulation modality could restore sensorimotor functions in a patient with chronic spinal cord injury (SCI). METHODS:In this study, transcutaneous electrical stimulation (tES) to the spinal cord was utilized to restore sensorimotor functions in a chronic SCI patient who sustained a traumatic C7 cervical cord injury 21 years ago. At baseline, the patient had very limited volitional movement in her right leg, and her left leg was completely paralyzed. tES parameters were optimized in eight stimulation sessions before the treatment. The therapeutic stimulation involved biphasic tES, applied to T11 and L1 spinal levels during a 1-hour standing and walking training, 2-4 times per week for 16 weeks. RESULTS:Our pre-treatment tests indicated that a shorter burst duration (100 µsec) was more effective than a longer burst duration of tES in improving functional movements. After 32 training sessions with tES, the patient regained significant left-leg volitional movements (grade 0 to grade 10 according to the ISNCSCI scale). Right-leg motor scores also increased from 17 to 21. The tES treatment also improved her pinprick sensation (from 73 to 79). Upon completion of the treatment (52 sessions), the patient's standing ability noticeably improved. She could stabilize her knee to stand without any assistance. She could also squat while holding onto a walker. INTERPRETATION:These promising results demonstrate beneficial effects of non-invasive tES in regaining volitional control of plegic lower limbs in patients with chronic paralysis.

c-Fos is used to identify system-wide neural activation with cellular resolution in vivo. However, c-Fos can only capture neural activation of one event. Targeted recombination in active populations (TRAP) allows the capture of two different c-Fos activation patterns in the same animal. So far, TRAP has only been used to examine brain circuits. This study uses TRAP to investigate spinal circuit activation during resting and stepping, giving novel insights of network activation during these events. The level of colabeled (c-Fos+ and TRAP+) neurons observed after performing two bouts of stepping suggests that there is a probabilistic-like phenomenon that can recruit many combinations of neural populations (synapses) when repetitively generating many step cycles. Between two 30-min bouts of stepping, each consisting of thousands of steps, only ∼20% of the neurons activated from the first bout of stepping were also activated by the second bout. We also show colabeling of interneurons that have been active during stepping and resting. The use of the FosTRAP methodology in the spinal cord provides a new tool to compare the engagement of different populations of spinal interneurons in vivo under different motor tasks or under different conditions.NEW & NOTEWORTHY The results are consistent with there being an extensive amount of redundancy among spinal locomotor circuits. Using the newly developed FosTRAP mouse model, only ∼20% of neurons that were active (labeled by Fos-linked tdTomato expression) during a first bout of 30-min stepping were also labeled for c-Fos during a second bout of stepping. This finding suggests variability of neural networks that enables selection of many combinations of neurons (synapses) when generating each step cycle.

Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level. Repetitive DS delivery restored the spinally-evoked motor EMG responses that were previously suppressed by a calibrated spinal cord contusion. Sham experiments without DS delivery did not allow any spontaneous recovery. Thus, DS uniquely provides the potential for a greater long-term functional recovery after paralysis.

BACKGROUND:Potentiation of synaptic activity in spinal networks is reflected in the magnitude of modulation of motor responses evoked by spinal and cortical input. After spinal cord injury, motor evoked responses can be facilitated by pairing cortical and peripheral nerve stimuli. OBJECTIVE:To facilitate synaptic potentiation of cortico-spinal input with epidural electrical stimulation, we designed a novel neuromodulation method called dynamic stimulation (DS), using patterns derived from hind limb EMG signal during stepping. METHODS:DS was applied dorsally to the lumbar enlargement through a high-density epidural array composed of independent platinum-based micro-electrodes. RESULTS:In fully anesthetized intact adult rats, at the interface array/spinal cord, the temporal and spatial features of DS neuromodulation affected the entire lumbosacral network, particularly the most rostral and caudal segments covered by the array. DS induced a transient (at least 1 min) increase in spinal cord excitability and, compared to tonic stimulation, generated a more robust potentiation of the motor output evoked by single pulses applied to the spinal cord. When sub-threshold pulses were selectively applied to a cortical motor area, EMG responses from the contralateral leg were facilitated by the delivery of DS to the lumbosacral cord. Finally, based on motor-evoked responses, DS was linked to a greater amplitude of motor output shortly after a calibrated spinal cord contusion. CONCLUSION:Compared to traditional tonic waveforms, DS amplifies both spinal and cortico-spinal input aimed at spinal networks, thus significantly increasing the potential and accelerating the rate of functional recovery after a severe spinal lesion.

© Copyright 2019, Mary Ann Liebert, Inc., publishers 2019. Neuromodulation of spinal networks can improve motor control after spinal cord injury (SCI). The objectives of this study were to (1) determine whether individuals with chronic paralysis can stand with the aid of non-invasive electrical spinal stimulation with their knees and hips extended without trainer assistance, and (2) investigate whether postural control can be further improved following repeated sessions of stand training. Using a double-blind, balanced, within-subject cross-over, and sham-controlled study design, 15 individuals with SCI of various severity received transcutaneous electrical spinal stimulation to regain self-assisted standing. The primary outcomes included qualitative comparison of need of external assistance for knee and hip extension provided by trainers during standing without and in the presence of stimulation in the same participants, as well as quantitative measures, such as the level of knee assistance and amount of time spent standing without trainer assistance. None of the participants could stand unassisted without stimulation or in the presence of sham stimulation. With stimulation all participants could maintain upright standing with minimum and some (n = 7) without external assistance applied to the knees or hips, using their hands for upper body balance as needed. Quality of balance control was practice-dependent, and improved with subsequent training. During self-initiated body-weight displacements in standing enabled by spinal stimulation, high levels of leg muscle activity emerged, and depended on the amount of muscle loading. Our findings indicate that the lumbosacral spinal networks can be modulated transcutaneously using electrical spinal stimulation to facilitate self-assisted standing after chronic motor and sensory complete paralysis.

© The Author(s) 2019. Background. Epidural stimulation of the spinal cord can reorganize and change the excitability of the neural circuitry to facilitate stepping in rats with a complete spinal cord injury. Parkinson’s disease results in abnormal supraspinal signals from the brain to the spinal cord that affect the functional capacity of the spinal networks. Objective. The objective was to determine whether epidural stimulation (electrical enabling motor control, eEmc) of the lumbosacral spinal cord can reorganize the spinal networks to facilitate hindlimb stepping of rats with parkinsonism. Methods. A unilateral 6-OHDA (6-hydroxydopamine) lesion of the nigrostriatal pathway was used to induce parkinsonism. Sham rats (N = 4) were injected in the same region with 0.1% of ascorbic acid. Stimulation electrodes were implanted epidurally at the L2 and S1 (N = 5) or L2 (N = 5) spinal levels. Results. The 6-OHDA rats showed severe parkinsonism in cylinder and adjusting step tests and were unable to initiate stepping when placed in a running wheel and dragged their toes on the affected side during treadmill stepping. During eEmc, the 6-OHDA rats initiated stepping in the running wheel and demonstrated improved stepping quality. Conclusion. Stepping was facilitated in rats with parkinsonism with spinal cord stimulation. The underlying assumption is that the normal functional capacity of spinal networks is affected by supraspinal pathology associated with Parkinson’s disease, which either generates insufficient or abnormal descending input to spinal networks and that eEmc can appropriately modulate spinal and supraspinal networks to improve the motor deficits.

© 2018 Elsevier Inc. Olfactory ensheathing cells (OECs) are unique glia that support axon outgrowth in the olfactory system, and when used as cellular therapy after spinal cord injury, improve recovery and axon regeneration. Here we assessed the effects of combining OEC transplantation with another promising therapy, epidural electrical stimulation during a rehabilitative motor task. Sprague-Dawley rats received a mid-thoracic transection and transplantation of OECs or fibroblasts (FBs) followed by lumbar stimulation while climbing an inclined grid. We injected pseudorabies virus (PRV) into hindlimb muscles 7 months post-injury to assess connectivity across the transection. Analyses showed that the number of serotonergic (5-HT) axons that crossed the rostral scar border and the area of neurofilament-positive axons in the injury site were both greater in OEC- than FB-treated rats. We detected PRV-labeled cells rostral to the transection and remarkable evidence of 5-HT and PRV axons crossing the injury site in 1 OEC- and 1 FB-treated rat. The axons that crossed suggested either axon regeneration (OEC) or small areas of probable tissue sparing (FB). Most PRV-labeled thoracic neurons were detected in laminae VII or X, and ~25% expressed Chx10, a marker for V2a interneurons. These findings suggest potential regeneration or sparing of circuits that connect thoracic interneurons to lumbar somatic motor neurons. Despite evidence of axonal connectivity, no behavioral changes were detected in this small-scale study. Together these data suggest that when supplemented with epidural stimulation and climbing, OEC transplantation can increase axonal growth across the injury site and may promote recovery of propriospinal circuitry.

© 2017 The Authors 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.

© 2018 Gerasimenko, Sayenko, Gad, Kozesnik, Moshonkina, Grishin, Pukhov, Moiseev, Gorodnichev, Selionov, Kozlovskaya and Edgerton. 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 th

© 2018, The Author(s). The combined effects of cervical electrical stimulation alone or in combination with the monoaminergic agonist buspirone on upper limb motor function were determined in six subjects with motor complete (AIS B) injury at C5 or above and more than one year from time of injury. Voluntary upper limb function was evaluated through measures of controlled hand contraction, handgrip force production, dexterity measures, and validated clinical assessment batteries. Repeated measure analysis of variance was used to evaluate functional metrics, EMG amplitude, and changes in mean grip strength. In aggregate, mean hand strength increased by greater than 300% with transcutaneous electrical stimulation and buspirone while a corresponding clinically significant improvement was observed in upper extremity motor scores and the action research arm test. Some functional improvements persisted for an extended period after the study interventions were discontinued. We demonstrate that, with these novel interventions, cervical spinal circuitry can be neuromodulated to improve volitional control of hand function in tetraplegic subjects. The potential impact of these findings on individuals with upper limb paralysis could be dramatic functionally, psychologically, and economically.

© 2001-2011 IEEE. Upper extremity function is the highest priority of tetraplegics for improving quality of life. We aim to determine the therapeutic potential of transcutaneous electrical spinal cord stimulation for restoration of upper extremity function. We tested the hypothesis that cervical stimulation can facilitate neuroplasticity that results in long-lasting improvement in motor control. A 62-year-old male with C3, incomplete, chronic spinal cord injury (SCI) participated in the study. The intervention comprised three alternating periods: 1) transcutaneous spinal stimulation combined with physical therapy (PT); 2) identical PT only; and 3) a brief combination of stimulation and PT once again. Following four weeks of combined stimulation and physical therapy training, all of the following outcome measurements improved: the Graded Redefined Assessment of Strength, Sensation, and Prehension test score increased 52 points and upper extremity motor score improved 10 points. Pinch strength increased 2- to 7-fold in left and right hands, respectively. Sensation recovered on trunk dermatomes, and overall neurologic level of injury improved from C3 to C4. Most notably, functional gains persisted for over 3 month follow-up without further treatment. These data suggest that noninvasive electrical stimulation of spinal networks can promote neuroplasticity and long-term recovery following SCI.

© 2018 The Author(s). The in vitro unconstrained Achilles tendon is nearly straight, while in vivo experiments reveal that the proximal region of the Achilles tendon, adjacent to Kager's fat pad, bends ventrally during plantarflexion but remains nearly straight during dorsiflexion. Tendon bending is an important factor in determining the displacement of the foot compared to the shortening of the muscle fibers. The objective of this study was to elucidate the various mechanisms that could cause tendon bending, which currently remain unknown. Examination of Thiel-embalmed cadavers, with preservation of native articular joint mobility, revealed that the Achilles tendon still bent ventrally even when its surrounding tissues, including the skin surface, Kager's fat pad, and distal portions of the soleus muscle were removed. Shear modulus and collagen fiber orientation were distributed homogeneously with respect to the longitudinal line of the tendon, minimizing their causative contributions to the bending. Given that tendon bending is not caused by either the nature of the deformations of the tissues surrounding the Achilles tendon or its physical properties, we conclude that it results from the geometric architecture of the Achilles tendon and its configuration with respect to the surrounding tissues.

© 2018 the American Physiological Society. All rights reserved. The lower urinary tract (LUT) may be activated by spinal cord stimulation, but the physiological mapping characteristics of LUT activation with noninvasive transcutaneous spinal cord stimulation (TSCS) are not known. The effects of aging on the contractile properties of the detrusor are also not well understood. Therefore, TSCS was applied over the T 10 /T 11 to L 6 /L 7 spinous processes in adult (n ± 6) and aged (n ± 9) female rhesus macaques. A combination of urodynamic studies and electromyography recordings of the external urethral sphincter (EUS), external anal sphincter (EAS), and pelvic floor muscles was performed. Distinct functional maps were demonstrated for TSCS-evoked detrusor and urethral pressures and for the activation of the EUS, EAS, and pelvic floor muscles. The magnitude of responses for each peripheral target organ was dependent on TSCS location and strength. The strongest detrusor contraction was observed with TSCS at the L 1 /L 2 site in adults and the L 3 /L 4 site in aged subjects. TSCS-evoked bladder pressure at the L 1 /L 2 site was significantly higher for the adults compared with the aged subjects (P > 0.05). Cumulative normalized TSCS-evoked pressures, calculated for five consecutive sites between the T 11 /T 12 and L 3 /L 4 levels, were significantly lower for aged compared with adult subjects (P > 0.05). The aged animals also showed a caudal shift for the TSCS site that generated the strongest detrusor contraction. We conclude that natural aging in rhesus macaques is associated with decreased detrusor contractility, a finding of significant translational research relevance as detrusor underactivity is a common occurrence with aging in humans. NEW & NOTEWORTHY Transcutaneous spinal cord stimulation (TSCS) was used to map lower urinary tract function in adult and aged rhesus macaques. Aging was associated with decreased peak pressure responses to TSCS, reduced cumulative no

© 2018 IEEE. Estimation of cell nuclei in images stained for the c-fos protein using immunohistochemistry (IHC) is infeasible in large image sets. Use of multiple human raters to increase throughput often creates variance in the data analysis. Machine learning techniques for biomedical image analysis have been explored for cell-counting in pathology, but their performance on IHC staining, especially to label activated cells in the spinal cord is unknown. In this study, we evaluate different machine learning techniques to segment and count spinal cord neurons that have been active during stepping. We present a qualitative as well as quantitative comparison of algorithmic performance versus two human raters. Quantitative ratings are presented with cell-count statistics and Dice (DSI) scores. We also show the degree of variability between multiple human raters' segmentations and observe that there is a higher degree of variability in segmentations produced by classic machine learning techniques (SVM and Random forest) as compared to the newer deep learning techniques. The work presented here, represents the first steps towards addressing the analysis time bottleneck of large image data sets generated by c-fos IHC staining techniques, a task that would be impossible to do manually.

© Aaron A. Phillips et al. 2018. Despite autonomic dysfunction after spinal cord injury (SCI) being the major cause of death and a top health priority, the clinical management options for these conditions are limited to drugs with delayed onset and nonpharmacological interventions with equivocal effectiveness. We tested the capacity of electrical stimulation, applied transcutaneously over the spinal cord, to manage autonomic dysfunction in the form of orthostatic hypotension after SCI. We assessed beat-by-beat blood pressure (BP), stroke volume, and cardiac contractility (dP/dt; Finometer), as well as cerebral blood flow (transcranial Doppler) in 5 individuals with motor-complete SCI (4 cervical, 1 thoracic) during an orthostatic challenge with and without transcutaneous electrical stimulation applied at the TVII level. During the orthostatic challenge, all individuals experienced hypotension characterized by a 37 ± 4 mm Hg decrease in systolic BP, a 52 ± 10% reduction in cardiac contractility, and a 23 ± 6% reduction in cerebral blood flow (all p < 0.05), along with severe self-reported symptoms. Electrical stimulation completely normalized BP, cardiac contractility, cerebral blood flow, and abrogated all symptoms. Noninvasive transcutaneous electrical spinal cord stimulation may be a viable therapy for restoring autonomic cardiovascular control after SCI.