Reggie Edgerton

BackgroundAfter stroke, restoring safe, independent, and efficient walking is a top rehabilitation priority. However, in nearly 70% of stroke survivors asymmetrical walking patterns and reduced walking speed persist. This case series study aims to investigate the effectiveness of transcutaneous spinal cord stimulation (tSCS) in enhancing walking ability of persons with chronic stroke.MethodsEight participants with hemiparesis after a single, chronic stroke were enrolled. Each participant was assigned to either the Stim group (N = 4, gait training + tSCS) or Control group (N = 4, gait training alone). Each participant in the Stim group was matched to a participant in the Control group based on age, time since stroke, and self-selected gait speed. For the Stim group, tSCS was delivered during gait training via electrodes placed on the skin between the spinous processes of C5–C6, T11–T12, and L1–L2. Both groups …

A neuromodulation system, device, and method are disclosed. In an embodiment, a neuromodulation system includes a processor, a signal generator, a first electrode, and a second electrode. The processor in cooperation with the signal generator, the first electrode, and the second electrode are configured to deliver a transcutaneous stimulation to a mammal. The transcutaneous stimulation is configured by the processor for inducing voluntary movement in the mammal. The first electrode is positioned transcutaneously on a spinal cord and/or spinal cord dorsal roots of the mammal. Additionally, the second electrode is placed transcutaneously on or over at least one of the spinal cord and/or the spinal cord dorsal roots, a muscle, a nerve, or on or near a target end organ or bodily structure of the mammal. The second electrode is in communication with the first electrode through a hardwire or wireless connection.

Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle …

Methods of enabling locomotor control, postural control, voluntary control of body movements (eg, in non-weight bearing conditions), and/or autonomic functions in a human subject having a spinal cord injury, a brain injury, or a neurological neuromotor disease are described.

A wireless implant and associated system for motor function recovery after spinal cord injury, and more particularly a multi-channel wireless implant with small package size. The wireless implant can further be used in various medical applications, such as retinal prostheses, gastrointestinal implant, vagus nerve stimulation, and cortical neuromodulation. The system also includes a method and its implementation to acquire the impedance model of the electrode-tissue interface of the implant.

Background Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target. Methods We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test. Results In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal …

The paralysis that occurs after a spinal cord injury, particularly during the early stages of post-lesion recovery (~6 weeks), appears to be attributable to the inability to activate motor pools well beyond their motor threshold. In the later stages of recovery, however, the inability to perform a motor task effectively can be attributed to abnormal activation patterns among motor pools, resulting in poor coordination. We have tested this hypothesis on four adult male Rhesus monkeys (Macaca mulatta), ages 6-10 years, by recording the EMG activity levels and patterns of multiple proximal and distal muscles controlling the upper limb of the Rhesus when performing three tasks requiring different levels of skill before and up to 24 weeks after a lateral hemisection at C7. During the recovery period the animals were provided routine daily care, including access to a large exercise cage (5’ x 7’ x 10’) and tested every 3-4 weeks for each of the three motor tasks. At approximately 6-8 weeks the animals were able to begin to step on a treadmill, perform a spring-loaded task with the upper limb, and reaching, grasping, and eating a grape placed on a vertical stick. The predominant changes that occurred, beginning at ~6-8 weeks of the recovery of these tasks was an elevated level of activation of most motor pools well beyond the pre-lesion level. As the chronic phase progressed there was a slight reduction in the EMG burst amplitudes of some muscles and less incidence of co-contraction of agonists and antagonists, probably contributing to an improved ability to selectively activate motor pools in a more effective temporal pattern. Relative to pre-lesion, however, the …

Research ObjectivesTo investigate the safety and efficacy of breathing low oxygen (acute intermittent hypoxia, AIH) as a pretreatment to enhance the functional benefits of transcutaneous spinal neuromodulation (TSN) on walking training (WALK+TSN) in people with chronic, motor-incomplete spinal cord injury (iSCI).DesignDouble-blind, placebo-controlled multisite randomized clinical trial.SettingSpaulding Rehabilitation Hospital; Boston, MA and Shirley Ryan AbilityLab; Chicago, IL.ParticipantsWe plan to enroll 60 adults (18-70 yrs.) with chronic (>1 yr. post injury) iSCI who are ambulatory.InterventionsAll participants will receive two weeks of high intensity (8, 60min sessions) walking practice (WALK) before randomly receiving either two weeks (8 sessions) of AIH (15 episodes; 90s at 10% O2, 60s intervals of room air) pretreatment to WALK+TSN, SHAM (15 episodes; 90s at 21% O2, with 60s intervals of room air …

(1) Background: Restoring arm and hand function is a priority for individuals with cervical spinal cord injury (cSCI) for independence and quality of life. Transcutaneous spinal cord stimulation (tSCS) promotes the upper extremity (UE) motor function when applied at the cervical region. The aim of the study was to determine the effects of cervical tSCS, combined with an exoskeleton, on motor strength and functionality of UE in subjects with cSCI. (2) Methods: twenty-two subjects participated in the randomized mix of parallel-group and crossover clinical trial, consisting of an intervention group (n = 15; tSCS exoskeleton) and a control group (n = 14; exoskeleton). The assessment was carried out at baseline, after the last session, and two weeks after the last session. We assessed graded redefined assessment of strength, sensibility, and prehension (GRASSP), box and block test (BBT), spinal cord independence measure III (SCIM-III), maximal voluntary contraction (MVC), ASIA impairment scale (AIS), and WhoQol-Bref; (3) Results: GRASSP, BBT, SCIM III, cylindrical grip force and AIS motor score showed significant improvement in both groups (p ≤ 0.05), however, it was significantly higher in the intervention group than the control group for GRASSP strength, and GRASSP prehension ability (p ≤ 0.05); (4) Conclusion: our findings show potential advantages of the combination of cervical tSCS with an exoskeleton to optimize the outcome for UE.

Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALKtSTIM) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALKtSTIM therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALKtSTIM on walking recovery in persons with chronic SCI. We hypothesize that daily (eight sessions, 2 weeks) tAIH + WALKtSTIM will elicit faster, more persistent improvements in walking recovery than either treatment alone. To test our hypothesis, we are conducting a placebo-controlled clinical trial on 60 SCI participants who randomly receive one of three …

Following spinal cord injury (SCI), sensory and motor functions are severely disrupted yet the spinal circuitry below the injury site continues to maintain active and functional neuronal properties (Edgerton, 2004). The spinal cord is endogenously capable of several forms of adaptive plasticity, including functional re-training with exercise, instrumental, and Pavlovian learning. The paw withdrawal learning (PaWL) paradigm represents a simple spinal instrumental learning model (Jindrich 2019). Briefly, in mice whose spinal cords are completely transected (ST) at mid-thoracic (T7-T9) level, the tibialis anterior (TA) muscle is given a sub maximal threshold shock to a hind leg when the leg is extended below a 1mm imposed threshold from a baseline starting position. The contingent group mice learn to maintain the shocked leg, in a flexed position while the experimentally coupled noncontingent group of mice do not …

This chapter is designed to reassess some of the common assumptions regarding the different strategies to recover locomotor function after severe spinal injuries. Emphasis is placed on findings derived from in vivo experiments with a focus on systems level physiology to understand the levels and components of integration that occurs in controlling normal locomotion. These principles can provide guidelines informing rehabilitative procedures that facilitate recovery of function. There is a focus on the role of proprioception in developing activity-dependent interventions and its importance in activating different “primitives” in controlling locomotion. A final primary target also is to summarize the authors' views of the variability and redundancy design features of the locomotor control system.

A neuromodulation system, device, and method are disclosed. In an embodiment, a neuromodulation system includes a processor, a signal generator, a first electrode, and a second electrode. The processor in cooperation with the signal generator, the first electrode, and the second electrode are configured to deliver a transcutaneous stimulation to a mammal. The transcutaneous stimulation is configured by the processor for inducing voluntary movement in the mammal. The first electrode is positioned transcutaneously on a spinal cord and/or spinal cord dorsal roots of the mammal. Additionally, the second electrode is placed transcutaneously on or over at least one of the spinal cord and/or the spinal cord dorsal roots, a muscle, a nerve, or on or near a target end organ or bodily structure of the mammal. The second electrode is in communication with the first electrode through a hardwire or wireless connection.

INTRODUCTION AND OBJECTIVECompared to healthy individuals, stroke survivors with neurogenic lower urinary tract dysfunction (NLUTD) exhibit decreased cortical activity in response to bladder filling and emptying. The use of transcutaneous spinal cord stimulation (TSCS) has been shown to reduce frequency, urgency and incontinence episodes in these individuals. The objective of this study was to determine whether TSCS also leads to normalization of micturition-related brain activity, as compared to healthy controls.METHODSTwelve stroke patients with post-stroke NLUTD received 12 weeks of TSCS. Each subject also completed simultaneous urodynamics (UDS) and blood-oxygen-level-dependent (BOLD) fMRI before initiation of TSCS and within 72 hours of completing the final TSCS session. Healthy subjects without LUTS completed an identical fMRI-UDS protocol. BOLD signal during the period of …

Motor dysfunction in individuals with cerebral palsy (CP) such as the inability to initiate voluntary movements, walking with compensatory movement patterns, and debilitating spasticity is due to the aberrant neural connectivity between the brain and spinal cord. We tested the efficacy of noninvasive spinal cord neuromodulation (SCiPTM, SpineX Inc.) with activity-based neurorehabilitation therapy (ABNT) in improving the sensorimotor function in six children with CP. Children received 8 weeks of either SCiPTM or sham therapy with ABNT (n=3 per group). At the end of 8 weeks, all participants received 8 weeks of SCiPTM therapy with ABNT. Follow up assessments were done at week 26 (10 weeks after the last therapy session). Sensorimotor function was measured by the Gross Motor Function Measure 88 (GMFM88) test. We observed minimal change in sham group (mean 6% improvement), however, eight weeks of SCiPTM therapy with ABNT resulted in statistically and clinically relevant improvement in GMFM88 scores (mean 23% increase from baseline). We also observed reduced scores on the modified Ashworth scale only with SCiPTM therapy (-11% vs. +5.53% with sham). Similar improvements were observed in sham group but only after the cross over to SCiPTM therapy group at the end of the first eight weeks. Finally, sixteen weeks of SCiPTM therapy with ABNT resulted in further improvement of GMFM88 score. The improvement in GMFM88 scores were maintained at week 26 (10 weeks after the end of therapy), suggesting a sustained effect of SCiPTM therapy.

INTRODUCTION AND OBJECTIVEUnlike the brain, functional imaging of the spinal cord has been elusive. This is due to the small size of the spinal cord and limitations of the neuroimaging techniques. The functional ultrasound imaging (fUSI) is a novel neuroimaging technique with superior spatiotemporal properties that can detect microvascular changes correlated to changes in neural activity. The objective of this study is to determine whether fUSI can detect and characterize the spatial and temporal hemodynamic changes in the human spinal cord in response to bladder filling and emptying.METHODSFour patients, who were undergoing standard-of-care implantation of a spinal cord stimulator, were enrolled in the study. Following exposure of the spinal cord during implantation of the spinal cord stimulator, the fUSI probe was positioned over the spinal cord at thoracic level 10. Images were acquired during two …

Spinal cord injuries (SCI) can result in sensory and motor dysfunctions, which were long considered permanent. Recent advancement in electrical neuromodulation has been proven to restore sensorimotor function in people with SCI. These stimulation protocols, however, were mostly invasive, expensive, and difficult to implement. In this study, transcutaneous electrical stimulation (tES) was used to restore over-ground walking of an individual with 21 years of chronic paralysis from a cervical SCI. After a total of 66 weeks of rehabilitation training with tES, which included standing, functional reaching, reclined sit-up, treadmill walking, and active biking, significant improvement in lower-limb volitional movements and overall light touch sensation were shown as measured by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) score. By the end of the study, the participant could walk in a 4-m walking test with the aid of a walking frame and ankle–foot orthoses. The successful sensorimotor recovery of our study participant sheds light on the future of non-invasive neuromodulation treatment for SCI paralysis.

BackgroundSpinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target.MethodsWe created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test.ResultsIn macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency induced more apoptosis of oligodendrocytes and demyelination at the lesion site, leading to worsened motor function compared to normal zinc condition …

Methods:Patients who developed storage LUTD after a stroke and healthy volunteers without LUTD were recruited. Patients and healthy volunteers underwent simultaneous urodynamics (UDS) and functional magnetic resonance imaging (fMRI). Patients then completed 24 biweekly sessions of TSCS and underwent another simultaneous UDS-fMRI study. Clinical outcomes were assessed using validated questionnaires and voiding diary.Results:Fifteen patients and 16 healthy volunteers completed the study. Following TSCS, patients exhibited increased blood-oxygen-level dependent (BOLD) activity in areas including periaqueductal grey, the insula, the lateral prefrontal cortex, and motor cortex. Prior to TSCS therapy, healthy controls exhibited higher BOLD activity in 17 regions, including multiple regions in the prefrontal cortex and basal ganglia. These differences were attenuated after TSCS with no frontal brain …

Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs on the dorsal cord and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation …

The present review focuses on the physiological states of spinal networks, which are stochastically modulated by continuously changing ensembles of proprioceptive and supraspinal input resulting in highly redundant neural networks. Spinal epidural interfaces provide a platform for probing spinal network dynamics and connectivity among multiple motor pool-specific spinal networks post-injury under in vivo experimental conditions. Continuous epidural low-frequency pulses at low intensity can evoke motor responses of stochastically changing amplitudes and with an oscillatory pattern of modulation. The physiological significance of this oscillatory pattern, intrinsic to “resting” spinal networks and observed in both uninjured and injured locomotor circuits, is unclear. This neural variability among spinal networks appears to be a fundamental mechanism of the network's design and not a “noise” interfering with …

It has been suggested that neuroplasticity-promoting neuromodulation can restore sensory-motor pathways after spinal cord injury (SCI), reactivating the dormant locomotor neuronal circuitry. We introduce a neuro-rehabilitative approach that leverages locomotor training with multi-segmental spinal cord transcutaneous electrical stimulation (scTS). We hypothesized that scTS neuromodulates spinal networks, complementing the neuroplastic effects of locomotor training, result in a functional progression toward recovery of locomotion. We conducted a case-study to test this approach on a 27-year-old male classified as AIS A with chronic SCI. The training regimen included task-driven non-weight-bearing training (1 month) followed by weight-bearing training (2 months). Training was paired with multi-level continuous and phase-dependent scTS targeting function-specific motor pools. Results suggest a convergence of cross-lesional networks, improving kinematics during voluntary non-weight-bearing locomotor-like stepping. After weight-bearing training, coordination during stepping improved, suggesting an important role of afferent feedback in further improvement of voluntary control and reorganization of the sensory-motor brain-spinal connectome.

Spinal cord injury (SCI) is a devastating condition that impacts multiple organ systems. Neurogenic bowel dysfunction (NBD) frequently occurs after a SCI leading to reduced sensation of bowel fullness and bowel movement often leading to constipation or fecal incontinence. Spinal Neuromodulation has been proven to be a successful modality to improve sensorimotor and autonomic function in patients with spinal cord injuries. The pilot data presented here represents the first demonstration of using spinal neuromodulation to activate the anorectal regions of patients with spinal cord injuries and the acute and chronic effects of stimulation. We observed that spinal stimulation induces contractions as well as changes in sensation and pressure profiles along the length of the anorectal region. In addition, we present a case report of a patient with a SCI and the beneficial effect of spinal neuromodulation on the patient’s bowel program.

The integration of functional responses in the human spinal cord into the nervous system is not well understood. Herein we demonstrate the first in-human functional ultrasound imaging (fUSI) of spinal cord response to epidural electrical stimulation. fUSI is a minimally invasive neuroimaging technique that can record blood flow at a level of spatial and temporal precision not previously achieved in the human spinal cord. By leveraging fUSI and epidural electrical spinal cord stimulation in patients who underwent surgery, we recorded and characterized for the first-time hemodynamic responses of the human spinal cord to an electrical neuromodulatory intervention commonly used for treating pain, and increasingly used for sensory-motor and autonomic functions. We found that the hemodynamic response to epidural stimulation reflects a spatiotemporal modulation of the spinal cord circuitry not previously recognized. The impact of this analytical capability is significant for several reasons. It offers a mechanism to assess blood flow changes with a new level of precision which can be obtained in real time under in vivo conditions. Additionally, we demonstrate that fUSI can successfully decode the spinal cord state in a single trial, which is of fundamental importance for developing real-time closed-loop neuromodulation systems. Also, we show that spinal cord hemodynamic changes due to epidural electrical stimulation occur primarily at the level of small vessels. Overall, our work is a critical step towards developing a vital technique to study spinal cord function and understand the potential effects of clinical neuromodulation for spinal cord and other …

Spinal cord stimulation enhanced restoration of motor function following spinal cord injury (SCI) in unblinded studies. To determine whether training combined with transcutaneous electrical spinal cord stimulation (tSCS), with or without systemic serotonergic treatment with buspirone (busp), could improve hand function in individuals with severe hand paralysis following SCI, we assessed ten subjects in a double-blind, sham-controlled, crossover study. All treatments—busp, tSCS, and the busp plus tSCS—reduced muscle tone and spasm frequency. Buspirone did not have any discernible impact on grip force or manual dexterity when administered alone or in combination with tSCS. In contrast, grip force, sinusoidal force generation and grip-release rate improved significantly after 6 weeks of tSCS in 5 out of 10 subjects who had residual grip force within the range of 0.1–1.5 N at the baseline evaluation. Improved …

IntroductionThe significance of the spinal cord in controlling postural and locomotor functions largely reemerged in the mid-1970s under the leadership of Sten Grillner, demonstrating key phenomena of ‘central pattern generation’ and ‘fictive locomotion’ with an evolutionary perspective. These concepts raised the question of how much function can be recovered after paralysis, given the intrinsic automaticity of spinal networks in injured and uninjured states in adults.Areas coveredThis review explores biological mechanisms governing spinal control of movements such as posture and locomotion. We focus on concepts that have evolved from experiments performed over the past decade. Rather than a comprehensive review of the vast literature on the neural control of posture and locomotion, we focus on the various mechanisms underlying functional automaticity, and their clinical relevance.Expert opinionWe …

In various embodiments a method of synergistically using a neuromodulation stimulator and a robotic exoskeleton for the restoration of voluntary movement and greater muscle activation in chronically paralyzed subjects is provided. The noninvasive neuromodulation system delivers signals to facilitate the restoration and/or enhancement of neurological function where at least one effect is strengthened stepping capacity that can be further substantiated when coupled with robotic exoskeleton assistance.

In various embodiments, non-invasive methods to induce motor control in a mammal subject to spinal cord or other neurological injuries are provided. In some embodiments the methods involve administering transcutaneous electrical spinal cord stimulation (tSCS) to the mammal at a frequency and intensity that induces locomotor activity.

In various embodiments, non-invasive methods to induce motor control in a mammal subject to spinal cord or other neurological injuries are provided. In some embodiments the methods involve administering transcutaneous electrical spinal cord stimulation (tSCS) to the mammal at a frequency and intensity that induces locomotor activity.

BackgroundOveractive bladder (OAB) affects 12 to 30% of the world’s population. The accompanying urinary urgency, frequency and incontinence can have a profound effect on quality of life, leading to depression, social isolation, avoidance of sexual activity and loss of productivity. Conservative measures such as lifestyle modification and pelvic floor physical therapy are the first line of treatment for overactive bladder. Patients who fail these may go on to take medications, undergo neuromodulation or receive injection of botulinum toxin into the bladder wall. While effective, medications have side effects and suffer from poor adherence. Neuromodulation and botulinum toxin injection are also effective but are invasive and not acceptable to some patients.MethodsWe have developed a novel transcutaneous spinal cord neuromodulator (SCONE™,) that delivers multifrequency electrical stimulation to the spinal cord …

Cerebral Palsy (CP) is the most common pediatric motor disability with multiple symptoms and etiologies. CP is exhibited through sensorimotor delays, impaired posture resulting in limited activities and participation. Our recently concluded, single arm, unblinded, pilot study (NCT04882592) explored whether an intervention combining non-invasive spinal neuromodulation during an activity-based neurorehabilitation therapy (ABNT) can improve voluntary sensory-motor function captured via the Gross Motor Function Measure (GMFM-88) scores (primary outcome). Sixteen children diagnosed with CP with Gross Motor Function Classification Scale levels I-V were recruited and received the same intervention (2x/week for 8 weeks) to correct the dysfunctional connectivity between supraspinal and spinal networks using the normally developed proprioception. We demonstrate that the intervention was associated with …

In various embodiments electrical stimulators are provided for transcutaneous and/or epidural stimulation. In certain embodiments the stimulator provides one or more channels configured to provide one or more of the following stimulation patterns: i) monophasic electrical stimulation with a DC offset; ii) monophasic electrical stimulation with charge balance; iii) delayed biphasic electrical stimulation with a DC offset; iv) delayed biphasic electrical stimulation with charge balance; v) amplitude modulated dynamic stimulation; and/or vi) frequency modulated dynamic stimulation.

While the loss of sensorimotor and autonomic function often occurs due to multiple trauma and pathologies, spinal cord injury is one of the few traumatic pathologies that severely affects multiple organ systems both upstream and downstream of the injury. Current standard of care therapies primarily maintains health and avoids secondary complications. They do not address the underlying neurological condition. Multiple modalities including spinal neuromodulation have shown promise as potential therapies. The objective of this study was to demonstrate the impact of activity-based neurorehabilitation in presence of epidural spinal stimulation to enable simultaneous global recovery of sensorimotor and autonomic functions in patients with complete motor paralysis due to spinal cord injury. These data are unique in that it quantifies simultaneously changes multiple organ systems within only 2 months of intense …

Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation is a non-invasive method that can modify the functional state of the sensory-motor system. We hypothesize that eEmc delivery, together with hand training, improves hand function in healthy subjects more than either intervention alone by inducing plastic changes at spinal and cortical levels. Ten voluntary participants were included in the following three interventions: (i) hand grip training, (ii) eEmc, and (iii) eEmc with hand training. Functional evaluation included the box and blocks test (BBT) and hand grip maximum voluntary contraction (MVC), spinal and cortical motor evoked potential (sMEP and cMEP), and resting motor thresholds (RMT), short interval intracortical inhibition (SICI), and F wave in the abductor pollicis brevis muscle. eEmc combined with hand training retained MVC and increased F wave amplitude and persistency, reduced cortical RMT and facilitated cMEP amplitude. In contrast, eEmc alone only increased F wave amplitude, whereas hand training alone reduced MVC and increased cortical RMT and SICI. In conclusion, eEmc combined with hand grip training enhanced hand motor output and induced plastic changes at spinal and cortical level in healthy subjects when compared to either intervention alone. These data suggest that electrical neuromodulation changes spinal and, perhaps, supraspinal networks to a more malleable state, while a concomitant use-dependent mechanism drives these networks to a higher functional state.

Although children with cerebral palsy seem to have the neural networks necessary to generate most movements, they are markedly dysfunctional, largely attributable to abnormal patterns of muscle activation, often characterized as spasticity, largely reflecting a functionally abnormal spinal-supraspinal connectivity. While it is generally assumed that the etiologies of the disruptive functions associated with cerebral palsy can be attributed primarily to supraspinal networks, we propose that the more normal connectivity that persists between peripheral proprioception-cutaneous input to the spinal networks can be used to guide the reorganization of a more normal spinal-supraspinal connectivity. The level of plasticity necessary to achieve the required reorganization within and among different neural networks can be achieved with a combination of spinal neuromodulation and specific activity-dependent mechanisms. By engaging these two concepts, we hypothesize that bidirectional reorganization of proprioception-spinal cord-brain connectivity to higher levels of functionality can be achieved without invasive surgery.

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 …

Serotonergic agents can improve the recovery of motor ability after a spinal cord injury. Herein, we compare the effects of buspirone, a 5-HT1A receptor partial agonist, to fluoxetine, a selective serotonin reuptake inhibitor, on forelimb motor function recovery after a C4 bilateral dorsal funiculi crush in adult female rats. After injury, single pellet reaching performance and forelimb muscle activity decreased in all rats. From 1 to 6 weeks after injury, rats were tested on these tasks with and without buspirone (1–2 mg/kg) or fluoxetine (1–5 mg/kg). Reaching and grasping success rates of buspirone-treated rats improved rapidly within 2 weeks after injury and plateaued over the next 4 weeks of testing. Electromyography (EMG) from selected muscles in the dominant forelimb showed that buspirone-treated animals used new reaching strategies to achieve success after the injury. However, forelimb performance dramatically …

In various embodiments, methods are provided for applying transcutaneous and/or epidural spinal cord stimulation with and without selective pharmaceuticals to restore voluntary control of hand function in tetraplegic subjects.(60) Provisional application No. 61/883,694, filed on Sep.

Having observed that electrical spinal cord stimulation and training enabled four patients with paraplegia with motor complete paralysis to regain voluntary leg movement, the underlying mechanisms involved in forming the newly established supraspinal-spinal functional connectivity have become of great interest. van den Brand et al. (Science 336: 1182–1185, 2012) subsequently, demonstrated the recovery, in response to spinal electro-neuromodulation and locomotor training, of voluntary stepping of the lower limbs in rats that received a lesion that is assumed to eliminate all long-descending cortical axons that project to lumbosacral segments. Here, we used a similar spinal lesion in rats to eliminate long-descending axons to determine whether a novel, trained motor behavior triggered by a unique auditory cue learned before a spinal lesion, could recover after the lesion. Hindlimb stepping recovered 1 mo after …

A wide range of dysfunction can occur after a stroke including symptoms such as urinary urgency, frequency, and urge incontinence. The Spinal Cord Neuromodulator (SCONETM) reactivates and retrains spinal neural networks. The present case study introduces initial evidence that home-based, self-administered SCONE therapy may be a safe and effective method of delivering this neuromodulation modality and may have the ability to minimize clinic visits, which is especially salient in today's public health environment.

Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation offers promise in improving hand function. However, it is still unknown which stimulus intensity or which muscle force level could be better for this improvement. Nine healthy individuals received the following interventions: (i) eEmc intensities at 80%, 90% and 110% of abductor pollicis brevis motor threshold combined with hand training consisting in 100% handgrip strength; (ii) hand training consisting in 100% and 50% of maximal handgrip strength combined with 90% eEmc intensity. The evaluations included box and blocks test (BBT), maximal voluntary contraction (MVC), F wave persistency, F/M ratio, spinal and cortical motor evoked potentials (MEP), recruitment curves of spinal MEP and cortical MEP and short-interval intracortical inhibition. The results showed that: (i) 90% eEmc intensity increased BBT, MVC, F wave persistency, F/M ratio and cortical MEP recruitment curve; 110% eEmc intensity increased BBT, F wave persistency and cortical MEP and recruitment curve of cortical MEP; (ii) 100% handgrip strength training significantly modulated MVC, F wave persistency, F/M wave and cortical MEP recruitment curve in comparison to 50% handgrip strength. In conclusion, eEmc intensity and muscle strength during training both influence the results for neuromodulation at the cervical level.

Spinal cord injury (SCI) commonly results in permanent loss of motor, sensory, and autonomic function. Recent clinical studies have shown that epidural spinal cord stimulation may provide a beneficial adjunct for restoring lower extremity and other neurological functions. Herein, we review the recent clinical advances of lumbosacral epidural stimulation for restoration of sensorimotor function in individuals with motor complete SCI and we discuss the putative neural pathways involved in this promising neurorehabilitative approach. We focus on three main sections: review recent clinical results for locomotor restoration in complete SCI; discuss the contemporary understanding of electrical neuromodulation and signal transduction pathways involved in spinal locomotor networks; and review current challenges of motor system modulation and future directions toward integrative neurorestoration. The current …

Buspirone, widely used as a neuropsychiatric drug, has also shown potentials for motor function recovery of injured spinal cord. However, the optimum dosages of such treatment remain unclear. In this study, we investigated the dose-response of Buspirone treatment on reaching and grasping function in cervical cord injured rats. Seventeen adult Sprague-Dawley rats were trained to reach and grasp sugar pellets before a C4 bilateral dorsal column crush injury. After 1 week post-injury, the rats were divided into 3 groups to receive 1 of 3 different dosages of Buspirone (i.p., 1 dose/day: 1.5, n = 5; 2.5, n = 6 and 3.5 mg/kg b.w., n = 6). Forelimb reaching and grip strength test were recorded once per week, within 1 hour of Buspirone administration for 11 weeks post-injury. Different dose groups began to exhibit differences in reaching scores from 4 weeks post-injury. From 4-11 weeks post-injury, the reaching scores …

Spinal neuromodulation and activity-based rehabilitation triggers neural network reorganization and enhances sensory-motor performances involving the lower limbs, the trunk, and the upper limbs. This study reports the acute effects of Transcutaneous Electrical Spinal Cord Neuromodulation (SCONE™, SpineX Inc.) on 12 individuals (ages 2 to 50) diagnosed with cerebral palsy (CP) with Gross Motor Function Classification Scale (GMFCS) levels ranging from I to V. Acute spinal neuromodulation improved the postural and locomotor abilities in 11 out of the 12 patients including the ability to generate bilateral weight bearing stepping in a 2-year-old (GMFCS level IV) who was unable to step. In addition, we observed independent head-control and weight bearing standing with stimulation in a 10-year-old and a 4-year old (GMFCS level V) who were unable to hold their head up or stand without support in the absence …

Traumatic cervical spinal cord injury (cSCI) can lead to damage of bulbospinal pathways to the respiratory motor nuclei and consequent life-threatening respiratory insufficiency due to respiratory muscle paralysis/paresis. Reports of electrical epidural stimulation (EES) of the lumbosacral spinal cord to enable locomotor function after SCI are encouraging, with some evidence of facilitating neural plasticity. Here, we detail the development and success of EES in recovering locomotor function, with consideration of stimulation parameters and safety measures to develop effective EES protocols. EES is just beginning to be applied in other motor, sensory, and autonomic systems; however, there has only been moderate success in preclinical studies aimed at improving breathing function after cSCI. Thus, we explore the rationale for applying EES to the cervical spinal cord, targeting the phrenic motor nucleus for the …

It is well-documented that neural control of stepping and standing can be generated in mammals within the spinal neuronal networks. Having a high level of automaticity, these locomotorrelated neuronal circuits can produce a “stepping” movement pattern in the absence of input from the brain and/or peripheral afferent inputs. Recent observations have provided important insight into the properties of the spinal and supraspinal circuitry that are involved in movement control. We have shown that the spinal circuitry in mice, rats, cats, and humans can be neuromodulated to regain sensorimotor function after complete paralysis (Gerasimenko et al., 2008). We have also shown that with epidural spinal cord stimulation at the lumbar level, full weight-bearing standing, and voluntary movements of the lower limb can be recovered in humans with complete paralysis (Angeli et al., 2014). Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Recent breakthrough studies reported that chronically paralyzed individuals regained the over-ground walking with balance assistance through interleaved continous lumbosacral (L1-S1) epidural stimulation and task specific locomotor training (Angeli et al., 2018; Gill et al., 2018). We have developed a novel method of non-invasive transcutaneous spinal cord stimulation (scTS) which can modulate the excitability of spinal circuitry via electrodes placed on the skin overlying the cervical, lower thoracic, lumbosacral, and coccygeal vertebrae using a special form of electrical pulses delivered at a high frequency (Gerasimenko et al., 2015a). This methodology was able to …

Spinal cord injury results in neurogenic lower urinary tract dysfunction (NLUTD) leading to reduced bladder capacity, loss of bladder sensation and inability to initiate bladder voiding. Transcutaneous Electrical Spinal Cord Neuromodulation (TESCoN) was developed to activate and retrain the spinal circuits to enable function. In this pilot study, we developed a novel method to retrain the bladder by externally filling and voluntarily emptying the bladder with saline in the presence of TESCoN. We successfully demonstrated the use of TESCoN in improving bladder capacity, regaining sensation and enabling voluntary voiding with increased voiding efficiency in an individual with complete chronic paralysis.

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 …

The objective of this work is to understand how passive structural components in skeletal muscle provide effective load transmission as the dimensions of the muscle change. In addition to forces transmitted along muscle fibers, there is a growing recognition that other structural components may transmit contractile loads laterally from myofibrils to the muscle sarcolemma and even between muscle fibers. This loading path is presumed to be mediated by several structural molecules which link myofibrils to the sarcolemma and endomysium and even link across the extracellular space to other muscle fibers. A challenging question is how such forces can be transmitted along the muscle by passive structures such as the endomysium as the dimensions of the muscle change. Corresponding changes in the dimensions of passive materials will influence their ability to transmit mechanical loading due to their force/length …

In various embodiments methods and devices are provided for regulating bladder function in a subject after a spinal cord and/or brain injury. In certain embodiments the methods comprise applying a pattern of electrical stimulation to the Lumbosacral spinal cord at a frequency and intensity sufficient to initiate micturition and/or to improve the amount of bladder emptying. In certain embodiments the electrical stimulation is at a frequency and intensity sufficient to improve the amount of bladder emptying (eg, to provide at least 30% emptying or at least 40% emptying, or at least 50% emptying, or at least 60% emptying, or at least 70% emptying, or at least 80% emptying, or at least 90% emptying, or at least 95% emptying.

Epidural electrical stimulation (ES) of the lumbar spinal cord combined with daily locomotor training has been demonstrated to enhance stepping ability after complete spinal transection in rodents and clinically complete spinal injuries in humans. Although functional gain is observed, plasticity mechanisms associated with such recovery remain mostly unclear. Here, we investigated how ES and locomotor training affected expression of chondroitin sulfate proteoglycans (CSPG), perineuronal nets (PNN), and synaptic plasticity on spinal motoneurons. To test this, adult rats received a complete spinal transection (T9–T10) followed by daily locomotor training performed under ES with administration of quipazine (a serotonin (5-HT) agonist) starting 7 days post-injury (dpi). Excitatory and inhibitory synaptic changes were examined at 7, 21, and 67 dpi in addition to PNN and CSPG expression. The total amount of CSPG expression significantly increased with time after injury, with no effect of training. An interesting finding was that γ-motoneurons did not express PNNs, whereas α-motoneurons demonstrated well-defined PNNs. This remarkable difference is reflected in the greater extent of synaptic changes observed in γ-motoneurons compared to α-motoneurons. A medium negative correlation between CSPG expression and changes in putative synapses around α-motoneurons was found, but no correlation was identified for γ-motoneurons. These results suggest that modulation of γ-motoneuron activity is an important mechanism associated with functional recovery induced by locomotor training under ES after a complete spinal transection.

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 …

Neurostimulator devices are described. An example neurostimulator device includes a stimulation assembly connectable to a plurality of electrodes, wherein the plurality of electrodes are configured to stimulate a spinal cord. The neurostimulator device also includes an interface and at least one processor configured to modify at least one complex stimulation pattern deliverable by the plurality of electrodes by integrating data from the interface and performing a machine learning algorithm on the at least one complex stimulation pattern.

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 …

A mid-thoracic spinal cord injury (SCI) severely impairs activation of the lower limb sensorimotor spinal networks, leading to paralysis. Various neuromodulatory techniques including electrical and pharmacological activation of the spinal networks have been successful in restoring locomotor function after SCI. We hypothesized that the combination of self-training in a natural environment with epidural stimulation (ES), quipazine (Quip), and strychnine (Strych) would result in greater activity in a cage environment after paralysis compared to either intervention alone. To assess this, we developed a method measuring and characterizing the chronic EMG recordings from tibialis anterior (TA) and soleus (Sol) muscles while rats were freely moving in their home cages. We then assessed the relationship between the change in recorded activity over time and motor-evoked potentials (MEPs) in animals receiving treatments. We found that the combination of ES, Quip, and Strych (sqES) generated the greatest level of recovery followed by ES + Quip (qES) while ES + Strych (sES) and ES alone showed least improvement in recorded activity. Further, we observed an exponential relationship between late response (LR) component of the MEPs and spontaneously generated step-like activity. Our data demonstrate the feasibility and potential importance of quantitatively monitoring mechanistic factors linked to activity-dependence in response to combinatorial interventions compared to individual therapies after SCI.

Since the discovery that reparative interventions have the potential to enhance functional recovery after experimental spinal cord injury (SCI), several experimental animal models have been established, ranging from rodents to primates. In order to maximize the likelihood for a translation into patient benefit, the clinical eloquence of these models has to be considered. Despite the remarkable conservation among the mammalian nervous system, the nervous systems of rodents, primates, and humans have some obvious differences in size, neuroanatomical, neurophysiological, and behavioural characteristics as well as inflammatory and immunological responses. As this chapter deals mainly with recovery of locomotion, it is important to highlight some differences of the corticospinal tract (CST) which exerts supraspinal input onto the locomotor centres in the lumbar cord. Most apparent is the fact that the CST in rodents runs through the dorsal column of the spinal cord and projects to dorsal horn neurons and premotor spinal circuits. In contrast, in primates the CST runs through the lateral columns and projects onto ventral horn neurons and interneurons. Furthermore, compared to the rodent, the numbers of corticospinal axons from the neocortex down to the spinal cord has greatly increased in primates (× 40). In humans, the number of CST axons is around 1.1 million, representing a 100-fold increase when compared to rodents.Despite these interspecies discrepancies, great effort has been put into mimicking a human SCI using contusion models through weight-drop, compression models through clip-compression, and transection models involving …

This disclosure provides non-invasive methods to induce motor control in a mammal subject to spinal cord or other neurological injuries. In certain embodiments the method involves administering transcutaneous electrical spinal cord stimulation (tSCS) to the mammal at a frequency and intensity that induces the desired locomotor activity.

BackgroundPotentiation 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.ObjectiveTo 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.MethodsDS was applied dorsally to the lumbar enlargement through a high-density epidural array composed of independent platinum-based micro-electrodes.ResultsIn 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 …

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 …

In certain embodiments an electrode array for epidural stimulation of the spinal cord is provided where the array comprises a plurality of electrodes disposed on a flexible polymer substrate; said electrodes being electrically connected to one or more lead wires and/or connection points on an electrical connector; where the electrodes of said array are bonded to said polymer so that the electrodes can carry an electrical stimulation signal having a voltage, frequency, and current sufficient to provide epidural stimulation of a spinal cord and/or brain in vivo or in a physiological saline solution, without separation of all or a part of an electrode from the polymer substrate.

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.

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.