Claudia A. Angeli

Effect of Epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study

BACKGROUND Repeated periods of stimulation of the spinal cord and training increased the ability to control movement in animal models of spinal cord injury. We hypothesised that tonic epidural spinal cord stimulation can modulate spinal circuitry in human beings into a physiological state that enables sensory input from standing and stepping movements to serve as a source of neural control to undertake these tasks. METHODS A 23-year-old man who had paraplegia from a C7-T1 subluxation as a result of a motor vehicle accident in July 2006, presented with complete loss of clinically detectable voluntary motor function and partial preservation of sensation below the T1 cord segment. After 170 locomotor training sessions over 26 months, a 16-electrode array was surgically placed on the dura (L1-S1 cord segments) in December 2009, to allow for chronic electrical stimulation. Spinal cord stimulation was done during sessions that lasted up to 250 min. We did 29 experiments and tested several stimulation combinations and parameters with the aim of the patient achieving standing and stepping. FINDINGS Epidural stimulation enabled the man to achieve full weight-bearing standing with assistance provided only for balance for 4·25 min. The patient achieved this standing during stimulation using parameters identified as specific for standing while providing bilateral load-bearing proprioceptive input. We also noted locomotor-like patterns when stimulation parameters were optimised for stepping. Additionally, 7 months after implantation, the patient recovered supraspinal control of some leg movements, but only during epidural stimulation. INTERPRETATION Task-specific training with epidural stimulation might reactivate previously silent spared neural circuits or promote plasticity. These interventions could be a viable clinical approach for functional recovery after severe paralysis. FUNDING National Institutes of Health and Christopher and Dana Reeve Foundation.

Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans

Previously, we reported that one individual who had a motor complete, but sensory incomplete spinal cord injury regained voluntary movement after 7 months of epidural stimulation and stand training. We presumed that the residual sensory pathways were critical in this recovery. However, we now report in three more individuals voluntary movement occurred with epidural stimulation immediately after implant even in two who were diagnosed with a motor and sensory complete lesion. We demonstrate that neuromodulating the spinal circuitry with epidural stimulation, enables completely paralysed individuals to process conceptual, auditory and visual input to regain relatively fine voluntary control of paralysed muscles. We show that neuromodulation of the sub-threshold motor state of excitability of the lumbosacral spinal networks was the key to recovery of intentional movement in four of four individuals diagnosed as having complete paralysis of the legs. We have uncovered a fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury.

Neuromodulation of evoked muscle potentials induced by epidural spinal-cord stimulation in paralyzed individuals

Epidural stimulation (ES) of the lumbosacral spinal cord has been used to facilitate standing and voluntary movement after clinically motor-complete spinal-cord injury. It seems of importance to examine how the epidurally evoked potentials are modulated in the spinal circuitry and projected to various motor pools. We hypothesized that chronically implanted electrode arrays over the lumbosacral spinal cord can be used to assess functionally spinal circuitry linked to specific motor pools. The purpose of this study was to investigate the functional and topographic organization of compound evoked potentials induced by the stimulation. Three individuals with complete motor paralysis of the lower limbs participated in the study. The evoked potentials to epidural spinal stimulation were investigated after surgery in a supine position and in one participant, during both supine and standing, with body weight load of 60%. The stimulation was delivered with intensity from 0.5 to 10 V at a frequency of 2 Hz. Recruitment curves of evoked potentials in knee and ankle muscles were collected at three localized and two wide-field stimulation configurations. Epidural electrical stimulation of rostral and caudal areas of lumbar spinal cord resulted in a selective topographical recruitment of proximal and distal leg muscles, as revealed by both magnitude and thresholds of the evoked potentials. ES activated both afferent and efferent pathways. The components of neural pathways that can mediate motor-evoked potentials were highly dependent on the stimulation parameters and sensory conditions, suggesting a weight-bearing-induced reorganization of the spinal circuitries.

Effects of Lumbosacral Spinal Cord Epidural Stimulation for Standing after Chronic Complete Paralysis in Humans

Sensory and motor complete spinal cord injury (SCI) has been considered functionally complete resulting in permanent paralysis with no recovery of voluntary movement, standing or walking. Previous findings demonstrated that lumbosacral spinal cord epidural stimulation can activate the spinal neural networks in one individual with motor complete, but sensory incomplete SCI, who achieved full body weight-bearing standing with independent knee extension, minimal self-assistance for balance and minimal external assistance for facilitating hip extension. In this study, we showed that two clinically sensory and motor complete participants were able to stand over-ground bearing full body-weight without any external assistance, using their hands to assist balance. The two clinically motor complete, but sensory incomplete participants also used minimal external assistance for hip extension. Standing with the least amount of assistance was achieved with individual-specific stimulation parameters, which promoted overall continuous EMG patterns in the lower limbs’ muscles. Stimulation parameters optimized for one individual resulted in poor standing and additional need of external assistance for hip and knee extension in the other participants. During sitting, little or negligible EMG activity of lower limb muscles was induced by epidural stimulation, showing that the weight-bearing related sensory information was needed to generate sufficient EMG patterns to effectively support full weight-bearing standing. In general, electrode configurations with cathodes selected in the caudal region of the array at relatively higher frequencies (25–60 Hz) resulted in the more effective EMG patterns for standing. These results show that human spinal circuitry can generate motor patterns effective for standing in the absence of functional supraspinal connections; however the appropriate selection of stimulation parameters is critical.

Soleus H-Reflex Gain, Threshold, and Amplitude as Function of Body Posture and Load in Spinal Cord Intact and Injured Subjects

In this study, we established parameters of the soleus H-reflex excitability in response to changes of posture and load in 8 chronic spinal cord injured (SCI) and 10 spinal-intact subjects. The soleus H-reflex recruitment curve was established in all subjects while they were supine, seated, and standing on a stable treadmill. During standing, body weight support (BWS) was provided via an upper body harness and ranged in SCI subjects from 20%–50% and in spinal-intact subjects was set at 0% and 50%. Stimuli corresponding to the H-threshold (Hth), maximal H-reflex amplitude (Hmax), and 50% of Hmax as well as the reflex gain were estimated based on a sigmoid function of the ascending limb of the soleus H-reflex recruitment curve. The soleus H-reflex gain, Hmax amplitude, and stimuli corresponding to Hth, 50% of Hmax, and Hmax were increased in SCI subjects regardless of the body position and loading. Further, the reflex gain was not modulated appropriately during conditions of weight bearing in SCI subjects. Impaired spinal reflex excitability in SCI subjects is accompanied by changes of the H-reflex recruitment curve parameters regardless of presence or absence of body loading.

Spinal segment-specific transcutaneous stimulation differentially shapes activation pattern among motor pools in humans

Transcutaneous and epidural electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Recently, we observed selective activation of proximal and distal motor pools during epidural spinal stimulation. In the present study, we hypothesized that the characteristics of recruitment curves obtained from leg muscles will reflect a relative preferential activation of proximal and distal motor pools based on their arrangement along the lumbosacral enlargement. The purpose was to describe the electrophysiological responses to transcutaneous stimulation in leg muscles innervated by motoneurons from different segmental levels. Stimulation delivered along the rostrocaudal axis of the lumbosacral enlargement in the supine position resulted in a selective topographical recruitment of proximal and distal leg muscles, as described by threshold intensity, slope of the recruitment curves, and plateau point intensity and magnitude. Relatively selective recruitment of proximal and distal motor pools can be titrated by optimizing the site and intensity level of stimulation to excite a given combination of motor pools. The slope of the recruitment of particular muscles allows characterization of the properties of afferents projecting to specific motoneuron pools, as well as to the type and size of the motoneurons. The location and intensity of transcutaneous spinal electrical stimulation are critical to target particular neural structures across different motor pools in investigation of specific neuromodulatory effects. Finally, the asymmetry in bilateral evoked potentials is inevitable and can be attributed to both anatomical and functional peculiarities of individual muscles or muscle groups.

Effects of Stand and Step Training with Epidural Stimulation on Motor Function for Standing in Chronic Complete Paraplegics

Individuals affected by motor complete spinal cord injury are unable to stand, walk, or move their lower limbs voluntarily; this diagnosis normally implies severe limitations for functional recovery. We have recently shown that the appropriate selection of epidural stimulation parameters was critical to promoting full-body, weight-bearing standing with independent knee extension in four individuals with chronic clinically complete paralysis. In the current study, we examined the effects of stand training and subsequent step training with epidural stimulation on motor function for standing in the same four individuals. After stand training, the ability to stand improved to different extents in the four participants. Step training performed afterwards substantially impaired standing ability in three of the four individuals. Improved standing ability generally coincided with continuous electromyography (EMG) patterns with constant levels of ground reaction forces. Conversely, poorer standing ability was associated with more variable EMG patterns that alternated EMG bursts and longer periods of negligible activity in most of the muscles. Stand and step training also differentially affected the evoked potentials amplitude modulation induced by sitting-to-standing transition. Finally, stand and step training with epidural stimulation were not sufficient to improve motor function for standing without stimulation. These findings show that the spinal circuitry of motor complete paraplegics can generate motor patterns effective for standing in response to task-specific training with optimized stimulation parameters. Conversely, step training can lead to neural adaptations resulting in impaired motor function for standing.

Motor recovery after activity-based training with spinal cord epidural stimulation in a chronic motor complete paraplegic

The prognosis for recovery of motor function in motor complete spinal cord injured (SCI) individuals is poor. Our research team has demonstrated that lumbosacral spinal cord epidural stimulation (scES) and activity-based training can progressively promote the recovery of volitional leg movements and standing in individuals with chronic clinically complete SCI. However, scES was required to perform these motor tasks. Herein, we show the progressive recovery of voluntary leg movement and standing without scES in an individual with chronic, motor complete SCI throughout 3.7 years of activity-based interventions utilizing scES configurations customized for the different motor tasks that were specifically trained (standing, stepping, volitional leg movement). In particular, this report details the ongoing neural adaptations that allowed a functional progression from no volitional muscle activation to a refined, task-specific activation pattern and movement generation during volitional attempts without scES. Similarly, we observed the re-emergence of muscle activation patterns sufficient for standing with independent knee and hip extension. These findings highlight the recovery potential of the human nervous system after chronic clinically motor complete SCI.

Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury

Objective Locomotor training (LT) as a therapeutic intervention following spinal cord injury (SCI) is an effective rehabilitation strategy for improving motor outcomes, but its impact on non-locomotor functions is unknown. Given recent results of our labs’ pre-clinical animal SCI LT studies and existing overlap of lumbosacral spinal circuitries controlling pelvic-visceral and locomotor functions, we addressed whether LT can improve bladder, bowel and sexual function in humans at chronic SCI time-points (> two years post-injury). Study design Prospective cohort study; pilot trial with small sample size. Methods Eight SCI research participants who were undergoing 80 daily one-hour sessions of LT on a treadmill using body-weight support, or one-hour of LT and stand training on alternate days, as part of another research study conducted at the Kentucky Spinal Cord Injury Research Center, University of Louisville, were enrolled in this pilot trial. Urodynamic assessments were performed and International Data Set questionnaire forms completed for bladder, bowel and sexual functions at pre-and post-training time points. Four usual care (non-trained; regular at-home routine) research participants were also enrolled in this study and had the same assessments collected twice, at least 3 months apart. Results Filling cystometry documented significant increases in bladder capacity, voiding efficiency and detrusor contraction time as well as significant decreases in voiding pressure post-training relative to baseline. Questionnaires revealed a decrease in the frequency of nocturia and urinary incontinence for several research participants as well as a significant decrease in time required for defecation and a significant increase in sexual desire post-training. No significant differences were found for usual care research participants. Conclusions These results suggest that an appropriate level of sensory information provided to the spinal cord, generated through task-specific stepping and/or loading, can positively benefit the neural circuitries controlling urogenital and bowel functions. Trial registration ClinicalTrials.gov NCT03036527

Normalization of Blood Pressure With Spinal Cord Epidural Stimulation After Severe Spinal Cord Injury

Chronic low blood pressure and orthostatic hypotension remain challenging clinical issues after severe spinal cord injury (SCI), affecting health, rehabilitation, and quality of life. We previously reported that targeted lumbosacral spinal cord epidural stimulation (scES) could promote stand and step functions and restore voluntary movement in patients with chronic motor complete SCI. This study addresses the effects of targeted scES for cardiovascular function (CV-scES) in individuals with severe SCI who suffer from chronic hypotension. We tested the hypothesis that CV-scES can increase resting blood pressure and attenuate chronic hypotension in individuals with chronic cervical SCI. Four research participants with chronic cervical SCI received an implant of a 16-electrode array on the dura (L1–S1 cord segments, T11–L1 vertebrae). Individual-specific CV-scES configurations (anode and cathode electrode selection, voltage, frequency, and pulse width) were identified to maintain systolic blood pressure within targeted normative ranges without skeletal muscle activity of the lower extremities as assessed by electromyography. These individuals completed five 2-h sessions using CV-scES in an upright, seated position during measurement of blood pressure and heart rate. Noninvasive continuous blood pressure was measured from a finger cuff by plethysmograph technique. For each research participant there were statistically significant increases in mean arterial pressure in response to CV-scES that was maintained within normative ranges. This result was reproducible over the five sessions with concomitant decreases or no changes in heart rate using individual-specific CV-scES that was modulated with modest amplitude changes throughout the session. Our study shows that stimulating dorsal lumbosacral spinal cord can effectively and safely activate mechanisms to elevate blood pressures to normal ranges from a chronic hypotensive state in humans with severe SCI with individual-specific CV-scES.