Intrathecal and Oral Baclofen Use in Adults With Spinal Cord Injury: A Systematic Review of Efficacy in Spasticity Reduction, Functional Changes, Dosing, and Adverse Events.

OBJECTIVE: To examine the efficacy, dosing, and safety profiles of intrathecal and oral baclofen in treating spasticity after spinal cord injury (SCI). DATA SOURCES: PubMed and Cochrane Databases were searched from 1970-2018 with keywords baclofen, spinal cord injury, and efficacy. STUDY SELECTION: The database search yielded 588 sources and 10 additional relevant publications. After removal of duplicates, 398 publications were screened. DATA EXTRACTION: Data were extracted using the following population, intervention, comparator, outcomes, and study designs criteria: studies including adult patients with SCI with spasticity; the intervention could be oral or intrathecal administration of baclofen; selection was inclusive for control groups, surgical management, rehabilitation, and alternative pharmaceutical agents; outcomes were efficacy, dosing, and adverse events. Randomized controlled trials, observational studies, and case reports were included. Meta-analyses and systematic reviews were excluded. DATA SYNTHESIS: A total of 98 studies were included with 1943 patients. Only 4 randomized, double-blinded, and placebo-controlled trials were reported. Thirty-nine studies examined changes in the Modified Ashworth Scale (MAS; 34 studies) and Penn Spasm scores (Penn Spasm Frequency; 19 studies), with average reductions of 1.7±1.3 and 1.6±1.4 in individuals with SCI, respectively. Of these data, a total of 6 of the 34 studies (MAS) and 2 of the 19 studies (Penn Spasm Frequency) analyzed oral baclofen. Forty-three studies addressed adverse events with muscle weakness and fatigue frequently reported. CONCLUSIONS: Baclofen is the most commonly-prescribed antispasmodic after SCI. Surprisingly, there remains a significant lack of large, placebo-controlled, double-blinded clinical trials, with most efficacy data arising from small studies examining treatment across different etiologies. In the studies reviewed, baclofen effectively improved spasticity outcome measures, with increased efficacy through intrathecal administration. Few studies assessed how reduced neural excitability affected residual motor function and activities of daily living. A host of adverse events were reported that may negatively affect quality of life. Comparative randomized controlled trials of baclofen and alternative treatments are warranted because these have demonstrated promise in relieving spasticity with reduced adverse events and without negatively affecting residual motor function.

Targeted Selection of Stimulation Parameters for Restoration of Motor and Autonomic Function in Individuals With Spinal Cord Injury.

STUDY DESIGN: This is a report of methods and tools for selection of task and individual configurations targeted for voluntary movement, standing, stepping, blood pressure stabilization, and facilitation of bladder storage and emptying using tonic-interleaved excitation of the lumbosacral spinal cord. OBJECTIVES: This study aimed to present strategies used for selection of stimulation parameters for various motor and autonomic functions. CONCLUSIONS: Tonic-interleaved functionally focused neuromodulation targets a myriad of consequences from spinal cord injury with surgical implantation of the epidural electrode at a single location. This approach indicates the sophistication of the human spinal cord circuitry and its important role in the regulation of motor and autonomic functions in humans.

Historical development and contemporary use of neuromodulation in human spinal cord injury.

PURPOSE OF REVIEW: There is a long history of neuromodulation of the spinal cord after injury in humans with recent momentum of studies showing evidence for therapeutic potential. Nonrandomized, mechanistic, hypothesis-driven, small cohort, epidural stimulation proof of principle studies provide insight into the human spinal circuitry functionality and support the pathway toward clinical treatments. RECENT FINDINGS: Individuals living with spinal cord injury can recover motor, cardiovascular, and bladder function even years after injury using neuromodulation. Integration of continuous feedback from sensory information, task-specific training, and optimized excitability state of human spinal circuitry are critical spinal mechanisms. Neuromodulation activates previously undetectable residual supraspinal pathways to allow intentional (voluntary) control of motor movements. Further discovery unveiled the human spinal circuitry integrated regulatory control of motor and autonomic systems indicating the realistic potential of neuromodulation to improve the capacity incrementally, but significantly for recovery after severe spinal cord injury. SUMMARY: The discovery that both motor and autonomic function recovers with lumbosacral spinal cord placement of the electrode reveals exciting avenues for a synergistic overall improvement in function, health, and quality of life for those who have been living with the consequences of spinal cord injury even for decades.

Spinal cord imaging markers and recovery of standing with epidural stimulation in individuals with clinically motor complete spinal cord injury.

Spinal cord epidural stimulation (scES) is an intervention to restore motor function in those with severe spinal cord injury (SCI). Spinal cord lesion characteristics assessed via magnetic resonance imaging (MRI) may contribute to understand motor recovery. This study assessed relationships between standing ability with scES and spared spinal cord tissue characteristics at the lesion site. We hypothesized that the amount of lateral spared cord tissue would be related to independent extension in the ipsilateral lower limb. Eleven individuals with chronic, clinically motor complete SCI underwent spinal cord MRI, and were subsequently implanted with scES. Standing ability and lower limb activation patterns were assessed during an overground standing experiment with scES. This assessment occurred prior to any activity-based intervention with scES. Lesion hyperintensity was segmented from T2 axial images, and template-based analysis was used to estimate spared tissue in anterior, posterior, right, and left spinal cord regions. Regression analysis was used to assess relationships between imaging and standing outcomes. Total volume of spared tissue was related to left (p = 0.007), right (p = 0.005), and bilateral (p = 0.011) lower limb extension. Spared tissue in the left cord region was related to left lower limb extension (p = 0.019). A positive trend (p = 0.138) was also observed between right spared cord tissue and right lower limb extension. In this study, MRI measures of spared spinal cord tissue were significantly related to standing outcomes with scES. These preliminary results warrant future investigation of roles of supraspinal input and MRI-detected spared spinal cord tissue on lower limb motor responsiveness to scES.

Predictors of volitional motor recovery with epidural stimulation in individuals with chronic spinal cord injury.

Spinal cord epidural stimulation (scES) has enabled volitional lower extremity movements in individuals with chronic and clinically motor complete spinal cord injury and no clinically detectable brain influence. The aim of this study was to understand whether the individuals' neuroanatomical characteristics or positioning of the scES electrode were important factors influencing the extent of initial recovery of lower limb voluntary movements in those with clinically motor complete paralysis. We hypothesized that there would be significant correlations between the number of joints moved during attempts with scES prior to any training interventions and the amount of cervical cord atrophy above the injury, length of post-traumatic myelomalacia and the amount of volume coverage of lumbosacral enlargement by the stimulation electrode array. The clinical and imaging records of 20 individuals with chronic and clinically motor complete spinal cord injury who underwent scES implantation were reviewed and analysed using MRI and X-ray integration, image segmentation and spinal cord volumetric reconstruction techniques. All individuals that participated in the scES study (n = 20) achieved, to some extent, lower extremity voluntary movements post scES implant and prior to any locomotor, voluntary movement or cardiovascular training. The correlation results showed that neither the cross-section area of spinal cord at C3 (n = 19, r = 0.33, P = 0.16) nor the length of severe myelomalacia (n = 18, r = -0.02, P = 0.93) correlated significantly with volitional lower limb movement ability. However, there was a significant, moderate correlation (n = 20, r = 0.59, P = 0.006) between the estimated percentage of the lumbosacral enlargement coverage by the paddle electrode as well as the position of the paddle relative to the maximal lumbosacral enlargement and the conus tip (n = 20, r = 0.50, P = 0.026) with the number of joints moved volitionally. These results suggest that greater coverage of the lumbosacral enlargement by scES may improve motor recovery prior to any training, possibly because of direct modulatory effects on the spinal networks that control lower extremity movements indicating the significant role of motor control at the level of the spinal cord.

Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury.

Persons with motor complete spinal cord injury, signifying no voluntary movement or sphincter function below the level of injury but including retention of some sensation, do not recover independent walking. We tested intense locomotor treadmill training with weight support and simultaneous spinal cord epidural stimulation in four patients 2.5 to 3.3 years after traumatic spinal injury and after failure to improve with locomotor training alone. Two patients, one with damage to the mid-cervical region and one with damage to the high-thoracic region, achieved over-ground walking (not on a treadmill) after 278 sessions of epidural stimulation and gait training over a period of 85 weeks and 81 sessions over a period of 15 weeks, respectively, and all four achieved independent standing and trunk stability. One patient had a hip fracture during training. (Funded by the Leona M. and Harry B. Helmsley Charitable Trust and others; ClinicalTrials.gov number, NCT02339233 .).

Effect of Different Forms of Activity-Based Recovery Training on Bladder, Bowel, and Sexual Function After Spinal Cord Injury.

OBJECTIVES: To investigate whether the urogenital and bowel functional gains previously demonstrated post-locomotor step training after chronic spinal cord injury could have been derived due to weight-bearing alone or from exercise in general. DESIGN: Prospective cohort study; pilot trial with small sample size. SETTING: Urogenital and bowel scientific core facility at a rehabilitation institute and spinal cord injury research center in the United States. PARTICIPANTS: Men and women (N=22) with spinal cord injury (American Spinal Injury Association Impairment Scale grades of A-D) participated in this study. INTERVENTIONS: Approximately 80 daily 1-hour sessions of either stand training or nonweight-bearing arm crank ergometry. Comparisons were made with previously published locomotor training data (step; N=7). MAIN OUTCOME MEASURES: Assessments at both pre- and post-training timepoints included cystometry for bladder function and International Data Set Questionnaires for bowel and sexual functions. RESULTS: Cystometry measurements revealed a significant decrease in bladder pressure and limited improvement in compliance with nonweight-bearing exercise but not with standing. Although International Data Set questionnaires revealed profound bowel dysfunction and marked deficits in sexual function pretraining, no differences were identified poststand or after nonweight-bearing exercise. CONCLUSIONS: These pilot trial results suggest that, although stand and weight-bearing alone do not benefit pelvic organ functions after spinal cord injury, exercise in general may contribute at least partially to the lowering of bladder pressure and the increase in compliance that was seen previously with locomotor training, potentially through metabolic, humoral, and/or cardiovascular mechanisms. Thus, to maximize activity-based recovery training benefits for functions related to storage and emptying, an appropriate level of sensory input to the spinal cord neural circuitries controlling bladder and bowel requires task-specific stepping.

Effects of NMES pulse width and intensity on muscle mechanical output and oxygen extraction in able-bodied and paraplegic individuals.

PURPOSE: Neuromuscular Electrical Stimulation (NMES) is commonly used in neuromuscular rehabilitation protocols, and its parameters selection substantially affects the characteristics of muscle activation. Here, we investigated the effects of short pulse width (200 µs) and higher intensity (short-high) NMES or long pulse width (1000 µs) and lower intensity (long-low) NMES on muscle mechanical output and fractional oxygen extraction. Muscle contractions were elicited with 100 Hz stimulation frequency, and the initial torque output was matched by adjusting stimulation intensity. METHODS: Fourteen able-bodied and six spinal cord-injured (SCI) individuals participated in the study. The NMES protocol (75 isometric contractions, 1-s on-3-s off) targeting the knee extensors was performed with long-low or short-high NMES applied over the midline between anterior superior iliac spine and patella protrusion in two different days. Muscle work was estimated by torque-time integral, contractile properties by rate of torque development and half-relaxation time, and vastus lateralis fractional oxygen extraction was assessed by Near-Infrared Spectroscopy (NIRS). RESULTS: Torque-time integral elicited by the two NMES paradigms was similar throughout the stimulation protocol, with differences ranging between 1.4% (p = 0.877; able-bodied, mid-part of the protocol) and 9.9% (p = 0.147; SCI, mid-part of the protocol). Contractile properties were also comparable in the two NMES paradigms. However, long-low NMES resulted in higher fractional oxygen extraction in able-bodied (+ 36%; p = 0.006). CONCLUSION: Long-low and short-high NMES recruited quadriceps femoris motor units that demonstrated similar contractile and fatigability properties. However, long-low NMES conceivably resulted in the preferential recruitment of vastus lateralis muscle fibers as detected by NIRS.

Clinical Trial Designs for Neuromodulation in Chronic Spinal Cord Injury Using Epidural Stimulation.

STUDY DESIGN: This is a narrative review focused on specific challenges related to adequate controls that arise in neuromodulation clinical trials involving perceptible stimulation and physiological effects of stimulation activation. OBJECTIVES: 1) To present the strengths and limitations of available clinical trial research designs for the testing of epidural stimulation to improve recovery after spinal cord injury. 2) To describe how studies can control for the placebo effects that arise due to surgical implantation, the physical presence of the battery, generator, control interfaces, and rehabilitative activity aimed to promote use-dependent plasticity. 3) To mitigate Hawthorne effects that may occur in clinical trials with intensive supervised participation, including rehabilitation. MATERIALS AND METHODS: Focused literature review of neuromodulation clinical trials with integration to the specific context of epidural stimulation for persons with chronic spinal cord injury. CONCLUSIONS: Standard of care control groups fail to control for the multiple effects of knowledge of having undergone surgical procedures, having implanted stimulation systems, and being observed in a clinical trial. The irreducible effects that have been identified as "placebo" require sham controls or comparison groups in which both are implanted with potentially active devices and undergo similar rehabilitative training.

Epidural stimulation for cardiovascular function increases lower limb lean mass in individuals with chronic motor complete spinal cord injury.

NEW FINDINGS: What is the central question of this study? Spinal cord injury results in paralysis and deleterious neuromuscular and autonomic adaptations. Lumbosacral epidural stimulation can modulate motor and/or autonomic functions. Does long-term epidural stimulation for normalizing cardiovascular function affect leg muscle properties? What is the main finding and its importance? Leg lean mass increased after long-term epidural stimulation for cardiovascular function, which was applied in the sitting position and did not activate the leg muscles. Leg muscle strength and fatigue resistance, assessed in a subgroup of individuals, also increased. These adaptations might support interventions for motor recovery and warrant further mechanistic investigation. ABSTRACT: Chronic motor complete spinal cord injury (SCI) results in paralysis and deleterious neuromuscular and autonomic adaptations. Paralysed muscles demonstrate atrophy, loss of force and increased fatigability. Also, SCI-induced autonomic impairment results in persistently low resting blood pressure and heart rate, among other features. We previously reported that spinal cord epidural stimulation (scES) optimized for cardiovascular (CV) function (CV-scES), which is applied in sitting position and does not activate the leg muscles, can maintain systolic blood pressure within a normotensive range during quiet sitting and during orthostatic stress. In the present study, dual-energy X-ray absorptiometry collected from six individuals with chronic clinically motor complete SCI demonstrated that 88 ± 11 sessions of CV-scES (7 days week-1 ; 2 h day-1 in four individuals and 5 h day-1 in two individuals) over a period of ∼6 months significantly increased lower limb lean mass (by 0.67 ± 0.39 kg or 9.4 ± 8.1%; P < 0.001). Additionally, muscle strength and fatigability data elicited by neuromuscular electrical stimulation in three of these individuals demonstrated a general increase (57 ± 117%) in maximal torque output (between 2 and 44 N m in 14 of the 17 muscle groups tested overall) and torque-time integral during intermittent, fatiguing contractions (63 ± 71%; between 7 and 230% in 16 of the 17 muscle groups tested overall). In contrast, whole-body mass and composition did not change significantly. In conclusion, long-term use of CV-scES can have a significant impact on lower limb muscle properties after chronic motor complete SCI.

Cardiovascular Autonomic Dysfunction in Spinal Cord Injury: Epidemiology, Diagnosis, and Management.

Spinal cord injury (SCI) disrupts autonomic circuits and impairs synchronistic functioning of the autonomic nervous system, leading to inadequate cardiovascular regulation. Individuals with SCI, particularly at or above the sixth thoracic vertebral level (T6), often have impaired regulation of sympathetic vasoconstriction of the peripheral vasculature and the splanchnic circulation, and diminished control of heart rate and cardiac output. In addition, impaired descending sympathetic control results in changes in circulating levels of plasma catecholamines, which can have a profound effect on cardiovascular function. Although individuals with lesions below T6 often have normal resting blood pressures, there is evidence of increases in resting heart rate and inadequate cardiovascular response to autonomic provocations such as the head-up tilt and cold face tests. This manuscript reviews the prevalence of cardiovascular disorders given the level, duration and severity of SCI, the clinical presentation, diagnostic workup, short- and long-term consequences, and empirical evidence supporting management strategies to treat cardiovascular dysfunction following a SCI.

Effects of Respiratory Training on Heart Rate Variability and Baroreflex Sensitivity in Individuals With Chronic Spinal Cord Injury.

OBJECTIVE: To evaluate the effects of pressure threshold respiratory training (RT) on heart rate variability and baroreflex sensitivity in persons with chronic spinal cord injury (SCI). DESIGN: Before-after intervention case-controlled clinical study. SETTING: SCI research center and outpatient rehabilitation unit. PARTICIPANTS: Participants (N=44) consisted of persons with chronic SCI ranging from C2 to T11 who participated in RT (n=24), and untrained control subjects with chronic SCI ranging from C2 to T9 (n=20). INTERVENTIONS: A total of 21±2 RT sessions performed 5 days a week during a 4-week period using a combination of pressure threshold inspiratory and expiratory devices. MAIN OUTCOME MEASURES: Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and beat-to-beat arterial blood pressure and heart rate changes during the 5-second-long maximum expiratory pressure maneuver (5s MEP) and the sit-up orthostatic stress test, acquired before and after the RT program. RESULTS: In contrast to the untrained controls, individuals in the RT group experienced significantly increased FVC and FEV1 (both P<.01) in association with improved quality of sleep, cough, and speech. Sympathetically (phase II) and parasympathetically (phase IV) mediated baroreflex sensitivity both significantly (P<.05) increased during the 5s MEP. During the orthostatic stress test, improved autonomic control over heart rate was associated with significantly increased sympathetic and parasympathetic modulation (low- and high-frequency change: P<.01 and P<.05, respectively). CONCLUSIONS: Inspiratory-expiratory pressure threshold RT is a promising technique to positively affect both respiratory and cardiovascular dysregulation observed in persons with chronic SCI.

Activity-Based Therapy: From Basic Science to Clinical Application for Recovery After Spinal Cord Injury.

BACKGROUND AND PURPOSE: Collaboration between scientists and clinicians effectively accelerated translation of scientific evidence for activity-based therapies (ABTs) into rehabilitation. This article addresses the basic scientific findings of activity-dependent plasticity that led to locomotor training, an ABT, and its principles to advance recovery in adult and pediatric populations with spinal cord injury (SCI). Expansion to new therapies based on these common principles is highlighted, for example, epidural stimulation. The article also describes a recently developed measure, the Neuromuscular Recovery Scale (NRS), and its psychometric properties. SUMMARY OF KEY POINTS: Locomotor training has led to recovery of walking in some individuals with motor-incomplete SCI even years after injury. Recent studies resulted in individuals with motor-complete SCI regaining some voluntary movements and standing in the presence of epidural stimulation. The level of success for locomotor training and epidural stimulation appears dependent on spinal networks maintaining the appropriate central state of excitability for the desired task. As these new advances in restorative therapies required an outcome measure that measured performance without compensation, the NRS was developed. The NRS has strong psychometric properties in adults, and a pediatric version is under development. Application of locomotor training in children is still novel. Preliminary evidence suggests that locomotor training can improve trunk control and also foster participation in children with chronic SCI. RECOMMENDATIONS FOR CLINICAL PRACTICE: ABTs may effectively promote neuromuscular recovery and improve function and participation in adults and children post-SCI. Evaluation of outcomes with valid measures, such as the NRS, is necessary to document the ability to perform functional tasks and to assess progress as function improves.

Effects of exercise training on urinary tract function after spinal cord injury.

Spinal cord injury (SCI) causes dramatic changes in the quality of life, including coping with bladder dysfunction which requires repeated daily and nightly catheterizations. Our laboratory has recently demonstrated in a rat SCI model that repetitive sensory information generated through task-specific stepping and/or loading can improve nonlocomotor functions, including bladder function (Ward PJ, Herrity AN, Smith RR, Willhite A, Harrison BJ, Petruska JC, Harkema SJ, Hubscher CH. J Neurotrauma 31: 819-833, 2014). To target potential underlying mechanisms, the current study included a forelimb-only exercise group to ascertain whether improvements may be attributed to general activity effects that impact target organ-neural interactions or to plasticity of the lumbosacral circuitry that receives convergent somatovisceral inputs. Male Wistar rats received a T9 contusion injury and were randomly assigned to three groups 2 wk postinjury: quadrupedal locomotion, forelimb exercise, or a nontrained group. Throughout the study (including preinjury), all animals were placed in metabolic cages once a week for 24 h to monitor water intake and urine output. Following the 10-wk period of daily 1-h treadmill training, awake cystometry data were collected and bladder and kidney tissue harvested for analysis. Metabolic cage frequency-volume measurements of voiding and cystometry reveal an impact of exercise training on multiple SCI-induced impairments related to various aspects of urinary tract function. Improvements in both the quadrupedal and forelimb-trained groups implicate underlying mechanisms beyond repetitive sensory information from the hindlimbs driving spinal network excitability of the lumbosacral urogenital neural circuitry. Furthermore, the impact of exercise training on the upper urinary tract (kidney) underscores the health benefit of activity-based training on the entire urinary system within the SCI population.

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.

Spinal cord transcutaneous stimulation in cervical spinal cord injury: A review examining upper extremity neuromotor control, recovery mechanisms, and future directions.

Cervical spinal cord injury (SCI) results in significant sensorimotor impairments below the injury level, notably in the upper extremities (UE), impacting daily activities and quality of life. Regaining UE function remains the top priority for individuals post cervical SCI. Recent advances in understanding adaptive plasticity within the sensorimotor system have led to the development of novel non-invasive neurostimulation strategies, such as spinal cord transcutaneous stimulation (scTS), to facilitate UE motor recovery after SCI. This comprehensive review investigates the neuromotor control of UE, the typical recovery trajectories following SCI, and the therapeutic potential of scTS to enhance UE motor function in individuals with cervical SCI. Although limited in number with smaller sample sizes, the included research articles consistently suggest that scTS, when combined with task-specific training, improves voluntary control of arm and hand function and sensation. Furthermore, the reported improvements translate to recovery of various UE functional tasks and positively impact the quality of life in individuals with cervical SCI. Several methodological limitations, including stimulation site selection and parameters, training strategies and sensitive outcome measures, require further advancements to allow successful translation of scTS from research to clinical settings. This review also summarizes the current literature and proposes future directions to support establishing approaches for scTS as a viable neuro-rehabilitative tool.

Robotic Postural Training With Epidural Stimulation for the Recovery of Upright Postural Control in Individuals With Motor Complete Spinal Cord Injury: A Pilot Study.

Activity-based training and lumbosacral spinal cord epidural stimulation (scES) have the potential to restore standing and walking with self-balance assistance after motor complete spinal cord injury (SCI). However, improvements in upright postural control have not previously been addressed in this population. Here, we implemented a novel robotic postural training with scES, performed with free hands, to restore upright postural control in individuals with chronic, cervical (n = 5) or high-thoracic (n = 1) motor complete SCI, who had previously undergone stand training with scES using a walker or a standing frame for self-balance assistance. Robotic postural training re-enabled and/or largely improved the participants' ability to control steady standing, self-initiated trunk movements and upper limb reaching movements while standing with free hands, receiving only external assistance for pelvic control. These improvements were associated with neuromuscular activation pattern adaptations above and below the lesion. These findings suggest that the human spinal cord below the level of injury can generate meaningful postural responses when its excitability is modulated by scES, and can learn to improve these responses. Upright postural control improvements can enhance functional motor recovery promoted by scES after severe SCI.