Efficacy of transcutaneous spinal cord stimulation combined with resistance training on motor function in motor-incomplete spinal cord injury: protocol for an open-label, single-blind randomized controlled trial.

Spinal cord injury (SCI) is damage to any part of the spinal cord resulting in paralysis, bowel and/or bladder incontinence, and loss of sensation and other bodily functions. Current treatments for chronic SCI are focused on managing symptoms and preventing further damage to the spinal cord with limited neuro-restorative interventions. Recent research and independent clinical trials of spinal cord stimulation (SCS) or intensive neuro-rehabilitation including neuro-robotics in participants with SCI have suggested potential malleability of the neuronal networks for neurological recovery. We hypothesize that epidural electrical stimulation (EES) delivered via SCS in conjunction with mental imagery practice and robotic neuro-rehabilitation can synergistically improve volitional motor function below the level of injury in participants with chronic clinically motor-complete SCI. In our pilot clinical RESTORES trial (RESToration Of Rehabilitative function with Epidural spinal Stimulation), we investigate the feasibility of this combined multi-modal approach in restoring volitional motor control and achieving independent overground locomotion in participants with chronic motor complete thoracic SCI. Secondary aims are to assess the safety of this combination therapy including the off-label SCS usage as well as improving functional outcome measures. To our knowledge, this is the first clinical trial that investigates the combined impact of this multi-modal EES and rehabilitation strategy in participants with chronic motor complete SCI. Two participants with chronic motor-complete thoracic SCI were recruited for this pilot trial. Both participants have successfully regained volitional motor control below their level of SCI injury and achieved independent overground walking within a month of post-operative stimulation and rehabilitation. There were no adverse events noted in our trial and there was an improvement in post-operative truncal stability score. Results from this pilot study demonstrates the feasibility of combining EES, mental imagery practice and robotic rehabilitation in improving volitional motor control below level of SCI injury and restoring independent overground walking for participants with chronic motor-complete SCI. Our team believes that this provides very exciting promise in a field currently devoid of disease-modifying therapies.

It is widely believed that intensive task-specific training enhances neurological recovery in people with spinal cord injury (SCI) by exploiting activity-dependent spinal plasticity. We aimed to determine whether 10 weeks of intensive task-specific training supplemented with strength training that targets motor function at and below the level of the lesion improves recovery following recent SCI. We conducted a pragmatic phase 3 superiority randomised controlled trial at 15 hospitals in Australia, Belgium, Italy, the Netherlands, Norway, and the UK (England and Scotland). People who sustained a SCI in the preceding 10 weeks, had some motor function below the level of injury, and were receiving inpatient rehabilitation were randomly assigned to usual care (control group) or usual care plus 12 h per week for 10 weeks of intensive task-specific training targeting voluntary motor function below the level of the lesion supplemented with strength training (intervention group). Randomisation was computer generated, concealed, and stratified by site and level of injury. The primary outcome was Total Motor Score of the International Standards for the Neurological Classification of SCI (0-100 points) at 10 weeks. The outcome assessors were blinded to group assignment. Serious adverse events were defined as those resulting in death, life-threatening conditions, prolongation of hospitalisation, or substantial disability. All analyses were conducted by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000091808; universal trial number: U1111-1264-1689). Between June 7, 2021, and Feb 5, 2025, 220 participants were randomly assigned to the control (n=111; 23 female and 88 male) or intervention (n=109; 28 female and 81 male) group. Data were available for 216 (98%) of 220 participants at 10 weeks (107 in the intervention group and 109 in the control group). The mean Total Motor Scores at 10 weeks were 78·76 (SD 17·34) for the control group and 78·36 (SD 17·00) for the intervention group. The mean between-group difference was 0·93 (95% CI -1·63 to 3·48; p=0·48). There were four serious adverse events (three in the intervention group and one in the control group) including two deaths in participants from the intervention group. Intensive task-specific training supplemented with strength training provided in people with recent SCI did not result in significant benefits on our primary and secondary clinical outcomes. The evidence does not support any beneficial effect of additional training for those receiving usual inpatient rehabilitation care from a multi-disciplinary team. New South Wales Ministry of Health, University of Sydney, and Wings for Life.

Introduction: Implanted spinal cord epidural stimulation (SCES) is an emerging neuromodulation approach that increases the excitability of the central pattern generator [CPG] and enhances tonic and rhythmic motor patterns after spinal cord injury (SCI). We determine the effects of exoskeleton-assisted walking [EAW] + epidural stimulation [ES] + resistance training [RT] on volitional motor control as a primary outcome, as well as autonomic cardiovascular profile, body composition, and bladder function compared to EAW + delayed ES + noRT in persons with motor-complete SCI AIS A and B. Methods and Analysis: Twenty male and female participants [age 18-60 years] with traumatic motor-complete SCI [2 years or more post injury], and level of injury below C5 were randomized into either EAW + ES + RT or EAW + delayed-ES + no-RT groups for more than 12 months. Baseline, post-interventions 1 and 2 were conducted six months apart. Measurements included body composition assessment using anthropometry, dual x-ray absorptiometry, and magnetic resonance imaging prior to implantation to evaluate the extent of spinal cord damage, neurophysiologic assessments to record H-reflexes, overground ambulation and peak torque for both groups, and the Walking Index for Spinal Cord Injury Scale [WISCI 2]. Metabolic profile measurements included the resting metabolic rate, fasting biomarkers of HbA1c, lipid panels, total testosterone CRP, IL-6, TNF-α, plasma IGF-I, IGFBP-3, and then a glucose tolerance test. Finally, urodynamic testing was conducted to assess functional bladder improvement due to ES. Results: The restoration of locomotion with ES and EAW may result in a reduction in psychosocial, cardiovascular, and metabolic bladder parameters and socioeconomic burden. The addition of the resistance training paradigm may further augment the outcomes of ES on motor function in persons with SCI. Conclusions: Percutaneous SCES appears to be a feasible and safe rehabilitation approach for the restoration of motor function in persons with SCI. The procedure may be successfully implemented with other task-specific training similar to EAW and resistance training.

BackgroundMulti-channel surface functional electrical stimulation (FES) for walking has been used to improve voluntary walking and balance in individuals with spinal cord injury (SCI).ObjectiveTo investigate short- and long-term benefits of 16 weeks of thrice-weekly FES-assisted walking program, while ambulating on a body weight support treadmill and harness system, versus a non-FES exercise program, on improvements in gait and balance in individuals with chronic incomplete traumatic SCI, in a randomized controlled trial design.MethodsIndividuals with traumatic and chronic (≥18 months) motor incomplete SCI (level C2 to T12, American Spinal Cord Injury Association Impairment Scale C or D) were recruited from an outpatient SCI rehabilitation hospital, and randomized to FES-assisted walking therapy (intervention group) or aerobic and resistance training program (control group). Outcomes were assessed at baseline, and after 4, 6, and 12 months. Gait, balance, spasticity, and functional measures were collected.ResultsSpinal cord independence measure (SCIM) mobility sub-score improved over time in the intervention group compared with the control group (baseline/12 months: 17.27/21.33 vs. 19.09/17.36, respectively). On all other outcome measures the intervention and control groups had similar improvements. Irrespective of group allocation walking speed, endurance, and balance during ambulation all improved upon completion of therapy, and majority of participants retained these gains at long-term follow-ups.ConclusionsTask-oriented training improves walking ability in individuals with incomplete SCI, even in the chronic stage. Further randomized controlled trials, involving a large number of participants are needed, to verify if FES-assisted treadmill training is superior to aerobic and strength training.

Objective: To determine the effects of activity-based therapy (ABT) and surface spinal stimulation (SSS) on spinal cord integrity for locomotion and neurological recovery in people with incomplete spinal cord injury (SCI). Method: Sample of adults (n = 5, men, mean age 28.6 years) with motor-incomplete (American Spinal Injury Association Impairment Scale grade C or D) SCI injury. Interventions were conducted as thrice weekly sessions, total of 9 hours per week, consisting of non-invasive SSS and ABT for a period of 24 weeks including developmental sequences; resistance training; repetitive, patterned, rhythmic motor activity, task-specific activities, and locomotor training using body weight support treadmill training. Neurological function (International Standards for Neurological Classification of Spinal Cord Injury), the somatosensory evoked potential for tibial nerve, walking index for spinal cord injury, spinal cord injury functional ambulatory index (SCI-FAI), and spinal cord independence measure-III. Results: Significant improvements in neurologic function were noted for lower limb motor scores, pin prick, light touch sensations, gait parameter, 2-minute walk test, and the total score of SCI-FAI. Conclusions: ABT and surface spinal stimulation have the potential to influence the spinal cord integrity in individuals with chronic, motor-incomplete SCI. However, a larger sample size is required to be studied for further understanding and leads to gain insights into meaningful clinical benefits.

Clawson LL, Cudkowicz M, Krivickas L, Brooks BR, Sanjak M, Allred P, Atassi N, Swartz A, Steinhorn G, Uchil A, Riley KM, Yu H, Shoenfeld DA, Maragakis NJ. A randomized controlled trial of resistance and endurance exercise in amyotrophic lateral sclerosis. Amyotrophic Lateral Scler Frontotemporal Degene. 2018;19(3–4):250–8.Amyotrophic lateral sclerosis (ALS) is classified as a neurodegenerative disease that results in destruction of motor neurons in the brain and spinal cord (1). The cause of this disease is unknown, with 90% of all cases being nonfamilial (1). As ALS progresses, it results in cachexia, loss of muscle mass and movement coordination, paralysis, and eventual death (1). It is estimated that 30,000 people in the US (1) and 1,400 people in Australia (2) are living with ALS.According to the American Academy of Neurology the current standard of care for persons with ALS includes static stretching and passive range of motion to offset muscle and joint stiffness caused by neurologic decline (3). Low powered studies and conflicting research results of the effect of resistance (weights lifting) and/or aerobic exercise on ALS have led to difficulty determining recommendations for these modes of exercise (3). Some researchers indicate that vigorous aerobic or intense resistance training may increase the risk of (4) or exacerbate the progression (3) of ALS. Because of this, some clinicians instruct patients to avoid these forms of exercise. On the contrary, authors of several studies in mice (5) and humans (6) suggest resistance and aerobic exercise have multiple benefits for ALS, including delayed onset of symptoms, slowed progression, and improved quality of life, without being a major risk factor (7). The aim of this study was to determine the tolerance and compliance of exercise when comparing resistance, aerobic, and stretching or passive range of motion exercises in persons with ALS.This 24-week, randomized controlled trial included persons with ALS who met these inclusion criteria: (a) classified as having lab-supported probable or definite ALS, confirmed by a neurologist and (b) willingness to participate in this study. Exclusion criteria were not mentioned. Due to difficulty with the recruitment of persons with ALS who were willing to perform exercises, this study began in April 2012, with the last participant enrolled in September 2015.Fifty-nine participants were randomly assigned to resistance training (n = 21), aerobic exercise (n = 18), or static stretching or passive range of motion [S-ROM] (n = 20). Tolerability was defined as each participant completing ≥50% of total repetitions assigned for resistance training and S-ROM and ≥50% of aerobic exercise duration programmed at a specific heart rate and perceived exertions scale (Borg 6–20) rating. Compliance was defined as each participant attempting ≥50% of all exercise sessions for the 24-week period. Broad compliance measures were implemented with anticipation of rapid progression of ALS and inability to perform higher intensity or longer duration exercise. As a result, broad compliance measures afforded participants greater consistency with exercise completion at each session. To improve retention and avoid travel to treatment center, home-based exercise was programmed for all participants. The participants' “home exercise partner” was initially trained by a physical therapist, and appropriate exercise form was evaluated at follow-up visits throughout the course of the intervention. Outcome measures included exercise compliance and tolerance with secondary measures, including ALS Functional Rating Scale-Revised, ALS Scale for Quality of Life-Revised (3), Fatigue Severity Scale, Ash-worth Spasticity Scale (6), and Visual Analog Scale. Follow-up measures were taken at weeks 12 and 24. Training logs and teleconferences were used to track at-home exercise compliance and tolerance.All groups performed 3 exercise sessions per week. Resistance training included 2 sets of 8 repetitions with use of ankle or wrist weights. Initial intensity was 40% 1 repetition maximum (1RM) and was increased to 50% 1RM at week 4 and 70% 1RM at week 6. 1RM testing was conducted at baseline. Aerobic exercise included the use of a minicycle with 10 min of upper and lower body cycling, respectively, at 50%–70% heart rate reserve and 13–15 on the Borg scale. S-ROM exercise included 4 sets of 30-second static stretches for each exercise. For a list of exercises, see the Supplemental Material (https://www.tandfonline.com/doi/suppl/10.1080/21678421.2017.1404108).Analysis of all primary and secondary outcomes was conducted at 12 and 24 weeks. Over the course of the study, there were 4 serious adverse events resulting in withdrawal from the study, none of which were deemed a direct result of the exercise intervention or resulted in death. In addition, another 11 participants were lost to follow up (n = 4), co-enrollment in another study (n = 1), difficulty with travel (n = 1), or complication associated with disease progression (n = 2). Minor adverse events that are frequently seen in persons with ALS included musculoskeletal injury, fatigue, and falling, which did not differ between the groups.When assessing the proportion of participants that were able to tolerate exercise, the S-ROM, resistance, and aerobic groups were 77%, 65%, and 51% compliant. These results indicated all 3 modes of exercise are well tolerated by persons with ALS and safe to perform, with greatest compliance occurring in the S-ROM and resistance groups. There were no differences at 12 or 24 weeks regarding any of the secondary measures, which suggests that resistance and aerobic training did not exacerbate or cause accelerated progression of disease, reduce quality of life, or increase fatigue in this sample of participants.This is one of the first studies to demonstrate that resistance and aerobic exercise is safe and well tolerated for persons with ALS, and compliance with resistance training is comparable with standard care (S-ROM). The findings of this study are supported by previous researchers (6,8) that demonstrate short-term improvement in disability associated with supervised resistance and aerobic training. It is possible that differences in exercise adherence can be attributed to the intensity parameters being too low for resistance training or too high for aerobic training, resulting in lower compliance rates associated with the S-ROM, respectively. Future researchers will need to focus on specific frequency, intensity, type, and volume of exercise programming for the management of ALS. Although the clinical exercise physiologist should interpret the results of this study with caution, the use of resistance and aerobic training should be considered as a management technique for patients diagnosed with ALS.Quinn L, Hamana K, Kelson M, Dawes H, Collett J, Townsen J, Raymund R, van der Plas AA, Reilmann R, Frich JC, Rickards H, Rosser A, Busse M. A randomized, controlled trial of a multi-modal exercise intervention in Huntington's disease. Parkinsonism Relat Disord. 2016;31:4–52.Huntington's disease (HD) is a genetically linked neurodegenerative disease that is progressive and results in neuronal damage to the substantia nigra and cerebral cortex of the brain (1). HD is associated with nonmotor symptoms such as cognitive impairment, dementia, memory loss, and disorientation, as well as motor symptoms including chorea (irregular or rapid) and athetosis (slow or writhing involuntary) movements of the hands, feet, face, and trunk (1). Currently, there are approximately 30,000 people in the US (1) and 1,500 people in Australia (2) who are living with HD.The effectiveness of exercise as a management technique for HD is a relatively new research focus with limited studies. It is suggested that multimodal rehabilitation programs can improve physical function, quality of life (3), and possibly cognition (4) in persons with HD. Many challenges exist with determining the effectiveness of exercise-based interventions on HD, including level of supervision, appropriately programmed intensity, variability of cognitive impairment, exercise preference or tolerance, and comfort with exercise settings (5,6). These factors can lead to reduced initiation and adherence to exercise for persons with HD. Therefore, the aim of this study is to determine the effectiveness of a multimodal exercise program on persons with mild to moderate HD to determine safety, feasibility regarding retention and adherence, and improvement of physical fitness, motor control, physical function, and cognition.This was a randomized, controlled, multicenter trial, that assigned 32 of 312 screened participants to an exercise (n = 17) or control (n = 15) group for a 12-week intervention and 26-week follow up. Inclusion criteria were (a) genetically confirmed cases of HD, (b) ≥18 years of age, and (c) stable medication regime of antichoreic drugs for 4 weeks. Participants were excluded if they were (a) unable to use an exercise bike, (b) had psychological or physical limitation precluding exercise testing, and (c) currently in an exercise program. All participants who met inclusion criteria were screened for cardiovascular risk factors and underwent electrocardiogram testing to ensure safety with initiation of exercise.The control (CT) group was instructed to carry on with normal activity for the full duration of the intervention. Participants in the exercise (EX) group participated in three 50-min exercise sessions per week for a total of 12 weeks. Follow-up assessment occurred at week 13 and was compared with the baseline. Exercise included 25 min of cycling at 55%–85% age-predicted maximum heart rate (APMHR), 10–15 min of resistance training (2 sets of 15 repetitions), and 5 min of static stretching. For full details on the exercise program, see the Supplemental Material (https://www.prd-journal.com/article/S1353-8020(16)30243-7/fulltext#supplementaryMaterial). Participants could choose between their home or a medical fitness center to perform the exercise. An exercise professional provided gym-based supervision and at-home exercise for all 3 sessions during weeks 1–2, which was then tapered to 2 sessions for weeks 3–6, and 1 session for the final 6 weeks.Primary outcome measures included retention (completion of intervention) and adherence (completion of sessions), which was predetermined as >75% of supervised and unsupervised sessions and maintaining APMHR intensities for >75% (19/25 min) of the cycling duration. A series of secondary measures were also collected at baseline and follow-up assessment to determine improvement in motor control, quality of life, and physical and cognitive function (7–10).Three participants from the EX group dropped out before the 13-week assessment due to concomitant conditions, and 10 (n = 5 EX and n = 5 CT) were unable to be contacted at the 26-week period. Two serious adverse events occurred in the CT group, both attempted suicides, with 1 possibly being related to the week 13 assessment. A total of 97% of the EX group completed the intervention. Ninety-three percent of the EX group were able to complete the required sessions of the intervention, with only 75% achieving APMHR at each exercise session. Blunted heart rate response can be attributed to autonomic dysfunction commonly associated with HD, resulting in the inability to reach a predetermined percentage for APMHR (1). The EX and CT groups showed no differences in fall occurrence, suggesting that supervised exercise does not incur a greater fall risk in this population.The EX group improved aerobic fitness (VO2 MAX), motor function, and reduced body weight compared with the CT group. A reduced body weight may not be considered a positive finding because HD can lead to rapid weight loss in some people, resulting in cachexia and negative health outcomes (11). Follow-up assessment at 26 weeks indicated that all EX participants returned to low levels of physical activity after the intervention was terminated, and there were no differences in measured health outcome between groups.This is the first study to demonstrate that a multimodal exercise program is safe and that persons with mild to moderate HD can adhere to exercise with and without supervision and in different settings. The authors of this study showed improvement in aerobic fitness and motor control, but no improvement in strength, physical function, or cognition, which can all reduce quality of life in persons with HD (3). The exclusion of those with cognitive deficit and mental health disease, which is commonly associate with HD, may have resulted in reduced applicability of this study. The resistance training protocol may have used an intensity and/ or volume that was too low for improvement in strength. Future researchers might investigate the effects of resistance versus aerobic training and allow for a more robust sample of participants with and without HD-related cognitive impairment. The clinical exercise physiologist should encourage persons with HD to remain physically active using a multimodal program when safe and appropriate for an individual.The current Research Highlights editor would like to thank the JCEP Editorial Board for the opportunity to contribute this journal by authoring the Research Highlights for the past several years. We welcome Dr. Elizabeth O'Neill, DPE (Springfield College, Springfield, MA) as the new Research Highlights editor.

Motor Recovery after Spinal Cord Injury Enhanced by Strengthening Corticospinal Synaptic Transmission

Activity-Based Therapy for Recovery of Walking in Individuals With Chronic Spinal Cord Injury: Results From a Randomized Clinical Trial

Polysialic Acid Glycomimetic Promotes Functional Recovery and Plasticity After Spinal Cord Injury in Mice

State of the Science Conference in Spinal Cord Injury Rehabilitation 2011: introduction

BACKGROUNDPosttraumatic syringomyelia (PTS) refers to an elongated, intramedullary spinal cyst, representing a spectrum of severity and a variable interval after spinal cord injury (SCI). It typically presents with worsening motor and/or sensory function after a period of relative symptom stability following injury. The worsening ascends rostrally to include spinal cord levels previously intact above the level of injury. Rarely, PTS cavities extend rostrally to brainstem levels.OBSERVATIONSThe case presented demonstrates nearly the full spectrum of features associated with PTS. The onset of worsening occurred relatively early, about 1 year after motor complete SCI at the T2–3 level. The delayed onset of worsening symptoms of the PTS included asymmetric sensory and motor deficits that extended rostral to the upper extremities, face, and swallowing, and caudal to include back pain.LESSONSThe authors highlight key features of PTS, including 1) bilateral ascending expansile syrinx in the peridorsal horn gray matter, 2) medullary extension with trigeminal nucleus symptoms consistent with syringobulbia, and 3) evidence of spontaneous remission or collapsing cord sign. Additionally, risk factors for early PTS are discussed, including motor complete thoracic SCI with spinal stenosis on MRI. Operative management included hardware removal, laminectomy, spinal cord untethering with wide syringostomy, and duraplasty.https://thejns.org/doi/10.3171/CASE25797

A motor complete spinal cord injury (SCI) results in the loss of voluntary motor control below the point of injury. Some of these patients can regain partial motor function through inpatient rehabilitation; however, there is currently no biomarker to easily identify which patients have this potential. Evidence indicates that spasticity could be that marker. Patients with motor complete SCI who exhibit spasticity show preservation of descending motor pathways, the pathways necessary for motor signals to be carried from the brain to the target muscle. We hypothesized that the presence of spasticity predicts motor recovery after subacute motor complete SCI. Spasticity (Modified Ashworth Scale and pendulum test) and descending connectivity (motor evoked potentials) were tested in the rectus femoris muscle in patients with subacute motor complete (n = 36) and motor incomplete (n = 30) SCI. Motor recovery was assessed by using the International Standards for Neurological Classification of Spinal Cord Injury and the American Spinal Injury Association Impairment Scale (AIS). All measurements were taken at admission and discharge from inpatient rehabilitation. We found that motor complete SCI patients with spasticity improved in motor scores and showed AIS conversion to either motor or sensory incomplete. Conversely, patients without spasticity showed no changes in motor scores and AIS conversion. In incomplete SCI patients, motor scores improved and AIS conversion occurred regardless of spasticity. These findings suggest that spasticity represents an easy-to-use clinical outcome that might help to predict motor recovery after severe SCI. This knowledge can improve inpatient rehabilitation effectiveness for motor complete SCI patients. ANN NEUROL 2023.

Damage to corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). Here, we examined to what extent residual corticospinal connections and spasticity are present in muscles below the injury (quadriceps femoris and soleus) in humans with motor complete thoracic SCI. We found three distinct subgroups of people: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus; participants with spasticity and corticospinal responses in the quadriceps femoris only; and participants with no spasticity or corticospinalresponses in either muscle. Spasticity and corticospinal responses were present in the quadriceps but never only in the soleus muscle, suggesting a proximal to distal gradient of symptoms of hyperreflexia. These results suggest that concomitant patterns of residual corticospinal connectivity and spasticity exist in humans with motor complete SCI and that a clinical examination of spasticity might be a good predictor of residual descending motor pathways in people with severe paralysis. The loss of corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). However, the extent to which residual corticospinal connections and spasticity are present across muscles below the injury remains unknown. To address this question, we tested spasticity using the Modified Ashworth Scale and transmission in the corticospinal pathway by examining motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the leg motor cortex (cortical MEPs) and by direct activation of corticospinal axons by electrical stimulation over the thoracic spine (thoracic MEPs), in the quadriceps femoris and soleus muscles, in 30 individuals with motor complete thoracic SCI. Cortical MEPs were also conditioned by thoracic electrical stimulation at intervals allowing their summation or collision. We found three distinct subgroups of participants: 47% showed spasticity in the quadriceps femoris and soleus muscles; 30% showed spasticity in the quadriceps femoris muscle only; and 23% showed no spasticity in either muscle. Although cortical MEPs were present only in the quadriceps in participants with spasticity, thoracic MEPs were present in both muscles when spasticity was present. Thoracic electrical stimulation facilitated and suppressed cortical MEPs, showing that both forms of stimulation activated similar corticospinal axons. Cortical and thoracic MEPs correlated with the degree of spasticity in both muscles. These results provide the first evidence that related patterns of residual corticospinal connectivity and spasticity exist in muscles below the injury after motor complete thoracic SCI and highlight that a clinical examination of spasticity can predict residual corticospinal connectivity after severe paralysis.

AANS: American Association of Neurological Surgeons AIS: Abbreviated Injury Scale ASIA: American Spinal Injury Association CNS: Congress of Neurological Surgeons CSFD: cerebrospinal fluid drainage FDA: Food and Drug Administration FGF: fibroblast growth factor G-CSF: granulocyte colony-stimulating factor HGF: hepatocyte growth factor IL: interleukin iPSC: induced pluripotent stem cell MAP: mean arterial blood pressure MPSS: methylprednisolone sodium succinate MSC: mesenchymal stem cell NASCIS: National Acute Spinal Cord Injury Studies Nogo: neurite outgrowth inhibitor NgR: Nogo receptor NPC: neural precursor cell NSS: Neuro-Spinal Scaffold OEC: olfactory ensheathing cell OPC: oligodendrocyte progenitor cell PEG: polyethylene glycol PLGA: poly(lactic-co-glycolic acid) SCI: spinal cord injury TH: therapeutic hypothermia TNF: tumor necrosis factor Traumatic spinal cord injury (SCI) is a devastating event caused by trauma to the spine which leads to mechanical disruption of the spinal cord. The incidence of SCI varies worldwide. Focusing on developed regions, North America (39 per million) has a higher annual incidence than Australia (16 per million) or Western Europe (15 per million).1 Direct costs for lifetime patient care reach $1.1 to 4.6 million per patient, which further underscores the need for the development of effective SCI treatments.2 Substantial research effort has been dedicated to uncovering the pathophysiology of SCI. This has led to the development of pharmacologic and cell-based therapies, which are now demonstrating functional motor recovery in animal models. Among these, several promising therapeutic agents are already being investigated in clinical trials for SCI. This review will summarize the pathophysiology and current evidence-based clinical strategies to manage an acute spinal cord injury followed by a discussion of key emerging treatments including pharmacological approaches, cell-based therapies, biomaterials and physiological approaches. PATHOPHYSIOLOGY Phases of SCI Tissue damage after SCI has been divided into primary and secondary injury phases.3,4 The physical forces of the initial trauma cause the primary injury and this is the main determinant of the severity of SCI. The axons, blood vessels, and cell membranes are disrupted by physical forces such as compression, shearing, laceration, and acute stretch. Secondary injury refers to delayed, progressive damage which continues after the primary injury and represents an additional important determinant of neurological deficits (Figure).5,6 Due to the disruption of the blood–spinal cord barrier following the primary injury, infiltration of inflammatory cells such as macrophages, microglia, T-cells, and neutrophils can be observed. Inflammatory cytokines such as tumor necrosis factor (TNF) α, interleukin (IL)-1α, IL-1β, and IL-6 are released by these cells, with levels of these cytokines peaking 6 to 12 h after injury and remaining elevated up to 4 d after injury.7 Increases in intracellular calcium are caused by the disruption of ionic homeostasis after SCI and activates calcium-dependent proteases (eg, phospholipases, calpain, caspase, and nitric oxide synthase). These proteases trigger dysfunction of mitochondria which leads to cell death.8 Oligodendrocytes are highly susceptible to apoptotic loss and apoptosis has been observed, not only at the lesion epicenter, but also distant from the epicenter leading to demyelination of preserved axons.9-11 Furthermore, delayed necrosis and apoptosis are induced by reactive oxygen species which are released by phagocytic inflammatory cells.12-14 Moreover, the disrupted cells release excitatory amino acids (eg, glutamate and asparate) after SCI15,16 and the excessive activation of excitatory amino acid receptors causes further loss of neurons and glia by both necrotic and apoptotic cell death.17 To achieve repair and regeneration of the injured spinal cord, researchers have attempted to disrupt elements of the secondary injury pathway with the aim of neural preservation, inhibition of the barriers to axonal regeneration, and replacement of the damaged cells by cell transplantation therapy. From a pathophysiological perspective, it is likely that the optimal therapy will be a combinatorial one consisting of administration of drugs to reduce secondary injury at the acute phase, followed by cell transplantation or other regenerative therapies to regenerate the damaged spinal cord tissue in the subacute to chronic phases.18,19 These therapies are discussed in greater detail below.FIGURE: Three pathophysiological phases after SCI including acute (eg, hemorrhage, edema, and inflammation), subacute (eg, demyelination and axonal dieback), and chronic (eg, cavity formation) phases. Primary injury is caused by the physical forces of the initial traumatic event. Secondary injury refers to delayed, progressive damage which includes inflammation, loss of ionic homeostasis, oxidative damage, excitotoxicity, apoptosis, and necrosis. Oligodendrocytes are highly susceptible to apoptotic loss resulting in axonal demyelination. Cystic cavitation forms in the center of the spinal cord, with surrounding glial scar in the subacute and chronic phases. Nonastrocyte cells mainly form a chemical barrier by secreting growth inhibitory CSPGs.Barriers to Regeneration The adult mammalian Congress of Neurological Surgeons (CNS), including the spinal cord, has generally been considered to have limited regenerative capacity due to the finite number of available regenerative cells and the restricted plasticity of the adult CNS.20 While recent research has shown that the spinal cord has more regenerative capacity than was previously thought,21,22 compared with the peripheral nervous system, the regenerative capacity of the CNS is lower and it gradually decreases with increasing age.23 Schwab et al24 reported the inhibitory nature of CNS myelin in 1985. Myelin-associated proteins, such as neurite outgrowth inhibitor A (Nogo A),25,26 oligodendrocyte-myelin glycoprotein,27 and myelin-associated glycoprotein28,29 function through Nogo receptors (NgR). The NgRs lack an intracellular signaling domain and transduce inhibitory signals by forming coreceptor complexes with TNF receptor family proteins (eg, p75, TROY, and LIGO-1) to activate the GTPase Rho A. The downstream effector of Rho A is Rho-associated protein kinase which affects changes in the actin cytoskeleton and leads to growth cone collapse of regenerating axons, neurite retraction, and increasing apoptosis. SCI is accompanied by mechanically induced and excitotoxic cell death, with associated demyelination. The lost parenchyma is replaced by cystic cavitation and regeneration is often hindered by the presence of this cystic cavity which lacks the substrate to support axonal growth and cell migration.30 Furthermore, at the site of injury, glial and fibrotic scarring is also present (Figure). Glial and fibrotic scarring results when pericytes, hypertrophied astrocytes, fibroblast lineage cells, and inflammatory cells form a physical barrier, walling off injured tissue from healthy tissue.31,32 Recent research has shown that both astrocytes and nonastrocyte cells can form a physical and chemical barrier by secreting growth inhibitory chondroitin sulfate proteoglycans (CSPGs) such as neurocan, versican, brevican, phosphacan, and NG2.33 A fibroblast-derived scar can also be located in the perilesional region and is associated with the deposition of inhibitory extracellular matrix molecules. Similar to myelin-associated inhibitors, these molecules act as chemical barriers to the regeneration of axons. CURRENT CLINICAL STRATEGIES Early Surgical Intervention To reduce the effects of cord compression and resultant ischemia, early bony and ligamentous surgical decompression is performed to provide relief from the mechanical pressure. To elucidate the effectiveness of early decompression, a prospective cohort study, The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) was conducted with 313 cervical SCI patients.34 After adjusting for confounders, the early decompression group (<24 h after SCI) was 2.8 times as likely to demonstrate an Abbreviated Injury Scale (AIS) improvement of 2 or more grades at 6 mo after SCI compared with the late decompression group (≥24 h after SCI). A subsequent prospective Canadian cohort study (including cervical, thoracic, and lumbar SCI, n = 84) also revealed that early decompression was associated with a 2 or more grade AIS improvement at the time of rehabilitation facility discharge.35 The findings of these studies support the concept of "Time is Spine" which emphasizes the importance of early diagnosis and intervention to improve long-term outcomes. Central Cord Syndrome Central cord injury is characterized by greater weakness in the upper extremities than the lower extremities, variable sensory loss, variable bowel/bladder dysfunction, and, usually, early rapid improvements in neurological function. Early decompression has traditionally been avoided in cases of central cord injury with patients being allowed to plateau in their recovery over a number of weeks before any intervention.36 However, for patients with pre-existing canal stenosis, recent evidence suggests that early surgery may improve long-term outcomes. A systematic review demonstrated that patients undergoing early decompression (<24 h after SCI) had American Spinal Injury Association (ASIA) motor scores that were 6.31 points higher, and a greater chance of improvement in ASIA grade (odds ratio of 2.81) at 12-mo follow-up than those undergoing late decompression (≥24 h after SCI).37 Although the prospective randomized controlled Comparing Surgical Decompression Versus Conservative Treatment in Incomplete Spinal Cord Injury (COSMIC, NCT01367405) trial was initiated in 2013, it was terminated in 2016 due to difficulties in enrolling patients. Blood Pressure Augmentation The neuroprotective effects of blood pressure augmentation act through enhancing systemic perfusion. Several studies have shown that high-normal mean arterial blood pressures (MAPs) of 85 to 90 mm Hg may improve outcomes in SCI patients.38-40 The guidelines of the American Association of Neurological Surgeons (AANS) and (CNS) recommend MAP targets of 85 to 90 mm Hg as an option in SCI to be initiated as early as possible and maintained for 7 d after injury.41 This MAP elevation requires invasive blood pressure monitoring, maintenance of slightly hypervolemic state, and central venous access for continuous infusion of vasopressors. A noninferiority trial named Mean Arterial Blood Pressure Treatment for Acute Spinal Cord Injury (MAPS; NCT02232165) comparing MAP ≥ 85 mm Hg and MAP ≥ 65 mm Hg has been developed to assess the efficacy of lower targets. ASIA motor scores at 1 yr postinjury will be evaluated, and this trial is expected to complete in March 2017. Steroids for SCI Methylprednisolone sodium succinate (MPSS) is the only agent from completed clinical trials that has entered clinical use. It acts by reducing oxidative stress to enhance neural cell survival in animal models of traumatic SCI. Three landmark National Acute Spinal Cord Injury Studies (NASCIS) examined the use of MPSS for acute SCI.42-47 Although no neurological benefit in the MPSS-treated group was observed in the overall analyses of these studies, a subgroup analysis in the NASCIS II and III trials demonstrated that use of the drug in a higher dosing regimen than that used in NASCIS I within 8 h of injury resulted in neurological improvement, and that MPSS bolus 3 to 8 h after injury improved neurological function when it was administered for 48 h rather than 24 h.44-47 Recent evidence further supports the use of MPSS for SCI. A 2012 Cochrane meta-analysis and review demonstrated a 4 point greater ASIA motor score improvement in the group that received MPSS for acute SCI and that its administration was not associated with a significant increase in the risk of complications.48 Nevertheless, the 2013 AANS/CNS Section on Disorders of the Spine and Peripheral Nerves guideline provided a level I recommendation against the administration of MPSS which represents a marked change from the previous version despite little change in the evidence considered. Accordingly, an updated AOSpine guideline suggests that 24 h of MPSS IV be administered within 8 h of SCI to patients without medical contraindication.49 Emerging Therapies for SCI Key emerging technologies for SCI treatment include pharmacological approaches, cell-based therapies, biomaterials, and physiological approaches. A summary of these technologies is provided in Table.TABLE: Key Emerging Technologies for Acute SCIPharmacological Approaches Riluzole Riluzole is a benzothiazole antiepileptic which acts via sodium channel blockade. It is approved by the US Food and Drug Administration (FDA), European Medicines Agency, and Health Canada for the treatment of amyotrophic lateral sclerosis.50,51 Its role in neuroprotection stems from its ability to mitigate excitotoxicity and block sodium influx to neurons in addition to restricting the presynaptic release of glutamate.52 In animal studies, Riluzole has been shown to reduce neuronal loss and cavity size which led to improvements in motor function and electrophysiology.53-55 In the phase I trial for acute SCI was recently completed, and 36 patients were enrolled.56 Although elevations of liver enzyme levels were observed temporarily, no serious adverse events were attributed to the drug. Regarding the neurological outcomes, cervical SCI patients treated with riluzole showed the better improvement in ASIA motor score compared with non-riluzole treated patients matched from an historical registry cohort. The phase II/III RCT entitled riluzole in Spinal Cord Injury Study (RISCIS; NCT01597518) is recruiting patients with acute C4-8 injuries with ASIA grade A, B, or C and will compare riluzole versus placebo and assess AIS, Spinal Cord Independence Measure, and brief pain inventory. This study which was initiated in 2014 has to date recruited 70 patients and is expected to conclude in 2020. Minocycline Minocycline is a second-generation semisynthetic tetracycline antibiotic that has the ability to cross the blood–brain barrier. It also has potent anti-inflammatory properties and inhibits microglial activation, TNF-α, IL-1β, cyclooxygenase-2, and matrix metalloproteinases.57-60 In animal studies, minocycline treatment after acute SCI has been shown to protect against neuron loss and reduce the lesion size.61,62 A phase II study showed that patients with incomplete cervical SCI (n = 25) demonstrated an ASIA score improvement of 14 points with minocycline treatment compared to placebo (P = .05).63 The follow-up Phase III Minocycline in Acute Spinal Cord Injury (MASC; NCT01828203) study will compare IV minocycline for 7 d and is expected to conclude in 2018. VX-210 (Cethrin) The Rho pathway is known to negatively impact axonal and neurite growth.64 A toxin produced by Clostridium botulinum, C3 transferase (cethrin), has been shown to inhibit Rho-mediated inhibition of axonal growth which promoted neural regeneration and motor function recovery in rodent SCI models.65 Cethrin is a permeable material intended for application to the dura mater at the site of SCI during decompressive surgery in the acute phase. A phase I/IIa multicenter, dose-escalation human trial evaluating this drug in a human population was published in 201166; no serious adverse events were attributed to the drug.66 Cervical patients treated with 3 mg of cethrin showed improvement in ASIA motor score at 12 mo and this was shown to be superior to historical recovery rates. A phase IIb/III study of cethrin has commenced in cervical SCI patients in 2016 and is expected to conclude in 2018. Anti-Nogo-A antibody (ATI-355) A monoclonal antibody of major inhibitory fractions within CNS myelin, IN-1, has been shown to promote axonal sprouting and functional recovery following SCI in animal models.67 The humanized anti-Nogo antibody, ATI-355, has been shown to promote axonal sprouting and functional recovery following SCI in numerous animal models and is a rare therapeutic in that it has been demonstrated to improve functional outcomes in a primate model.26 A phase I human trial of humanized anti-Nogo antibody (ATI-355) was completed in Europe, rather than the US, as the FDA expressed concerns with the infusion pump. Although this trial has been completed, it has not been published. A phase II study of ATI-355 is about to commence in Europe. Granulocyte Colony Stimulating Factor Granulocyte colony-stimulating factor (G-CSF) has been shown to increase the mobilization of bone marrow stromal cells from the bone marrow and to increase their presence at the site of SCI. In a rodent model, G-CSF enhances neurogenesis, reduces apoptosis, and decreases expression of TNF-α and IL-1β. These positive effects are associated with white matter sparing and improved hind-limb function.68 The phase I/IIa trials, which were nonrandomized, showed no increase in serious adverse events with G-CSF administration alongside AIS grade improvement.69,70 G-CSF is currently in a phases III clinical trial in Japan with results expected in 2018. Hepatocyte Growth Factor Hepatocyte growth factor (HGF) is mainly secreted by mesenchymal cells and promotes cellular growth and motility. HGF enhances neuron survival, decreases lesion size, and reduces oligodendrocyte apoptosis to improve behavioral outcomes in rodent models.71 Moreover, in a primate model of cervical SCI, HGF improved hand dexterity which is one of the most important key functions of the upper limb.72 A phase I/II clinical trial (NCT02193334) comparing intrathecal HGF (KP100IT) versus placebo is now underway with results expected in 2017. Magnesium (AC105) Magnesium is a physiological antagonist of NMDA receptors which decreases excitotoxicity and also functions as an anti-inflammatory agent. Magnesium with polyethylene glycol (PEG) improves cerebrospinal fluid levels without requiring large magnesium doses.73-75 The use of magnesium with PEG in the treatment of animal models of SCI has been shown to enhance tissue sparing and improve motor functional recovery.76,77 However, a phase I/II clinical trial (NCT01750684) of magnesium with PEG (AC105) was terminated in 2015 due to difficulties in enrolling patients. Fibroblast Growth Factor Fibroblast growth factor (FGF) plays a key role in preserving motor neurons adjacent to the SCI site and reduces acute respiratory deficits resulting from the loss of ventral horn neurons by reducing glutamate-mediated excitotoxicity in animal models.78,79 Although a phase I/II trial (NCT01502631) of the FGF-analog (SUN13837) has been completed, the results have not been published to date. Cell-Based Therapies Regenerative therapies based on transplanted multipotent and differentiated cells are an exciting therapeutic approach showing promising results in translational studies. Initial research focused on embryonic stem cell lines derived from aborted early-stage embryos, however, ethical considerations and limited numbers of donor cells created challenges. More recently, the discovery of induced pluripotent stem cells (iPSCs), which can be derived within weeks from any somatic cell source, has revolutionized the field by providing a nearly limitless source of pluripotent cells for research and therapeutic purposes.80 Furthermore, iPSCs can potentially be derived from autologous tissue reducing or eliminating the risk of graft rejection.80 While unforeseen challenges in iPSC technology, such as epigenetic memory and early senescence, have been found, they continue to be a substantial technological advance in spinal cord regeneration.81 The most translationally relevant cell therapies derived from pluripotent stem cells or harvested from adult tissue are discussed cells are known to peripheral regeneration by providing a and support to axons. In rodent models of SCI, have been shown to reduce lesion size, axons, and provide motor The to has a phase trial (n = to assess for patients with chronic AIS grade injuries in the cervical or The study is expected to conclude in 2018. additional phase I trial (n = of derived for AIS grade A injuries has with results expected in ensheathing cells olfactory neurons and provide from and the In animal models of SCI, they have been to enhance neurite outgrowth and resulting in significant functional the are now and for chronic While a meta-analysis of several of these trials (n = no increase in serious adverse efficacy has to be due to concerns within the A previous study showed the of transplanted on from the into the spinal clinical trials of for chronic SCI have been completed and in a meta-analysis which no significant increase in to the stem cells are multipotent tissue cells of into and to repair ability to the and systemic inflammatory led to their application in SCI they were to promote tissue sparing through signaling and of is now a Phase II/III randomized trial of autologous via and intrathecal for patients with AIS grade cervical SCI within 12 mo of The study is expected to conclude in precursor cells are multipotent CNS cells of to astrocytes, and to lost cells and provide are most the central canal of the spinal cord and after however, their numbers are limited of or stem a promising In animal models of cervical and SCI, transplanted have been shown to reduce cystic axons, and improve behavioral outcomes over In 2 phase II trials led by were terminated early due to The studies were the effects of human CNS stem cell for and cervical The results of these trials have not been however, provide evidence that cell are in on emerging it is likely that further to the transplanted cells their will be to enhance motor outcomes. progenitor cells have multipotent to but they to to axons. Several studies have and functional recovery after A phase I/II trial (n = is now underway by to assess with results expected by have the of several of biomaterials with to SCI. These can be with stem cells, to growth and can be to over Moreover, they are being to cavitation with a that the extracellular In rodent biomaterials such as and have been shown to improve and behavioral to clinical Neuro-Spinal Scaffold is a and poly(lactic-co-glycolic currently in phase III trial by n = The trial will the effects of in with AIS grade A injuries and no as a was provided by the FDA this a The study is expected to conclude by Approaches to to via a of has been shown to reduce CNS injury after and These reduce the of the CNS and the systemic inflammatory to SCI, is tissue sparing and improvements in behavioral recovery in the In patients with AIS grade A a study (n = early therapeutic hypothermia to be associated with better neurological A phase II/III trial by the to entitled for Traumatic of the currently The study will assess of initiated within 6 h of injury to both efficacy and treatment is known to be a of the secondary injury Similar to MAP cerebrospinal fluid drainage to improve early spinal cord pressure to reduce the While an initial trial (n = to recent studies have that drainage and MAP augmentation can act to enhance spinal cord blood A phase (n = randomized trial and MAP elevation is now underway to the treatment can improve neurological outcomes for patients with acute AIS grade A, B, or C injuries from The study is expected to conclude in The of SCI research is and findings are being with from SCI clinical To achieve in clinical trials in SCI, the of and to In with to level of injury as as ASIA grade have been in of the clinical trials including the cethrin and riluzole The of SCI is likely to the administration of drugs to mitigate the secondary injury at the acute phase, followed by cell transplantation therapy to regenerate damaged spinal cord tissue from subacute to chronic that the therapeutic discussed in this review and the continuous in and clinical research are a to regenerative for SCI. This is by Canadian of Health AOSpine North in and and The support from the in and Regeneration and the is a for and and a for The other have no or in any of the or in this for this

SummaryEpidural electrical stimulation of the spinal cord is an emergent strategy for the neurological recovery of lower-extremity motor function. Motoneuron pools are thought to be recruited by stimulation of posterior roots. Here, we linked electromyographic data of epidurally evoked lower-extremity responses of 34 individuals with upper motoneuron disorders to a population model of the spinal cord constructed using anatomical parameters of thousands of individuals. We identified a relationship between segmental stimulation sites and activated spinal cord segments, which made spinal motor mapping from epidural space possible despite the complex anatomical interface imposed by the posterior roots. Our statistical approach provided evidence for low-threshold sites of posterior roots and effects of monopolar and bipolar stimulation previously predicted by computer modeling and allowed us to test the impact of different upper motoneuron disorders on the evoked responses. Finally, we revealed a statistical association between intraoperative and postoperative mapping of the spinal cord.