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Scientific Advances in Neural Regeneration After Spinal Cord Injury
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The landscape of therapeutic deep brain stimulation (DBS) for locomotor function recovery is rapidly evolving. This review provides an overview of electrical neuromodulation effects on spinal cord injury (SCI), focusing on DBS for motor functional recovery in human and animal models. We highlight research providing insight into underlying cellular and molecular mechanisms. A literature review via Web of Science and PubMed databases from 1990 to May 29, 2024, reveals a growing body of evidence for therapeutic DBS in SCI recovery. Advances in techniques like optogenetics and whole-brain tractogram have helped elucidate DBS mechanisms. Neuronal targets sites for SCI functional recovery include the mesencephalic locomotor region (MLR), cuneiform nucleus (CNF), and nucleus raphe magnus (NRG), with pedunculopontine nucleus (PPN), periaqueductal gray (PAG), and nucleus ventroposterolateral thalami (VPL) for post-injury functional recovery treatment. Radiologically guided DBS optimization and combination therapy with classical rehabilitation have become an effective therapeutic method, though ongoing interventional trials are needed to enhance understanding and validate DBS efficacy in SCI. On the pre-clinical front, standardization of pre-clinical approaches are essential to enhance the quality of evidence on DBS safety and efficacy. Mapping brain targets and optimizing DBS protocols, aided by combined DBS and medical imaging, are critical endeavors. Overall, DBS holds promise for neurological and functional recovery after SCI, akin to other electrical stimulation approaches.
A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space–time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LHVglut2) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking. We translated this discovery into a deep brain stimulation therapy of the LH (DBSLH) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBSLH immediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBSLH was turned off. There were no serious adverse events related to DBSLH. These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI. Further trials must establish the safety and efficacy profile of DBSLH, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions.
Background and objectives
Muscle strength and function are essential facets of rehabilitation for incomplete spinal cord injury (iSCI) patients. Various methods are being used to improve these outcome measures, but no gold standard method exists. Transcranial direct current stimulation (tDCS) is a relatively inexpensive, portable, readily available, and easy-to-use modality. It has shown promising results in many psychiatric and neurological conditions like stroke, cerebral palsy, and depression, but its role in spinal cord injury (SCI) is relatively unexplored. The study's objectives are to investigate the effect of anodal tDCS on lower limb muscle strength, quality of Life (QoL), and function in individuals with iSCI.
Methods
A randomized single-blinded sham control parallel-group study was conducted at the Indian Spinal Injuries Centre in New Delhi, India. There were 32 iSCI participants (28 males and four females) with 23 traumatic and nine non-traumatic etiologies. Participants were randomly assigned to receive 40 minutes of 2 mA anodal or sham stimulation over the targeted motor cortex areas for five sessions per week over two weeks.
The following outcome measures were measured at baseline after one and two weeks of the intervention: Lower Extremity Motor Score (LEMS), Spinal Cord Independence Measure (SCIM III), and WHO Quality of Life Bref (WHO QoL Bref).
Results
There was no significant difference at one week and two weeks of intervention for LEMS (p = 0.675, p = 0.978), SCIM III (p = 0.170, p = 0.133), WHO QoL Bref Domain 1 (p = 0.376, p = 0.282), Domain 2 (p = 0.728, p = 0.450), Domain 3 (p = 0.641, p = 0.993), Domain 4 (p = 0.294, p = 0.422), overall perception of QoL (p = 0.492, p = 1.000), and overall perception of their health (p = 0.300, p = 0.854) in the anodal and sham tDCS groups.
Conclusion
These primary findings suggest that anodal tDCS is ineffective in improving the QoL and motor and functional capabilities of individuals with iSCI. Further studies are necessary to determine whether it can be effective as a long-term rehabilitation strategy for the abovementioned population.
A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain–spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals³ and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4–6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.
Background
Satisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity.
Objective
RILUSCI is a phase 1b–2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI.
Methods
In this multicenter double-blind trial, adults (aged 18–65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period.
Conclusion
To the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI.
Trial registration
The clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792.
Trial sponsor
Assistance Publique–Hôpitaux de Marseille.
A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1–3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6–9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.
Introduction
Chondroitinase ABC (chABC) is an enzyme could improve regeneration and thereby improving functional recovery of spinal cord injury (SCI) in rodent models. Degradation of the active enzyme and diffusion away from the lesion are the causes of using hydrogels as a scaffold to deliver the chABC into the lesion site. In this meta-analysis, we investigated the effects of chABC embedded in a scaffold or hydrogel on the functional recovery after SCI.
Method
Databases were searched based on keywords related to chABC and spinal cord injury (SCI). Primary and secondary screening was performed to narrow down study objectives and inclusion criteria, and finally the data were included in the meta-analysis. The standard mean difference of the score of the functional recovery that measured by Basso, Beattie, Bresnahan (BBB) test after SCI was used to analyze the results of the reported studies. Subgroup analysis was performed based on SCI model, severity of SCI, transplantation type, and the follow-up time. Quality control of articles was also specified.
Results
The results showed that embedding chABC within the scaffold increased significantly the efficiency of functional recovery after SCI in animal models (SMD = 1.95; 95% CI 0.71–3.2; p = 0.002) in 9 studies. SCI model, severity of SCI, injury location, transplantation type, and the follow-up time did not affect the overall results and in all cases scaffold effect could not be ignored. However, due to the small number of studies, this result is not conclusive and more studies are needed.
Conclusion
The results could pave the way for the use of chABC embedded in the scaffold for the treatment of SCI and show that this method of administration is superior to chABC injection alone.
Regaining arm control is a top priority for people with paralysis. Unfortunately, the complexity of the neural mechanisms underlying arm control has limited the effectiveness of neurotechnology approaches. Here, we exploited the neural function of surviving spinal circuits to restore voluntary arm and hand control in three monkeys with spinal cord injury, using spinal cord stimulation. Our neural interface leverages the functional organization of the dorsal roots to convey artificial excitation via electrical stimulation to relevant spinal segments at appropriate movement phases. Stimulation bursts targeting specific spinal segments produced sustained arm movements, enabling monkeys with arm paralysis to perform an unconstrained reach-and-grasp task. Stimulation specifically improved strength, task performances and movement quality. Electrophysiology suggested that residual descending inputs were necessary to produce coordinated movements. The efficacy and reliability of our approach hold realistic promises of clinical translation. This paper describes a neurotechnology that interacts with neural circuits in the spinal cord to restore arm and hand control after injury. With this implant, monkeys with paralysis recovered the ability to reach and grasp just a few days after injury.
Ischemic stroke (IS) is a severe neurological disease that is difficult to recovery. Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic approach, while the exact therapy mechanisms of rTMS in improving neural functional recovery remain unclear. Furthermore, the inflammatory environment may influence the rehabilitation efficacy. Our study shows that long-term rTMS stimulation will significantly promote neurogenesis, inhibit apoptosis, and control inflammation. rTMS inhibits the activation of transcription factors nuclear factor kappa b (NF-κB) and signal transducer and activator of transcription 6 (STAT6) and promotes the anti-inflammatory polarization of microglia. Obvious promotion of anti-inflammatory cytokines production is observed both in vitro and in vivo through rTMS stimulation on microglia. In addition, neural stem cells (NSCs) cultured in conditioned medium (CM) from microglia treated with rTMS showed downregulation of apoptosis and upregulation of neuronal differentiation. Overall, our results illustrate that rTMS can modulate microglia with anti-inflammatory polarization variation, promote neurogenesis, and improve neural function recovery.
Individuals with spinal cord injury (SCI) may benefit less from exercise training due to consequences of their injury, leading to lower cardiorespiratory fitness and higher risks of developing cardiovascular diseases. Arm-crank exercise (ACE) is the most common form of volitional aerobic exercise used by people with SCI outside a hospital. However, evidence regarding the specific effects of ACE alone on fitness and health in adults with SCI is currently lacking. Hence, this review aimed to determine the effects of ACE on cardiorespiratory fitness, body composition, cardiovascular disease (CVD) risk factors, motor function, health-related quality of life (QoL), and adverse events in adults with chronic SCI. Inclusion criteria were: inactive adults (≥18 years) with chronic SCI (>12 months post injury); used ACE alone as an intervention; measured at least one of the following outcomes; cardiorespiratory fitness, body composition, cardiovascular disease risk factors, motor function, health-related QoL, and adverse events. Evidence was synthesized and appraised using GRADE. Eighteen studies with a combined total of 235 participants having an injury between C4 to L3 were included. There was a moderate certainty of the body of evidence on ACE improving cardiorespiratory fitness. Exercise prescriptions from the included studies were 30–40 min of light to vigorous-intensity exercise, 3–5 times per week for 2–16 weeks. GRADE confidence ratings were very low for ACE improving body composition, CVD risks factors, motor function, or health-related QoL. No evidence suggests ACE increases the risk of developing shoulder pain or other injuries. Overall, this review recommends adults with chronic SCI should engage in regular ACE to improve cardiorespiratory fitness. More high-quality, larger-scale studies are needed to increase the level of evidence of ACE in improving cardiorespiratory fitness and to determine the effects of ACE on other outcomes.
Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_reco rd.php?ID=CRD42021221952], identifier [CRD42021221952].
Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial (www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI.
Study design
Clinical trial.
Objective
To demonstrate that a 12-week exoskeleton-based robotic gait training regimen can lead to a clinically meaningful improvement in independent gait speed, in community-dwelling participants with chronic incomplete spinal cord injury (iSCI).
Setting
Outpatient rehabilitation or research institute.
Methods
Multi-site (United States), randomized, controlled trial, comparing exoskeleton gait training (12 weeks, 36 sessions) with standard gait training or no gait training (2:2:1 randomization) in chronic iSCI (>1 year post injury, AIS-C, and D), with residual stepping ability. The primary outcome measure was change in robot-independent gait speed (10-meter walk test, 10MWT) post 12-week intervention. Secondary outcomes included: Timed-Up-and-Go (TUG), 6-min walk test (6MWT), Walking Index for Spinal Cord Injury (WISCI-II) (assistance and devices), and treating therapist NASA-Task Load Index.
Results
Twenty-five participants completed the assessments and training as assigned (9 Ekso, 10 Active Control, 6 Passive Control). Mean change in gait speed at the primary endpoint was not statistically significant. The proportion of participants with improvement in clinical ambulation category from home to community speed post-intervention was greatest in the Ekso group (>1/2 Ekso, 1/3 Active Control, 0 Passive Control, p < 0.05). Improvements in secondary outcome measures were not significant.
Conclusions
Twelve weeks of exoskeleton robotic training in chronic SCI participants with independent stepping ability at baseline can improve clinical ambulatory status. Improvements in raw gait speed were not statistically significant at the group level, which may guide future trials for participant inclusion criteria. While generally safe and tolerable, larger gains in ambulation might be associated with higher risk for non-serious adverse events.
Objective
To understand the benefits and harms of physical activity in people who may require a wheelchair with a focus on people with multiple sclerosis (MS), cerebral palsy (CP), and spinal cord injury (SCI).
Data Sources: Searches were conducted in MEDLINE®, CINAHL®, PsycINFO®, Cochrane CENTRAL, Embase®, (January 2008 through November 2020).
Study Selection
Randomized controlled trials (RCTs), nonrandomized trials, and cohort studies of observed physical activity (at least 10 sessions on 10 days) in participants with MS, CP, and SCI.
Data Extraction
We conducted dual data abstraction, quality assessment, and strength of evidence. Measures of physical functioning are reported individually where sufficient data exist and grouped as “function” where data are scant.
Data Synthesis
No studies provided evidence for prevention of cardiovascular conditions, development of diabetes, or obesity. Among 168 included studies, 44% enrolled participants with MS (38% CP, 18% SCI). Studies in MS found walking ability may be improved with treadmill training and multimodal exercises; function with treadmill, balance exercises, and motion gaming; balance is likely improved with balance exercises and may be improved with aquatic exercises, robot-assisted gait training (RAGT), motion gaming, and multimodal exercises; activities of daily living (ADL), female sexual function, and spasticity may be improved with aquatic therapy, sleep may be improved with aerobic exercises and aerobic fitness with multimodal exercises. In CP, balance may be improved with hippotherapy and motion gaming; function with cycling, treadmill, and hippotherapy. In SCI, ADL may be improved with RAGT.
Conclusion
Depending on population and type of exercise, physical activity was associated with improvements in walking, function, balance, depression, sleep, ADL, spasticity, female sexual function, and aerobic capacity. Few harms of physical activity were reported in studies. Future studies are needed to address evidence gaps and to confirm findings.
Study design
Randomized sham-controlled clinical trial.
Objectives
The objective of this study is to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) compared to sham stimulation, on the development of lower limb muscle strength and gait function during rehabilitation of spinal cord injury (SCI).
Setting
SCI rehabilitation hospital in Viborg, Denmark.
Methods
Twenty individuals with SCI were randomized to receive rTMS (REAL, n = 11) or sham stimulation (SHAM, n = 9) and usual care for 4 weeks. rTMS (20 Hz, 1800 pulses per session) or sham stimulation was delivered over leg M1 Monday–Friday before lower limb resistance training or physical therapy. Lower limb maximal muscle strength (MVC) and gait function were assessed pre- and post intervention. Lower extremity motor score (LEMS) was assessed at admission and at discharge.
Results
One individual dropped out due to seizure. More prominent increases in total leg (effect size (ES): 0.40), knee flexor (ES: 0.29), and knee extensor MVC (ES: 0.34) were observed in REAL compared to SHAM; however, repeated-measures ANOVA revealed no clear main effects for any outcome measure (treatment p > 0.15, treatment × time p > 0.76, time p > 0.23). LEMS improved significantly for REAL at discharge, but not for SHAM, and REAL demonstrated greater improvement in LEMS than SHAM ( p < 0.02). Similar improvements in gait performance were observed between groups.
Conclusions
High-frequency rTMS may increase long-term training-induced recovery of lower limb muscle strength following SCI. The effect on short-term recovery is unclear. Four weeks of rTMS, when delivered in conjunction with resistance training, has no effect on recovery of gait function, indicating a task-specific training effect.
Increased mTOR activity has been shown to enhance regeneration of injured axons by increasing neuronal protein synthesis, while PTEN signaling can block mTOR activity to attenuate protein synthesis. MicroRNAs (miRs) have been implicated in regulation of PTEN and mTOR expression, and previous work in spinal cord showed an increase in miR-199a-3p after spinal cord injury (SCI) and increase in miR-21 in SCI animals that had undergone exercise. Pten mRNA is a target for miR-21 and miR-199a-3p is predicted to target mTor mRNA. Here, we show that miR-21 and miR-199a-3p are expressed in adult dorsal root ganglion (DRG) neurons, and we used culture preparations to test functions of the rat miRs in adult DRG and embryonic cortical neurons. miR-21 increases and miR-199a-3p decreases in DRG neurons after in vivo axotomy. In both the adult DRG and embryonic cortical neurons, miR-21 promotes and miR-199a-3p attenuates neurite growth. miR-21 directly bound to Pten mRNA and miR-21 overexpression decreased Pten mRNA levels. Conversely, miR-199a-3p directly bound to mTor mRNA and miR-199a-3p overexpression decreased mTor mRNA levels. Overexpressing miR-21 increased both overall and intra-axonal protein synthesis in cultured DRGs, while miR-199a-3p overexpression decreased this protein synthesis. The axon growth phenotypes seen with miR-21 and miR-199a-3p overexpression were reversed by co-transfecting PTEN and mTOR cDNA expression constructs with the predicted 3' untranslated region (UTR) miR target sequences deleted. Taken together, these studies indicate that injury-induced alterations in miR-21 and miR-199a-3p expression can alter axon growth capacity by changing overall and intra-axonal protein synthesis through regulation of the PTEN/mTOR pathway.
Objectives
The objective of this review was to summarize and appraise evidence on functional electrical stimulation (FES) cycling exercise after spinal cord injury (SCI), in order to inform the development of evidence-based clinical practice guidelines.
Methods
PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, SPORTDiscus, and CINAHL were searched up to April 2021 to identify FES cycling exercise intervention studies including adults with SCI. In order to capture the widest array of evidence available, any outcome measure employed in such studies was considered eligible. Two independent reviewers conducted study eligibility screening, data extraction, and quality appraisal using Cochranes’ Risk of Bias or Downs and Black tools. Each study was designated as a Level 1, 2, 3 or 4 study, dependent on study design and quality appraisal scores. The certainty of the evidence for each outcome was assessed using GRADE ratings (‘High’, ‘Moderate’, ‘Low’, or ‘Very low’).
Results
Ninety-two studies met the eligibility criteria, comprising 999 adults with SCI representing all age, sex, time since injury, lesion level and lesion completeness strata. For muscle health (e.g., muscle mass, fiber type composition), significant improvements were found in 3 out of 4 Level 1–2 studies, and 27 out of 32 Level 3–4 studies (GRADE rating: ‘High’). Although lacking Level 1–2 studies, significant improvements were also found in nearly all of 35 Level 3–4 studies on power output and aerobic fitness (e.g., peak power and oxygen uptake during an FES cycling test) (GRADE ratings: ‘Low’).
Conclusion
Current evidence indicates that FES cycling exercise improves lower-body muscle health of adults with SCI, and may increase power output and aerobic fitness. The evidence summarized and appraised in this review can inform the development of the first international, evidence-based clinical practice guidelines for the use of FES cycling exercise in clinical and community settings of adults with SCI.
Registration review protocol : CRD42018108940 (PROSPERO)
Background
Through improvements in trauma care there has been a decline in injury mortality, as more people survive severe trauma. Patients who survive severe trauma are at risk of long-term disabilities which may place a high economic burden on society. The purpose of this study was to estimate the health care and productivity costs of severe trauma patients up to 24 months after sustaining the injury. Furthermore, we investigated the impact of injury severity level on health care utilization and costs and determined predictors for health care and productivity costs.
Methods
This prospective cohort study included adult trauma patients with severe injury (ISS≥16). Data on in-hospital health care use, 24-month post-hospital health care use and productivity loss were obtained from hospital registry data and collected with the iMTA Medical Consumption and Productivity Cost Questionnaire. The questionnaires were completed 1 week and 1, 3, 6, 12 and 24 months after injury. Log-linked gamma generalized linear models were used to investigate the drivers of health care and productivity costs.
Results
In total, 174 severe injury patients were included in this study. The median age of participants was 55 years and the majority were male (66.1%). The mean hospital stay was 14.2 (SD = 13.5) days. Patients with paid employment returned to work 21 weeks after injury. In total, the mean costs per patient were €24,760 with in-hospital costs of €11,930, post-hospital costs of €7,770 and productivity costs of €8,800. Having an ISS ≥25 and lower health status were predictors of high health care costs and male sex was associated with higher productivity costs.
Conclusions
Both health care and productivity costs increased with injury severity, although large differences were observed between patients. It is important for decision-makers to consider not only in-hospital health care utilization but also the long-term consequences and associated costs related to rehabilitation and productivity loss.
Phantom limb pain is a form of chronic neuropathic pain by which 50-80% of the amputees feel the pain that is not adequately controlled by analgesics. When pain management through pharmacological treatment alone is unsuccessful, surgical treatment options are proven to be effective. We report a case of 61-year-old man who sought consultation with phantom limb pain after his motor vehicular accident and below elbow amputation three years before the consultation. His pain was not relieved by analgesics alone and opted for spinal cord stimulation. Chronic Dual Channel dorsal column stimulation was done using Medtronic Prime Advance SCS System. He was in good pain relief and his VAS decreased from (8/10) to (2/10) but since the last six months follow-up he is complaining of pain again (4/10) for which he is taking analgesics too.
Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1,2,3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord¹⁰, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury¹¹, and restored walking after paralysis¹². Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This ‘neuroprosthetic baroreflex’ controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.
Paralysis of the upper extremity severely restricts independence and quality of life after spinal cord injury. Regaining control of hand and arm movements is the highest treatment priority for people with paralysis, 6-fold higher than restoring walking ability. Nevertheless, current approaches to improve upper extremity function typically do not restore independence. Spinal cord stimulation is an emerging neuromodulation strategy to restore motor function. Recent studies using surgically implanted electrodes demonstrate impressive improvements in voluntary control of standing and stepping. Here we show that transcutaneous electrical stimulation of the spinal cord leads to rapid and sustained recovery of hand and arm function, even after complete paralysis. Notably, the magnitude of these improvements matched or exceeded previously reported results from surgically implanted stimulation. Additionally, muscle spasticity was reduced and autonomic functions including heart rate, thermoregulation, and bladder function improved. Perhaps most striking is that all six participants maintained their gains for at least three to six months beyond stimulation, indicating functional recovery mediated by long-term neuroplasticity. Several participants resumed their hobbies that require fine motor control, such as playing the guitar and oil painting, for the first time in up to 12 years since their injuries. Our findings demonstrate that non-invasive transcutaneous electrical stimulation of the spinal networks restores movement and function of the hands and arm for people with both complete paralysis and long-term spinal cord injury.
Recovery of the upper extremity (UE) and hand function is considered the highest priority for people with tetraplegia, because these functions closely integrate with their activities of daily living. Spinal cord transcutaneous stimulation (scTS) has great potential to facilitate functional restoration of paralyzed limbs by neuro-modulating the excitability of the spinal network. Recently, this approach has been demonstrated effective in improving UE function in people with motor complete and incomplete cervical SCI. However, the research thus far is limited by the lack of a comprehensive assessment of functional improvement and neurological recovery throughout the intervention. The goal of this study was to investigate whether scTS can also facilitate UE functional restoration in an individual with motor and sensory complete tetraplegia. A 38-year-old male with a C5 level, ASIA Impairment Scale-A SCI (15 years post-injury, left hand dominant pre- and post-injury), received 18 sessions (60 minutes/session) of scTS combined with task-specific hand training over the course of 8 weeks. The total score of the Graded Redefined Assessment of Strength, Sensibility, and Prehension significantly improved from 72/232 to 96/232 at post-intervention, and maintained ranging from 82/232 to 86/232 during the three months follow-up without any further treatment. The bilateral handgrip force improved by 283.4% (left) and 30.7% (right), respectively at post-intervention. These strength gains were sustained at 233.5% -250% (left) and 11.5% -73.1% (right) during the follow-up evaluation visits. Neuromuscular Recovery Scale demonstrated dramatic and long-lasting improvements following the completion of the intervention. Changes of spinal motor evoked potentials from pre- to post-intervention indicated an increased level of spinal network excitability. The present data offer preliminary evidence that the novel scTS intervention combined with hand training can enhance UE functional use in people with motor and sensory complete SCI.
Background: Patients with spinal cord injury (SCI) usually present different motor impairments including a deterioration of upper limb motor function (UL-MF), causing an important limitation in the performance of activities of daily living, and a loss of quality of life. Virtual reality (VR) is using in neurological rehabilitation for the assessment and treatment of physical of this condition.
Objective: A systematic review and meta-analysis was conducted to evaluate the effectiveness of VR on UL-MF in patients with SCI, compared to conventional physical therapy.
Methods: The search was performed during October-December 2019 in Embase, Web of Science, CINAHL, Scopus, Medline, PEDro, PubMed, and Cochrane Central Register of Controlled Trials. The criteria followed to select the registries were (1) adults with SCI, (2) intervened with VR, (3) compared with conventional physical therapy, (4) reporting outcomes related to UL-MF, and (5) controlled clinical trials as study design. The Cochrane Collaboration’s tool was employed to evaluate the risk of bias. The RevMan 5.3 statistical software was used to obtain the meta-analysis according to the standardized mean difference (SMD) and 95% confidence intervals (CI).
Results: Six articles were included in this systematic review. Four of them contributed information to the meta-analysis. 105 subjects were analyzed, and all of them used semi-immersive or non-immersive systems. Statistical analysis showed not conclusive results for: Nine Hole Peg Test (SMD -0.93, 95% CI -1.95 to 0.09); Muscle Balance test (SMD -0.27, 95% CI -0.82 to 0.27); Motricity Index (SMD 0.16, 95% CI −0.37 to 0.68); Jebsen Taylor Hand Function Test (JHFT) writing (SMD -0.10, 95% CI -4.01 to 3.82), simulated page turning (SMD -0.99, 95% CI -2.01 to 0.02), simulated feeding (SMD -0.64, 95% CI -1.61 to 0.32), stacking checkers (SMD 0.99, 95% CI -0.02 to 2.00), picking up large light objects (SMD -0.42, 95% CI -1.37 to 0.54), picking up large heavy objects (SMD 0.52, 95% CI -0.44 to 1.49); Range of Motion of shoulder abduction/adduction (SMD -0.23, 95% CI -1.48 to 1.03), shoulder flexion/extension (SMD 0.56, 95% CI -1.24 to 2.36), elbow flexion (SMD -0.36, 95% CI -1.14 to 0.42), elbow extension (SMD -0.21, 95% CI -0.99 to 0.57), wrist extension (SMD 1.44, 95% CI -2.19 to 5.06), elbow supination (SMD -0.18, 95% CI -1.80 to 1.44). Favorable results were found for the JHFT picking up small common objects (SMD -1.33, 95% CI -2.42 to -0.24).
Conclusions: The current evidence of VR interventions to improve UL-MF in patients with SCI is limited. Future studies employing immersive systems and the identification of the key aspects that increase the clinical impact of VR interventions are needed. Therefore, further research is needed to prove the use of VR in the rehabilitation of patients with SCI in clinical setting.
Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules—primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)—which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.
Abstract Functional electrical stimulation is a technique to produce functional movements after paralysis. Electrical discharges are applied to a person’s muscles making them contract in a sequence that allows performing tasks such as grasping a key, holding a toothbrush, standing, and walking. The technology was developed in the sixties, during which initial clinical use started, emphasizing its potential as an assistive device. Since then, functional electrical stimulation has evolved into an important therapeutic intervention that clinicians can use to help individuals who have had a stroke or a spinal cord injury regain their ability to stand, walk, reach, and grasp. With an expected growth in the aging population, it is likely that this technology will undergo important changes to increase its efficacy as well as its widespread adoption. We present here a series of functional electrical stimulation systems to illustrate the fundamentals of the technology and its applications. Most of the concepts continue to be in use today by modern day devices. A brief description of the potential future of the technology is presented, including its integration with brain–computer interfaces and wearable (garment) technology.
Spinal cord injury (SCI) is associated with significant and life-long disability. Yet, despite decades of research, no regenerative treatment has reached clinical practice. Cell-based therapies are one possible regenerative strategy beginning to transfer to human trials from a more extensive pre-clinical basis.
We therefore conducted a scoping review to synthesise all cell-based trials in SCI to consider the current state of the field and the cell transplant type or strategy with greatest promise. A search strategy of MEDLINE returned 1513 results. All clinical trials including adult human patients with acute or chronic, compete or incomplete SCI and a recorded ASIA score were sought. Exclusion criteria included non-traumatic SCI, paediatric patients and animal studies. A total of 43 studies, treating 1061 patients, were identified. Most trials evaluated cells from the bone marrow (22 papers, 660 patients) or the olfactory bulb (10 papers, 245 patients).
Cell transplantation does appear to be safe, with no serious adverse effects being reported in the short-term. 86% of trials described efficacy as a primary outcome. However, varying degrees of outcome reporting prevented meta-analysis. No emerging cell type or technique was identified. The majority of trials, 53%, took place in developing countries, which may suggest more stringent regulatory requirements within Western countries.
We believe cell-based transplantation translation remains in its infancy and that, although further robust clinical research is required, it is an important strategy to consider in the treatment of SCI.
Spinal fusion is one of the most common procedures performed in spine surgery. As rates of spinal fusion continue to increase, rates of complications such as nonunions continue to increase as well. Current evidence supporting the use of electrical stimulation to promote fusion is inconclusive. This review aimed to determine if postoperative electrical stimulation is more efficacious than no stimulation or placebo in promoting radiographic fusion in patients undergoing spinal fusion. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, CINAHL and MEDLINE from date of inception to current. Ongoing clinical trials were also identified and reference lists of included studies were manually searched for relevant articles. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Data were pooled using the Mantel-Haenszel method. Trialists were contacted for any missing or incomplete data. Of 1184 articles screened, 7 studies were eligible for final inclusion (n = 941). A total of 487 patients received postoperative electrical stimulation and 454 patients received control or sham stimulation. All evidence was of moderate quality. Electrical stimulation (pulsed electromagnetic fields, direct current, and capacitive coupling) increased the odds of a successful fusion by 2.5-fold relative to control (OR = 2.53, 95% CI 1.86 to 3.43, p < 0.00001). A test for subgroup interaction by stimulation type, smoking status, and number of levels fused was not significant (p = 0.93, p = 0.82 and p = 0.65, respectively). This systematic review and meta-analysis found moderate-quality evidence supporting the use of postoperative electrical stimulation as an adjunct to spinal fusion surgery. Patients treated with electrical stimulation have significantly greater rates of successful fusion. The level of evidence for this study is therapeutic level I.
Systematic review and meta-analysis.
We aimed to investigate the effects of anodal transcranial direct current stimulation (tDCS) against sham on muscle strength and motor functionality after incomplete spinal cord injury (iSCI).
University of São Paulo, Brazil.
A preplanned protocol was registered (PROSPERO, CRD42016050444). Pubmed, Embase, Web of Science, Cochrane Central Library and BVS databases were searched independently by two authors up to March 2018. Cochrane Collaboration’s Tool was used for the risk of bias assessments. Generic inverse variance and random-effects model were used to calculate pooled effect sizes (ES), 95% confidence intervals (CIs) and p-values in meta-analyses.
Six randomized clinical trials met inclusion criteria (n = 78 iSCI individuals) and were included in the meta-analysis. Results showed a marginal significant pooled effect of active tDCS in improving motor functionality with a small ES (SMD = 0.26, 95% CI = −0.00 to 0.53, p = 0.05, I² = 0%). On the other hand, the pooled effect of active tDCS on muscle strength did not reach statistical significance, in parallel with a small ES (SMD = 0.35, 95% CI = −0.21 to 0.92, p = 0.22, I² = 0%) when compared with sham tDCS. No significant adverse events were reported.
Overall, there was a significant effect of tDCS in improving motor functionality following iSCI. However, a small ES and the marginal p-value suggest that these results should be interpreted with caution. Further high-quality clinical trials are needed to support or refute the use of tDCS in daily clinical practice.
Background:
Spinal cord injury (SCI) is often associated with long-term impairments related to functional limitations in the sensorimotor system. The use of virtual reality (VR) technology may lead to increased motivation and engagement, besides allowing a wide range of possible tasks/exercises to be implemented in rehabilitation programs. The present review aims to investigate the possible benefits and efficacy of VR-based rehabilitation in individuals with SCI.
Methods:
An electronically systematic search was performed in multiple databases (PubMed, BVS, Web of Science, Cochrane Central, and Scielo) up to May 2019. MESH terms and keywords were combined in a search strategy. Two reviewers independently selected the studies in accordance with eligibility criteria. The PEDro scale was used to score the methodological quality and risk of bias of the selected studies.
Results:
Twenty-five studies (including 482 participants, 47.6 ± 9.5 years, 73% male) were selected and discussed. Overall, the studies used VR devices in different rehabilitation protocols to improve motor function, driving skills, balance, aerobic function, and pain level, as well as psychological and motivational aspects. A large amount of heterogeneity was observed as to the study design, VR protocols, and outcome measures used. Only seven studies (28%) had an excellent/good quality of evidence. However, substantial evidence for significant positive effects associated with VR therapy was found in most of the studies (88%), with no adverse events (88%) being reported.
Conclusion:
Although the current evidence is limited, the findings suggest that VR-based rehabilitation in subjects with SCI may lead to positive effects on aerobic function, balance, pain level, and motor function recovery besides improving psychological/motivational aspects. Further high-quality studies are needed to provide a guideline to clinical practice and to draw robust conclusions about the potential benefits of VR therapy for SCI patients. Protocol details are registered on PROSPERO (registration number: CRD42016052629).
Central nervous system (CNS) injuries persist for years, and currently there are no therapeutics that can address the complex injury cascade that develops over this time-scale. 17β-estradiol (E2) has broad tropism within the CNS, targeting and inducing beneficial phenotypic changes in myriad cells following injury. To address the unmet need for vastly prolonged E2 release, we report first-generation poly(pro-E2) biomaterial scaffolds that release E2 at nanomolar concentrations over the course of 1–10 years via slow hydrolysis in vitro. As a result of their finely tuned properties, these scaffolds demonstrate the ability to promote and guide neurite extension ex vivo and protect neurons from oxidative stress in vitro. The design and testing of these materials reported herein demonstrate the first step towards next-generation implantable biomaterials with prolonged release and excellent regenerative potential.
Neurological disease encompasses a diverse group of disorders of the central and peripheral nervous systems, which collectively are the leading cause of disease burden globally. The scope of treatment options for neurological disease is limited, and drug approval rates for improved treatments remain poor when compared with other therapeutic areas. Stem cell therapy provides hope for many patients, but should be tempered with the realisation that the scientific and medical communities are still to fully unravel the complexities of stem cell biology, and to provide satisfactory data that support the rational, evidence-based application of these cells from a therapeutic perspective. We provide an overview of the application of stem cells in neurological disease, starting with basic principles, and extending these to describe the clinical trial landscape and progress made over the last decade. Many forms of stem cell therapy exist, including the use of neural, haematopoietic and mesenchymal stem cells. Cell therapies derived from differentiated embryonic stem cells and induced pluripotent stem cells are also starting to feature prominently. Over 200 clinical studies applying various stem cell approaches to treat neurological disease have been registered to date (Clinicaltrials.gov), the majority of which are for multiple sclerosis, stroke and spinal cord injuries. In total, we identified 17 neurological indications in clinical stage development. Few studies have progressed into large, pivotal investigations with randomised clinical trial designs. Results from such studies will be essential for approval and application as mainstream treatments in the future.
Study design:
Randomized trial.
Objectives:
To evaluate the effectiveness of a 5-week sprint interval training (SIT) protocol on an arm-crank ergometer in individuals with sub-acute spinal cord injury (SCI).
Setting:
Inpatient rehabilitation.
Methods:
Individuals with SCI (N = 20; 9 tetraplegia/11 paraplegia; time since injury, 14-182 days; age, 46 ± 16 years; 15 M/5 F) were randomized to SIT or moderate-intensity continuous training (MICT). SIT consisted of 3 × 20 s. 'all-out' cycle sprints (≥100% peak power output) interspersed with 2 min of active recovery (10% peak power output; total time commitment, 10 mins). MICT involved 20 min of cycling (45% peak power output; total time commitment, 25 mins). Both training interventions were delivered 3 times/week for 5 weeks. Heart rate and Borg's Rating of Perceived Exertion (RPE; 6-20) were monitored throughout training sessions. Maximal and sub-maximal power outputs were assessed on an arm-crank ergometer. Exercise enjoyment, exercise self-efficacy, and pain were assessed at the end of the intervention.
Results:
During training sessions, heart rate (135 bpm vs. 119 bpm; p = 0.05), peripheral RPE (16 vs. 12; p = 0.000), and central RPE (15 vs. 11; p = 0.004) responses were higher in the SIT group, yet total work performed was greater in MICT. Peak power output increased significantly with training (36%), with no difference between groups (39% vs. 33%; p = 0.524). Similarly, improvements in sub-maximal power output were not different across groups. There were no between-group differences in exercise enjoyment (p = 0.385), exercise self-efficacy (p = 0.930), or pain (p = 0780).
Conclusions:
Five weeks of SIT improved physical capacity to the same extent as MICT in individuals with sub-acute SCI, despite a significantly lower time commitment with SIT.
Significant progress has been made in the treatment of spinal cord injury (SCI). Advances in post-trauma management and intensive rehabilitation have significantly improved the prognosis of SCI and converted what was once an "ailment not to be treated" into a survivable injury, but the cold hard fact is that we still do not have a validated method to improve the paralysis of SCI. The irreversible functional impairment of the injured spinal cord is caused by the disruption of neuronal transduction across the injury lesion, which is brought about by demyelination, axonal degeneration, and loss of synapses. Furthermore, refractory substrates generated in the injured spinal cord inhibit spontaneous recovery. The discovery of the regenerative capability of central nervous system neurons in the proper environment and the verification of neural stem cells in the spinal cord once incited hope that a cure for SCI was on the horizon. That hope was gradually replaced with mounting frustration when neuroprotective drugs, cell transplantation, and strategies to enhance remyelination, axonal regeneration, and neuronal plasticity demonstrated significant improvement in animal models of SCI but did not translate into a cure in human patients. However, recent advances in SCI research have greatly increased our understanding of the fundamental processes underlying SCI and fostered increasing optimism that these multiple treatment strategies are finally coming together to bring about a new era in which we will be able to propose encouraging therapies that will lead to appreciable improvements in SCI patients. In this review, we outline the pathophysiology of SCI that makes the spinal cord refractory to regeneration and discuss the research that has been done with cell replacement and biomaterial implantation strategies, both by itself and as a combined treatment. We will focus on the capacity of these strategies to facilitate the regeneration of neural connectivity necessary to achieve meaningful functional recovery after SCI.
Background:
Body weight supported treadmill training (BWSTT) is a frequently used approach for restoring the ability to walk after spinal cord injury (SCI). However, the duration of BWSTT is usually limited by fatigue of the therapists and patients. Robotic-assisted body weight supported treadmill training (RABWSTT) was developed to tackle the aforesaid limitation. Currently, limited randomized controlled trials are available to investigate its effectiveness, especially on cardiopulmonary function. The aim of this two-arm, parallel-group randomized controlled trial is to examine the feasibility of adapting an EMG-biofeedback system for assist-as-needed RABWSTT and its effects on walking and cardiopulmonary function in people with SCI.
Methods:
Sixteen incomplete SCI subjects were recruited and randomly allocated into an intervention group or control group. The intervention group received 30 min of RABWSTT with EMG biofeedback system over the vastus lateralis muscle to enhance active participation. Dose equivalent passive lower limbs mobilization exercise was provided to subjects in the control group.
Results:
Significant time-group interaction was found in the Walking Index for Spinal Cord Injury version II (WISCI II) (p = 0.020), Spinal Cord Independence Measure version III (SCIM III) mobility sub-score (p < 0.001), bilateral symmetry (p = 0.048), maximal oxygen consumption (p = 0.014) and peak expiratory flow rate (p = 0.048). Wilcoxon signed-rank test showed that the intervention group had significant improvement in the above-mentioned outcomes after the intervention except WISCI II, which also yielded marginal significance level.
Conclusion:
The present study demonstrated that the use of EMG-biofeedback RABWSTT enhanced the walking performance for SCI subjects and improve cardiopulmonary function. Positive outcomes reflect that RABSTT training may be able to enhance their physical fitness.
Trial registration:
The study protocol was approved by the Research Ethics Committee (Kowloon Central/ Kowloon East), Hospital Authority on 6 December 2013, and the Human Subjects Ethics Sub-committee of The Hong Kong Polytechnic University on 15 May 2013, with reference numbers KC/KC-13-0181/ER-2 and HSEARS20130510002 respectively. The study was registered in ClinicalTrials.gov on 20 November 2013, with reference number NCT01989806 .).
Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives.
Background: Recent studies in nondisabled individuals have demonstrated that low-volume high-intensity interval training (HIIT) can improve cardiometabolic health similar to moderate-intensity training (MIT) despite requiring 20% of the overall time commitment. To date, there have been no studies assessing the effects of HIIT for improving cardiometabolic health in individuals with SCI. Objectives: The primary purpose of this pilot study was to compare the effects of 6 weeks of low-volume HIIT vs MIT using arm crank ergometer exercise to improve body composition, cardiovascular fitness, glucose tolerance, blood lipids, and blood pressure in a cohort of individuals with longstanding SCI. Methods: Participants were randomized to 6 weeks of HIIT or MIT arm crank exercise training. Aerobic capacity, muscular strength, blood lipids, glucose tolerance, blood pressure, and body composition were assessed at baseline and 6 weeks post training. Results: Seven individuals (6 male, 1 female; n = 3 in MIT and n = 4 in HIIT; mean age 51.3 ± 10.5 years) with longstanding SCI completed the study. The preliminary findings from this pilot study demonstrated that individuals with SCI randomized to either 6 weeks of HIIT or MIT displayed improvements in (a) insulin sensitivity, (b) cardiovascular fitness, and (c) muscular strength (p < .05). However, MIT led to greater improvements in arm fat percent and chest press strength compared to HIIT (p < .05). Conclusion: No differences between MIT and HIIT were observed. Both conditions led to improvements in insulin sensitivity, aerobic capacity, muscle strength, and blood lipids in individuals with SCI. Future larger cohort studies are needed to determine if the shorter amount of time required from HIIT is preferable to current MIT exercise recommendations.
Induced pluripotent stem cells (iPSCs) are cells genetically reprogrammed from somatic cells, which can be differentiated into neurological lineages with the aim to replace or assist damaged neurons in the treatment of spinal cord injuries (SCIs) caused by physical trauma. Here, we review studies addressing the functional use of iPSC‐derived neural cells in SCIs and perform a meta‐analysis to determine if significant motor improvement is restored after treatment with iPSC‐derived neural cells compared with treatments using embryonic stem cell (ESC)‐derived counterpart cells and control treatments. Overall, based on locomotion scales in rodents and monkeys, our meta‐analysis indicates a therapeutic benefit for SCI treatment using neural cells derived from either iPSCs or ESCs, being this of importance due to existing ethical and immunological complications using ESCs. Results from these studies are evidence of the successes and limitations of iPSC‐derived neural cells in the recovery of motor capacity. Stem Cells Translational Medicine 2019 Traumatic spinal cord injuries can lead to impairment of motor movement, and iPSCs‐derived neural cells can be used for treatment as indicated in the left side of the illustration. Here, we review studies using this cell transplantation treatment in rodent models, as shown in the right side of the illustration, with the goal to evaluate its effectiveness for motor recovery.
Riluzole is sodium-glutamate antagonist which attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favourable results in promoting recovery in preclinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of Riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with ASIA Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 hours from injury were randomized to receive either Riluzole, at an oral dose of 100mg twice per day (BID) for the first 24 hours followed by 50mg BID for the following 13 days, or placebo. The primary efficacy endpoint was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the preplanned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the Riluzole treated patients compared to placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor (TOTM) scores (CI:-6.79-12.52). No drug related serious adverse events were associated with the use of Riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, Riluzole was associated with significant improvement in total motor scores (Estimate: SE 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the SCIM score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the SF-36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received Riluzole had a higher average gain in neurological levels at 6-months compared to placebo (mean 0.50 levels gained vs 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined endpoint of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with Riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.
Study design:
Pilot study.
Objectives:
To examine if functional electrical stimulation therapy (FEST) improves neuromuscular factors underlying upper limb function in individuals with SCI.
Setting:
A tertiary spinal cord rehabilitation center specialized in spinal cord injury care in Canada.
Methods:
We examined 29 muscles from 4 individuals living with chronic, cervical, and incomplete SCI. The analysis was focused on the changes in muscle activation, as well as on how the treatment could change the ability to control a given muscle or on how multiple muscles would be coordinated during volitional efforts.
Results:
There was evidence of gains in muscle strength, activation, and median frequency after the FEST. Gains in muscle activation indicated the activation of a greater number of motor units and gains in muscle median frequency the involvement of higher threshold, faster motor units. In some individuals, these changes were smaller but accompanied by increased control over muscle contraction, evident in a greater ability to sustain a volitional contraction, reduce the co-contraction of antagonist muscles, and provide cortical drive.
Conclusions:
FEST increases muscle strength and activation. Enhanced control of muscle contraction, reduced co-contraction of antagonist muscles, and a greater presence of cortical drive were some of the findings supporting the effects of FEST at the sensory-motor integration level.
Background:
Post spinal cord injury (SCI), sitting balance is considered a prerequisite for the effective performance of activities of daily living. Virtual Reality Training (VRT) may provide an interactive medium of rehabilitation, preventing a reduction in active participation of the patients while allowing for the training of sitting balance.
Aim:
The aim of this study was to evaluate the effect of the addition of VRT to conventional therapy in improving sitting balance in persons with SCI.
Subjects and methods:
This was a single blinded randomized control trial conducted on 21 subjects with SCI (level of injury: D10 or below). They were randomly allocated into two groups; both groups received their routine exercise program. In addition, the intervention group, that is, Group B (n = 11) received 30 min of VRT in the seated position using Xbox-Kinect, while the conventional therapy group, that is, Group A (n = 10) received 30 min of additional conventional therapy to equalize the duration of the intervention (3 days/week, 4 weeks). The modified functional reach test and T-shirt test were measured at the beginning and at the end of 4 weeks.
Results:
MFRT changes for forward (Group A: 1.7 ± 1.09 cm; Group B: 4.83 ± 2.95 cm), right lateral (Group A: 2.43 ± 2.81 cm, Group B: 5.08 ± 1.85 cm), left lateral (Group A: 3.05 ± 4.65 cm, Group B: 6.19 ± 1.51 cm) were statistically significant for Group B (P < 0.05). No significant difference was observed between the two groups for T-shirt test (P > 0.05).
Conclusion:
VRT can be used as a part of a comprehensive rehabilitation program to improve sitting balance post-SCI.
Orthostatic hypotension is a cardinal feature of multiple-system atrophy. The upright posture provokes syncopal episodes that prevent patients from standing and walking for more than brief periods. We implanted a system to restore regulation of blood pressure and enable a patient with multiple-system atrophy to stand and walk after having lost these abilities because of orthostatic hypotension. This system involved epidural electrical stimulation delivered over the thoracic spinal cord with accelerometers that detected changes in body position. (Funded by the Defitech Foundation.).
INTRODUCTIONː Spinal cord injuries (SCI) have physiological, emotional, and economic consequences in the lives of affected people. Resistance training (RT) is efficient in improving several physiological factors, quality of life, and body composition.
EVIDENCE ACQUISITIONː Due to the scarce literature on RT analyzed separately, the objective of this systematic review is to analyze the effects of RT with no association to other techniques, in aspects related to the quality of life and body composition of people The research for the articles was carried out in the Pubmed, Cochrane, and Web of Science databases using the terms "Spinal cord injuries" AND "Resistance Training" OR "Strength training". Given the scarcity of evidence on the subject, no deadline was set for the study to be eligible for analysis.
EVIDENCE SYNTHESISː The research for the articles was carried out in November of 2020 and returned 349 results, of which 220 remained after the elimination of duplicates, with 145 being excluded after title analysis. Seventy-five abstracts were analyzed and 70 studies were excluded, leaving 5 complete articles for a thorough analysis with SCI. Despite the I2 being 87%, the meta-analysis revealed an overall effect of Z= 4.79 (P<0.00001)
CONCLUSIONSː After analyzing the main results, we concluded that RT is feasible, secure, and promotes significant improvements in maximum strength, local muscular endurance, power, and muscular isometric voluntary contraction in people with spinal cord injury.
A randomized, sham-controlled clinical trial.
To test the effects of tDCS, combined with robotic training, on gait disability in SCI. Our hypothesis was that participants who received active tDCS would experience greater walking gains, as indexed by the WISCI-II, than those who received sham tDCS.
University of São Paulo, Brazil.
This randomized, double-blind study comprised 43 participants with incomplete SCI who underwent 30 sessions of active (n = 21) or sham (n = 22) tDCS (20 min, 2 mA) before every Lokomat session of 30 min (3 times a week over 12 weeks or 5 times a week over 6 weeks). The main outcome was the improvement in WISCI-II. Participants were assessed at baseline, after 15 and 30 sessions of Lokomat, and after three months of treatment.
There was a significant difference in the percentage of participants that improved in WISCI-II at the 30-session, compared with baseline: 33.3% in the sham group and 70.0% in the active group (p = 0.046; OR: 3.7; 95% CI: 1.0–13.5). At the follow-up, the improvement compared with baseline in the sham group was 35.0% vs. 68.4% for the active group (p = 0.046; OR: 3.7; 95% CI: 1.0–13.5). There was no significant difference at the 15-session.
Thirty sessions of active tDCS is associated with a significant improvement in walking, compared to sham. Moreover, 15 sessions had no significant effect. The improvement in WISCI-II can be related to different aspects of motor learning, including motor recovery and compensation.
Systematic review and meta-analysis.
Traditional forms of upper-body moderate intensity exercise consistently provide little cardiovascular benefits for persons with spinal cord injury (PwSCI). Explorations of new training methods are vital to improve cardiovascular fitness among PwSCI. This study sought to evaluate the effectiveness of vigorous training on cardiorespiratory fitness in PwSCI.
Database search through PubMed, Web of Science, Scopus, SportDiscus, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) was conducted from the databases’ inception to November 2020 to identify relevant exercise studies with PwSCI. Two independent reviewers screened articles for inclusion. Data were extracted from included studies and methodological quality evaluated.
Sixteen trials (eight pre-post trials and eight controlled trials [CTs]) with a total of 145 participants were analyzed. Results from pre-post studies revealed significant improvements in cardiorespiratory fitness following high-intensity interval training (HIIT) (Peak Oxygen Uptake [VO2peak], standardized mean difference [SMD] = 0.81; 95% CI 0.23–1.39; P < 0.01 and Peak Power Output [PPO], SMD = 0.91; 95% CI 0.32–1.5; P < 0.01) and circuit resistance training (CRT) (VO2peak, MD = 0.38; 95% CI 0.19–0.57; P < 0.01 and PPO, MD = 20.17; 95% CI 8.26–32.08; P < 0.01). Meta-analysis of CTs did not demonstrate significant improvements in cardiorespiratory fitness following vigorous training interventions in comparison to lower intensity training interventions.
Evidence from HIIT and CRT interventions suggest benefits for cardiovascular functions; however, vigorous training was not more beneficial than other forms of endurance training. More CTs are needed to better understand the effectiveness of vigorous training on cardiorespiratory fitness in PwSCI.
Objectives
This scoping review was undertaken to synthetize and appraise the literature on the potential mechanisms of action of functional electrical stimulation therapy in combination with task-specific training (FEST + TST) in the rehabilitation following stroke, spinal cord injury, traumatic brain injury, or multiple sclerosis.
Materials and Methods
The literature search was performed using multiple databases (including APA, PsycInfo, Medline, PubMed, EMBASE, CCRCT, and Cochrane Database of Systematic Reviews) from 1946 to June 2020. The literature search used the following terms: (spinal cord injury, paraplegia, tetraplegia, quadriplegia, stroke, multiple sclerosis, traumatic brain injury, or acquired brain injury) AND (functional electrical stimulation or FES). The search included clinical and preclinical studies without limits to language.
Results
Of the 8209 titles retrieved from the primary search, 57 publications fulfilled the inclusion and exclusion criteria for this scoping review. While most publications were clinical studies (n = 50), there were only seven preclinical studies using animal models. The results of this review suggest that FEST + TST can result in multiple effects on different elements from the muscle to the cerebral cortex. However, most studies were focused on the muscle changes after FEST + TST.
Conclusions
The results of this scoping review suggest that FEST + TST can result in multiple effects on different elements of the neuromuscular system, while most research studies were focused on the muscle changes after FEST + TST. Despite the efficacy of the FEST + TST in the neurorehabilitation after CNS injury or disease, the results of this review underline an important knowledge gap with regards to the actual mechanism of action of FEST + TST.
Objective: To examine the therapeutic value of lower extremity functional electrical stimulation (FES) - evoked cycling on functional independence, health status, gait parameters, pulmonary functions, and biochemical values in patients with chronic complete/incomplete spinal cord injury (SCI).
Materials and Methods: Fifteen patients with SCI (duration of more than 6 months) who were able to stand up and walk with long leg braces or assistive devices and had stable neurological status and trunk balance undertook FES cycling for 6 weeks (three times per week). The main outcomes were: Functional Independence Measure (FIM), Nottingham Health Profile (NHP), 6-minute walk test (6MWT), and 20-meter walk test (20MWT). Secondary outcomes include measurements of pulmonary function tests and biochemical values. All parameters were evaluated at the beginning and end of the program.
Results: Improvements were seen in motor and total scores of FIM (p = 0.007), physical mobility subscale of NHP (p = 0.011), 6MWT (p = 0.001), and 20MWT (p = 0.011). In pulmonary functions, only forced vital capacity (FVC) levels demonstrated a significant increase compared with baseline (p = 0.011). Biochemical values reached no significant level.
Conclusion: The results of this study showed that the FES cycling exercise program improves motor and total FIM scores, gait parameters, and FVC values of pulmonary functions in patients with chronic SCI experience. The FES cycle might be a valuable and well-tolerated intervention in clinical rehabilitation.
Objective
To determine the effects of exercise on individual cardiometabolic syndrome (CMS) risk factors in adults with chronic spinal cord injury (SCI).
Data sources
English language searches of PubMed, Web of Science, EMBASE, and Scopus (01/01/1970 to 31/07/2019).
Study Selection
Articles were included if they met the following criteria: (1) original articles with statistical analysis, (2) participants were adults with a SCI sustained ≥ 1-year ago, (3) exercise intervention duration ≥ 2 weeks, and (4) included any CMS risk factor as an outcome.
Data Extraction
The methodological quality of articles was assessed using the Downs and Black score.
Data Synthesis
Sixty-five studies were included for the final analysis, including nine studies classified as high quality (≥66%), 35 studies classified as fair quality (50-66%), and 21 studies classified as low quality (<50%). Improvements in waist circumference (4/6 studies) and markers of hepatic insulin sensitivity (4/5 studies) were reported following upper-body aerobic exercise training, but no improvements in fasting glucose (8/8 studies), lipid profile (6/8 studies), systolic (8/9 studies) or diastolic blood pressure (9/9 studies) were observed. Improvements in markers of peripheral insulin sensitivity (5/6 studies) were observed following functional electrical stimulation (FES)-cycling. Improvements in lipid profile (4/5 studies) were observed following upper-body resistance training (RT) (with or without aerobic exercise). No consistent improvements in CMS risk factors were observed following assisted ambulation, FES-hybrid, FES-rowing, and FES-RT.
Conclusions
Upper-body aerobic exercise training (>75% maximum heart rate) appears to improve waist circumference and hepatic insulin sensitivity, but appears insufficient for improving fasting glucose, lipid profile, or resting blood pressure. The addition of RT to upper-body aerobic exercise may elicit favourable changes in the lipid profile. More high-quality studies are needed to confirm if FES-cycling is effective at improving peripheral insulin sensitivity.
Prospective, quasi-experimental study, pre- and post-design, single arm study.
Investigate whether persons affected by SCI can safely experience walking function using Robotic Exoskeletons and Functional Electrical Stimulation (FES).
Inpatient
52 persons with SCI were recruited (36 completed the protocol) and assigned to one of two groups based on their Lower Limb Motor Scores (LEMS): Group A: LEMS ≥ 10 and Group B: LEMS < 10. Participants in Group A (n = 19) underwent 20 sessions of Robot-Assisted Gait Training (RAGT) on a treadmill followed by 20 sessions of FES during Overground Gait (FES-OG). Participants in Group B (n = 17) received 20 sessions of FES-cycling followed by 20 sessions of overground RAGT. The main outcome measures were: WISCI-II, 10MWT, 6MWT, TUG and SCIM-II.
36 persons completed the study with no complications; only 4 of the 16 dropped out because of mild complications during the RAGT. Participants in Group A exhibited significant improvements in WISCI-II, 10MWT, 6MWT and TUG (p < 0.05), while those in Group B did not significantly improve their gait function but their walking velocity and resistance with the assistance of the robotic exoskeleton increased. SCIM-II scores increased followed therapy only in Group A.
Persons affected by SCI can safely experience their walking function with RAGT and FES therapy; only few mild complications were observed. Our data provides initial evidence of the potential value of these technologies, especially in persons with SCI having LEMS > 10.
Objective:
To: assess safety and feasibility for persons with acute spinal cord injury (SCI) using the robotic exoskeleton.
Design:
Case series observational study.
Setting:
A level one trauma center in Canada with both acute and tertiary inpatient SCI rehabilitation units.
Participants:
Eight male and three female (total N=11) participants were recruited with a mean age of 41 years and with neurologic level of injury: C6-L2 and severity: AIS A-D (American Spinal Injury Association Impairment Scale). Time since injury: range 3-15 weeks at the onset of training.
Interventions:
Up to 25 one-hour sessions of exoskeletal-assisted walking gait training, with participants less than 6 months from initial SCI.
Main outcome:
Measures:Cardiopulmonary outcomes including blood pressure, heart rate and peripheral oxygen saturation; and perceived physical exertion using the BORG CR10 were recorded. Gait parameters were measured by 6-minute walk test (6MWT) and 10-meter walk test (10MWT). Up Time, walk time, and number of steps were detailed longitudinally. Safety was assessed with regard to pain, falls and skin integrity.
Results:
No serious adverse events occurred. Blood pressure decreased following initial sit to stand and increased during walking. Symptoms of hypotension were rare and improved with increased number of sessions. Perceived exertion was reported on average to be moderate (mean of 3.1). There was no significant increase in pain scores by visual analog scale. On 6MWT, participants covered more distance (mean = 117.1+/- 11.7m) in session 25 compared to session 2 (mean = 47.6 +/- 6.6m). On the 10MWT, all participants showed consistently improved gait speed; with participants traveling an average of 3.2 times faster during their last training session (0.40 ± 0.04 m/s) in comparison to session 2 (0.12 ± 0.01 m/s).
Conclusions:
Exoskeletal-assisted walking in acute rehabilitation (< 6 months) following SCI appears to be both safe and feasible.
Objective: To investigate the effect of a short-term, robotic-assisted (exoskeleton) gait training (RGT) program on central and peripheral hemodynamic measures in patients with spinal cord injury (SCI).
Design: Parallel group, non-randomized trial with before (baseline) and after (follow-up) assessments.
Setting: Single-center, community-based neuro-physiotherapy practice.
Participants: Twelve individuals with SCI (ASI A to C).
Interventions: Participants completed either a 5-day RGT program plus physiotherapy (n = 6), or a usual care physiotherapy only program (control group; n = 6). The RGT program consisted of daily 60-min physiotherapy and 90-min of RGT. Outcome measures were measured before and after the rehabilitation program.
Main outcome measure(s): The primary outcome measure was arterial wave reflection (Augmentation index [AIx]), with central and peripheral blood pressures also reported. Data are presented as mean (SD) and effect sizes (partial eta squared; η²p).
Results: There was a significant reduction in AIx (30 ± 18–21 ± 15%; η²p=0.75) and mean arterial pressure (89 ± 11–82 ± 10 mmHg; η²p=0.47) following completion of the RGT program (both P < 0.05). There were no changes in these measures for the control group. Although not significantly different, medium to large effects were observed in favor of RGT for all other central and peripheral measures (η²p=0.06–0.21), except for heart rate and pulse pressure (η²p<0.04).
Conclusions: RGT using an exoskeleton is a promising therapy for improving cardiovascular health in patients with SCI. Specifically, this study indicates decreased arterial wave reflection and supports the need for larger randomized controlled trials.
Trial Registration: Clinical trials Registry (https://clinicaltrials.gov/; NCT03611803).
The precise location and functional organization of the spinal neuronal locomotor-related networks in adult mammals remains unclear. Our recent neurophysiological findings provided empirical evidence that the rostral lumbar spinal cord segments play a critical role in the initiation and generation of the rhythmic activation patterns necessary for hindlimb locomotion in adult spinal rats. Since added epidural stimulation at the S1 segments significantly enhanced the motor output generated by L2 stimulation, these data also suggested that the sacral spinal cord provides a strong facilitory influence in rhythm initiation and generation. However, whether L2 will initiate hindlimb locomotion in the absence of S1 segments, and whether S1 segments can facilitate locomotion in the absence of L2 segments remains unknown. Herein, adult rats received complete spinal cord transections at T8 and then at either L2 or S1. Rats with spinal cord transections at T8 and S1 remained capable of generating coordinated hindlimb locomotion when receiving epidural stimulation at L2 and when ensembles of locomotor related loadbearing input were present. In contrast, minimal locomotion was observed when S1 stimulation was delivered after spinal cord transections at T8 and L2. Results were similar when the non-specific serotonergic agonists were administered. These results demonstrate in adult rats that rostral lumbar segments are essential for the regulation of hindlimb locomotor rhythmicity. In addition, the more caudal spinal networks alone cannot control locomotion in the absence of the rostral segments around L2 even when loadbearing rhythmic proprioceptive afferent input is imposed.