Different approaches are available to compensate gait in persons with spinal cord injury, including passive orthoses, functional electrical stimulation (FES), and robotic exoskeletons. However, ...several drawbacks arise from each specific approach. Orthotic gait is energy-demanding for the user and functionally ineffective. FES uses the muscles as natural actuators to generate gait, providing not only functional but also psychological benefits to the users. However, disadvantages are also related to the early appearance of muscle fatigue and the control of joint trajectories. Robotic exoskeletons that provide joint moment compensation or substitution to the body during walking have been developed in recent years. Significant advances have been achieved, but the technology itself is not mature yet because of many limitations related to both physical and cognitive interaction as well as portability and energy-management issues. Meanwhile, the combination of FES technology and exoskeletons has emerged as a promising approach to both gait compensation and rehabilitation, bringing together technologies, methods, and rehabilitation principles that can overcome the drawbacks of each individual approach. This article presents an overview of hybrid lower-limb exoskeletons, related technologies, and advances in actuation and control systems. Also, we highlight the functional assessment of individuals with spinal cord injury.
Traumatic spinal cord injury (SCI) is a devastating neurological disease for which an accurate, cost-effective prediction of motor function recovery is in pressing need. A plethora of neurochemical ...changes involved in the pathophysiological process of SCI may serve as a new source of biomarkers for patient outcomes. Five dogs were included in this study. We characterized the plasma cytokine profiles in acute phase (0, 1, and 3 days after SCI) and subacute phase (7, 14, and 21 days after SCI) with microarray analysis. The motor function recovery following SCI was monitored by Olby scores. The expression level of differentially expressed proteins (DEPs) was measured with enzyme-linked immunosorbent assay (ELISA). Then, correlations with the Olby scores and receiver operating characteristic curve (ROC) analysis were performed. We identified 12 DEPs including 10 pro-inflammatory and 2 anti-inflammatory cytokines during the 21-day study period. Among those, the expression levels of erythropoietin (EPO), IL-17A, and IFNγ significantly correlated with the Olby scores with
R
2
values of 0.870, 0.740, and 0.616, respectively. The results of the ROC analysis suggested that plasma EPO, IL-17A, and IFNγ exhibited a significant predictive power with an area under the curve (AUC) of 0.656, 0.848, and 0.800 for EPO, IL-17A, and IFNγ, respectively. Our results provide a longitudinal description of the changes in plasma cytokine expression in the acute and subacute stages of canine SCI. These data reveal novel panels of inflammation-related cytokines which have the potential to be evaluated as biomarkers for predicting motor function prognosis after SCI.
After traumatic spinal cord injury, functional deficits increase as axons die back from the center of the lesion and the glial scar forms. Axonal dieback occurs in two phases: an initial axon ...intrinsic stage that occurs over the first several hours and a secondary phase which takes place over the first few weeks after injury. Here, we examine the secondary phase, which is marked by infiltration of macrophages. Using powerful time-lapse multi-photon imaging, we captured images of interactions between Cx3cr1+/GFP macrophages and microglia and Thy-1YFP axons in a mouse dorsal column crush spinal cord injury model. Over the first few weeks after injury, axonal retraction bulbs within the lesion are static except when axonal fragments are lost by a blebbing mechanism in response to physical contact followed by phagocytosis by mobile Cx3Cr1+/GFP cells. Utilizing a radiation chimera model to distinguish marrow-derived cells from radio-resistant CNS-resident microglia, we determined that the vast majority of accumulated cells in the lesion are derived from the blood and only these are associated with axonal damage. Interestingly, CNS-resident Cx3Cr1+/GFP microglia did not increasingly accumulate nor participate in neuronal destruction in the lesion during this time period. Additionally, we found that the blood-derived cells consisted mainly of singly labeled Ccr2+/RFP macrophages, singly labeled Cx3Cr1+/GFP macrophages and a small population of double-labeled cells. Since all axon destructive events were seen in contact with a Cx3Cr1+/GFP cell, we infer that the CCR2 single positive subset is likely not robustly involved in axonal dieback. Finally, in our model, deletion of CCR2, a chemokine receptor, did not alter the position of axons after dieback. Understanding the in vivo cellular interactions involved in secondary axonal injury may lead to clinical treatment candidates involving modulation of destructive infiltrating blood monocytes.
•Secondary axonal dieback in a dorsal column injury can be imaged in vivo over time.•Accumulating CX3CR1+ cells in traumatic spinal cord injury are blood derived.•CX3CR1+ monocytes, but not microglia, have destructive effects on axons.•The destructive monocyte subtype in the lesion is CX3CR1hi.•Axonal dieback is CCR2 independent.
Stem cells have a high therapeutic potential for the treatment of spinal cord injury (SCI). We have shown previously that endogenous stem cell potential is confined to ependymal cells in the adult ...spinal cord which could be targeted for non-invasive SCI therapy. However, ependymal cells are an understudied cell population. Taking advantage of transgenic lines, we characterize the appearance and potential of ependymal cells during development. We show that spinal cord stem cell potential in vitro is contained within these cells by birth. Moreover, juvenile cultures generate more neurospheres and more oligodendrocytes than adult ones. Interestingly, juvenile ependymal cells in vivo contribute to glial scar formation after severe but not mild SCI, due to a more effective sealing of the lesion by other glial cells. This study highlights the importance of the age-dependent potential of stem cells and post-SCI environment in order to utilize ependymal cell's regenerative potential.
Schematic representation of different cell type responses to spinal cord injury (SCI) in juvenile and adult mice. In vitro juvenile ependymal cells have higher intrinsic self-renewal capacity with or without SCI compared to adults. After differentiation, juvenile ependymal cells can generate more oligodendrocytes than adult ones before or after SCI. In vivo juvenile spinal cord shows better recovery by sealing the lesion more efficiently: more dense astrocytic interaction, less astrogliosis, less infiltrating pericytes, microglia and blood-derived macrophages. After SCI, ependymal cells do not get activated in juvenile mild lesion due to the higher self-repair efficiency, while they are required for wound healing in mature adults or after a more severe lesion in juveniles. Thus, the activation of ependymal cells depends on age and lesion size despite their higher intrinsic stem cell potential at the juvenile stage. This study suggests that juvenile animals have higher self-repair efficiency and spinal cord environment and age should be taken into consideration to design further therapies. P21=postnatal day 21, DFT=dorsal funiculi transection, DH=dorsal hemisection. Display omitted
•All spinal cord stem cell potential is contained within ependymal cells by birth but decreases over time.•Recruitment of ependymal cells after injury is age- and lesion-dependent.•Juvenile endogenous spinal cord glial cells better seal the lesion than in adults.
Spinal cord (SC) injury is an incurable condition. It leads to permanent paralysis and loss of sensation. Many cell therapies have been tested for treatment but limitations remain due to limited knowledge of the SC following injury. We used transgenic mice to study young and mature SC after injury. We found that the SC stem cells, a cell type that can generate other cells for recovery, are present from postnatal stage. Furthermore, we discovered that these stem cells are recruited differently in an age- and lesion-dependent matter affecting their repair potential. This has important implications for further design of therapies.
Lesion-induced scarring is a major impediment for regeneration of injured axons in the central nervous system (CNS). The collagen-rich glial-fibrous scar contains numerous axon growth inhibitory ...factors forming a regeneration-barrier for axons. We demonstrated previously that the combination of the iron chelator 2,2'-bipyridine-5,5'-decarboxylic acid (BPY-DCA) and 8-Br-cyclic AMP (cAMP) inhibits scar formation and collagen deposition, leading to enhanced axon regeneration and partial functional recovery after spinal cord injury. While BPY-DCA is not a clinical drug, the clinically approved iron chelator deferoxamine mesylate (DFO) may be a suitable alternative for anti-scarring treatment (AST). In order to prove the scar-suppressing efficacy of DFO we modified a recently published in vitro model for CNS scarring. The model comprises a co-culture system of cerebral astrocytes and meningeal fibroblasts, which form scar-like clusters when stimulated with transforming growth factor-β (TGF-β). We studied the mechanisms of TGF-β-induced CNS scarring and compared the efficiency of different putative pharmacological scar-reducing treatments, including BPY-DCA, DFO and cAMP as well as combinations thereof. We observed modulation of TGF-β-induced scarring at the level of fibroblast proliferation and contraction as well as specific changes in the expression of extracellular matrix molecules and axon growth inhibitory proteins. The individual and combinatorial pharmacological treatments had distinct effects on the cellular and molecular aspects of in vitro scarring. DFO could be identified as a putative anti-scarring treatment for CNS trauma. We subsequently validated this by local application of DFO to a dorsal hemisection in the rat thoracic spinal cord. DFO treatment led to significant reduction of scarring, slightly increased regeneration of corticospinal tract as well as ascending CGRP-positive axons and moderately improved locomotion. We conclude that the in vitro model for CNS scarring is suitable for efficient pre-screening and identification of putative scar-suppressing agents prior to in vivo application and validation, thus saving costs, time and laboratory animals.
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.
When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these ...interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9‐ to 13‐week interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5–T6) and second (left T10–T11) hemisections, coordination of the fore‐ and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short‐latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid‐ and long‐latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid‐ and long‐latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short‐, mid‐ and long‐latency responses maintained their phase‐dependent modulation. We also observed reduced durations of short‐latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short‐latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery.
Key points
Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle.
Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination.
We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats.
We showed a loss/reduction of mid‐ and long‐latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore‐ and hindlimbs and impaired balance.
Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.
figure legend Contacting an obstacle during locomotion activates cutaneous afferents to maintain balance and coordinate all four limbs. Spinal cord injuries disrupt neural communications between spinal networks controlling the fore‐ and hindlimbs, impairing balance and limb coordination. Cutaneous reflex pathways can be used to develop therapeutic approaches for restoring ascending and descending transmission to facilitate locomotor recovery.
One of many types of injuries following an earthquake is spinal cord injury (SCI) which is a life-long medically complex injury and high-cost health problem. Despite several negative consequences, ...some persons with SCI are resilient enough to achieve positive adjustment, greater acceptance, and better quality of life. Since resilience is influenced by several factors and can vary by context, it is beneficial to explore factors that affect the resilience of people who sustained spinal cord injury from the 2015 earthquake in Nepal.
A descriptive cross-sectional study included 82 participants from the Spinal Injury Rehabilitation Center and communities in Nepal. Participants completed the Demographic and Injury-related Questionnaire, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Moorong Self-efficacy Scale, Intrinsic Spirituality Scale, and Patient Health Questionnaire-9. Pearson's correlation and point biserial correlation analyses were performed to examine associations between resilience and independent variables. A hierarchical regression analysis was used to identify the influence of certain factors.
Findings indicated significant associations between resilience and social support (r = 0.42, p < 0.001), self-efficacy (r = 0.53, p < 0.001), depressive mood (r = - 0.50, p < 0.001) and demographic variables which included sex (r = 0.47, p < 0.001), employment (r = 0.27, p = 0.016), and current living location (r = 0.24, p = 0.029). There was a non-significant association between resilience and spirituality (r = - 0.12, p > 0.05). In hierarchical regression analysis, an overall regression model explained 46% of the variance in resilience. Self-efficacy (β = 0.28, p = 0.007) and depressive mood (β = - 0.24, p = 0.016) significantly determined resilience after controlling the effect of demographic variables. Among the demographic factors, being male significantly explained the variance in resilience (β = 0.31, p = 0.001).
Multiple psychosocial and demographic factors were associated with resilience in people who sustained an earthquake-related SCI. Mental health professionals should demonstrate concern and consider such factors in allocating care in this group. Development of intervention research concerning resilience is recommended to strengthen resilience in order to improve rehabilitation outcomes and enhance reintegration of individuals with SCI into their communities.
Current recommendations support early surgical decompression and blood pressure augmentation after traumatic spinal cord injury (SCI). Elevated intraspinal pressure (ISP), however, has probably been ...underestimated in the pathophysiology of SCI. Recent studies provide some evidence that ISP measurements and durotomy may be beneficial for individuals suffering from SCI. Compression of the spinal cord against the meninges in SCI patients causes a "compartment-like" syndrome. In such cases, intentional durotomy with augmentative duroplasty to reduce ISP and improve spinal cord perfusion pressure (SCPP) may be indicated. Prior to performing these procedures routinely, profound knowledge of the spinal meninges is essential. Here, we provide an in-depth review of relevant literature along with neuroanatomical illustrations and imaging correlates.
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