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The effects and potential mechanisms of locomotor training on improvements of functional recovery after spinal cord injury
CHAPTER EIGHT
The effects and potential mechanisms of locomotor training on improvements of functional recovery after spinal cord injury Panpan Yua, Wei Zhanga, Yansheng Liub, Caihong Shengb, Kwok-Fai Soa, Libing Zhoua,*, Hui Zhub,*
a Guangdong-Hongkong-Macau Institute of CNS Regeneration; Ministry of Education Joint International Research Laboratory of CNS Regeneration, Jinan University, Guangzhou, China b Academician Workstation for Spinal Cord Injury, Kunming Tongren Hospital, Kunming, China *Corresponding authors: e-mail address: [email protected]; [email protected]
Contents 1. Introduction 2. Body-weight-supported locomotor training 2.1 Body-weight-supported overground walking training 2.2 Body-weight-supported treadmill training 3. Factors influencing functional outcomes of locomotor training 3.1 Injury severity and phase of injury 3.2 The optimal intensity and duration of training 4. Achieve overground walking after chronic motor complete SCI with epidural stimulation coupled with intensive locomotor training 5. Mechanisms of locomotor training on functional recovery following SCI 5.1 Effects of locomotor training on motoneurons and local circuits in the lumbar spinal cord as well as their musculatures 5.2 Sprouting and reorganization of spared descending pathways and propriospinal projections 5.3 Effect of locomotor training on astroglioss and oligodendrogenesis 5.4 Potential molecular mechanisms of locomotor training on neuroplasticity 6. Conclusions Acknowledgments References
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Abstract Body-weight-supported locomotor training is an activity-based therapy used frequently to train individuals with spinal cord injury (SCI) for restoring walking ability. Locomotor training after SCI is developed on the basic scientific findings of activity-dependent neuroplasticity. Based on the research from animal SCI models, there exists a spinal neural International Review of Neurobiology, Volume 147 ISSN 0074-7742 https://doi.org/10.1016/bs.irn.2019.08.003
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networks for locomotion which can be reactivated by intense repetitive locomotor training. Notably, the effectiveness of locomotor training depends largely on the severity of injury and time after injury. Locomotor training, using body-weight-supported walking overground or on a treadmill, with assistance manually or robotically, with a variety of training intensity and training programs, has been shown to elicit improvements in locomotor function for incomplete SCI individuals. For chronic and motor complete SCI, other interventions with proven effectiveness such as epidural stimulation might be applied in addition to locomotor training to improve the chance of locomotor recovery. In this chapter, we review the factors that influence the functional outcomes of locomotor training. We also summarize the circuitry, cellular and molecular levels of mechanisms underlying the positive role of locomotor training in inducing neuroplasticity and functional recovery following SCI.
1. Introduction Traumatic spinal cord injury (SCI) is one of the most devastating and life-changing events one may experience, often leading to profound and permanent neurological deficits and disability. According to the World Health Organization (WHO), there are estimated 200,000–500,000 new cases of SCI each year worldwide, mostly from vehicle crashes, falls and violence. With the improvement in the quality of care, especially the advances in medical and surgical care at acute and subacute phases, the survival rate and life expectancy for people suffering SCI have significantly increased over the past decades. As a result, the number of people that live with paralysis related to SCI increased relatively. Therefore, recovery of neurological functions to regain as much independence as possible is highly desirable. Animal models of SCI have played important roles in identifying disease pathogenesis, developing and preclinical evaluating potential therapeutic approaches, as well as understanding their mechanisms of action. Most interventions that have currently been used in human studies for treatment of SCI, such as locomotor training, were originally based on findings from basic research using animal models. More than one century ago, scientists found dogs or cats with a complete transection of spinal cord were capable of generating rhythmic alternating patterns of leg movements even without supraspinal inputs. In early 1980s, experiments on thoracic spinal cord transected cats showed that improvement in locomotor function of the hindlimbs was achieved through treadmill training (Forssberg, Grillner, & Halbertsma, 1980; Forssberg, Grillner, Halbertsma, & Rossignol, 1980). It is believed that locomotor circuitries within the spinal cord below the level of injury can be activated by repetitive and intensive locomotor training which
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provides appropriate afferent feedback (Rossignol et al., 2011). This provides important implications on developing effective rehabilitation strategies for people with SCI (Behrman & Harkema, 2000). Since then, the effects and mechanisms of locomotor training on enhancing functional recovery following SCI have been investigated extensively in both animal and human studies (Battistuzzo, Callister, Callister, & Galea, 2012; Harkema et al., 2012) Locomotor training is a non-invasive, activity-based therapy used in humans after SCI to improve strength and restore motor function (Harkema et al., 2012). With retraining participants to stand and walk as its ultimate goal, locomotor training is believed to be able to improve sensory and motor function, increase independence, promote general well-being and quality of life for individuals sustaining a SCI (Behrman et al., 2005; Field-Fote & Roach, 2011; Harkema et al., 2012; Musselman, Fouad, Misiaszek, & Yang, 2009; van der Scheer et al., 2017; Wernig, Muller, Nanassy, & Cagol, 1995). Notably, the functional outcomes of locomotor training is highly dependent on the severity of injury. In general, individuals with motor incomplete SCI often benefit more from locomotor training on recovery of walking ability. For motor complete SCI, other potential interventions such as intra-dural decompression and untethering surgery (Zhu et al., 2008; Zhu et al., 2016) or epidural stimulation (Angeli et al., 2018) might be applied in addition to locomotor training to increase the chance of recovery in standing and walking abilities. Although a much lower chance for individuals with chronic or motor complete SCI to regain walking through locomotor training, an improvement in bowel and bladder function, or sexual function might occur (Hubscher et al., 2018), both of which are regarded as high priority and contribute significantly to the quality of life (Anderson, 2004).
2. Body-weight-supported locomotor training Locomotor training with a body-weight-support system is among the most widely used rehabilitation strategies to retrain standing and walking abilities after SCI (Dietz, 2008; Wessels, Lucas, Eriks, & de Groot, 2010). Unweighting with an overhead suspension system improves trunk control and balance avoiding falls, allows the patients to stand and take forced stepping movements under manual or robotic assistance. It can be applied early after SCI before individuals develop weight bearing. There are various approaches of locomotor training, most frequently used including body-weight-supported overground walking and body-weight-supported treadmill training. During the training, individuals are often suspended by
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a harness to alleviate weight bearing of the lower extremities, leg movements are assisted either manually by therapists or robotically with an orthosis. Electrical stimulation may also be applied to activate paralyzed muscles for inducing stepping movements. Each locomotor training approach (overground or treadmill, manual-assisted or robotic-assisted) has its own advantages and limits. A few studies compared the effectiveness of these different forms of training approaches and concluded that there was insufficient evidence showing one gait training strategy is superior to another (Alexeeva et al., 2011; Colombo, Wirz, & Dietz, 2001; Dobkin et al., 2006; Mehrholz, Harvey, Thomas, & Elsner, 2017).
2.1 Body-weight-supported overground walking training Overground walking training does not require expensive device and can be undertaken simply using a rolling walker to provide partial weight support. It is more closely resemble natural walking condition in daily life compared to walk on a treadmill. It’s likely to achieve patient’s full engagement and encourages voluntary movements. However, it is only suitable for motor incomplete high functioning SCI individuals, although the emerging of the overhead track system and the robotic weight support system allows motor complete SCI individuals to perform overground locomotor training. We have established a set of overground training system and protocols for SCI individuals with different functional levels in our rehabilitation center as shown in Fig. 1. The functional level for each individual is determined based on the standing and locomotion capability evaluated by a Kuming 10-grade locomotion scoring system we developed previously (Zhu et al., 2008). Overground training plan is then designed for each individual accordingly, starting from standing with or without the help of a therapist in fixing the knee, then to walk in a rolling walk with assistance as needed. The duration of each training session is dependent on each individual’s endurance and ability. With the recovery of voluntary movements, the duration of overground training increases gradually.
2.2 Body-weight-supported treadmill training Treadmill based locomotor training, with a harness attached to an overhead lift system to provide partial or full body-weight-support, has emerged as a therapeutic strategy to improve functional ambulation in people with SCI since 1990s. It was brought about by the finding that cats with a complete
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Fig. 1 The Kuming 10-grade locomotion scoring system. Grade I, not able to stand; grade II, able to stand with weight support and help in fixing the knee; grade III, able to stand with weight support; grade IV, able to walk with wheeled weight support and help in fixing the knee of weight bearing leg; grade V, able to walk with wheeled weight support; grade VI, able to walk with the help of a light four-leg support; grade VII, able to walk with a pair of crutches; grade VIII, able to walk with a cane; grade IX, able to walk without support but staggeringly; X, able to walk stably without support. Adapted from Zhu, H., Feng, Y. P., Young, W., You, S. W., Shen, X. F., Liu, Y. S., et al., (2008). Early neurosurgical intervention of spinal cord contusion: An analysis of 30 cases. Chinese Medical Journal, 121(24), 2473–2478.
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spinal cord transection were able to step on a treadmill with weight bearing and adapt their walking movements to increased treadmill speed after several weeks of intensive training on a treadmill (Forssberg, Grillner, & Halbertsma, 1980). Compared to conventional overground walking, treadmill training offers more repetitive stepping practice and is able to reach a higher training intensity over the same period of time. During treadmill training, the amount of body-weight-support and the speed of treadmill are adjustable according to the level of disability. Manual assistance by a team of two or three therapists are often required to facilitate stepping and weight shifting. Therefore, the training session for manual-assisted treadmill is often relatively short. To offer a prolonged training session and to relieve the physical load imposed on the therapists, robotic driven gait orthosis has been developed and evolved rapidly during the past two decades to assist walking movements for longer duration (Nam et al., 2017). As the driving force, weight support level and speed are adjustable, robotic-assistance enables SCI individuals with sever motor function loss to exercise on a treadmill.
3. Factors influencing functional outcomes of locomotor training A large numbers of clinical studies have proved the effectiveness of locomotor training on improvements in functional recovery after SCI. However, the outcomes are largely dependent on the injury severity and the time after injury. In addition, there are also considerable variations in the training protocols regarding the intensity and duration of training, the way and amount of assistance, all of which are important factors affecting the neurological outcomes (Yang & Musselman, 2012).
3.1 Injury severity and phase of injury The American Spinal Injury Association Impairment Scale (AIS) is widely used to classify the severity of injury in SCI individuals, with motor complete (AIS grade A and grade B), motor incomplete (AIS grade C and grade D), or normal (AIS grade E) (Kirshblum et al., 2011). The functional recovery after SCI, to a large extent, is determined by the completeness of injury. In addition, SCI individuals are more likely to obtain some degree of recovery within the first year after injury. It’s well accepted that locomotor training started at early stage after injury can accelerate the locomotion recovery in individuals with motor incomplete SCI (AIS grade C and grade D), and recovery becomes more occasionally after longer periods (Piira et al., 2019). A few studies reported functional improvements after locomotor training in chronic
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incomplete SCI individuals (Alexeeva et al., 2011; Field-Fote & Roach, 2011), both the chance and the degree of recovery are much lower, and it may take a longer time compared with starting exercise training at acute/subacute phases (<6 months after SCI). The probability is scarce for complete SCI to recover standing or walking by locomotor training alone (Dietz, Colombo, & Jensen, 1994; Dietz, Colombo, Jensen, & Baumgartner, 1995).
3.2 The optimal intensity and duration of training Although body-weight-supported locomotor training has been widely used in humans for SCI rehabilitation, the training protocols such as types of training, training time, training speed, walking distance, and the amount of body-weight-support, are varied markedly from center to center. Systematic and conclusive studies are required to test the optimal intensity and duration of training to produce a difference in function. In addition, there is also a lack of standardized ways for quantification of training intensity. One emerging consensus is that a more intensive and long-term training program may lead to better functional outcomes. Brain-derived neurotrophic factor (BDNF) has been known to play important roles in exercise-induced neuroplasticity (Gomez-Pinilla, Ying, Roy, Molteni, & Edgerton, 2002). One study compared the level of BDNF in the serum of motor incomplete SCI individuals after locomotor training with different intensities. Results showed that the serum BDNF level was significantly higher in individuals trained with high-intensity as compared to those with moderate- or lowintensity. One animal study indicated that continued training might be required for maintenance of the recovery (Singh, Balasubramanian, Murray, Lemay, & Houle, 2011). In Kuming, we recommend starting overground walking training as soon as the individuals are medical stable and the time for exercise training is 30 min each session during the initial stage, then the time gradually increases to 3–4 h per day, 5 days a week, and one training period lasts at least 3 months. In some cases, the walking training time is subject to further increase to as much as 6 h with typically 3 h in the morning and 3 h in the afternoon (Zhu et al., 2016).
4. Achieve overground walking after chronic motor complete SCI with epidural stimulation coupled with intensive locomotor training Chronic clinically motor complete SCI individuals hardly recover walking after locomotor training. The majority of motor complete (AIS grade A and grade B) SCI individuals do have some axons sparing.
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However, for some reason, these spared axons failed to be reactivated by locomotor training. Therefore, additional interventions are required to reactivate these silent spared neural circuits. Epidural stimulation is also an activity-based therapy, which has been used for SCI treatment. Restoration of full body weight bearing standing in complete SCI (AIS grade A or B) individuals has recently been achieved when the lumbosacral spinal cord was epidurally stimulated (Harkema et al., 2011; Rejc, Angeli, & Harkema, 2015). More recently, successful regaining of walk ability for two chronic motor complete individuals through epidural stimulation coupled with intensive locomotor training has been reported (Angeli et al., 2018). In this case study, four chronic motor complete participants (2 with AIS grade A and 2 with AIS grade B) began this study treatment 2.5–3.3 years after injury. They first received intense body-weight-supported treadmill locomotor training over a period of 8 or 9 weeks before starting epidural stimulation, but resulted in no changes to locomotor ability. After applying epidural stimulation at the lumbosacral level together with intensive locomotor training, two AIS grade B participants were able to walk overground with assistance. Notably, one achieved overground walking after 278 sessions of epidural stimulation and treadmill training over a period of 85 weeks. Restoration of some degree of independent stepping on a treadmill with body-weight-support but not overground walking was also achieved in the other two motor and sensory complete (AIS grade A) participants (Angeli et al., 2018).
5. Mechanisms of locomotor training on functional recovery following SCI The locomotor training strategy is founded on the principals of motor learning and neural plasticity (Edgerton, Tillakaratne, Bigbee, de Leon, & Roy, 2004; Lynskey, Belanger, & Jung, 2008), which is largely based on scientific findings from animal studies. In the past decades, great efforts have been made on understanding the neural control of movements (Kiehn, 2016). Early work from spinal cord completely transected cats suggests that the re-expression of stepping movements is largely attributed to the activitydependent reorganization of neural sensorimotor circuits for locomotion at the lumbar spinal cord induced by locomotor treadmill training. For incomplete SCI, functional recovery depends on cooperative mechanisms of plasticity within the caudal spinal cord, sprouting of spared descending pathways, and the formation of propriospinal relay (Blesch & Tuszynski, 2009;
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Hansen et al., 2016). A growing body of evidence from animal studies suggests that spinal cord exhibits the potential of motor learning and undergoes activity-dependent plasticity after SCI (Courtine et al., 2009; Martinez, Delivet-Mongrain, Leblond, & Rossignol, 2012), and these plastic changes can be boosted by intense repetitive locomotor training (Smith & Knikou, 2016). Recent studies have also made significant advances toward uncovering the circuitry, cellular and molecular levels of mechanisms underlying the positive role of locomotor training in functional recovery following SCI.
5.1 Effects of locomotor training on motoneurons and local circuits in the lumbar spinal cord as well as their musculatures Extensive studies on spinal cord completely transected cats and dogs suggest the spinal capacity of locomotion even in the absence of descending supraspinal inputs (Forssberg, Grillner, & Halbertsma, 1980; Lovely, Gregor, Roy, & Edgerton, 1986). Body-weight-supported treadmill training is able to recover the stepping movements in spinal cord transected animals by activating and remodeling the lumbar spinal cord circuit referred to as central pattern generator (CPG) for generating the alternating hindlimb locomotor pattern (de Leon, Hodgson, Roy, & Edgerton, 1998; Gossard et al., 2015; Guertin, 2009). The upper lumbar spinal cord is an integration center which initiates and promotes walking. In normal condition, neural circuits within the lumbar spinal cord integrate information from descending cortical, subcortical inputs as well as the segmental afferents to coordinate the firing of motoneuron pools. Motoneurons located in the ventral horn of the lumbar spinal cord directly project axons to the skeleton muscles controlling leg movements. When an injury to the spinal cord occurs above the lumbar level, although survived and anatomically intact, the motoneurons within the lumbar segment reduce excitability and undergo dendritic atrophy attributing to denervation from supraspinal descending inputs. Profound muscle atrophy in the legs occurs rapidly after SCI due to loss of neuromuscular activity and muscle disuse. Locomotor training, through repetitively providing appropriate proprioceptive feedback, has been shown to play an effective role in triggering and shaping adaptive remodeling of the spinal sensorimotor circuits caudal to the lesion (Cote & Gossard, 2004; Harkema et al., 1997). Locomotor training can increase motoneuron excitability and decrease muscle atrophy after SCI by maintaining or inducing reorganization of synaptic inputs on the spinal motoneurons and preventing their dendritic atrophy. After a low thoracic hemisection in mice, treadmill training significantly improved the
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locomotor function of hindlinmbs and attenuated muscle atrophy, correlating with maintenance of synaptic markers synaptophysin and PSD95 on motoneurons (Goldshmit, Lythgo, Galea, & Turnley, 2008). After a complete thoracic spinal cord transection in rats, repetitive limb exercise on a motorized device significantly prevented dendritic atrophy of the motor neurons below the injury (Gazula, Roberts, Luzzio, Jawad, & Kalb, 2004). Extensive and long-term treadmill training also promoted dendritic plasticity, increased synaptic density in the lumbar motorneurons, and therefore promoted functional recovery in a rat moderate contusive SCI model (Wang et al., 2015). Interneurons in the spinal cord play a critical role in conveying motor commands from descending pathways to motoneuron pools. Their synaptic derive and strength also undergo plastic changes after exercise training (Harkema, 2008). In addition to changes in the motoneurons and interneurons in the lumbar spinal cord caudal to the injury, the proprioceptive feedback pathways and transmission in reflex pathways also undergo plastic changes by intense repetitive stepping training (Cote & Gossard, 2004).
5.2 Sprouting and reorganization of spared descending pathways and propriospinal projections Traumatic injury to the spinal cord leads to the interruption of descending supraspinal pathways including corticospinal projections and brainstem pathways. Majority of the human SCI cases are anatomically incomplete even for those clinically classified as motor complete individuals with the AIS grade A and grade B. Therefore, reactivation of these spared pathways has been a promising strategy to promote functional recovery after SCI. Spontaneous sprouting of corticospinal axons, reticulospinal axons or rubrospinal axons has been identified after incomplete SCI in rodents or primates (Perrin & Noristani, 2019; Rosenzweig et al., 2010; Siegel, Fink, Strittmatter, & Cafferty, 2015). Propriospinal networks which are intrinsic spinal cord pathways and project intersegmentally to terminate at other spinal levels, also undergo spontaneous sprouting and remodeling after SCI (Filli et al., 2014). Compensatory sprouting of these spared supraspinal and propriospinal projections, and the formation of detour pathways that reroute supraspinal inputs with interneuron and/or motoneuron pools located below the lesion via propriospinal connections are thought to contribute to spontaneous recovery after SCI (Courtine et al., 2008; Filli et al., 2014). Augmentation of these mechanisms by rehabilitation training may lead to improvements in functional recovery.
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Although unable to induce long-distance axonal regeneration across the lesion after SCI, exercise training promoted sprouting of spared descending axons and subsequent synaptic integration into spinal neural networks. An increase in corticospinal tract function by intensive treadmill training in human subjects after incomplete SCI has been reported (Thomas & Gorassini, 2005). The increase in connectivity of the corticospinal tract as assessed by the motor-evoked potentials (MEPs) recording in response to incrementing levels of transcranial magnetic stimulation over the leg area of the primary motor cortex, was positively correlated to the improvement in locomotor function and the increased peak locomotor EMG activity. Treadmill exercised mice showed increased axonal regrowth and collateral sprouting proximal to the lesion site following a low thoracic hemisection, with maintenance of synaptic markers on motoneurons in the ventral horn and decreased muscle atrophy (Goldshmit et al., 2008). Following a moderate T9 contusive SCI in mice, wheel running stimulated sprouting of serotonin fibers in the vicinity of the lesion, which may be correlated to the exercise-induced locomotor improvements (Engesser-Cesar et al., 2007). In mice with genetic absence of the corticospinal tract within the spinal cord, we found wheel running significantly induced collateral sprouting of descending monoaminergic and rubrospinal axons and promoted their synaptic formation with motorneurons (Zhang et al., 2019). The plastic changes in spinal neural networks after exercise correlated with improvement in fine motor skills. One group investigated the effects of exercise training after a lateral spinal hemisection on the synaptic properties of interneurons in the lesion vicinity (Flynn et al., 2013). A marked increase in evoked excitatory synaptic currents responding to dorsal column stimulation was recorded in treadmill trained animals, which indicated an increase in the efficacy of synaptic connections from descending pathways to propriospinal interneurons located in the vicinity of the spinal cord lesion site (Flynn et al., 2013; Rank et al., 2015). Formation of these detour pathways through intersegmental projecting propriospinal neurons that relay descending inputs from brain to its target in the spinal cord caudal to the lesion, is one important mechanism to achieve functional recovery after SCI. The role of spared descending pathways in locomotor recovery after bodyweight-supported treadmill training through inducing neuroplasticity in lumbar spinal cord was also reported in cat and rat models of incomplete SCI (Singh et al., 2011).
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5.3 Effect of locomotor training on astroglioss and oligodendrogenesis Injury to the spinal cord results in axonal demyelination and activation of astrocytes around the injury site (Gaudet & Fonken, 2018). Loss of myelin in the intact axonal tracts contributes significantly to functional impairments. While reactive gliosis followed by the formation of a glial scar limits neuroplasticity by presenting a barrier to regrowing axons. Voluntary wheel running exercise was shown to promote oligodendrogenesis in intact spinal cord (Krityakiarana et al., 2010). After thoracic dorsal spinal cord hemisection in mice, voluntary wheel running exercise also reduced astrogliosis and myelin loss, supporting the rewiring of supraspinal circuits and functional recovery (Loy et al., 2018). Using the corticospinal tract deficient mice, we recently found wheel running exercise also significantly promoted oligodendrogenesis and increased the expression of myelin basic protein (Zhang et al., 2019), which implies that enhancing remyelination may be one of the mechanisms for exercise contributing to the functional improvements after SCI.
5.4 Potential molecular mechanisms of locomotor training on neuroplasticity The reported molecular mechanisms of locomotor training leading to spinal plasticity after injury include increasing the expression of various neurotrophins such as BDNF, reducing inflammation, and modulating microRNAs that regulate intrinsic axonal growth pathways. Neurotrophic factors play important roles in inducing neuroplasticity. After a spinal cord hemisection, voluntary wheel running exercise significantly increased the mRNA expression of BDNF, NT-3, and the downstream effectors of BDNF on synaptic plasticity synapsin I and CREB (Ying et al., 2008; Ying, Roy, Edgerton, & Gomez-Pinilla, 2005). Treadmill training also increased BDNF expression in the lumbar motor neurons after spinal cord contusion in rats (Wang et al., 2015). A significant increase in serum BDNF in individuals with motor incomplete SCI after locomotor training was detected recently which are related to the exercise intensity (Leech & Hornby, 2017). A large proportion of SCI individuals develop neuropathic pain, at least partly due to aberrant sprouting of nociceptive fibers in the dorsal horn after SCI. Early wheel walking exercise after SCI reduces the development of neuropathic pain by preventing aberrant sprouting of nociceptive fibers
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in the dorsal horn and decreasing the number of macrophages present in the dorsal root ganglions (DRG) (Chhaya, Quiros-Molina, Tamashiro-Orrego, Houle, & Detloff, 2019; Detloff, Smith, Quiros Molina, Ganzer, & Houle, 2014). Treadmill training can also decrease the density of calcitonin generelated peptide (CGRP) positive fibers and partially resolve signs of pain (Nees et al., 2016). Systemic inflammation was also reduced by exercise in humans with chronic SCI, as evident by significant decrease in the plasma levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and plasma C-reactive protein (CRP) after exercise training (NeefkesZonneveld, Bakkum, Bishop, van Tulder, & Janssen, 2015; RosetyRodriguez et al., 2014). Another potential molecular mechanism for exercise exerting beneficial effect on functional improvements after SCI, is acting through modulation of microRNAs and their targets that contribute to the functional regulation of apoptosis or axonal regeneration/sprouting. Cycling exercise was found to affect the expression of microRNAs associated with apoptosis, and the ones targeting PTEN/mTOR pathway. The changes in the microRNAs expression after exercise correlated with changes in expression of their target genes: increase in anti-apoptotic Bcl-2 mRNA, decrease in the expression of PTEN and increase in the expression of mTOR (Liu, Detloff, Miller, Santi, & Houle, 2012; Liu, Keeler, Zhukareva, & Houle, 2010).
6. Conclusions Locomotor training, with various forms and different protocols, can accelerate and enhance recovery of walking mostly in people with incomplete SCI. The reported degrees of improvement are highly variable from study to study, most likely attributing to the considerable diversity in the training methods used among centers. Therefore, the optimal training methods to maximize locomotor recovery remain to be determined. Further studies are also required to establish standardized quantitative training protocols as well as sensitive outcome measures for evaluating recovery quantitatively. Although often not being able to regain walking, individuals with chronic and severe SCI may still benefit from locomotor training on improving cardiovascular function, respiratory function, or bladder and bowel function. Through increasing the intensity and sessions of training, and combining with other activity-based therapeutic approaches, significant differences may be achieved. After incomplete SCI, spontaneous local axonal collateral/regenerative sprouting and subsequent reorganization of
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neural circuits contribute to spontaneous functional recovery. Locomotor training, to some extent promotes the sprouting from spared axons, and more importantly plays a critical role in shaping and strengthening the reorganized functional neural networks for locomotion. As adult mammalian neurons in the central nervous system have overall very poor capacity to regenerate their axons after injury, the enhanced local axonal regrowth/ sprouting after locomotor training remains limited, and long-distance axonal regrowth is not likely to be achieved by locomotor training alone. Therefore, for severe SCI cases in which majority of the descending axons are interrupted, the amount of sprouting induced by locomotor training may be far too inadequate to reorganize an alternative neural networks for re-establishing walking. Additional treatments such as pharmacological interventions, transplantation, and other spinal cord stimulation strategies, coupled with an intensive and long-term locomotor training program may evoke a synergistic improvement in locomotor recovery for sever SCI individuals.
Acknowledgments This work was supported by the Hong Kong Spinal Cord Injury Fund and the Groungdong grant “Key technologies for treatment of brain disorders” (No. 2018B030332001).
References Alexeeva, N., Sames, C., Jacobs, P. L., Hobday, L., Distasio, M. M., Mitchell, S. A., et al. (2011). Comparison of training methods to improve walking in persons with chronic spinal cord injury: A randomized clinical trial. The Journal of Spinal Cord Medicine, 34(4), 362–379. https://doi.org/10.1179/2045772311Y.0000000018. Anderson, K. D. (2004). Targeting recovery: Priorities of the spinal cord-injured population. Journal of Neurotrauma, 21(10), 1371–1383. https://doi.org/10.1089/neu.2004.21.1371. Angeli, C. A., Boakye, M., Morton, R. A., Vogt, J., Benton, K., Chen, Y., et al. (2018). Recovery of over-ground walking after chronic motor complete spinal cord injury. The New England Journal of Medicine, 379(13), 1244–1250. https://doi.org/10.1056/ NEJMoa1803588. Battistuzzo, C. R., Callister, R. J., Callister, R., & Galea, M. P. (2012). A systematic review of exercise training to promote locomotor recovery in animal models of spinal cord injury. Journal of Neurotrauma, 29(8), 1600–1613. https://doi.org/10.1089/ neu.2011.2199. Behrman, A. L., & Harkema, S. J. (2000). Locomotor training after human spinal cord injury: A series of case studies. Physical Therapy, 80(7), 688–700. Behrman, A. L., Lawless-Dixon, A. R., Davis, S. B., Bowden, M. G., Nair, P., Phadke, C., et al. (2005). Locomotor training progression and outcomes after incomplete spinal cord injury. Physical Therapy, 85(12), 1356–1371. Blesch, A., & Tuszynski, M. H. (2009). Spinal cord injury: Plasticity, regeneration and the challenge of translational drug development. Trends in Neurosciences, 32(1), 41–47. https://doi.org/10.1016/j.tins.2008.09.008.
Locomotor training on spinal cord injury
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Chhaya, S. J., Quiros-Molina, D., Tamashiro-Orrego, A. D., Houle, J. D., & Detloff, M. R. (2019). Exercise-induced changes to the macrophage response in the dorsal root ganglia prevent neuropathic pain after spinal cord injury. Journal of Neurotrauma, 36(6), 877–890. https://doi.org/10.1089/neu.2018.5819. Colombo, G., Wirz, M., & Dietz, V. (2001). Driven gait orthosis for improvement of locomotor training in paraplegic patients. Spinal Cord, 39(5), 252–255. https://doi. org/10.1038/sj.sc.3101154. Cote, M. P., & Gossard, J. P. (2004). Step training-dependent plasticity in spinal cutaneous pathways. The Journal of Neuroscience, 24(50), 11317–11327. https://doi.org/10.1523/ JNEUROSCI.1486-04.2004. Courtine, G., Gerasimenko, Y., van den Brand, R., Yew, A., Musienko, P., Zhong, H., et al. (2009). Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nature Neuroscience, 12(10), 1333–1342. https://doi.org/10.1038/ nn.2401. Courtine, G., Song, B., Roy, R. R., Zhong, H., Herrmann, J. E., Ao, Y., et al. (2008). Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nature Medicine, 14(1), 69–74. https://doi.org/10.1038/nm1682. de Leon, R. D., Hodgson, J. A., Roy, R. R., & Edgerton, V. R. (1998). Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. Journal of Neurophysiology, 79(3), 1329–1340. https://doi.org/10.1152/ jn.1998.79.3.1329. Detloff, M. R., Smith, E. J., Quiros Molina, D., Ganzer, P. D., & Houle, J. D. (2014). Acute exercise prevents the development of neuropathic pain and the sprouting of nonpeptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Experimental Neurology, 255, 38–48. https://doi.org/10.1016/j.expneurol.2014.02.013. Dietz, V. (2008). Body weight supported gait training: From laboratory to clinical setting. Brain Research Bulletin, 76(5), 459–463. https://doi.org/10.1016/j.brainresbull. 2008.02.034. Dietz, V., Colombo, G., & Jensen, L. (1994). Locomotor activity in spinal man. Lancet, 344(8932), 1260–1263. https://doi.org/10.1016/s0140-6736(94)90751-x. Dietz, V., Colombo, G., Jensen, L., & Baumgartner, L. (1995). Locomotor capacity of spinal cord in paraplegic patients. Annals of Neurology, 37(5), 574–582. https://doi.org/ 10.1002/ana.410370506. Dobkin, B., Apple, D., Barbeau, H., Basso, M., Behrman, A., Deforge, D., et al. (2006). Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI. Neurology, 66(4), 484–493. https://doi.org/10.1212/01.wnl. 0000202600.72018.39. Edgerton, V. R., Tillakaratne, N. J., Bigbee, A. J., de Leon, R. D., & Roy, R. R. (2004). Plasticity of the spinal neural circuitry after injury. Annual Review of Neuroscience, 27, 145–167. https://doi.org/10.1146/annurev.neuro.27.070203.144308. Engesser-Cesar, C., Ichiyama, R. M., Nefas, A. L., Hill, M. A., Edgerton, V. R., Cotman, C. W., et al. (2007). Wheel running following spinal cord injury improves locomotor recovery and stimulates serotonergic fiber growth. The European Journal of Neuroscience, 25(7), 1931–1939. https://doi.org/10.1111/j.1460-9568.2007.05469.x. Field-Fote, E. C., & Roach, K. E. (2011). Influence of a locomotor training approach on walking speed and distance in people with chronic spinal cord injury: A randomized clinical trial. Physical Therapy, 91(1), 48–60. https://doi.org/10.2522/ptj.20090359. Filli, L., Engmann, A. K., Zorner, B., Weinmann, O., Moraitis, T., Gullo, M., et al. (2014). Bridging the gap: A reticulo-propriospinal detour bypassing an incomplete spinal cord injury. The Journal of Neuroscience, 34(40), 13399–13410. https://doi.org/10.1523/ JNEUROSCI.0701-14.2014.
214
Panpan Yu et al.
Flynn, J. R., Dunn, L. R., Galea, M. P., Callister, R., Callister, R. J., & Rank, M. M. (2013). Exercise training after spinal cord injury selectively alters synaptic properties in neurons in adult mouse spinal cord. Journal of Neurotrauma, 30(10), 891–896. https://doi.org/ 10.1089/neu.2012.2714. Forssberg, H., Grillner, S., & Halbertsma, J. (1980). The locomotion of the low spinal cat. I. Coordination within a hindlimb. Acta physiologica Scandinavica, 108(3), 269–281. https:// doi.org/10.1111/j.1748-1716.1980.tb06533.x. Forssberg, H., Grillner, S., Halbertsma, J., & Rossignol, S. (1980). The locomotion of the low spinal cat. II. Interlimb coordination. Acta physiologica Scandinavica, 108(3), 283–295. https://doi.org/10.1111/j.1748-1716.1980.tb06534.x. Gaudet, A. D., & Fonken, L. K. (2018). Glial cells shape pathology and repair after spinal cord injury. Neurotherapeutics, 15(3), 554–577. https://doi.org/10.1007/s13311-018-0630-7. Gazula, V. R., Roberts, M., Luzzio, C., Jawad, A. F., & Kalb, R. G. (2004). Effects of limb exercise after spinal cord injury on motor neuron dendrite structure. The Journal of Comparative Neurology, 476(2), 130–145. https://doi.org/10.1002/cne.20204. Goldshmit, Y., Lythgo, N., Galea, M. P., & Turnley, A. M. (2008). Treadmill training after spinal cord hemisection in mice promotes axonal sprouting and synapse formation and improves motor recovery. Journal of Neurotrauma, 25(5), 449–465. https://doi.org/ 10.1089/neu.2007.0392. Gomez-Pinilla, F., Ying, Z., Roy, R. R., Molteni, R., & Edgerton, V. R. (2002). Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. Journal of Neurophysiology, 88(5), 2187–2195. https://doi.org/10.1152/jn.00152.2002. Gossard, J. P., Delivet-Mongrain, H., Martinez, M., Kundu, A., Escalona, M., & Rossignol, S. (2015). Plastic changes in lumbar locomotor networks after a partial spinal cord injury in cats. The Journal of Neuroscience, 35(25), 9446–9455. https://doi.org/ 10.1523/JNEUROSCI.4502-14.2015. Guertin, P. A. (2009). The mammalian central pattern generator for locomotion. Brain Research Reviews, 62(1), 45–56. https://doi.org/10.1016/j.brainresrev.2009.08.002. Hansen, C. N., Faw, T. D., White, S., Buford, J. A., Grau, J. W., & Basso, D. M. (2016). Sparing of descending axons rescues interneuron plasticity in the lumbar cord to allow adaptive learning after thoracic spinal cord injury. Frontiers in Neural Circuits, 10, 11. https://doi.org/10.3389/fncir.2016.00011. Harkema, S. J. (2008). Plasticity of interneuronal networks of the functionally isolated human spinal cord. Brain Research Reviews, 57(1), 255–264. https://doi.org/10.1016/j. brainresrev.2007.07.012. Harkema, S., Gerasimenko, Y., Hodes, J., Burdick, J., Angeli, C., Chen, Y., et al. (2011). Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: A case study. Lancet, 377(9781), 1938–1947. https://doi.org/10.1016/S0140-6736(11)60547-3. Harkema, S. J., Hillyer, J., Schmidt-Read, M., Ardolino, E., Sisto, S. A., & Behrman, A. L. (2012). Locomotor training: As a treatment of spinal cord injury and in the progression of neurologic rehabilitation. Archives of Physical Medicine and Rehabilitation, 93(9), 1588–1597. https://doi.org/10.1016/j.apmr.2012.04.032. Harkema, S. J., Hurley, S. L., Patel, U. K., Requejo, P. S., Dobkin, B. H., & Edgerton, V. R. (1997). Human lumbosacral spinal cord interprets loading during stepping. Journal of Neurophysiology, 77(2), 797–811. https://doi.org/10.1152/jn.1997.77.2.797. Hubscher, C. H., Herrity, A. N., Williams, C. S., Montgomery, L. R., Willhite, A. M., Angeli, C. A., et al. (2018). Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury. PLoS One, 13(1). e0190998https://doi.org/10.1371/journal.pone.0190998. Kiehn, O. (2016). Decoding the organization of spinal circuits that control locomotion. Nature Reviews. Neuroscience, 17(4), 224–238. https://doi.org/10.1038/nrn.2016.9.
Locomotor training on spinal cord injury
215
Kirshblum, S. C., Burns, S. P., Biering-Sorensen, F., Donovan, W., Graves, D. E., Jha, A., et al. (2011). International standards for neurological classification of spinal cord injury (revised 2011). The Journal of Spinal Cord Medicine, 34(6), 535–546. https://doi.org/ 10.1179/204577211X13207446293695. Krityakiarana, W., Espinosa-Jeffrey, A., Ghiani, C. A., Zhao, P. M., Topaldjikian, N., Gomez-Pinilla, F., et al. (2010). Voluntary exercise increases oligodendrogenesis in spinal cord. The International Journal of Neuroscience, 120(4), 280–290. https://doi.org/ 10.3109/00207450903222741. Leech, K. A., & Hornby, T. G. (2017). High-intensity locomotor exercise increases brainderived neurotrophic factor in individuals with incomplete spinal cord injury. Journal of Neurotrauma, 34(6), 1240–1248. https://doi.org/10.1089/neu.2016.4532. Liu, G., Detloff, M. R., Miller, K. N., Santi, L., & Houle, J. D. (2012). Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Experimental Neurology, 233(1), 447–456. https://doi.org/10.1016/j.expneurol.2011.11.018. Liu, G., Keeler, B. E., Zhukareva, V., & Houle, J. D. (2010). Cycling exercise affects the expression of apoptosis-associated microRNAs after spinal cord injury in rats. Experimental Neurology, 226(1), 200–206. https://doi.org/10.1016/j.expneurol.2010.08.032. Lovely, R. G., Gregor, R. J., Roy, R. R., & Edgerton, V. R. (1986). Effects of training on the recovery of full-weight-bearing stepping in the adult spinal cat. Experimental Neurology, 92(2), 421–435. Loy, K., Schmalz, A., Hoche, T., Jacobi, A., Kreutzfeldt, M., Merkler, D., et al. (2018). Enhanced voluntary exercise improves functional recovery following spinal cord injury by impacting the local neuroglial injury response and supporting the rewiring of supraspinal circuits. Journal of Neurotrauma, 35(24), 2904–2915. https://doi.org/ 10.1089/neu.2017.5544. Lynskey, J. V., Belanger, A., & Jung, R. (2008). Activity-dependent plasticity in spinal cord injury. Journal of Rehabilitation Research and Development, 45(2), 229–240. Martinez, M., Delivet-Mongrain, H., Leblond, H., & Rossignol, S. (2012). Incomplete spinal cord injury promotes durable functional changes within the spinal locomotor circuitry. Journal of Neurophysiology, 108(1), 124–134. https://doi.org/10.1152/ jn.00073.2012. Mehrholz, J., Harvey, L. A., Thomas, S., & Elsner, B. (2017). Is body-weight-supported treadmill training or robotic-assisted gait training superior to overground gait training and other forms of physiotherapy in people with spinal cord injury? A systematic review. Spinal Cord, 55(8), 722–729. https://doi.org/10.1038/sc.2017.31. Musselman, K. E., Fouad, K., Misiaszek, J. E., & Yang, J. F. (2009). Training of walking skills overground and on the treadmill: Case series on individuals with incomplete spinal cord injury. Physical Therapy, 89(6), 601–611. https://doi.org/10.2522/ptj.20080257. Nam, K. Y., Kim, H. J., Kwon, B. S., Park, J. W., Lee, H. J., & Yoo, A. (2017). Robotassisted gait training (Lokomat) improves walking function and activity in people with spinal cord injury: A systematic review. Journal of Neuroengineering and Rehabilitation, 14(1), 24. https://doi.org/10.1186/s12984-017-0232-3. Neefkes-Zonneveld, C. R., Bakkum, A. J., Bishop, N. C., van Tulder, M. W., & Janssen, T. W. (2015). Effect of long-term physical activity and acute exercise on markers of systemic inflammation in persons with chronic spinal cord injury: A systematic review. Archives of Physical Medicine and Rehabilitation, 96(1), 30–42. https://doi.org/10.1016/ j.apmr.2014.07.006. Nees, T. A., Tappe-Theodor, A., Sliwinski, C., Motsch, M., Rupp, R., Kuner, R., et al. (2016). Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury. Pain, 157(3), 687–697. https://doi.org/10.1097/j.pain. 0000000000000422.
216
Panpan Yu et al.
Perrin, F. E., & Noristani, H. N. (2019). Serotonergic mechanisms in spinal cord injury. Experimental Neurology, 318, 174–191. https://doi.org/10.1016/j.expneurol. 2019.05.007. Piira, A., Lannem, A. M., Sorensen, M., Glott, T., Knutsen, R., Jorgensen, L., et al. (2019). Manually assisted body-weight supported locomotor training does not re-establish walking in non-walking subjects with chronic incomplete spinal cord injury: A randomized clinical trial. Journal of Rehabilitation Medicine, 51(2), 113–119. https://doi.org/ 10.2340/16501977-2508. Rank, M. M., Flynn, J. R., Battistuzzo, C. R., Galea, M. P., Callister, R., & Callister, R. J. (2015). Functional changes in deep dorsal horn interneurons following spinal cord injury are enhanced with different durations of exercise training. The Journal of Physiology, 593(1), 331–345. https://doi.org/10.1113/jphysiol.2014.282640. Rejc, E., Angeli, C., & Harkema, S. (2015). Effects of lumbosacral spinal cord epidural stimulation for standing after chronic complete paralysis in humans. PLoS One, 10(7). e0133998https://doi.org/10.1371/journal.pone.0133998. Rosenzweig, E. S., Courtine, G., Jindrich, D. L., Brock, J. H., Ferguson, A. R., Strand, S. C., et al. (2010). Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nature Neuroscience, 13(12), 1505–1510. https://doi.org/ 10.1038/nn.2691. Rosety-Rodriguez, M., Camacho, A., Rosety, I., Fornieles, G., Rosety, M. A., Diaz, A. J., et al. (2014). Low-grade systemic inflammation and leptin levels were improved by arm cranking exercise in adults with chronic spinal cord injury. Archives of Physical Medicine and Rehabilitation, 95(2), 297–302. https://doi.org/10.1016/j.apmr.2013.08.246. Rossignol, S., Frigon, A., Barriere, G., Martinez, M., Barthelemy, D., Bouyer, L., et al. (2011). Chapter 16--spinal plasticity in the recovery of locomotion. Progress in Brain Research, 188, 229–241. https://doi.org/10.1016/B978-0-444-53825-3.00021-8. Siegel, C. S., Fink, K. L., Strittmatter, S. M., & Cafferty, W. B. (2015). Plasticity of intact rubral projections mediates spontaneous recovery of function after corticospinal tract injury. The Journal of Neuroscience, 35(4), 1443–1457. https://doi.org/10.1523/ JNEUROSCI.3713-14.2015. Singh, A., Balasubramanian, S., Murray, M., Lemay, M., & Houle, J. (2011). Role of spared pathways in locomotor recovery after body-weight-supported treadmill training in contused rats. Journal of Neurotrauma, 28(12), 2405–2416. https://doi.org/10.1089/ neu.2010.1660. Smith, A. C., & Knikou, M. (2016). A review on locomotor training after spinal cord injury: Reorganization of spinal neuronal circuits and recovery of motor function. Neural Plasticity, 2016, 1216258. https://doi.org/10.1155/2016/1216258. Thomas, S. L., & Gorassini, M. A. (2005). Increases in corticospinal tract function by treadmill training after incomplete spinal cord injury. Journal of Neurophysiology, 94(4), 2844–2855. https://doi.org/10.1152/jn.00532.2005. van der Scheer, J. W., Martin Ginis, K. A., Ditor, D. S., Goosey-Tolfrey, V. L., Hicks, A. L., West, C. R., et al. (2017). Effects of exercise on fitness and health of adults with spinal cord injury: A systematic review. Neurology, 89(7), 736–745. https://doi.org/10.1212/ WNL.0000000000004224. Wang, H., Liu, N. K., Zhang, Y. P., Deng, L., Lu, Q. B., Shields, C. B., et al. (2015). Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury. Experimental Neurology, 271, 368–378. https://doi.org/10.1016/j.expneurol.2015.07.004. Wernig, A., Muller, S., Nanassy, A., & Cagol, E. (1995). Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons. The European Journal of Neuroscience, 7(4), 823–829.
Locomotor training on spinal cord injury
217
Wessels, M., Lucas, C., Eriks, I., & de Groot, S. (2010). Body weight-supported gait training for restoration of walking in people with an incomplete spinal cord injury: A systematic review. Journal of Rehabilitation Medicine, 42(6), 513–519. https://doi.org/ 10.2340/16501977-0525. Yang, J. F., & Musselman, K. E. (2012). Training to achieve over ground walking after spinal cord injury: A review of who, what, when, and how. The Journal of Spinal Cord Medicine, 35(5), 293–304. https://doi.org/10.1179/2045772312Y.0000000036. Ying, Z., Roy, R. R., Edgerton, V. R., & Gomez-Pinilla, F. (2005). Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Experimental Neurology, 193(2), 411–419. https://doi.org/10.1016/j.expneurol.2005.01.015. Ying, Z., Roy, R. R., Zhong, H., Zdunowski, S., Edgerton, V. R., & Gomez-Pinilla, F. (2008). BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience, 155(4), 1070–1078. https://doi.org/10.1016/ j.neuroscience.2008.06.057. Zhang, W., Yang, B., Weng, H., Liu, T., Shi, L., Yu, P., et al. (2019). Wheel running improves motor function and spinal cord plasticity in mice with genetic absence of the corticospinal tract. Frontiers in Cellular Neuroscience, 13, 106. https://doi.org/ 10.3389/fncel.2019.00106. Zhu, H., Feng, Y. P., Young, W., You, S. W., Shen, X. F., Liu, Y. S., et al. (2008). Early neurosurgical intervention of spinal cord contusion: An analysis of 30 cases. Chinese Medical Journal, 121(24), 2473–2478. Zhu, H., Poon, W., Liu, Y., Leung, G. K., Wong, Y., Feng, Y., et al. (2016). Phase I-II clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury. Cell Transplantation, 25(11), 1925–1943. https://doi.org/10.3727/096368916X691411.
The effects and potential mechanisms of locomotor training on improvements of functional recovery after spinal cord injury Panpan Yua, Wei Zhanga, Yansheng Liub, Caihong Shengb, Kwok-Fai Soa, Libing Zhoua,*, Hui Zhub,*
a Guangdong-Hongkong-Macau Institute of CNS Regeneration; Ministry of Education Joint International Research Laboratory of CNS Regeneration, Jinan University, Guangzhou, China b Academician Workstation for Spinal Cord Injury, Kunming Tongren Hospital, Kunming, China *Corresponding authors: e-mail address: [email protected]; [email protected]
Contents 1. Introduction 2. Body-weight-supported locomotor training 2.1 Body-weight-supported overground walking training 2.2 Body-weight-supported treadmill training 3. Factors influencing functional outcomes of locomotor training 3.1 Injury severity and phase of injury 3.2 The optimal intensity and duration of training 4. Achieve overground walking after chronic motor complete SCI with epidural stimulation coupled with intensive locomotor training 5. Mechanisms of locomotor training on functional recovery following SCI 5.1 Effects of locomotor training on motoneurons and local circuits in the lumbar spinal cord as well as their musculatures 5.2 Sprouting and reorganization of spared descending pathways and propriospinal projections 5.3 Effect of locomotor training on astroglioss and oligodendrogenesis 5.4 Potential molecular mechanisms of locomotor training on neuroplasticity 6. Conclusions Acknowledgments References
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Abstract Body-weight-supported locomotor training is an activity-based therapy used frequently to train individuals with spinal cord injury (SCI) for restoring walking ability. Locomotor training after SCI is developed on the basic scientific findings of activity-dependent neuroplasticity. Based on the research from animal SCI models, there exists a spinal neural International Review of Neurobiology, Volume 147 ISSN 0074-7742 https://doi.org/10.1016/bs.irn.2019.08.003
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networks for locomotion which can be reactivated by intense repetitive locomotor training. Notably, the effectiveness of locomotor training depends largely on the severity of injury and time after injury. Locomotor training, using body-weight-supported walking overground or on a treadmill, with assistance manually or robotically, with a variety of training intensity and training programs, has been shown to elicit improvements in locomotor function for incomplete SCI individuals. For chronic and motor complete SCI, other interventions with proven effectiveness such as epidural stimulation might be applied in addition to locomotor training to improve the chance of locomotor recovery. In this chapter, we review the factors that influence the functional outcomes of locomotor training. We also summarize the circuitry, cellular and molecular levels of mechanisms underlying the positive role of locomotor training in inducing neuroplasticity and functional recovery following SCI.
1. Introduction Traumatic spinal cord injury (SCI) is one of the most devastating and life-changing events one may experience, often leading to profound and permanent neurological deficits and disability. According to the World Health Organization (WHO), there are estimated 200,000–500,000 new cases of SCI each year worldwide, mostly from vehicle crashes, falls and violence. With the improvement in the quality of care, especially the advances in medical and surgical care at acute and subacute phases, the survival rate and life expectancy for people suffering SCI have significantly increased over the past decades. As a result, the number of people that live with paralysis related to SCI increased relatively. Therefore, recovery of neurological functions to regain as much independence as possible is highly desirable. Animal models of SCI have played important roles in identifying disease pathogenesis, developing and preclinical evaluating potential therapeutic approaches, as well as understanding their mechanisms of action. Most interventions that have currently been used in human studies for treatment of SCI, such as locomotor training, were originally based on findings from basic research using animal models. More than one century ago, scientists found dogs or cats with a complete transection of spinal cord were capable of generating rhythmic alternating patterns of leg movements even without supraspinal inputs. In early 1980s, experiments on thoracic spinal cord transected cats showed that improvement in locomotor function of the hindlimbs was achieved through treadmill training (Forssberg, Grillner, & Halbertsma, 1980; Forssberg, Grillner, Halbertsma, & Rossignol, 1980). It is believed that locomotor circuitries within the spinal cord below the level of injury can be activated by repetitive and intensive locomotor training which
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provides appropriate afferent feedback (Rossignol et al., 2011). This provides important implications on developing effective rehabilitation strategies for people with SCI (Behrman & Harkema, 2000). Since then, the effects and mechanisms of locomotor training on enhancing functional recovery following SCI have been investigated extensively in both animal and human studies (Battistuzzo, Callister, Callister, & Galea, 2012; Harkema et al., 2012) Locomotor training is a non-invasive, activity-based therapy used in humans after SCI to improve strength and restore motor function (Harkema et al., 2012). With retraining participants to stand and walk as its ultimate goal, locomotor training is believed to be able to improve sensory and motor function, increase independence, promote general well-being and quality of life for individuals sustaining a SCI (Behrman et al., 2005; Field-Fote & Roach, 2011; Harkema et al., 2012; Musselman, Fouad, Misiaszek, & Yang, 2009; van der Scheer et al., 2017; Wernig, Muller, Nanassy, & Cagol, 1995). Notably, the functional outcomes of locomotor training is highly dependent on the severity of injury. In general, individuals with motor incomplete SCI often benefit more from locomotor training on recovery of walking ability. For motor complete SCI, other potential interventions such as intra-dural decompression and untethering surgery (Zhu et al., 2008; Zhu et al., 2016) or epidural stimulation (Angeli et al., 2018) might be applied in addition to locomotor training to increase the chance of recovery in standing and walking abilities. Although a much lower chance for individuals with chronic or motor complete SCI to regain walking through locomotor training, an improvement in bowel and bladder function, or sexual function might occur (Hubscher et al., 2018), both of which are regarded as high priority and contribute significantly to the quality of life (Anderson, 2004).
2. Body-weight-supported locomotor training Locomotor training with a body-weight-support system is among the most widely used rehabilitation strategies to retrain standing and walking abilities after SCI (Dietz, 2008; Wessels, Lucas, Eriks, & de Groot, 2010). Unweighting with an overhead suspension system improves trunk control and balance avoiding falls, allows the patients to stand and take forced stepping movements under manual or robotic assistance. It can be applied early after SCI before individuals develop weight bearing. There are various approaches of locomotor training, most frequently used including body-weight-supported overground walking and body-weight-supported treadmill training. During the training, individuals are often suspended by
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a harness to alleviate weight bearing of the lower extremities, leg movements are assisted either manually by therapists or robotically with an orthosis. Electrical stimulation may also be applied to activate paralyzed muscles for inducing stepping movements. Each locomotor training approach (overground or treadmill, manual-assisted or robotic-assisted) has its own advantages and limits. A few studies compared the effectiveness of these different forms of training approaches and concluded that there was insufficient evidence showing one gait training strategy is superior to another (Alexeeva et al., 2011; Colombo, Wirz, & Dietz, 2001; Dobkin et al., 2006; Mehrholz, Harvey, Thomas, & Elsner, 2017).
2.1 Body-weight-supported overground walking training Overground walking training does not require expensive device and can be undertaken simply using a rolling walker to provide partial weight support. It is more closely resemble natural walking condition in daily life compared to walk on a treadmill. It’s likely to achieve patient’s full engagement and encourages voluntary movements. However, it is only suitable for motor incomplete high functioning SCI individuals, although the emerging of the overhead track system and the robotic weight support system allows motor complete SCI individuals to perform overground locomotor training. We have established a set of overground training system and protocols for SCI individuals with different functional levels in our rehabilitation center as shown in Fig. 1. The functional level for each individual is determined based on the standing and locomotion capability evaluated by a Kuming 10-grade locomotion scoring system we developed previously (Zhu et al., 2008). Overground training plan is then designed for each individual accordingly, starting from standing with or without the help of a therapist in fixing the knee, then to walk in a rolling walk with assistance as needed. The duration of each training session is dependent on each individual’s endurance and ability. With the recovery of voluntary movements, the duration of overground training increases gradually.
2.2 Body-weight-supported treadmill training Treadmill based locomotor training, with a harness attached to an overhead lift system to provide partial or full body-weight-support, has emerged as a therapeutic strategy to improve functional ambulation in people with SCI since 1990s. It was brought about by the finding that cats with a complete
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Fig. 1 The Kuming 10-grade locomotion scoring system. Grade I, not able to stand; grade II, able to stand with weight support and help in fixing the knee; grade III, able to stand with weight support; grade IV, able to walk with wheeled weight support and help in fixing the knee of weight bearing leg; grade V, able to walk with wheeled weight support; grade VI, able to walk with the help of a light four-leg support; grade VII, able to walk with a pair of crutches; grade VIII, able to walk with a cane; grade IX, able to walk without support but staggeringly; X, able to walk stably without support. Adapted from Zhu, H., Feng, Y. P., Young, W., You, S. W., Shen, X. F., Liu, Y. S., et al., (2008). Early neurosurgical intervention of spinal cord contusion: An analysis of 30 cases. Chinese Medical Journal, 121(24), 2473–2478.
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spinal cord transection were able to step on a treadmill with weight bearing and adapt their walking movements to increased treadmill speed after several weeks of intensive training on a treadmill (Forssberg, Grillner, & Halbertsma, 1980). Compared to conventional overground walking, treadmill training offers more repetitive stepping practice and is able to reach a higher training intensity over the same period of time. During treadmill training, the amount of body-weight-support and the speed of treadmill are adjustable according to the level of disability. Manual assistance by a team of two or three therapists are often required to facilitate stepping and weight shifting. Therefore, the training session for manual-assisted treadmill is often relatively short. To offer a prolonged training session and to relieve the physical load imposed on the therapists, robotic driven gait orthosis has been developed and evolved rapidly during the past two decades to assist walking movements for longer duration (Nam et al., 2017). As the driving force, weight support level and speed are adjustable, robotic-assistance enables SCI individuals with sever motor function loss to exercise on a treadmill.
3. Factors influencing functional outcomes of locomotor training A large numbers of clinical studies have proved the effectiveness of locomotor training on improvements in functional recovery after SCI. However, the outcomes are largely dependent on the injury severity and the time after injury. In addition, there are also considerable variations in the training protocols regarding the intensity and duration of training, the way and amount of assistance, all of which are important factors affecting the neurological outcomes (Yang & Musselman, 2012).
3.1 Injury severity and phase of injury The American Spinal Injury Association Impairment Scale (AIS) is widely used to classify the severity of injury in SCI individuals, with motor complete (AIS grade A and grade B), motor incomplete (AIS grade C and grade D), or normal (AIS grade E) (Kirshblum et al., 2011). The functional recovery after SCI, to a large extent, is determined by the completeness of injury. In addition, SCI individuals are more likely to obtain some degree of recovery within the first year after injury. It’s well accepted that locomotor training started at early stage after injury can accelerate the locomotion recovery in individuals with motor incomplete SCI (AIS grade C and grade D), and recovery becomes more occasionally after longer periods (Piira et al., 2019). A few studies reported functional improvements after locomotor training in chronic
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incomplete SCI individuals (Alexeeva et al., 2011; Field-Fote & Roach, 2011), both the chance and the degree of recovery are much lower, and it may take a longer time compared with starting exercise training at acute/subacute phases (<6 months after SCI). The probability is scarce for complete SCI to recover standing or walking by locomotor training alone (Dietz, Colombo, & Jensen, 1994; Dietz, Colombo, Jensen, & Baumgartner, 1995).
3.2 The optimal intensity and duration of training Although body-weight-supported locomotor training has been widely used in humans for SCI rehabilitation, the training protocols such as types of training, training time, training speed, walking distance, and the amount of body-weight-support, are varied markedly from center to center. Systematic and conclusive studies are required to test the optimal intensity and duration of training to produce a difference in function. In addition, there is also a lack of standardized ways for quantification of training intensity. One emerging consensus is that a more intensive and long-term training program may lead to better functional outcomes. Brain-derived neurotrophic factor (BDNF) has been known to play important roles in exercise-induced neuroplasticity (Gomez-Pinilla, Ying, Roy, Molteni, & Edgerton, 2002). One study compared the level of BDNF in the serum of motor incomplete SCI individuals after locomotor training with different intensities. Results showed that the serum BDNF level was significantly higher in individuals trained with high-intensity as compared to those with moderate- or lowintensity. One animal study indicated that continued training might be required for maintenance of the recovery (Singh, Balasubramanian, Murray, Lemay, & Houle, 2011). In Kuming, we recommend starting overground walking training as soon as the individuals are medical stable and the time for exercise training is 30 min each session during the initial stage, then the time gradually increases to 3–4 h per day, 5 days a week, and one training period lasts at least 3 months. In some cases, the walking training time is subject to further increase to as much as 6 h with typically 3 h in the morning and 3 h in the afternoon (Zhu et al., 2016).
4. Achieve overground walking after chronic motor complete SCI with epidural stimulation coupled with intensive locomotor training Chronic clinically motor complete SCI individuals hardly recover walking after locomotor training. The majority of motor complete (AIS grade A and grade B) SCI individuals do have some axons sparing.
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However, for some reason, these spared axons failed to be reactivated by locomotor training. Therefore, additional interventions are required to reactivate these silent spared neural circuits. Epidural stimulation is also an activity-based therapy, which has been used for SCI treatment. Restoration of full body weight bearing standing in complete SCI (AIS grade A or B) individuals has recently been achieved when the lumbosacral spinal cord was epidurally stimulated (Harkema et al., 2011; Rejc, Angeli, & Harkema, 2015). More recently, successful regaining of walk ability for two chronic motor complete individuals through epidural stimulation coupled with intensive locomotor training has been reported (Angeli et al., 2018). In this case study, four chronic motor complete participants (2 with AIS grade A and 2 with AIS grade B) began this study treatment 2.5–3.3 years after injury. They first received intense body-weight-supported treadmill locomotor training over a period of 8 or 9 weeks before starting epidural stimulation, but resulted in no changes to locomotor ability. After applying epidural stimulation at the lumbosacral level together with intensive locomotor training, two AIS grade B participants were able to walk overground with assistance. Notably, one achieved overground walking after 278 sessions of epidural stimulation and treadmill training over a period of 85 weeks. Restoration of some degree of independent stepping on a treadmill with body-weight-support but not overground walking was also achieved in the other two motor and sensory complete (AIS grade A) participants (Angeli et al., 2018).
5. Mechanisms of locomotor training on functional recovery following SCI The locomotor training strategy is founded on the principals of motor learning and neural plasticity (Edgerton, Tillakaratne, Bigbee, de Leon, & Roy, 2004; Lynskey, Belanger, & Jung, 2008), which is largely based on scientific findings from animal studies. In the past decades, great efforts have been made on understanding the neural control of movements (Kiehn, 2016). Early work from spinal cord completely transected cats suggests that the re-expression of stepping movements is largely attributed to the activitydependent reorganization of neural sensorimotor circuits for locomotion at the lumbar spinal cord induced by locomotor treadmill training. For incomplete SCI, functional recovery depends on cooperative mechanisms of plasticity within the caudal spinal cord, sprouting of spared descending pathways, and the formation of propriospinal relay (Blesch & Tuszynski, 2009;
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Hansen et al., 2016). A growing body of evidence from animal studies suggests that spinal cord exhibits the potential of motor learning and undergoes activity-dependent plasticity after SCI (Courtine et al., 2009; Martinez, Delivet-Mongrain, Leblond, & Rossignol, 2012), and these plastic changes can be boosted by intense repetitive locomotor training (Smith & Knikou, 2016). Recent studies have also made significant advances toward uncovering the circuitry, cellular and molecular levels of mechanisms underlying the positive role of locomotor training in functional recovery following SCI.
5.1 Effects of locomotor training on motoneurons and local circuits in the lumbar spinal cord as well as their musculatures Extensive studies on spinal cord completely transected cats and dogs suggest the spinal capacity of locomotion even in the absence of descending supraspinal inputs (Forssberg, Grillner, & Halbertsma, 1980; Lovely, Gregor, Roy, & Edgerton, 1986). Body-weight-supported treadmill training is able to recover the stepping movements in spinal cord transected animals by activating and remodeling the lumbar spinal cord circuit referred to as central pattern generator (CPG) for generating the alternating hindlimb locomotor pattern (de Leon, Hodgson, Roy, & Edgerton, 1998; Gossard et al., 2015; Guertin, 2009). The upper lumbar spinal cord is an integration center which initiates and promotes walking. In normal condition, neural circuits within the lumbar spinal cord integrate information from descending cortical, subcortical inputs as well as the segmental afferents to coordinate the firing of motoneuron pools. Motoneurons located in the ventral horn of the lumbar spinal cord directly project axons to the skeleton muscles controlling leg movements. When an injury to the spinal cord occurs above the lumbar level, although survived and anatomically intact, the motoneurons within the lumbar segment reduce excitability and undergo dendritic atrophy attributing to denervation from supraspinal descending inputs. Profound muscle atrophy in the legs occurs rapidly after SCI due to loss of neuromuscular activity and muscle disuse. Locomotor training, through repetitively providing appropriate proprioceptive feedback, has been shown to play an effective role in triggering and shaping adaptive remodeling of the spinal sensorimotor circuits caudal to the lesion (Cote & Gossard, 2004; Harkema et al., 1997). Locomotor training can increase motoneuron excitability and decrease muscle atrophy after SCI by maintaining or inducing reorganization of synaptic inputs on the spinal motoneurons and preventing their dendritic atrophy. After a low thoracic hemisection in mice, treadmill training significantly improved the
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locomotor function of hindlinmbs and attenuated muscle atrophy, correlating with maintenance of synaptic markers synaptophysin and PSD95 on motoneurons (Goldshmit, Lythgo, Galea, & Turnley, 2008). After a complete thoracic spinal cord transection in rats, repetitive limb exercise on a motorized device significantly prevented dendritic atrophy of the motor neurons below the injury (Gazula, Roberts, Luzzio, Jawad, & Kalb, 2004). Extensive and long-term treadmill training also promoted dendritic plasticity, increased synaptic density in the lumbar motorneurons, and therefore promoted functional recovery in a rat moderate contusive SCI model (Wang et al., 2015). Interneurons in the spinal cord play a critical role in conveying motor commands from descending pathways to motoneuron pools. Their synaptic derive and strength also undergo plastic changes after exercise training (Harkema, 2008). In addition to changes in the motoneurons and interneurons in the lumbar spinal cord caudal to the injury, the proprioceptive feedback pathways and transmission in reflex pathways also undergo plastic changes by intense repetitive stepping training (Cote & Gossard, 2004).
5.2 Sprouting and reorganization of spared descending pathways and propriospinal projections Traumatic injury to the spinal cord leads to the interruption of descending supraspinal pathways including corticospinal projections and brainstem pathways. Majority of the human SCI cases are anatomically incomplete even for those clinically classified as motor complete individuals with the AIS grade A and grade B. Therefore, reactivation of these spared pathways has been a promising strategy to promote functional recovery after SCI. Spontaneous sprouting of corticospinal axons, reticulospinal axons or rubrospinal axons has been identified after incomplete SCI in rodents or primates (Perrin & Noristani, 2019; Rosenzweig et al., 2010; Siegel, Fink, Strittmatter, & Cafferty, 2015). Propriospinal networks which are intrinsic spinal cord pathways and project intersegmentally to terminate at other spinal levels, also undergo spontaneous sprouting and remodeling after SCI (Filli et al., 2014). Compensatory sprouting of these spared supraspinal and propriospinal projections, and the formation of detour pathways that reroute supraspinal inputs with interneuron and/or motoneuron pools located below the lesion via propriospinal connections are thought to contribute to spontaneous recovery after SCI (Courtine et al., 2008; Filli et al., 2014). Augmentation of these mechanisms by rehabilitation training may lead to improvements in functional recovery.
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Although unable to induce long-distance axonal regeneration across the lesion after SCI, exercise training promoted sprouting of spared descending axons and subsequent synaptic integration into spinal neural networks. An increase in corticospinal tract function by intensive treadmill training in human subjects after incomplete SCI has been reported (Thomas & Gorassini, 2005). The increase in connectivity of the corticospinal tract as assessed by the motor-evoked potentials (MEPs) recording in response to incrementing levels of transcranial magnetic stimulation over the leg area of the primary motor cortex, was positively correlated to the improvement in locomotor function and the increased peak locomotor EMG activity. Treadmill exercised mice showed increased axonal regrowth and collateral sprouting proximal to the lesion site following a low thoracic hemisection, with maintenance of synaptic markers on motoneurons in the ventral horn and decreased muscle atrophy (Goldshmit et al., 2008). Following a moderate T9 contusive SCI in mice, wheel running stimulated sprouting of serotonin fibers in the vicinity of the lesion, which may be correlated to the exercise-induced locomotor improvements (Engesser-Cesar et al., 2007). In mice with genetic absence of the corticospinal tract within the spinal cord, we found wheel running significantly induced collateral sprouting of descending monoaminergic and rubrospinal axons and promoted their synaptic formation with motorneurons (Zhang et al., 2019). The plastic changes in spinal neural networks after exercise correlated with improvement in fine motor skills. One group investigated the effects of exercise training after a lateral spinal hemisection on the synaptic properties of interneurons in the lesion vicinity (Flynn et al., 2013). A marked increase in evoked excitatory synaptic currents responding to dorsal column stimulation was recorded in treadmill trained animals, which indicated an increase in the efficacy of synaptic connections from descending pathways to propriospinal interneurons located in the vicinity of the spinal cord lesion site (Flynn et al., 2013; Rank et al., 2015). Formation of these detour pathways through intersegmental projecting propriospinal neurons that relay descending inputs from brain to its target in the spinal cord caudal to the lesion, is one important mechanism to achieve functional recovery after SCI. The role of spared descending pathways in locomotor recovery after bodyweight-supported treadmill training through inducing neuroplasticity in lumbar spinal cord was also reported in cat and rat models of incomplete SCI (Singh et al., 2011).
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5.3 Effect of locomotor training on astroglioss and oligodendrogenesis Injury to the spinal cord results in axonal demyelination and activation of astrocytes around the injury site (Gaudet & Fonken, 2018). Loss of myelin in the intact axonal tracts contributes significantly to functional impairments. While reactive gliosis followed by the formation of a glial scar limits neuroplasticity by presenting a barrier to regrowing axons. Voluntary wheel running exercise was shown to promote oligodendrogenesis in intact spinal cord (Krityakiarana et al., 2010). After thoracic dorsal spinal cord hemisection in mice, voluntary wheel running exercise also reduced astrogliosis and myelin loss, supporting the rewiring of supraspinal circuits and functional recovery (Loy et al., 2018). Using the corticospinal tract deficient mice, we recently found wheel running exercise also significantly promoted oligodendrogenesis and increased the expression of myelin basic protein (Zhang et al., 2019), which implies that enhancing remyelination may be one of the mechanisms for exercise contributing to the functional improvements after SCI.
5.4 Potential molecular mechanisms of locomotor training on neuroplasticity The reported molecular mechanisms of locomotor training leading to spinal plasticity after injury include increasing the expression of various neurotrophins such as BDNF, reducing inflammation, and modulating microRNAs that regulate intrinsic axonal growth pathways. Neurotrophic factors play important roles in inducing neuroplasticity. After a spinal cord hemisection, voluntary wheel running exercise significantly increased the mRNA expression of BDNF, NT-3, and the downstream effectors of BDNF on synaptic plasticity synapsin I and CREB (Ying et al., 2008; Ying, Roy, Edgerton, & Gomez-Pinilla, 2005). Treadmill training also increased BDNF expression in the lumbar motor neurons after spinal cord contusion in rats (Wang et al., 2015). A significant increase in serum BDNF in individuals with motor incomplete SCI after locomotor training was detected recently which are related to the exercise intensity (Leech & Hornby, 2017). A large proportion of SCI individuals develop neuropathic pain, at least partly due to aberrant sprouting of nociceptive fibers in the dorsal horn after SCI. Early wheel walking exercise after SCI reduces the development of neuropathic pain by preventing aberrant sprouting of nociceptive fibers
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in the dorsal horn and decreasing the number of macrophages present in the dorsal root ganglions (DRG) (Chhaya, Quiros-Molina, Tamashiro-Orrego, Houle, & Detloff, 2019; Detloff, Smith, Quiros Molina, Ganzer, & Houle, 2014). Treadmill training can also decrease the density of calcitonin generelated peptide (CGRP) positive fibers and partially resolve signs of pain (Nees et al., 2016). Systemic inflammation was also reduced by exercise in humans with chronic SCI, as evident by significant decrease in the plasma levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and plasma C-reactive protein (CRP) after exercise training (NeefkesZonneveld, Bakkum, Bishop, van Tulder, & Janssen, 2015; RosetyRodriguez et al., 2014). Another potential molecular mechanism for exercise exerting beneficial effect on functional improvements after SCI, is acting through modulation of microRNAs and their targets that contribute to the functional regulation of apoptosis or axonal regeneration/sprouting. Cycling exercise was found to affect the expression of microRNAs associated with apoptosis, and the ones targeting PTEN/mTOR pathway. The changes in the microRNAs expression after exercise correlated with changes in expression of their target genes: increase in anti-apoptotic Bcl-2 mRNA, decrease in the expression of PTEN and increase in the expression of mTOR (Liu, Detloff, Miller, Santi, & Houle, 2012; Liu, Keeler, Zhukareva, & Houle, 2010).
6. Conclusions Locomotor training, with various forms and different protocols, can accelerate and enhance recovery of walking mostly in people with incomplete SCI. The reported degrees of improvement are highly variable from study to study, most likely attributing to the considerable diversity in the training methods used among centers. Therefore, the optimal training methods to maximize locomotor recovery remain to be determined. Further studies are also required to establish standardized quantitative training protocols as well as sensitive outcome measures for evaluating recovery quantitatively. Although often not being able to regain walking, individuals with chronic and severe SCI may still benefit from locomotor training on improving cardiovascular function, respiratory function, or bladder and bowel function. Through increasing the intensity and sessions of training, and combining with other activity-based therapeutic approaches, significant differences may be achieved. After incomplete SCI, spontaneous local axonal collateral/regenerative sprouting and subsequent reorganization of
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neural circuits contribute to spontaneous functional recovery. Locomotor training, to some extent promotes the sprouting from spared axons, and more importantly plays a critical role in shaping and strengthening the reorganized functional neural networks for locomotion. As adult mammalian neurons in the central nervous system have overall very poor capacity to regenerate their axons after injury, the enhanced local axonal regrowth/ sprouting after locomotor training remains limited, and long-distance axonal regrowth is not likely to be achieved by locomotor training alone. Therefore, for severe SCI cases in which majority of the descending axons are interrupted, the amount of sprouting induced by locomotor training may be far too inadequate to reorganize an alternative neural networks for re-establishing walking. Additional treatments such as pharmacological interventions, transplantation, and other spinal cord stimulation strategies, coupled with an intensive and long-term locomotor training program may evoke a synergistic improvement in locomotor recovery for sever SCI individuals.
Acknowledgments This work was supported by the Hong Kong Spinal Cord Injury Fund and the Groungdong grant “Key technologies for treatment of brain disorders” (No. 2018B030332001).
References Alexeeva, N., Sames, C., Jacobs, P. L., Hobday, L., Distasio, M. M., Mitchell, S. A., et al. (2011). Comparison of training methods to improve walking in persons with chronic spinal cord injury: A randomized clinical trial. The Journal of Spinal Cord Medicine, 34(4), 362–379. https://doi.org/10.1179/2045772311Y.0000000018. Anderson, K. D. (2004). Targeting recovery: Priorities of the spinal cord-injured population. Journal of Neurotrauma, 21(10), 1371–1383. https://doi.org/10.1089/neu.2004.21.1371. Angeli, C. A., Boakye, M., Morton, R. A., Vogt, J., Benton, K., Chen, Y., et al. (2018). Recovery of over-ground walking after chronic motor complete spinal cord injury. The New England Journal of Medicine, 379(13), 1244–1250. https://doi.org/10.1056/ NEJMoa1803588. Battistuzzo, C. R., Callister, R. J., Callister, R., & Galea, M. P. (2012). A systematic review of exercise training to promote locomotor recovery in animal models of spinal cord injury. Journal of Neurotrauma, 29(8), 1600–1613. https://doi.org/10.1089/ neu.2011.2199. Behrman, A. L., & Harkema, S. J. (2000). Locomotor training after human spinal cord injury: A series of case studies. Physical Therapy, 80(7), 688–700. Behrman, A. L., Lawless-Dixon, A. R., Davis, S. B., Bowden, M. G., Nair, P., Phadke, C., et al. (2005). Locomotor training progression and outcomes after incomplete spinal cord injury. Physical Therapy, 85(12), 1356–1371. Blesch, A., & Tuszynski, M. H. (2009). Spinal cord injury: Plasticity, regeneration and the challenge of translational drug development. Trends in Neurosciences, 32(1), 41–47. https://doi.org/10.1016/j.tins.2008.09.008.
Locomotor training on spinal cord injury
213
Chhaya, S. J., Quiros-Molina, D., Tamashiro-Orrego, A. D., Houle, J. D., & Detloff, M. R. (2019). Exercise-induced changes to the macrophage response in the dorsal root ganglia prevent neuropathic pain after spinal cord injury. Journal of Neurotrauma, 36(6), 877–890. https://doi.org/10.1089/neu.2018.5819. Colombo, G., Wirz, M., & Dietz, V. (2001). Driven gait orthosis for improvement of locomotor training in paraplegic patients. Spinal Cord, 39(5), 252–255. https://doi. org/10.1038/sj.sc.3101154. Cote, M. P., & Gossard, J. P. (2004). Step training-dependent plasticity in spinal cutaneous pathways. The Journal of Neuroscience, 24(50), 11317–11327. https://doi.org/10.1523/ JNEUROSCI.1486-04.2004. Courtine, G., Gerasimenko, Y., van den Brand, R., Yew, A., Musienko, P., Zhong, H., et al. (2009). Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nature Neuroscience, 12(10), 1333–1342. https://doi.org/10.1038/ nn.2401. Courtine, G., Song, B., Roy, R. R., Zhong, H., Herrmann, J. E., Ao, Y., et al. (2008). Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nature Medicine, 14(1), 69–74. https://doi.org/10.1038/nm1682. de Leon, R. D., Hodgson, J. A., Roy, R. R., & Edgerton, V. R. (1998). Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. Journal of Neurophysiology, 79(3), 1329–1340. https://doi.org/10.1152/ jn.1998.79.3.1329. Detloff, M. R., Smith, E. J., Quiros Molina, D., Ganzer, P. D., & Houle, J. D. (2014). Acute exercise prevents the development of neuropathic pain and the sprouting of nonpeptidergic (GDNF- and artemin-responsive) c-fibers after spinal cord injury. Experimental Neurology, 255, 38–48. https://doi.org/10.1016/j.expneurol.2014.02.013. Dietz, V. (2008). Body weight supported gait training: From laboratory to clinical setting. Brain Research Bulletin, 76(5), 459–463. https://doi.org/10.1016/j.brainresbull. 2008.02.034. Dietz, V., Colombo, G., & Jensen, L. (1994). Locomotor activity in spinal man. Lancet, 344(8932), 1260–1263. https://doi.org/10.1016/s0140-6736(94)90751-x. Dietz, V., Colombo, G., Jensen, L., & Baumgartner, L. (1995). Locomotor capacity of spinal cord in paraplegic patients. Annals of Neurology, 37(5), 574–582. https://doi.org/ 10.1002/ana.410370506. Dobkin, B., Apple, D., Barbeau, H., Basso, M., Behrman, A., Deforge, D., et al. (2006). Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI. Neurology, 66(4), 484–493. https://doi.org/10.1212/01.wnl. 0000202600.72018.39. Edgerton, V. R., Tillakaratne, N. J., Bigbee, A. J., de Leon, R. D., & Roy, R. R. (2004). Plasticity of the spinal neural circuitry after injury. Annual Review of Neuroscience, 27, 145–167. https://doi.org/10.1146/annurev.neuro.27.070203.144308. Engesser-Cesar, C., Ichiyama, R. M., Nefas, A. L., Hill, M. A., Edgerton, V. R., Cotman, C. W., et al. (2007). Wheel running following spinal cord injury improves locomotor recovery and stimulates serotonergic fiber growth. The European Journal of Neuroscience, 25(7), 1931–1939. https://doi.org/10.1111/j.1460-9568.2007.05469.x. Field-Fote, E. C., & Roach, K. E. (2011). Influence of a locomotor training approach on walking speed and distance in people with chronic spinal cord injury: A randomized clinical trial. Physical Therapy, 91(1), 48–60. https://doi.org/10.2522/ptj.20090359. Filli, L., Engmann, A. K., Zorner, B., Weinmann, O., Moraitis, T., Gullo, M., et al. (2014). Bridging the gap: A reticulo-propriospinal detour bypassing an incomplete spinal cord injury. The Journal of Neuroscience, 34(40), 13399–13410. https://doi.org/10.1523/ JNEUROSCI.0701-14.2014.
214
Panpan Yu et al.
Flynn, J. R., Dunn, L. R., Galea, M. P., Callister, R., Callister, R. J., & Rank, M. M. (2013). Exercise training after spinal cord injury selectively alters synaptic properties in neurons in adult mouse spinal cord. Journal of Neurotrauma, 30(10), 891–896. https://doi.org/ 10.1089/neu.2012.2714. Forssberg, H., Grillner, S., & Halbertsma, J. (1980). The locomotion of the low spinal cat. I. Coordination within a hindlimb. Acta physiologica Scandinavica, 108(3), 269–281. https:// doi.org/10.1111/j.1748-1716.1980.tb06533.x. Forssberg, H., Grillner, S., Halbertsma, J., & Rossignol, S. (1980). The locomotion of the low spinal cat. II. Interlimb coordination. Acta physiologica Scandinavica, 108(3), 283–295. https://doi.org/10.1111/j.1748-1716.1980.tb06534.x. Gaudet, A. D., & Fonken, L. K. (2018). Glial cells shape pathology and repair after spinal cord injury. Neurotherapeutics, 15(3), 554–577. https://doi.org/10.1007/s13311-018-0630-7. Gazula, V. R., Roberts, M., Luzzio, C., Jawad, A. F., & Kalb, R. G. (2004). Effects of limb exercise after spinal cord injury on motor neuron dendrite structure. The Journal of Comparative Neurology, 476(2), 130–145. https://doi.org/10.1002/cne.20204. Goldshmit, Y., Lythgo, N., Galea, M. P., & Turnley, A. M. (2008). Treadmill training after spinal cord hemisection in mice promotes axonal sprouting and synapse formation and improves motor recovery. Journal of Neurotrauma, 25(5), 449–465. https://doi.org/ 10.1089/neu.2007.0392. Gomez-Pinilla, F., Ying, Z., Roy, R. R., Molteni, R., & Edgerton, V. R. (2002). Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. Journal of Neurophysiology, 88(5), 2187–2195. https://doi.org/10.1152/jn.00152.2002. Gossard, J. P., Delivet-Mongrain, H., Martinez, M., Kundu, A., Escalona, M., & Rossignol, S. (2015). Plastic changes in lumbar locomotor networks after a partial spinal cord injury in cats. The Journal of Neuroscience, 35(25), 9446–9455. https://doi.org/ 10.1523/JNEUROSCI.4502-14.2015. Guertin, P. A. (2009). The mammalian central pattern generator for locomotion. Brain Research Reviews, 62(1), 45–56. https://doi.org/10.1016/j.brainresrev.2009.08.002. Hansen, C. N., Faw, T. D., White, S., Buford, J. A., Grau, J. W., & Basso, D. M. (2016). Sparing of descending axons rescues interneuron plasticity in the lumbar cord to allow adaptive learning after thoracic spinal cord injury. Frontiers in Neural Circuits, 10, 11. https://doi.org/10.3389/fncir.2016.00011. Harkema, S. J. (2008). Plasticity of interneuronal networks of the functionally isolated human spinal cord. Brain Research Reviews, 57(1), 255–264. https://doi.org/10.1016/j. brainresrev.2007.07.012. Harkema, S., Gerasimenko, Y., Hodes, J., Burdick, J., Angeli, C., Chen, Y., et al. (2011). Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: A case study. Lancet, 377(9781), 1938–1947. https://doi.org/10.1016/S0140-6736(11)60547-3. Harkema, S. J., Hillyer, J., Schmidt-Read, M., Ardolino, E., Sisto, S. A., & Behrman, A. L. (2012). Locomotor training: As a treatment of spinal cord injury and in the progression of neurologic rehabilitation. Archives of Physical Medicine and Rehabilitation, 93(9), 1588–1597. https://doi.org/10.1016/j.apmr.2012.04.032. Harkema, S. J., Hurley, S. L., Patel, U. K., Requejo, P. S., Dobkin, B. H., & Edgerton, V. R. (1997). Human lumbosacral spinal cord interprets loading during stepping. Journal of Neurophysiology, 77(2), 797–811. https://doi.org/10.1152/jn.1997.77.2.797. Hubscher, C. H., Herrity, A. N., Williams, C. S., Montgomery, L. R., Willhite, A. M., Angeli, C. A., et al. (2018). Improvements in bladder, bowel and sexual outcomes following task-specific locomotor training in human spinal cord injury. PLoS One, 13(1). e0190998https://doi.org/10.1371/journal.pone.0190998. Kiehn, O. (2016). Decoding the organization of spinal circuits that control locomotion. Nature Reviews. Neuroscience, 17(4), 224–238. https://doi.org/10.1038/nrn.2016.9.
Locomotor training on spinal cord injury
215
Kirshblum, S. C., Burns, S. P., Biering-Sorensen, F., Donovan, W., Graves, D. E., Jha, A., et al. (2011). International standards for neurological classification of spinal cord injury (revised 2011). The Journal of Spinal Cord Medicine, 34(6), 535–546. https://doi.org/ 10.1179/204577211X13207446293695. Krityakiarana, W., Espinosa-Jeffrey, A., Ghiani, C. A., Zhao, P. M., Topaldjikian, N., Gomez-Pinilla, F., et al. (2010). Voluntary exercise increases oligodendrogenesis in spinal cord. The International Journal of Neuroscience, 120(4), 280–290. https://doi.org/ 10.3109/00207450903222741. Leech, K. A., & Hornby, T. G. (2017). High-intensity locomotor exercise increases brainderived neurotrophic factor in individuals with incomplete spinal cord injury. Journal of Neurotrauma, 34(6), 1240–1248. https://doi.org/10.1089/neu.2016.4532. Liu, G., Detloff, M. R., Miller, K. N., Santi, L., & Houle, J. D. (2012). Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Experimental Neurology, 233(1), 447–456. https://doi.org/10.1016/j.expneurol.2011.11.018. Liu, G., Keeler, B. E., Zhukareva, V., & Houle, J. D. (2010). Cycling exercise affects the expression of apoptosis-associated microRNAs after spinal cord injury in rats. Experimental Neurology, 226(1), 200–206. https://doi.org/10.1016/j.expneurol.2010.08.032. Lovely, R. G., Gregor, R. J., Roy, R. R., & Edgerton, V. R. (1986). Effects of training on the recovery of full-weight-bearing stepping in the adult spinal cat. Experimental Neurology, 92(2), 421–435. Loy, K., Schmalz, A., Hoche, T., Jacobi, A., Kreutzfeldt, M., Merkler, D., et al. (2018). Enhanced voluntary exercise improves functional recovery following spinal cord injury by impacting the local neuroglial injury response and supporting the rewiring of supraspinal circuits. Journal of Neurotrauma, 35(24), 2904–2915. https://doi.org/ 10.1089/neu.2017.5544. Lynskey, J. V., Belanger, A., & Jung, R. (2008). Activity-dependent plasticity in spinal cord injury. Journal of Rehabilitation Research and Development, 45(2), 229–240. Martinez, M., Delivet-Mongrain, H., Leblond, H., & Rossignol, S. (2012). Incomplete spinal cord injury promotes durable functional changes within the spinal locomotor circuitry. Journal of Neurophysiology, 108(1), 124–134. https://doi.org/10.1152/ jn.00073.2012. Mehrholz, J., Harvey, L. A., Thomas, S., & Elsner, B. (2017). Is body-weight-supported treadmill training or robotic-assisted gait training superior to overground gait training and other forms of physiotherapy in people with spinal cord injury? A systematic review. Spinal Cord, 55(8), 722–729. https://doi.org/10.1038/sc.2017.31. Musselman, K. E., Fouad, K., Misiaszek, J. E., & Yang, J. F. (2009). Training of walking skills overground and on the treadmill: Case series on individuals with incomplete spinal cord injury. Physical Therapy, 89(6), 601–611. https://doi.org/10.2522/ptj.20080257. Nam, K. Y., Kim, H. J., Kwon, B. S., Park, J. W., Lee, H. J., & Yoo, A. (2017). Robotassisted gait training (Lokomat) improves walking function and activity in people with spinal cord injury: A systematic review. Journal of Neuroengineering and Rehabilitation, 14(1), 24. https://doi.org/10.1186/s12984-017-0232-3. Neefkes-Zonneveld, C. R., Bakkum, A. J., Bishop, N. C., van Tulder, M. W., & Janssen, T. W. (2015). Effect of long-term physical activity and acute exercise on markers of systemic inflammation in persons with chronic spinal cord injury: A systematic review. Archives of Physical Medicine and Rehabilitation, 96(1), 30–42. https://doi.org/10.1016/ j.apmr.2014.07.006. Nees, T. A., Tappe-Theodor, A., Sliwinski, C., Motsch, M., Rupp, R., Kuner, R., et al. (2016). Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury. Pain, 157(3), 687–697. https://doi.org/10.1097/j.pain. 0000000000000422.
216
Panpan Yu et al.
Perrin, F. E., & Noristani, H. N. (2019). Serotonergic mechanisms in spinal cord injury. Experimental Neurology, 318, 174–191. https://doi.org/10.1016/j.expneurol. 2019.05.007. Piira, A., Lannem, A. M., Sorensen, M., Glott, T., Knutsen, R., Jorgensen, L., et al. (2019). Manually assisted body-weight supported locomotor training does not re-establish walking in non-walking subjects with chronic incomplete spinal cord injury: A randomized clinical trial. Journal of Rehabilitation Medicine, 51(2), 113–119. https://doi.org/ 10.2340/16501977-2508. Rank, M. M., Flynn, J. R., Battistuzzo, C. R., Galea, M. P., Callister, R., & Callister, R. J. (2015). Functional changes in deep dorsal horn interneurons following spinal cord injury are enhanced with different durations of exercise training. The Journal of Physiology, 593(1), 331–345. https://doi.org/10.1113/jphysiol.2014.282640. Rejc, E., Angeli, C., & Harkema, S. (2015). Effects of lumbosacral spinal cord epidural stimulation for standing after chronic complete paralysis in humans. PLoS One, 10(7). e0133998https://doi.org/10.1371/journal.pone.0133998. Rosenzweig, E. S., Courtine, G., Jindrich, D. L., Brock, J. H., Ferguson, A. R., Strand, S. C., et al. (2010). Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nature Neuroscience, 13(12), 1505–1510. https://doi.org/ 10.1038/nn.2691. Rosety-Rodriguez, M., Camacho, A., Rosety, I., Fornieles, G., Rosety, M. A., Diaz, A. J., et al. (2014). Low-grade systemic inflammation and leptin levels were improved by arm cranking exercise in adults with chronic spinal cord injury. Archives of Physical Medicine and Rehabilitation, 95(2), 297–302. https://doi.org/10.1016/j.apmr.2013.08.246. Rossignol, S., Frigon, A., Barriere, G., Martinez, M., Barthelemy, D., Bouyer, L., et al. (2011). Chapter 16--spinal plasticity in the recovery of locomotion. Progress in Brain Research, 188, 229–241. https://doi.org/10.1016/B978-0-444-53825-3.00021-8. Siegel, C. S., Fink, K. L., Strittmatter, S. M., & Cafferty, W. B. (2015). Plasticity of intact rubral projections mediates spontaneous recovery of function after corticospinal tract injury. The Journal of Neuroscience, 35(4), 1443–1457. https://doi.org/10.1523/ JNEUROSCI.3713-14.2015. Singh, A., Balasubramanian, S., Murray, M., Lemay, M., & Houle, J. (2011). Role of spared pathways in locomotor recovery after body-weight-supported treadmill training in contused rats. Journal of Neurotrauma, 28(12), 2405–2416. https://doi.org/10.1089/ neu.2010.1660. Smith, A. C., & Knikou, M. (2016). A review on locomotor training after spinal cord injury: Reorganization of spinal neuronal circuits and recovery of motor function. Neural Plasticity, 2016, 1216258. https://doi.org/10.1155/2016/1216258. Thomas, S. L., & Gorassini, M. A. (2005). Increases in corticospinal tract function by treadmill training after incomplete spinal cord injury. Journal of Neurophysiology, 94(4), 2844–2855. https://doi.org/10.1152/jn.00532.2005. van der Scheer, J. W., Martin Ginis, K. A., Ditor, D. S., Goosey-Tolfrey, V. L., Hicks, A. L., West, C. R., et al. (2017). Effects of exercise on fitness and health of adults with spinal cord injury: A systematic review. Neurology, 89(7), 736–745. https://doi.org/10.1212/ WNL.0000000000004224. Wang, H., Liu, N. K., Zhang, Y. P., Deng, L., Lu, Q. B., Shields, C. B., et al. (2015). Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury. Experimental Neurology, 271, 368–378. https://doi.org/10.1016/j.expneurol.2015.07.004. Wernig, A., Muller, S., Nanassy, A., & Cagol, E. (1995). Laufband therapy based on ‘rules of spinal locomotion’ is effective in spinal cord injured persons. The European Journal of Neuroscience, 7(4), 823–829.
Locomotor training on spinal cord injury
217
Wessels, M., Lucas, C., Eriks, I., & de Groot, S. (2010). Body weight-supported gait training for restoration of walking in people with an incomplete spinal cord injury: A systematic review. Journal of Rehabilitation Medicine, 42(6), 513–519. https://doi.org/ 10.2340/16501977-0525. Yang, J. F., & Musselman, K. E. (2012). Training to achieve over ground walking after spinal cord injury: A review of who, what, when, and how. The Journal of Spinal Cord Medicine, 35(5), 293–304. https://doi.org/10.1179/2045772312Y.0000000036. Ying, Z., Roy, R. R., Edgerton, V. R., & Gomez-Pinilla, F. (2005). Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Experimental Neurology, 193(2), 411–419. https://doi.org/10.1016/j.expneurol.2005.01.015. Ying, Z., Roy, R. R., Zhong, H., Zdunowski, S., Edgerton, V. R., & Gomez-Pinilla, F. (2008). BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience, 155(4), 1070–1078. https://doi.org/10.1016/ j.neuroscience.2008.06.057. Zhang, W., Yang, B., Weng, H., Liu, T., Shi, L., Yu, P., et al. (2019). Wheel running improves motor function and spinal cord plasticity in mice with genetic absence of the corticospinal tract. Frontiers in Cellular Neuroscience, 13, 106. https://doi.org/ 10.3389/fncel.2019.00106. Zhu, H., Feng, Y. P., Young, W., You, S. W., Shen, X. F., Liu, Y. S., et al. (2008). Early neurosurgical intervention of spinal cord contusion: An analysis of 30 cases. Chinese Medical Journal, 121(24), 2473–2478. Zhu, H., Poon, W., Liu, Y., Leung, G. K., Wong, Y., Feng, Y., et al. (2016). Phase I-II clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury. Cell Transplantation, 25(11), 1925–1943. https://doi.org/10.3727/096368916X691411.