Surgical intervention combined with weight-bearing walking training promotes recovery in patients with chronic spinal cord injury:a randomized controlled study

For patients with chronic spinal cord injury,the co nventional treatment is rehabilitation and treatment of spinal cord injury complications such as urinary tract infection,pressure sores,osteoporosis,and deep vein thrombosis.Surgery is rarely perfo rmed on spinal co rd injury in the chronic phase,and few treatments have been proven effective in chronic spinal cord injury patients.Development of effective therapies fo r chronic spinal co rd injury patients is needed.We conducted a randomized controlled clinical trial in patients with chronic complete thoracic spinal co rd injury to compare intensive rehabilitation(weight-bearing walking training)alone with surgical intervention plus intensive rehabilitation.This clinical trial was registered at ClinicalTrials.gov(NCT02663310).The goal of surgical intervention was spinal cord detethering,restoration of cerebrospinal fluid flow,and elimination of residual spinal cord compression.We found that surgical intervention plus weight-bearing walking training was associated with a higher incidence of American Spinal Injury Association Impairment Scale improvement,reduced spasticity,and more rapid bowel and bladder functional recovery than weight-bearing walking training alone.Overall,the surgical procedures and intensive rehabilitation were safe.American Spinal Injury Association Impairment Scale improvement was more common in T7-T11 injuries than in T2-T6 injuries.Surgery combined with rehabilitation appears to have a role in treatment of chronic spinal cord injury patients.

Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

Enhancement of motor functional recovery in thoracic spinal cord injury: voluntary wheel running versus forced treadmill exercise

Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.

Chx10+V2a interneurons in spinal motor regulation and spinal cord injury

Chx10-expressing V2 a(Chx10+V2 a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2 a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2 a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2 a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2 a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2 a interneurons also play an important role in rhythmic patterning maintenance, leftright alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2 a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2 a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2 a interneurons transplanted in spinal cord injury foci.

Neuroprotection and its molecular mechanism following spinal cord injury

Acute spinal cord injury initiates a complex cascade of molecular events termed ＇secondary injury＇, which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-AktJmTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury.

GDNF-Enhanced Axonal Regeneration and Myelination Following Spinal Cord Injury is Mediated by Primary Effects on Neurons

我们先前研究表明胶质细胞源性神经营养因子(GDNF)联合施万细胞移植能促进脊髓损伤后轴突再生和髓鞘形成。然而,GDNF介导这一过程的细胞靶点尚不清楚。在此,我们报道了GDNF可增加在体再生轴突的数目和直径,并促进体外背根神经节神经元的轴突向外生长,提示GDNF对神经元有直接作用。在施万细胞-背根神经节神经元共培养下,GDNF显著增加施万细胞生成的髓鞘数目;GDNF处理对孤立培养的施万细胞增殖无作用,但可促进已与神经轴突有突触联系的施万细胞增殖;GDNF可增加孤立施万细胞中分子量为140kDa的神经细胞黏附分子(NCAM)的表达,但对黏附分子L1表达或神经营养因子NGF、NT3及BDNF分泌没有影响。总之,这些结果支持假设:GDNF提高轴突再生和施万细胞髓鞘形成主要是通过GDNF对神经元的直接作用介导的,并且提示GDNF联合施万细胞移植可能是促进脊髓损伤后轴突再生和髓鞘形成的有效策略之一。

Breaking News in Spinal Cord Injury Research FDA Approved Phase I Clinical Trial of Human, Autologous Schwann Cell Transplantation in Patients with Spinal Cord Injuries

On July 31,2012, The Miami Project to Cure Paralysis at the University of Miami Miller School of Medicine received permission from the Food and Drug Administration （FDA） to begin a Phase I clinical trial to evaluate the safety of transplanting human autologous Schwann cells to treat patients with spinal cord injuries. This is the only FDA-approved cell therapy-based clinical trial for sub-acute spinal cord injury in the United States.

Laminin-coated multifilament entubulation, combined with Schwann cells and glial cell line-derived neurotrophic factor, promotes unidirectional axonal regeneration in a rat model of thoracic spinal cord hemisection

Biomaterial bridging provides physical substrates to guide axonal growth across the lesion.To achieve efficient directional guidance,combinatory strategies using permissive matrix,cells and trophic factors are necessary.In the present study,we evaluated permissive effect of poly(acrylonitrile-co-vinyl chloride)guidance channels filled by different densities of laminin-precoated unidirectional polypropylene filaments combined with Schwann cells,and glial cell line-derived neurotrophic factor for axonal regeneration through a T10 hemisected spinal cord gap in adult rats.We found that channels with filaments significantly reduced the lesion cavity,astrocytic gliosis,and inflammatory responses at the graft-host boundaries.The laminin coated low density filament provided the most favorable directional guidance for axonal regeneration which was enhanced by co-grafting of Schwann cells and glial cell line-derived neurotrophic factor.These results demonstrate that the combinatorial strategy of filament-filled guiding scaffold,adhesive molecular laminin,Schwann cells,and glial cell line-derived neurotrophic factor,provides optimal topographical cues in stimulating directional axonal regeneration following spinal cord injury.This study was approved by Indiana University Institutional Animal Care and Use Committees(IACUC#:11011)on October 29,2015.

Neurotrophin-3-mediated locomotor recovery: a novel therapeutic strategy targeting lumbar neural circuitry after spinal cord injury

Traumatic spinal cord injury(SCI)leads to chronic locomotor impairment and disability.Unfortunately,there are no effective treatments currently available for SCI patients(Bradbury and Burnside,2019).Developing novel repair interventions to mitigate the devastating nature of SCI and translating them clinically are urgent medical needs to improve the quality of life of patients with SCI.The lumbar spinal motoneurons(MNs)are the final common pathway for hindlimb locomotion since all neural activities that influence hindlimb movement converging upon these neurons.

Surgical intervention combined with weight-bearing walking training improves neurological recoveries in 320 patients with clinically complete spinal cord injury:a prospective self-controlled study

Although a large number of trials in the SCI field have been conducted,few proven gains have been realized for patients.In the present study,we determined the efficacy of a novel combination treatment involving surgical intervention and long-term weight-bearing walking training in spinal cord injury(SCI)subjects clinically diagnosed as complete or American Spinal Injury Association Impairment Scale(AIS)Class A(AIS-A).A total of 320 clinically complete SCI subjects(271 male and 49 female),aged 16–60 years,received early(≤7 days,n=201)or delayed(8–30 days,n=119)surgical interventions to reduce intraspinal or intramedullary pressure.Fifteen days post-surgery,all subjects received a weight-bearing walking training with the“Kunming Locomotion Training Program(KLTP)”for a duration of 6 months.The neurological deficit and recovery were assessed using the AIS scale and a 10-point Kunming Locomotor Scale(KLS).We found that surgical intervention significantly improved AIS scores measured at 15 days post-surgery as compared to the pre-surgery baseline scores.Significant improvement of AIS scores was detected at 3 and 6 months and the KLS further showed significant improvements between all pair-wise comparisons of time points of 15 days,3 or 6 months indicating continued improvement in walking scores during the 6-month period.In conclusion,combining surgical intervention within 1 month post-injury and weight-bearing locomotor training promoted continued and statistically significant neurological recoveries in subjects with clinically complete SCI,which generally shows little clinical recovery within the first year after injury and most are permanently disabled.This study was approved by the Science and Research Committee of Kunming General Hospital of PLA and Kunming Tongren Hospital,China and registered at ClinicalTrials.gov(Identifier:NCT04034108)on July 26,2019.

Protective effects of gonadal hormones on spinal motoneurons following spinal cord injury

Spinal cord injury（SCI） results in lesions that destroy tissue and disrupt spinal tracts, producing deficits in locomotor and autonomic function. The majority of treatment strategies after SCI have concentrated on the damaged spinal cord, for example working to reduce lesion size or spread, or encouraging regrowth of severed descending axonal projections through the lesion, hoping to re-establish synaptic connectivity with caudal targets. In our work, we have focused on a novel target for treatment after SCI, surviving spinal motoneurons and their target musculature, with the hope of developing effective treatments to preserve or restore lost function following SCI. We previously demonstrated that motoneurons, and the muscles they innervate, show pronounced atrophy after SCI. Importantly, SCI-induced atrophy of motoneuron dendrites can be attenuated by treatment with gonadal hormones, testosterone and its active metabolites, estradiol and dihydrotestosterone. Similarly, SCI-induced reductions in muscle fiber cross-sectional areas can be prevented by treatment with androgens. Together, these findings suggest that regressive changes in motoneuron and muscle morphology seen after SCI can be ameliorated by treatment with gonadal hormones, further supporting a role for steroid hormones as neurotherapeutic agents in the injured nervous system.

Rho A/Rho kinase in spinal cord injury

A spinal cord injury refers to an injury to the spinal cord that is caused by a trauma instead of diseases. Spinal cord injury includes a primary mechanical injury and a much more complex secondary injury process involving inflammation, oxidation, excitotoxicity, and cell death. During the secondary injury, many signal pathways are activated and play important roles in mediating the pathogenesis of spinal cord injury. Among them, the Rho A/Rho kinase pathway plays a particular role in mediating spinal degeneration and regeneration. In this review, we will discuss the role and mechanism of Rho A/Rho kinase-mediated spinal cord pathogenesis, as well as the potential of targeting Rho A/Rho kinase as a strategy for promoting both neuroprotection and axonal regeneration.

Interaction between Schwann cells and other cells during repair of peripheral nerve injury

Peripheral nerve injury(PNI)is common and,unlike damage to the central nervous system injured nerves can effectively regenerate depending on the location and severity of injury.Peripheral myelinating glia,Schwann cells(SCs),interact with various cells in and around the injury site and are important for debris elimination,repair,and nerve regeneration.Following PNI,Wallerian degeneration of the distal stump is rapidly initiated by degeneration of damaged axons followed by morphologic changes in SCs and the recruitment of circulating macrophages.Interaction with fibroblasts from the injured nerve microenvironment also plays a role in nerve repair.The replication and migration of injury-induced dedifferentiated SCs are also important in repairing the nerve.In particular,SC migration stimulates axonal regeneration and subsequent myelination of regenerated nerve fibers.This mobility increases SC interactions with other cells in the nerve and the exogenous environment,which influence SC behavior post-injury.Following PNI,SCs directly and indirectly interact with other SCs,fibroblasts,and macrophages.In addition,the inter-and intracellular mechanisms that underlie morphological and functional changes in SCs following PNI still require further research to explain known phenomena and less understood cell-specific roles in the repair of the injured peripheral nerve.This review provides a basic assessment of SC function post-PNI,as well as a more comprehensive evaluation of the literature concerning the SC interactions with macrophages and fibroblasts that can influence SC behavior and,ultimately,repair of the injured nerve.

Automated monitoring of early neurobehavioral changes in mice following traumatic brain injury

Traumatic brain injury often causes a variety of behavioral and emotional impairments that can develop into chronic disorders. Therefore, there is a need to shift towards identifying early symptoms that can aid in the prediction of traumatic brain injury outcomes and behavioral endpoints in patients with traumatic brain injury after early interventions. In this study, we used the Smart Cage system, an automated quantitative approach to assess behavior alterations in mice during an early phase of traumatic brain injury in their home cages. Female C57BL/6 adult mice were subjected to moderate controlled cortical impact（CCI） injury. The mice then received a battery of behavioral assessments including neurological score, locomotor activity, sleep/wake states, and anxiety-like behaviors on days 1, 2, and 7 after CCI. Histological analysis was performed on day 7 after the last assessment. Spontaneous activities on days 1 and 2 after injury were significantly decreased in the CCI group. The average percentage of sleep time spent in both dark and light cycles were significantly higher in the CCI group than in the sham group. For anxiety-like behaviors, the time spent in a light compartment and the number of transitions between the dark/light compartments were all significantly reduced in the CCI group than in the sham group. In addition, the mice suffering from CCI exhibited a preference of staying in the dark compartment of a dark/light cage. The CCI mice showed reduced neurological score and histological abnormalities, which are well correlated to the automated behavioral assessments. Our findings demonstrate that the automated Smart Cage system provides sensitive and objective measures for early behavior changes in mice following traumatic brain injury.

Mitochondrial integrity in neuronal injury and repair

The mitochondrion is the powerhouse of a cell.As the principal subcellular organelles that mediate adenosine triphosphate(ATP)production and calcium buffering,mitochondria actively distribute to areas of high energy demand and calcium flux.The highly polarized nerve cells in the central nervous system(CNS),which have unparalleled size and complexity and long-projection axons,are cells with high-energy requirements.Mitochondria are regionally organized within these neurons,with higher accumulations in the soma,the hillock,the nodes of Ranvier,and the axon terminals.In the synaptic region,mitochondria regulate calcium and ATP levels,thereby maintaining synaptic transmission and structure.Defects in mitochondrial dynamics can cause deficits in neuronal transport,transmission,and metabolism(Misgeld and Schwarz,2017).

Optogenetics and its application in neural degeneration and regeneration

Neural degeneration and regeneration are important topics in neurological diseases. There are limited options for therapeutic interventions in neurological diseases that provide simultaneous spatial and temporal control of neurons. This drawback increases side effects due to non-specific targeting. Optogenetics is a technology that allows precise spatial and temporal control of cells. Therefore, this technique has high potential as a therapeutic strategy for neurological diseases. Even though the application of optogenetics in understanding brain functional organization and complex behaviour states have been elaborated, reviews of its therapeutic potential especially in neurodegeneration and regeneration are still limited. This short review presents representative work in optogenetics in disease models such as spinal cord injury, multiple sclerosis, epilepsy, Alzheimer＇s disease and Parkinson＇s disease. It is aimed to provide a broader perspective on optogenetic therapeutic potential in neurodegeneration and neural regeneration.

Surgical decompression in acute spinal cord injury： A review of clinical evidence, animal model studies, and potential future directions of investigation

The goal for treatment in acute spinal cord injury （SCI） is to reduce the extent of secondary damage and facilitate neurologic regeneration and functional recovery. Although multiple studies have investigated potential new therapies for the treatment of acute SCI, outcomes and management protocols aimed at ameliorating neurologic injury in patients remain ineffective. More recent clinical and basic science research have shown surgical interventions to be a potentially valuable modality for treatment; however, the role and timing of surgical decompression, in addition to the optimal surgical intervention, remain one of the most controversial topics pertaining to surgical treatment of acute SCI. As an increasing number of potential treatment modalities emerge, animal models are pivotal for investigating its clinical application and translation into human trials. This review critically appraises the available literature for both clinical and basic science studies to highlight the extent of investigation that has occurred, specific therapies considered, and potential areas for future research.

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

Injury to the nervous system induces localized damage in neural structures and neuronal death through the primary insult, as well as delayed atrophy and impaired plasticity of the delicate dendritic fields necessary for intemeuronal communication. Excitotoxicity and other sec- ondary biochemical events contribute to morphological changes in neurons following injury. Evidence suggests that various transcription factors are involved in the dendritic response to injury and potential therapies. Transcription factors play critical roles in the intracellular regulation of neuronal morphological plasticity and dendritic growth and patteming. Mounting evidence supports a crucial role for epigenetic modifications via histone deacetylases, histone acetyltransferases, and DNA methyltransferases that modify gene expression in neuronal injury and repair processes. Gene regulation through epigenetic modification is of great interest in neurotrauma research, and an early picture is beginning to emerge conceming how injury triggers intracellular events that modulate such responses. This review provides an overview of injury-mediated influences on transcriptional regulation through epigenefic modification, the intracellular processes involved in the morphological consequences of such changes, and potential approaches to the therapeutic manipulation of neuronal epigenetics for regulating gene expression to facilitate growth and signaling through dendritic arborization following injury.

Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity

Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.