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.

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.

Acute penetrating injury of the spinal cord by a wooden spike with delayed surgery:a case report

Rarely,penetrating injuries to the spinal cord result from wooden objects,creating unique challenges to mitigate neurological injury and high rates of infection and foreign body reactions.We report a man who sustained a penetrating cervical spinal cord injury from a sharpened stick.While initially tetraparetic,he rapidly recovered function.The risks of neurological deterioration during surgical removal made the patient reluctant to consent to surgery despite the impalement of the spinal cord.A repeat MRI on day 3 showed an extension of edema indicating progressive inflammation.On the 7~(th)day after injury,fever and paresthesias occurred with a large increase in serum inflammatory indicators,and the patient agreed to undergo surgical removal of the wooden object.We discuss the management nuances related to wood,the longitudinal evolution of MRI findings,infection risk,surgical risk mitigation and technique,an inflammatory marker profile,long-term recovery,and the surprisingly minimal neurological deficits associated with low-velocity midline spinal cord injuries.The patient had an excellent clinical outcome.The main lessons are that a wooden penetrating central nervous system injury has a high risk for infection,and that surgical removal from the spinal cord should be performed soon after injury and under direct visualization.

抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制研究

目的探讨抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制。方法采用血小板源性生长因子(PDGF)10 ng/ml、喹硫平10μmol/L及两者混合物处理少突胶质前体细胞(OPCs)48 h,比较各组细胞周期、细胞周期退出指数及细胞分化情况。检测喹硫平干预后小鼠前额皮质8个细胞周期相关mRNA相对表达量。通过RNA干扰下调p21的表达,并分析其对细胞增殖和分化的影响。结果PDGF可诱导G0/G1期细胞百分比下降(P<0.05),S期和G2期细胞百分比升高(P<0.05);喹硫平可抑制PDGF诱导的S期或G2期细胞百分比升高,并阻止G0/G1期细胞百分比降低(P<0.05)。PDGF抑制细胞周期退出(P<0.05);喹硫平促进细胞周期退出(P<0.05),并阻断PDGF对细胞周期退出的影响(P<0.05)。喹硫平可提高OPCs细胞的成熟率,降低低分化细胞数(P<0.05)。喹硫平干预后p21表达升高(P<0.05);下调p21可增加S期细胞百分比,降低G2期细胞百分比(P<0.05),增加溴脱氧尿苷阳性细胞数(P<0.05),减少髓鞘碱性蛋白阳性细胞(P<0.05)。结论喹硫平可能通过调节少突胶质细胞的细胞周期来调节细胞分化。

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.

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.

Design and Analysis of a Novel Tension Control Method for Winding Machine

Filament winding has emerged as the main process for carbon fiber reinforced plastic(CFRP) fabrication, and tension control plays a key role in enhancing the quality of the winding products. With the continuous improvement of prod?uct quality and e ciency, the precision of the tension control system is constantly improving. In this paper, a novel tension control method is proposed, which can regulate the fiber tension and transport speed of the winding process by governing the outputs of three di erent driven rollers(the torque of the unwind roll, the torque of the magnetic powder brake roller, and the speed of the master speed roller) in three levels. The mechanical structures and dynamic models of the driven rollers and idle rollers are established by considering the time?varying features of the roller radius and inertia. Moreover, the influence of parameters and speed variation on fiber tension is investigated using the increment model. Subsequently, the control method is proposed by applying fiber tension in three levels accord?ing to the features of the three driven rollers. An adaptive fuzzy controller is designed for tuning the PID parameters online to control the speed of the master speed roller. Simulation is conducted for verifying the performance and sta?bility of the proposed tension control method by comparing with those of the conventional PID control method. The result reveals that the proposed method outperforms the conventional method. Finally, an experimental platform is constructed, and the proposed system is applied to a winding machine. The performance and stability of the tension control system are demonstrated via a series of experiments using carbon fiber under di erent reference speeds and tensions. This paper proposes a novel tension control method to regulate the fiber tension and transport speed.

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.

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.

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.

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.

Study on Robust H_∞ Filtering in Networked Environments

This paper is concerned with the robust H ∞ filter problem for networked environments, which are subject to both transmission delay and packet dropouts randomly. By employing random series which have Bernoulli distributions taking value of 0 or 1, the data transmission model is obtained. Based on state augmentation and stochastic theory, the sufficient condition for robust stability with H ∞ constraints is derived for the filtering error system. The robust filter is designed in terms of feasibility of one certain linear matrix inequality （LMI）, which is formed by adopting matrix congruence transformations. A numerical example is given to show the effectiveness of the proposed filtering method.

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.

Synchronization and Exponential Estimates of Complex Networks with Mixed Time-varying Coupling Delays

Exponential estimates and sufficient conditions for the exponential synchronization of complex dynamical networks with bounded time-varying delays are given in terms of linear matrix inequalities （LMIs）. A generalized complex networks model involving both neutral delays and retarded ones is presented. The exponential synchronization problem of the complex networks is converted equivalently into the exponential stability problem of a group of uncorrelated delay functional differential equations with mixed timevarying delays. By utilizing the free weighting matrix technique, a less conservative delay-dependent synchronization criterion is derived. An illustrative example is provided to demonstrate the effectiveness of the proposed method.

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).

LETTER FROM THE EDITORS-IN-CHIEF

In the past 11 years, Neural Regeneration Re- search （NRR） has evolved to become a frequent- ly cited journal in the field, receiving an impact factor that reflects the dedication and expertise of our editors and reviewers. In 2017, the jour- nal received an Impact Factor of 2.234, placing it in quartile 3 of neuroscience journals. We would like to take this opportunity to thank all contributors who have made this success possi- ble： our Editorial Board team, who always have supported and helped the journal＇s maturation; our reviewers, who have provided thoughtful critiques in a timely manner; our readers, who have deemed NRR papers to be of high enough quality to be cited; and last.

Celebration of the 10^th Anniversary of Neural Regeneration Research

Dear Readers,We are very excited to celebrate the 10th anniversary of Neural Regeneration Research（NRR）.With this first issue of 2017,we would like to express our sincere thanks for your continued support and wish you a Happy New Year!We would also like to share with you a brief overview of the growth of the journal in the past 10 years.

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.

LETTER FROM THE EDITORS-IN-CHIEF

Dear NRR Contributors and Reviewers,Time flies!It has been 14 years since the founding of Neural Regeneration Research(NRR).With your continued support,the journal now becomes one of the finest journals in the field of neural regeneration research.Looking ahead to 2020,we thought it is a good time to share our thinking on new ideas and directions for the journal in the year to come.