Rehabilitation following spinal cord injury:how animal models can help our understanding of exercise-induced neuroplasticity

Spinal cord injury is a devastating condition that is followed by long and often unsuccessful recovery after trauma. The state of the art approach to manage paralysis and concomitant impairments is rehabilitation, which is the only strategy that has proven to be effective and beneficial for the patients over the last decades. How rehabilitation influences the remodeling of spinal axonal connections in patients is important to understand, in order to better target these changes and define the optimal timing and onset of training. While clinically the answers to these questions remain difficult to obtain, rodent models of rehabilitation like bicycling, treadmill training, swimming, enriched environments or wheel running that mimic clinical rehabilitation can be helpful to reveal the axonal changes underlying motor recovery. This review will focus on the different animal models of spinal cord injury rehabilitation and the underlying changes in neuronal networks that are improved by exercise and rehabilitation.     

Evaluation of spinal cord injury animal models

Because there is no curative treatment for spinal cord injury, establishing an ideal animal model is important to identify injury mechanisms and develop therapies for individuals suffering from spinal cord injuries. In this article, we systematically review and analyze various kinds of animal models of spinal cord injury and assess their advantages and disadvantages for further studies.     

From animal models to humans: strategies for promoting CNS axon regeneration and recovery of limb function after spinal cord injury

There are currently no fully restorative therapies for human spinal cord injury (SCI). Here,we briefly review the different types of human SCI pathology as well as the most commonly used rodent and nonhuman primate models of SCI that are used to simulate these pathologies and to test potential therapies. We then discuss various high profile (sometimes controversial) experimental strategies that have reported CNS axon regeneration and functional recovery of limb movement using these animal models of SCI. We particularly focus upon strategies that have been tested both in rodents and in nonhuman primates, and highlight those which are currently transitioning to clinical tests or trials in humans. Finally we discuss ways in which animal studies might be improved and what the future may hold for physical therapists involved in rehabilitation of humans with SCI.     

Respiratory neuroplasticity and cervical spinal cord injury: translational perspectives

Paralysis of the diaphragm is a severe consequence of cervical spinal cord injury. This condition can be experimentally modeled by lateralized, high cervical lesions that interrupt descending inspiratory drive to the corresponding phrenic nucleus. Although partial recovery of ipsilateral diaphragm function occurs over time, recent findings show persisting chronic deficits in ventilation and phrenic motoneuron activity. Some evidence suggests, however, that spontaneous recovery can be enhanced by modulating neural pathways to phrenic motoneurons via synaptic circuitries which appear more complex than previously envisioned. The present review highlights these and other recent experimental multidisciplinary findings pertaining to respiratory neuroplasticity in the rat. Translational considerations are also emphasized, with specific attention directed at the clinical and interpretational strengths of different lesion models and outcome measures.     

Predictive model of muscle fatigue after spinal cord injury in humans

The fatigability of paralyzed muscle limits its ability to deliver physiological loads to paralyzed extremities during repetitive electrical stimulation. The purposes of this study were to determine the reliability of measuring paralyzed muscle fatigue and to develop a model to predict the temporal changes in muscle fatigue that occur after spinal cord injury (SCI). Thirty-four subjects underwent soleus fatigue testing with a modified Burke electrical stimulation fatigue protocol. The between-day reliability of this protocol was high (intraclass correlation, 0.96). We fit the fatigue index (FI) data to a quadratic-linear segmental polynomial model. FI declined rapidly (0.3854 per year) for the first 1.7 years, and more slowly (0.01 per year) thereafter. The rapid decline of FI immediately after SCI implies that a "window of opportunity" exists for the clinician if the goal is to prevent these changes. Understanding the timing of change in muscle endurance properties (and, therefore, load-generating capacity) after SCI may assist clinicians when developing therapeutic interventions to maintain musculoskeletal integrity.     

Animal models of axon regeneration after spinal cord injury

With advances in genetic and imaging techniques, investigating axon regeneration after spinal cord injury in vivo is becoming more common in the literature. However, there are many issues to consider when using animal models of axon regeneration, including species, strains and injury models. No single particular model suits all types of experiments and each hypothesis being tested requires careful selection of the appropriate animal model. in this review, we describe several commonly-used animal models of axon regeneration in the spinal cord and discuss their advantages and disadvantages.     

Abnormal spontaneous potentials in distal muscles in animal models of spinal cord injury

Spontaneous potentials in skeletal muscle distal to human spinal cord injury (SCI) have been reported in the literature. Two animal models of SCI were studied for the presence of similar potentials. Six rats and two cats with surgical transections of the thoracic spinal cord were followed for 4-6 weeks with serial electromyography. As a control for the effects of anesthesia and serial testing, three intact rats were anesthetized and tested weekly for 4 weeks. In rats with spinal cord transection, spontaneous potentials emerged 4-7 days after surgery and persisted for the duration of the study (28-32 days). Spontaneous potentials were absent in controls at all timepoints. In cats, spontaneous potentials were observed 8 days postinjury and gradually diminished, starting at 2 weeks. Spontaneous potentials therefore occur after SCI in animals as well as in humans. The utilization of animal models will facilitate the understanding of alterations that occur distal to spinal cord lesions and affect the function of lower motor neurons, leading to peripheral denervation after SCI.     

Lampreys as an animal model in regeneration studies after spinal cord injury

Spinal cord injuries are an important sanitary and economical problem for the society. In mammals, including humans, a traumatic injury to the spinal cord leads to a loss of motor and sensorial function, which is irreversible due to the low regenerative ability of the central nervous system. In contrast to mammals, functional recovery occurs spontaneously after a complete spinal cord transection in lampreys. Functional recovery occurs because in these animals about 50% of the reticulospinal axons regenerate after injury and also because of the occurrence of processes of reorganization and plasticity of the spinal circuits. In this review, we first analyze the characteristics and regeneration ability of lampreys as compared to mammals. Then, we compile the knowledge about the process of recovery after a spinal cord injury acquired in studies using the lampreys as animal model and finally we provide some general perspectives about the molecular processes implicated in regeneration that can be investigated in a very advantageous way in this animal model and which knowledge could allow to develop new therapies for patients suffering spinal cord injury.     

Design and testing of a controlled electromagnetic spinal cord impactor for use in large animal models of acute traumatic spinal cord injury

BackgroundSpinal cord injury (SCI) causes debilitating neurological dysfunction and has been observed in warfighters injured in IED blasts. Clinical benefit of SCI treatment remains elusive and better large animal models are needed to assess treatment options. Here, we describe a controlled electromagnetic spinal cord impactor for use in large animal models of SCI.MethodsA custom spinal cord impactor and platform were fabricated for large animals (e.g., pig, sheep, dog, etc.). Impacts were generated by a voice coil actuator; force and displacement were measured with a load cell and potentiometer respectively. Labview (National Instruments, Austin, TX) software was used to control the impact cycle and import force and displacement data. Software finite impulse response (FIR) filtering was employed for all input data. Silicon tubing was used a surrogate for spinal cord in order to test the device; repeated impacts were performed at 15, 25, and 40 Newtons.ResultsRepeated impacts demonstrated predictable results at each target force. The average duration of impact was 71.2 ± 6.1 ms. At a target force of 40 N, the output force was 41.5 ± 0.7 N. With a target of 25 N, the output force was 23.5 ± 0.6 N; a target of 15 Newtons revealed an output force of 15.2 ± 1.4 N. The calculated acceleration range was 12.5–21.2 m/s².ConclusionsThis custom spinal cord impactor reliably delivers precise impacts to the spinal cord and will be utilized in future research to study acute traumatic SCI in a large animal.     

Muscle after spinal cord injury

The morphological and contractile changes of muscles below the level of the lesion after spinal cord injury (SCI) are dramatic. In humans with SCI, a fiber‐type transformation away from type I begins 4–7 months post‐SCI and reaches a new steady state with predominantly fast glycolytic IIX fibers years after the injury. There is a progressive drop in the proportion of slow myosin heavy chain (MHC) isoform fibers and a rise in the proportion of fibers that coexpress both the fast and slow MHC isoforms. The oxidative enzymatic activity starts to decline after the first few months post‐SCI. Muscles from individuals with chronic SCI show less resistance to fatigue, and the speed‐related contractile properties change, becoming faster. These findings are also present in animals. Future studies should longitudinally examine changes in muscles from early SCI until steady state is reached in order to determine optimal training protocols for maintaining skeletal muscle after paralysis. Muscle Nerve, 2009     

Gentamicin disposition kinetics in humans with spinal cord injury

The disposition kinetics of gentamicin, an aminoglycoside antibiotic, were studied in seven tetraplegic and six paraplegic volunteers. The volume of distribution of gentamicin in l/kg of body weight varied in a statistically significant way from values of this parameter measured in normal subjects. The elimination of gentamicin in spinal man proceeded in a log-linear fashion accurately characterized by a one compartment open-model with a half-life of approximately 2 hours. The clinical significance of altered disposition kinetics and an increased intersubject variability in gentamicin disposition in spinal man as compared to normal subjects is unknown. The existence of these observed differences in pharmacokinetic parameters, however, emphasizes the need to define individual pharmacokinetic profiles and individualize dosing regimens in spinal man. The data presented are supportive of the hypothesis that spinal man constitutes a discreet therapeutic population.     

Hemorrhagic changes in experimental spinal cord injury models

Early hemorrhagic changes in the spinal cord were compared in three experimental spinal cord injury models in the rat in order to determine the nature and consistency of spinal cord hemorrhage following specific and quantitated forces of injury. The spinal cords were injured by weight-dropping, aneurysm clip and extradural balloon compression techniques. Hemorrhagic changes were assessed quantitatively by the image analyser at 1 and 3 hours after injury. Tissue damage was assessed by determining the percentage of total cross sectional area containing hemorrhage. The extent of hemorrhage at site of injury in the clip and balloon preparations was equal, but several times lower in the weight-drop induced injury. Within each experimental group no appreciable differences were observed at the site of injury between the 1 and 3 hours preparations. The variability of damage within experimental groups was most in the weight-dropping and balloon and least in the clip preparations. Differences were also indicated with respect to the distribution of hemorrhage in grey versus white matter. These findings may be of significance when functional recovery is considered in various experimental acute spinal cord injury models.     

脊髓慢性损伤模型的构建

背景：由于缺乏简单、理想的动物实验模型,脊髓病理改变及病理生理机制目前仍不明确。 目的：通过对脊髓慢性损伤动物模型综合叙述,为脊髓慢性损伤的动物实验研究提供参考,并进一步探讨脊髓慢性损伤摸型的建立与应用。 方法：以spinal cord injury,animal model,Models, Animal为检索词,应用计算机检索Medline等数据库相关文章,排除样本量太少及重复发表的文章,保留34篇文献做进一步分析。 结果与结论：脊髓损伤动物模型对于探求脊髓疾病的病因和病理机制,特别是对脊髓再生的神经生物学研究,评价脊髓损伤后有效的干预治疗措施有十分重要的作用。目前脊髓损伤动物模型虽然种类繁多,但各存优缺点,并且存在多种变异因素,如动物间个体差异、手术操作熟练程度及损伤装置的精密程度等,以致现有模型还无法准确控制脊髓损伤的范围和程度。故建立具有较强稳定性,能够反映特定病理变化的脊髓损伤动物模型一直是研究者追求的目标。     

比较脊髓损伤及制动后大鼠骨密度与生物力学变化的差异

背景：脊髓损伤及制动均可导致骨质疏松的发生。 目的：建立胸髓横断大鼠动物模型,建立大鼠失用性萎缩模型,观察及比较大鼠胸髓损伤大鼠和失用性骨质疏松大鼠的骨密度及生物力学改变。 设计、时间及地点： 随机对照动物实验,于2008-08/11在解放军第四军医大学骨科研究所实验室完成。 材料：将48只4月龄雌性大鼠分为3组：对照组(假手术组)、制动组、脊髓损伤组。 方法：脊髓损伤组及对照组大鼠麻醉后行T10椎板切除,脊髓损伤组用锐刀横切脊髓,对照组则仅进行椎板切除术而不干预脊髓,制动组大鼠左下肢用小夹板固定后绷带悬吊,室温下分笼饲养,标准大鼠饲料,自由饮水、摄食。 主要观察指标：术后3,6周检测大鼠腰4椎体、肱骨近端、股骨远端、骨盆 骨密度及生物力学变化。 结果：与对照组比较,术后3周,脊髓损伤组大鼠股骨远端骨密度显著下降(P < 0.05);术后6 周,股骨远端、骨盆骨密度显著下降(P < 0.01,P < 0.05),两组肱骨近端、腰椎骨密度无明显差异。与对照组比较,术后3周,制动组大鼠股骨远端、腰椎骨密度较对照组下降,差异无显著性意义;术后6 周,股骨远端、腰椎骨密度降低(P < 0.05)。制动组与对照组肱骨近端、骨盆骨密度差异无显著性意义。术后6周,脊髓损伤组骨盆、股骨远端骨密度低于制动组 (P < 0.05),腰椎骨密度高于制动组 (P < 0.05)。术后3周,脊髓损伤组及制动组大鼠腰椎、肱骨近端及骨盆最大载荷、结构刚度与对照组差异无显著性意义。术后3,6周,脊髓损伤组股骨远端最大载荷、结构刚度均低于对照组 (P < 0.05,P < 0.01),肱骨近端及腰椎差异无显著性意义。 结论：脊髓损伤及制动均可导致骨质疏松的发生,但骨密度及生物力学变化不同,即两种骨质疏松所发生的部位不同,即使同一部位发生骨质疏松,发生的程度也不相同。     

Tendon reflexes for predicting movement recovery after acute spinal cord injury in humans.

OBJECTIVE: Use the tendon reflex to examine spinal cord excitability after acute spinal cord injury (SCI), relating excitability findings to prognosis. METHODS: We conducted repeated measures of reflex responses to mechanical taps at the patellar and Achilles tendons of the lower limbs, and the wrist flexor tendons of the upper limbs in persons with acute SCI, beginning as early as the day of injury. The single largest EMG response (peak-to-peak) for each site was recorded. Subjects were compared based on level of injury and final neurologic status of lower limb motor function (i.e. absence of any voluntary recruitment in a lower limb muscle: motor-complete; voluntary recruitment in 1 or more lower-limb muscles: motor-incomplete). RESULTS: We studied 229 subjects with acute SCI. Persons with injury to the cervical or thoracic spinal cord and who were (or became) motor-incomplete showed large tendon responses, even at the time of initial evaluation. In combination with larger tendon response amplitudes, the presence of the 'crossed-adductor' response to patellar tendon taps at the acute stage was highly predictive of functional motor recovery following SCI. In marked contrast, tendon responses were small (e.g. < 0.1 mV) or absent in persons with acute, motor-complete injury (and which remained motor-complete), and the crossed-adductor response was never seen. Reflex amplitudes and the incidence of the crossed-adductor response increased somewhat over time in persons with motor-complete SCI, but did not approach the values seen in motor-incomplete subjects. CONCLUSIONS: Taken together, tendon response amplitude and reflex spread were sensitive and specific indicators of preserved supraspinal control over lower limb musculature in subjects with acute SCI. A simple algorithm using these outcome measures predicted a 'motor-complete' status with 100% accuracy, and a motor-incomplete status with accuracy exceeding 91%.     

Visual system pathology in humans and animal models of blast injury

Injury from blast exposure is becoming a more prevalent cause of death and disability worldwide. The devastating neurological impairments that result from blasts are significant and lifelong. Progress in the development of effective therapies to treat injury has been slowed by its heterogeneous pathology and the dearth of information regarding the cellular mechanisms involved. Within the last decade, a number of studies have documented visual dysfunction following injury. This brief review examines damage to the visual system in both humans and animal models of blast injury. The in vivo use of the retina as a surrogate to evaluate brain injury following exposure to blast is also highlighted.     

Neural plasticity after spinal cord injury

Plasticity changes of uninjured nerves can result in a novel neural circuit after spinal cord injury, which can restore sensory and motor functions to different degrees. Although processes of neural plasticity have been studied, the mechanism and treatment to effectively improve neural plasticity changes remain controversial. The present study reviewed studies regarding plasticity of the central nervous system and methods for promoting plasticity to improve repair of injured central nerves. The results showed that synaptic reorganization, axonal sprouting, and neurogenesis are critical factors for neural circuit reconstruction. Directed functional exercise, neurotrophic factor and transplantation of nerve-derived and non-nerve-derived tissues and cells can effectively ameliorate functional disturbances caused by spinal cord injury and improve quality of life for patients.