Emergence of functionally aberrant and subsequent reduction of neuromuscular connectivity and improved motor performance after cervical spinal cord injury in Rhesus.

Introduction: The paralysis that occurs after a spinal cord injury, particularly during the early stages of post-lesion recovery (∼6 weeks), appears to be attributable to the inability to activate motor pools well beyond their motor threshold. In the later stages of recovery, however, the inability to perform a motor task effectively can be attributed to abnormal activation patterns among motor pools, resulting in poor coordination. Method: We have tested this hypothesis on four adult male Rhesus monkeys (Macaca mulatta), ages 6-10 years, by recording the EMG activity levels and patterns of multiple proximal and distal muscles controlling the upper limb of the Rhesus when performing three tasks requiring different levels of skill before and up to 24 weeks after a lateral hemisection at C7. During the recovery period the animals were provided routine daily care, including access to a large exercise cage (5' × 7' × 10') and tested every 3-4 weeks for each of the three motor tasks. Results: At approximately 6-8 weeks the animals were able to begin to step on a treadmill, perform a spring-loaded task with the upper limb, and reaching, grasping, and eating a grape placed on a vertical stick. The predominant changes that occurred, beginning at ∼6-8 weeks of the recovery of these tasks was an elevated level of activation of most motor pools well beyond the pre-lesion level. Discussion: As the chronic phase progressed there was a slight reduction in the EMG burst amplitudes of some muscles and less incidence of co-contraction of agonists and antagonists, probably contributing to an improved ability to selectively activate motor pools in a more effective temporal pattern. Relative to pre-lesion, however, the EMG patterns even at the initial stages of recovery of successfully performing the different motor tasks, the level of activity of most muscle remained higher. Perhaps the most important concept that emerges from these data is the large combinations of adaptive strategies in the relative level of recruitment and the timing of the peak levels of activation of different motor pools can progressively provide different stages to regain a motor skill.

Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury.

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.

Restorative effects of human neural stem cell grafts on the primate spinal cord.

We grafted human spinal cord-derived neural progenitor cells (NPCs) into sites of cervical spinal cord injury in rhesus monkeys (Macaca mulatta). Under three-drug immunosuppression, grafts survived at least 9 months postinjury and expressed both neuronal and glial markers. Monkey axons regenerated into grafts and formed synapses. Hundreds of thousands of human axons extended out from grafts through monkey white matter and synapsed in distal gray matter. Grafts gradually matured over 9 months and improved forelimb function beginning several months after grafting. These findings in a 'preclinical trial' support translation of NPC graft therapy to humans with the objective of reconstituting both a neuronal and glial milieu in the site of spinal cord injury.

A Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates (Macaca mulatta).

The development of a non-human primate (NHP) model of spinal cord injury (SCI) based on mechanical and computational modeling is described. We scaled up from a rodent model to a larger primate model using a highly controllable, friction-free, electronically-driven actuator to generate unilateral C6-C7 spinal cord injuries. Graded contusion lesions with varying degrees of functional recovery, depending upon pre-set impact parameters, were produced in nine NHPs. Protocols and pre-operative magnetic resonance imaging (MRI) were used to optimize the predictability of outcomes by matching impact protocols to the size of each animal's spinal canal, cord, and cerebrospinal fluid space. Post-operative MRI confirmed lesion placement and provided information on lesion volume and spread for comparison with histological measures. We evaluated the relationships between impact parameters, lesion measures, and behavioral outcomes, and confirmed that these relationships were consistent with our previous studies in the rat. In addition to providing multiple univariate outcome measures, we also developed an integrated outcome metric describing the multivariate cervical SCI syndrome. Impacts at the higher ranges of peak force produced highly lateralized and enduring deficits in multiple measures of forelimb and hand function, while lower energy impacts produced early weakness followed by substantial recovery but enduring deficits in fine digital control (e.g., pincer grasp). This model provides a clinically relevant system in which to evaluate the safety and, potentially, the efficacy of candidate translational therapies.

Leveraging biomedical informatics for assessing plasticity and repair in primate spinal cord injury.

Recent preclinical advances highlight the therapeutic potential of treatments aimed at boosting regeneration and plasticity of spinal circuitry damaged by spinal cord injury (SCI). With several promising candidates being considered for translation into clinical trials, the SCI community has called for a non-human primate model as a crucial validation step to test efficacy and validity of these therapies prior to human testing. The present paper reviews the previous and ongoing efforts of the California Spinal Cord Consortium (CSCC), a multidisciplinary team of experts from 5 University of California medical and research centers, to develop this crucial translational SCI model. We focus on the growing volumes of high resolution data collected by the CSCC, and our efforts to develop a biomedical informatics framework aimed at leveraging multidimensional data to monitor plasticity and repair targeting recovery of hand and arm function. Although the main focus of many researchers is the restoration of voluntary motor control, we also describe our ongoing efforts to add assessments of sensory function, including pain, vital signs during surgery, and recovery of bladder and bowel function. By pooling our multidimensional data resources and building a unified database infrastructure for this clinically relevant translational model of SCI, we are now in a unique position to test promising therapeutic strategies' efficacy on the entire syndrome of SCI. We review analyses highlighting the intersection between motor, sensory, autonomic and pathological contributions to the overall restoration of function. This article is part of a Special Issue entitled SI: Spinal cord injury.

Development of a database for translational spinal cord injury research.

Efforts to understand spinal cord injury (SCI) and other complex neurotrauma disorders at the pre-clinical level have shown progress in recent years. However, successful translation of basic research into clinical practice has been slow, partly because of the large, heterogeneous data sets involved. In this sense, translational neurological research represents a "big data" problem. In an effort to expedite translation of pre-clinical knowledge into standards of patient care for SCI, we describe the development of a novel database for translational neurotrauma research known as Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI). We present demographics, descriptive statistics, and translational syndromic outcomes derived from our ongoing efforts to build a multi-center, multi-species pre-clinical database for SCI models. We leveraged archived surgical records, postoperative care logs, behavioral outcome measures, and histopathology from approximately 3000 mice, rats, and monkeys from pre-clinical SCI studies published between 1993 and 2013. The majority of animals in the database have measures collected for health monitoring, such as weight loss/gain, heart rate, blood pressure, postoperative monitoring of bladder function and drug/fluid administration, behavioral outcome measures of locomotion, and tissue sparing postmortem. Attempts to align these variables with currently accepted common data elements highlighted the need for more translational outcomes to be identified as clinical endpoints for therapeutic testing. Last, we use syndromic analysis to identify conserved biological mechanisms of recovery after cervical SCI between rats and monkeys that will allow for more-efficient testing of therapeutics that will need to be translated toward future clinical trials.

Animal models of neurologic disorders: a nonhuman primate model of spinal cord injury.

Primates are an important and unique animal resource. We have developed a nonhuman primate model of spinal cord injury (SCI) to expand our knowledge of normal primate motor function, to assess the impact of disease and injury on sensory and motor function, and to test candidate therapies before they are applied to human patients. The lesion model consists of a lateral spinal cord hemisection at the C7 spinal level with subsequent examination of behavioral, electrophysiological, and anatomical outcomes. Results to date have revealed significant neuroanatomical and functional differences between rodents and primates that impact the development of candidate therapies. Moreover, these findings suggest the importance of testing some therapeutic approaches in nonhuman primates prior to the use of invasive approaches in human clinical trials. Our primate model is intended to: 1) lend greater positive predictive value to human translatable therapies, 2) develop appropriate methods for human translation, 3) lead to basic discoveries that might not be identified in rodent models and are relevant to human translation, and 4) identify new avenues of basic research to "reverse-translate" important questions back to rodent models.

Methods for functional assessment after C7 spinal cord hemisection in the rhesus monkey.

BACKGROUND: Reliable outcome measures are essential for preclinical modeling of spinal cord injury (SCI) in primates. MEASURES: need to be sensitive to both increases and decreases in function in order to demonstrate potential positive or negative effects of therapeutics. OBJECTIVES: To develop behavioral tests and analyses to assess recovery of function after SCI in the nonhuman primate. METHODS: In all, 24 male rhesus macaques were subjected to complete C7 lateral hemisection. The authors scored recovery of function in an open field and during hand tasks in a restraining chair. In addition, EMG analyses were performed in the open field, during hand tasks, and while animals walked on a treadmill. Both control and treated monkeys that received candidate therapeutics were included in this report to determine whether the behavioral assays were capable of detecting changes in function over a wide range of outcomes. RESULTS: The behavioral assays are shown to be sensitive to detecting a wide range of motor functional outcomes after cervical hemisection in the nonhuman primate. Population curves on recovery of function were similar across the different tasks; in general, the population recovers to about 50% of baseline performance on measures of forelimb function. CONCLUSIONS: The behavioral outcome measures that the authors developed in this preclinical nonhuman primate model of SCI can detect a broad range of motor recovery. A set of behavioral assays is an essential component of a model that will be used to test efficacies of translational candidate therapies for SCI.