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.

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates.

Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species have not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than did rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys but nearly absent in rats. Our results uncover pronounced interspecies differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury reemphasizes the importance of primate models for designing clinically relevant treatments.

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.

Early social experience affects behavioral and physiological responsiveness to stressful conditions in infant rhesus macaques (Macaca mulatta).

Studies on early development have demonstrated the profound effects of early social experience on the behavioral development and physiology of young rhesus macaques. Given these relationships, we hypothesized that rhesus macaques exposed to different nursery-rearing conditions may develop unique biobehavioral profiles. If this is true, the assessment of temperament may allow us to pinpoint successful rearing environments, thus improving the overall health of nonhuman primates that are raised in captive environments. We conducted biobehavioral assessments in order to examine differences in the development of infants raised under four different peer-rearing conditions (continuous pairing (CP), intermittent pairing, CP with partner rotation, and intermittent rotational pairing) and compared these animals with data from a mother-reared control group. Overall, continuous rotationally paired animals were most similar to mother-reared controls on most behavioral and temperament measures, suggesting that more socially complex rearing environments (greater number of social partners) favor a more active behavioral style. Cortisol profiles of mother-reared controls were similar to both CP groups, and these three groups had higher cortisol concentrations than the intermittent rotational-pairing group. In addition, intermittently paired infants displayed a significantly higher frequency of self-stroke behavior during a human intruder challenge, an abnormal behavior also known as floating limb which has been shown to be a precursor of self-biting. Overall, the data are consistent with the idea that social complexity in the nursery, as operationalized in our continuous rotational pairing, leads to a biobehavioral profile that is most similar to that of infants raised by their mothers in large, socially complex, cages.

Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury.

Although axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, we administered C7 spinal cord hemisections to adult rhesus monkeys and analyzed behavioral, electrophysiological and anatomical adaptations. We found marked spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research.

The effects of four nursery rearing strategies on infant behavioral development in rhesus macaques (Macaca mulatta).

Nursery rearing is the single most important risk factor in the development of severe forms of abnormal behavior, such as self-biting, in rhesus macaques. This practice is common in research laboratories and typically involves continuous pair housing of infants without maternal contact. We examined the effects of variation in peer socialization on the behavioral development of rhesus infants by exposing 32 newborn infants to 4 different socialization routines: continuously paired; intermittently paired; continuously paired rotationally (partners rotated within the group once a week); and intermittently paired rotationally. Analyses revealed that infants paired intermittently exhibited 'floating limb' and self-biting behavior at significantly higher frequencies than those reared by using any other strategy. Results also suggested that continuous pairing was most effective in reducing the development of abnormal behaviors (that is, self-bite and floating limb), whereas intermittent pairing significantly reduced partner clinging and geckering. A principal component analysis revealed that floating limb behavior and self-biting are strongly associated. Self-biting began as early as 32 d of age, and a negative binomial regression on data of floating limb and self-biting revealed that early development of floating limb behavior predicts self-biting behavior later in development. Despite the significant effects of rearing strategies on the frequency of abnormal behaviors, we note that animals in all 4 treatment groups developed these traits to some degree. We suspect that the solitary incubator environment may be a trigger for the development of abnormal behaviors.

Reduced activity without hyperphagia contributes to obesity in Tubby mutant mice.

The Tub gene was originally identified as a spontaneous mutation in C57Bl/6J mice, and associated with adult-onset obesity (Tub MUT mice). Although the original Tub MUT mouse was identified over 15 years ago, there have been few reports on the animal's food intake, body fat percentage or energy expenditure. In this study, we report food intake, body weight from 5-20 weeks, body fat, body temperature and three different measures of physical activity behavior. Tub MUT mice display reduced food intake, uncharacteristic of many obese mouse models, and reduced voluntary wheel running with normal home cage ambulatory behavior. We conclude that motivation for food and exercise is an underlying defect in TUB MUT mice.