Progress continues in the development of reparative interventions to enhance recovery after experimental spinal cord injury (SCI). Here we discuss to what extent rodent models of SCI have limitations for ensuring the efficacy and safety of treatments for humans, and under what circumstances it would be advantageous or necessary to test treatments in nonhuman primates before clinical trials. We discuss crucial differences in the organization of the motor systems and behaviors among rodents, nonhuman primates and humans, and argue that studies in nonhuman primates are critical for the translation of some potential interventions to treat SCI in humans.Traumatic SCI has long-term health, economic and social consequences worldwide 1,2 , giving a sense of the urgency to the development of ways to treat it. Treatments that lead to at least partial functional recovery after SCI can substantially improve the quality of life of affected individuals. Consequently, there is considerable need to take to the clinic those interventions that have shown effectiveness in promoting functional improvement in laboratory animals.Progress continues in the identification of interventions that augment plasticity after injury by promoting axonal regeneration and sprouting in rodents [3][4][5][6] . Some of these treatments may be efficacious in patients with SCI, and have or are entering phase 1 clinical trials. Important differences exist, however, between the nervous systems of rodents and humans,

Locomotor training on treadmills can improve recovery of stepping in spinal cord injured animals and patients. Likewise, lesioned rats treated with antibodies against the myelin associated neurite growth inhibitory protein, Nogo-A, showed increased regeneration, neuronal reorganization and behavioural improvements. A detailed kinematic analysis showed that the hindlimb kinematic patterns that developed in anti-Nogo-A antibody treated versus treadmill trained spinal cord injured rats were significantly different. The synchronous combined treatment group did not show synergistic effects. This lack of synergistic effects could not be explained by an increase in pain perception, sprouting of calcitonin gene-related peptide (CGRP) positive fibres or by interference of locomotor training with anti-Nogo-A antibody induced regeneration and sprouting of descending fibre tracts. The differential mechanisms leading to behavioural recovery during task-specific training and in regeneration or plasticity enhancing therapies have to be taken into account in designing combinatorial therapies so that their potential positive interactive effects can be fully expressed.

Smaller spinal cord injuries often allow some degree of spontaneous behavioral improvements because of structural rearrangements within different descending fiber tracts or intraspinal circuits. In this study, we investigate whether rehabilitative training of the forelimb (forced limb use) influences behavioral recovery and plastic events after injury to a defined spinal tract, the corticospinal tract (CST). Female adult Lewis rats received a unilateral CST injury at the brainstem level. Use of the contralateral impaired forelimb was either restricted, by a cast, or forced, by casting the unimpaired forelimb immediately after injury for either 1 or 3 weeks. Forced use of the impaired forelimb was followed by full behavioral recovery on the irregular horizontal ladder, whereas animals that could not use their affected side remained impaired. BDA (biotinylated dextran amine) labeling of the intact CST showed lesion-induced growth across the midline where CST collaterals increased their innervation density and extended fibers toward the ventral and the dorsal horn in response to forced limb use. Gene chip analysis of the denervated ventral horn revealed changes in particular for growth factors, adhesion and guidance molecules, as well as components of synapse formation suggesting an important role for these factors in activity-dependent intraspinal reorganization after unilateral CST injury.

Central nervous system (CNS) injuries are particularly traumatic, owing to the limited capabilities of the mammalian CNS for repair. Nevertheless, functional recovery is observed in patients and experimental animals, but the degree of recovery is variable. We review the crucial characteristics of mammalian spinal cord function, tract development, injury and the current experimental therapeutic approaches for repair. Regenerative or compensatory growth of neurites and the formation of new, functional circuits require spontaneous and experimental reactivation of developmental mechanisms, suppression of the growth-inhibitory properties of the adult CNS tissue and specific targeted activation of new connections by rehabilitative training.

It is known that improvement in walking function can be achieved in patients suffering a movement disorder after stroke or spinal cord injury by providing intensive locomotor training. Rehabilitation robots allow for a longer and more intensive training than that achieved by conventional therapies. Robot assisted treadmill training also offers the ability to provide objective feedback within one training session and to monitor functional improvements over time. This article provides an overview of the technical features and reports the clinical data available for one of these systems known as "Lokomat". First, background information is given for the neural mechanisms of gait recovery. The basic technical approach of the Lokomat system is then described. Furthermore, new features are introduced including cooperative control strategies, assessment tools and augmented feedback. These features may be capable of further enhancing training intensity and patient participation. Findings from clinical studies are presented covering the feasibility as well as efficacy of Lokomat assisted treadmill training.

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