Restoring walking after spinal cord injury

Abstract

One of the most obvious deficits following a spinal cord injury is the difficulty in walking, forcing many patients to use wheelchairs for locomotion. Over the past decade considerable effort has been directed at promoting the recovery of walking and to find effective treatments for spinal cord injury. Advances in our knowledge of the neuronal control of walking have led to the development of a promising rehabilitative strategy in patients with partial spinal cord injury, namely treadmill training with partial weight support. The current focus is on developing more efficient training protocols and automating the training to reduce the physical demand for the therapists. Mechanisms underlying training-induced improvements in walking have been revealed to some extent in animal studies. Another strategy for improving the walking in spinal cord injured patients is the use of functional electric stimulation of nerves and muscles to assist stepping movements. This field has advanced significantly over the past decade as a result of developments in computer technology and the miniaturization of electronics. Finally, basic research on animals with damaged spinal cords has focused on enhancing walking and other motor functions by promoting growth and regeneration of damaged axons. Numerous important findings have been reported yielding optimism that techniques for repairing the injured spinal cord will be developed in the near future. However, at present no strategy involving direct treatment of the injured spinal cord has been established for routine use in spinal cord injured patients. It now seems likely that any successful protocol in humans will require a combination of a treatment to promote re-establishing functional connections to neuronal networks in the spinal cord and specialized rehabilitation training to shape the motor patterns generated by these networks for specific behavioral tasks.

Introduction

The restoration of motor and sensory function following damage or disease of the nervous system has emerged as one of the most pressing and challenging problems in clinical neuroscience. The sense of urgency is fueled by two major factors: numbers and cost. The incidence of persons living with disabilities due to central nervous system damage (e.g., stroke and spinal cord injury) and disease (e.g., Alzheimer’s and Parkinson’s disease) is increasing due to improvements in palliative care and a rising life expectancy in the general population. Apart from the obvious adverse impact on the quality of life and the social cost of disrupting families and social networks, the increasing numbers place an enormous demand on health care systems. The cost for treating some of these conditions is staggering. Spinal cord injury, for example, occurs most frequently in young adults (predominantly males) and life expectancy of paraplegic patients beyond the time of injury is normal. Thus injured individuals live with severe disabilities for decades. The total costs for the first year of care of paraplegic and quadriplegic patients has been estimated at US$ 152,000 and 417,000, respectively, and the lifetime care of a 25-year-old paraplegic patient is about US$ 750,000 (data from http://www.neurolaw.com).

The neuroscience community is responding vigorously to the challenge of restoring function after damage and disease of the nervous system, and is receiving substantial funding for this enterprise. Although the difficulty of the task is well-recognized, there is a sense of optimism that major advances will be made in the near future. The promise of new strategies based on increasing understanding of mechanisms of neuronal growth, growth cone collapse, neuronal death, and on the ability to engineer cells for specific functions, is fueling this optimism. This is especially true in the field of spinal cord injury as evidenced by the large number of recent reviews on strategies for repairing the damaged spinal cord and improving motor functions (Becker et al., 2003, Blits et al., 2002, David and Lacroix, 2003, Edgerton and Roy, 2002, Fawcett, 2002, Fouad et al., 2001, Gimenez y Ribotta et al., 2002, Harkema, 2001, Houle and Tessler, 2003, Hulsebosch, 2002, Priestley et al., 2002, Rossignol, 2000, Schwab, 2002, Selzer, 2003, Wickelgren, 2002). Many investigations have reported improved motor function by the application of procedures that facilitate axonal growth and regeneration and by strategies that promote use of the affected limbs. The main objective of this review is to evaluate the success of these procedures in enhancing one specific function, namely walking. Although restoration of walking is usually not the highest priority of patients with spinal cord injury (restoration of bladder, bowel and sexual function are generally regarded as more important), it is a behavior that is relatively easily quantified and thus used extensively for assessing the efficacy of procedures designed to improve function after spinal cord injury in animal models. Moreover, we now have a reasonably good understanding of the neuronal mechanisms generating the motor pattern for walking in animals (Grillner, 1981, McCrea, 2001, Pearson, 2003b) and substantial progress has been made in establishing these mechanisms in humans (Dietz and Duysens, 2000, Duysens and Van de Crommert, 1998) thus allowing insight into the neuronal events associated with improved function. For readers specifically interested in the restoration of other functions such as reaching, respiration and micturition in animal models of spinal cord injury we refer you to the following articles: reaching (Bradbury et al., 2002, Thallmair et al., 1998), respiration (Golder et al., 2003, Li et al., 2003, McCrea, 2001), micturition (Shefchyk, 2002).

In this review we concentrate on investigations reporting significant improvement in walking produced by two main procedures: intense training on a treadmill and promoting regeneration of axons in the spinal cord. We begin by outlining the main concepts related to the neuronal control of walking. Knowledge of these concepts is essential for any mechanistic interpretation of events underlying improvements in walking produced by any procedure, as well as for the rational development of procedures for enhancing walking in spinal cord injured patients. Although the basic concepts have come primarily from studies on the cat, less extensive studies on primates (humans and monkeys) and rodents (rats and mice) indicate that they are generally applicable to all mammals.