Restoring walking after spinal cord injury

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1 Progress in Neurobiology 73 (2004) Restoring walking after spinal cord injury Karim Fouad a,, Keir Pearson b a Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alta., Canada b Department of Physiology, University of Alberta, Edmonton, Alta., Canada Received 2 December 2003; accepted 20 April 2004 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 Elsevier Ltd. All rights reserved. Contents 1. Introduction Generation of the motor pattern for walking Central pattern generation Chemical modulation of central pattern generators Descending activation of central pattern generators Sensory regulation of stepping Enhancement of functional recovery of walking by training Enhancement in spinal cord injured patients Enhancement and mechanisms in rodents Enhancement and mechanisms in cats Enhancement of functional recovery of walking by regeneration of descending axons Strategies to repair the injured spinal cord Bridging the lesion site Administration of neurotrophic factors Blocking inhibitory molecules in the growth environment Abbreviations: 5-HT, 5-hydroxytryptamine; BDNF, brain derived neurotrophic factor; camp, cyclic adenosine monophosphate; CNS, central nervous system; CPG, central pattern generator; CST, corticospinal tract; EMG, electromyographic; FES, functional electrical stimulation; L-DOPA, l-dihydroxyphenylalanine; MAG, myelin associated glycuprotein; NMDA, N-methyl-d-aspartate; NT-3, neurotrophin 3; OEGs, olfactory ensheathing glia; GABA, gamma amino butyric acid Corresponding author. Tel.: ; fax: address: (K. Fouad) /$ see front matter 2004 Elsevier Ltd. All rights reserved. doi: /j.pneurobio

2 108 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) Assessing walking behavior Improved walking following treatments to promote regeneration Anatomically complete spinal cord injury Incomplete spinal cord injury Criteria for demonstrating functional regeneration Summary Acknowledgements References 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 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. 2. Generation of the motor pattern for walking 2.1. Central pattern generation A common feature of the motor pattern for walking in all mammals is rhythmic alternation of burst activity in flexor

3 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) and extensor muscles 1 of the limbs. In quadrupeds there is overwhelming evidence that neuronal networks in the spinal cord can generate rhythmic motor patterns in flexor and extensor motoneurons in the absence of sensory feedback for the limbs (Bem et al., 1993; Graham Brown, 1911; Grillner, 1981; Grillner and Zangger, 1979). These networks are referred to as central pattern generators (CPGs). A premise of much of the current research on promoting neuronal regeneration in the injured spinal cord is that functional connections to lumbar CPGs can be restored, thus promoting improvements in walking. In quadrupeds we know the CPG for each hind leg is distributed within the lumbar region of the spinal cord, with the more anterior segments (L2 to L4) appearing to contain the primary elements in the network (Cazalets et al., 1995; Deliagina et al., 1983; Kiehn and Kjaerulff, 1998; Kremer and Lev-Tov, 1997). An influential concept, originally proposed by Graham Brown (1911), was that separate networks generate bursts of activity in flexor and extensor motoneurons (which he referred to as half-centers) and that these two centers mutually inhibit each other. At present this concept is adequate for addressing many issues related to the neuronal control of walking, but it must be kept in mind that the central pattern generating networks can produce a variety of patterns depending on the manner in which they are activated, the chemical environment, and the extent of isolation from other neural tissue. In an attempt to account for this flexibility Grillner (1981) proposed that the CPG for each leg is actually composed of a set of unit burst generators (each set regulating burst activity in a group of synergist muscles) with the coupling between each set depending on the locomotor task (walking forward versus backward for example). So far, however, the characteristics of the putative unit-burst-generators have not been clearly defined for any mammalian walking system. The ultimate goal of research into strategies for reestablishing walking function after spinal cord injury is to develop procedures that can be safely and effectively applied to humans. It is essential, therefore, to know the similarities and differences in the neuronal control of walking in primates (especially humans) and the animal species used in basic research aimed at developing these strategies (mice, rats and cats). Uncertainties about whether non-primates are suitable models for human walking (Illis, 1995; Vilensky and O Connor, 1997) have not been resolved by recent studies on primate locomotion, although there is mounting evidence that some basic features are shared in primates and non-primates. Undoubtedly the greatest uncertainty is whether central pattern generating networks exist in the human spinal cord. If CPGs do exist then the minimal expectation is that patients with complete spinal cord injury should have the capacity to generate rhythmic leg movements with the underlying motor patterns displaying some features of the normal pattern for walking, e.g., reciprocal bursts of activity in flexors and extensors and alternating activity in the corresponding muscles of the two legs. 2 Rhythmic stepping movements are not common in patients with complete spinal cord injury (Bussel et al., 1988; Dimitrijevic et al., 1998; Kuhn, 1950), but have been frequently observed in patients with severe incomplete injuries, especially following locomotor training (Calancie et al., 1994; Dietz et al., 1995; Wernig et al., 1999). One interpretation of these facts is that CPGs exist but cannot be readily activated following complete injury. The fact that direct electrical stimulation of the lumbar cord in complete spinal cord injured patients can evoke locomotor-like activity (Dimitrijevic et al., 1998) supports this interpretation. Another interpretation is that the human locomotor system relies heavily on descending signals from supraspinal regions for the patterning of locomotor activity and that spinal pattern generating circuitry is of relatively minor importance in man as compared to quadrupeds (Vilensky and O Connor, 1997, 1998). Some additional support for the existence of central pattern generators in humans comes from recent studies on stepping in young infants (Lamb and Yang, 2000; Pang and Yang, 2000). Infants at birth will step continuously when the feet are placed on the belt of a moving treadmill. The regulation of infant stepping closely resembles stepping in spinal cats, in that the rate adapts to changes in treadmill speed and phase transitions are regulated by afferent signals from the hip-position and load-sensitive receptors (Pang and Yang, 2000). In young infants descending pathways from the brain to the spinal cord are immature and are not considered to be functional. Thus infant stepping is most likely regulated primarily by neuronal circuits in the spinal cord. The presence of phasic afferent signals in this behavior obviously excludes a definitive demonstration of the existence of locomotor CPGs, but the close similarity with the stepping behavior in spinal cats, where we know CPGs exist, provides indirect support for the CPG concept in humans. A likely scenario is that as descending pathways mature they play an increasingly important role in the patterning of locomotor activity to enable information needed for balance from the visual and vestibular systems to be integrated into the rhythmic pattern generating network. The encephalization of the walking system may lead to less autonomous functioning of the CPG networks but not necessarily a restructuring of these networks or permanently removing them. Functional suppression with retention of basic circuitry is known to occur in the sound localization system of the barn owl (Knudsen, 2002). 1 Not all muscles can be classified as strictly flexors or extensors, but in general each muscle is primarily active in only one phase of the step cycle. 2 A more stringent criterion is that these patterns should be generated in the absence of sensory feedback, but this is impractical for investigations on humans.

4 110 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) Apart from the issue about whether or not locomotor CPGs exist in humans, there is also uncertainty about whether CPGs are important elements in the pattern generating network in any primate (Vilensky and O Connor, 1998). An extensive study on Macaque monkeys with transected spinal cords failed to produce hind leg stepping using procedures similar to those used on cats (Eidelberg et al., 1981b) thus casting doubt about the existence of locomotor CPGs in primates. More recently, however, a Squirrel monkey with a transected spinal cord was trained to step on a treadmill by a slight modification of the earlier training procedure (Vilensky and O Connor, 1998). This procedure ensured that the hind legs supported much of the animal s weight during training. The only direct evidence for the existence of locomotor CPGs in primates is that fictive locomotion can be evoked in Marmoset monkeys following the administration of Clonidine (an alpha-2 receptor agonist) or NMDA (a glutamate receptor agonist) (Fedirchuk et al., 1998) Chemical modulation of central pattern generators It is well known that the activity in central patterns generators can be influenced strongly by drugs and chemicals related to naturally occurring transmitters in the spinal cord. Because this fact has important implications for understanding mechanisms underlying functional improvement of walking, we have reviewed recent investigations on chemical modulation of CPGs in the mammalian spinal cord. Ideally the examination of the action of modulators should be done in the absence of phasic sensory signal from peripheral receptors. However, the actions of drugs on stepping in spinalized animals and humans with partial and complete spinal cord injury are generally interpreted as actions on the locomotor CPGs. For this reason we include data from studies on stepping in the following summaries. An important early finding in spinal cats was that intravenous administration of L-DOPA enabled brief electrical stimulation of high-threshold afferents to evoked long-duration bursts of activity in flexor and extensor motoneurons, and in some instances, to short sequences of alternating burst activity in flexor and extensor muscles (Jankowska et al., 1967a,b). Concomitant application of Nialamide (a drug enhancing the action of noradrenaline) resulted in long sequences of alternating activity. These observations focused attention on the role of descending monoaminergic systems in the initiation and maintenance of locomotor activity. Subsequently Clonidine was discovered to enable stepping in acute spinal cats (Forssberg and Grillner, 1973) thus strengthening the view that noradrenergic systems were particularly important role in regulating walking. However, noradrenaline and other monoamines do not appear to be necessary for the production of stepping in normal cats, since their chemical removal does not prevent walking (Steeves et al., 1980). Under normal conditions, the initiation of walking in the cat may depend primarily on activity in descending glutamatergic systems (Chau et al., 2002; Douglas et al., 1993), with activity in the aminergic systems functioning to modulate ongoing rhythmic activity. This has been strongly implied by the fact the initiation of locomotion in other vertebrate systems (especially lamprey and tadpole swimming) is primarily dependent on input to spinal CPGs from descending glutamatergic systems, and supported by the fact that intrathecal application of NMDA can initiate fictive locomotion in acute decerebrate cats (Douglas et al., 1993). In addition, NMDA enhances stepping in spinal cats when applied 1 2 weeks after the transection of the spinal cord (Chau et al., 2002) while application of the NMDA receptor antagonist, AP5 abolishes locomotion in spinal cats (Chau et al., 2002). The action of NMDA and AP5 in intact cats has not been described in detail. Because the majority of studies aimed at enhancing function following spinal cord injury are currently being done on rodents (especially rats), it is particularly important to understand the intrinsic capacities of neuronal networks in the spinal cord in these animals. We know that spinal neuronal networks of rodents can produce rhythmic locomotor activity in the absence of sensory feedback from the periphery (see previous section) and that a variety of pharmacological agents influence these central pattern-generating networks. Perhaps the most potent is serotonin. Fictive locomotor activity is readily produced by the application of low concentrations of serotonin in adult and neonatal rats, while robust stepping can be produced in adult chronic spinal rats by intrathecal application of serotonin (Feraboli-Lohnherr et al., 1999). Of special interest, especially in regard to interpreting mechanisms for functional recovery following regeneration of descending axons, is that implantation of serotonergic neurons (derived from the Raphe nucleus) into the caudal thoracic segments of the spinal cord evokes stepping in adult spinal rats (Feraboli-Lohnherr et al., 1997; Gimenez y Ribotta et al., 1998a). This finding clearly demonstrates the capacity of the isolated lumbar cord of the rat to generate powerful locomotor patterns in the presence of appropriate levels of a specific amine. This raises the possibility that improved stepping of the hind legs following procedures to enhance neuronal growth and regeneration (see Section 4) may, in some instances, be due to a modification in the chemical environment of neurons in the lumbar region of the spinal cord and not due to the formation of neuronal connections from regenerated axons. Other pharmacological agents having marked influences on the locomotor pattern generator in rodents are L-DOPA (Iwahara et al., 1991; McCrea et al., 1994), dopamine (Kiehn and Kjaerulf, 1996), and NMDA (Cazalets et al., 1992; Cowley and Schmidt, 1995; Kiehn et al., 1996). NMDA alone is very effective in evoking locomotor rhythms in neonatal rats thus supporting the notion that the excitatory amino acid glutamate is especially important the activation of locomotor CPGs in mammals. Surprisingly, the

5 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) adrenergic drug Clonidine is ineffective in facilitating stepping in acute and chronic spinal rats (S. Rossignol, personal communication) and mice (Leblond et al., 2003). Based on current data from pharmacological studies on rodents, cats and humans it is quite clear that the actions of different drugs can be quite different in different species. For example, Clonidine is very effective in enabling locomotion in acute and chronic spinal cats, but is ineffective in rodents (Leblond et al., 2003). On the other hand, serotonin is effective in initiating rhythmic motor activity in rodents (Feraboli-Lohnherr et al., 1999) but does not have this action in cats (Barbeau and Rossignol, 1991), while in humans blocking the receptors for serotonin may help facilitate walking in patients with spinal cord injury (Fung et al., 1990). Thus positive results from animal studies must be treated cautiously when considering translation to human patients Descending activation of central pattern generators Intuitively it seems that attempts to enhance functional recovery of locomotion by promoting the growth and regeneration of damaged descending axons would benefit from knowledge about the identity of specific descending pathways normally involved in the initiation and maintenance of locomotion. This would allow targeting of these pathways for studies on regeneration. There is now considerable evidence that the major pathways initiating locomotion are located in the ventral region of the spinal cord in rodents, cats and primates (Schucht et al., 2002; Brustein and Rossignol, 1998; Eidelberg et al., 1981b). Axons in this region of the spinal cord originate from serotonergic neurons from the Raphe nucleus, noradrenergic neurons from the locus coeruleus, and glutamatergic neurons mainly from the nucleus reticularis gigantocellularis and the pontine reticular nucleus. All the transmitters used by these systems have been found to either initiate or strongly modulate locomotor activity (see previous section). Detailed investigations in cats, for example, have revealed that animals can neither support their hindquarters nor step with their hind legs immediately after ventral and ventrolateral lesions at low thoracic levels (Brustein and Rossignol, 1998; Eidelberg, 1981; Steeves and Jordan, 1980). On the other hand, lesions confined to the dorsolateral pathways (Jiang and Drew, 1996) and sparing small patches of tissue in the ventral and ventrolateral quadrants (Eidelberg et al., 1981a) results in relatively minor modifications in stepping. Two major descending pathways are located in the ventrolateral regions of the spinal cord: reticulospinal and vestibulospinal. The latter is involved in the maintenance of posture and balance during walking, while the former is most likely involved in the initiation and maintenance of locomotion. Indeed, fictive locomotion in acute decerebrate cats evoked by electrical stimulation of the mesencephalic locomotor region (a stimulation site known to indirectly activate descending reticulospinal neurons) is abolished by transection of ventrolateral tracts (Noga et al., 1991). Lesion studies in rodents and primates also indicate the importance of ventral pathways in controlling locomotion (Eidelberg, 1981; Eidelberg et al., 1981b; Schucht et al., 2002). A detailed analysis of the effects of lesions in the rat spinal cord on locomotion showed that preservation of a small number of axons in the ventral or lateral funiculus allowed some stepping of the hind legs, whereas sectioning these tracts and leaving small regions of tissue in the dorsal funiculus resulted in complete paraplegia (Loy et al., 2002a; Schucht et al., 2002). As with cats, the strongest relationship between stepping and the location of preserved tissues was spared white matter in the region of the reticulospinal tract. Although dorsally located pathways are incapable of initiating locomotion immediately after lesions to ventral pathways in experimental animals, it has been suggested that over time they establish functional input to spinal pattern generating networks (Bem et al., 1995; Brustein and Rossignol, 1998). Of some interest is that demanding locomotor tasks, such as walking on a grid, requires preservation of dorsal pathways in addition to ventral pathways. This is consistent with the notion that the dorsally located corticospinal and rubrospinal pathways are especially important in transmitting voluntary commands from the motor cortex to the spinal cord. The dorsal pathways may play a more prominent role in initiating stepping in humans since stepping can occur following surgery to interrupt transmission in ventral pathways (Nathan, 1994). Recent studies using transcranial magnetic stimulation have also suggested that the corticospinal pathways may be important in controlling the ongoing activity in leg muscles during walking in humans, especially during the swing phase (Capaday et al., 1999; Petersen et al., 2003) Sensory regulation of stepping An important factor in enhancing recovery of locomotion after spinal cord injury is sensory feedback from the moving legs. Phasic afferent signals play a major role in promoting stepping of the hind legs in spinal rats (Timoszyk et al., 2002) and cats (Bouyer and Rossignol, 2001), and stepping in humans with partial spinal cord injury (Harkema, 2001; Wernig et al., 1999). In Section 3, we review this evidence, but first we will summarize our current understanding of the role afferent feedback plays in the generation of the normal motor pattern for walking. Most of our knowledge about the afferent control of walking comes from investigations on the cat (see the following reviews for detailed summaries: McCrea, 2001; Pearson, 2003b). Less extensive data from investigations on rodents (Fouad and Pearson, 1997) and non-invasive investigations in humans (Duysens et al., 2000) indicate that the same features are common to rodents, cats and humans. In the cat, afferent feedback powerfully regulates the step cycle principally by controlling the duration of the stance phase and the magnitude of activity in muscles active during the stance phase (mainly extensors). Two sources of sensory information regulate stance duration:

6 112 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) stretch-sensitive receptors in hip flexors muscles (Grillner and Rossignol, 1978; Hiebert et al., 1996; Kriellaars et al., 1994) and load-sensitive receptors in the ankle extensor muscles (Duysens and Pearson, 1980; Whelan et al., 1995). The general rule governing afferent regulation of stance duration is that the initiation of swing requires the leg to be extended (signaled by hip afferents) and unloaded (signaled by load receptors in extensor muscles). The same rule has been identified in the walking system of human infants (Pang and Yang, 2002), and it may also be true for walking in rats (Fouad and Pearson, 1997). Whether or not this rule applies to walking in adult humans is uncertain (see Duysens et al., 2000 for discussion on this topic). In cats, afferent feedback from receptors in extensor muscles during the stance phase of walking has been estimated to enhance force production in the ankle extensors by about 30% (Stein et al., 2000) and to almost double the level of activity in ankle extensors during the early part of the stance phase in humans (Yang et al., 1991). This reinforcing action of muscle afferents in humans was originally attributed to activation of the primary muscle spindles but more recent studies have strongly implicated the source of the reinforcing signal as the secondary muscle spindles (Grey et al., 2001, 2002). On the other hand, in the cat, the reinforcing signal most likely arises from the load-sensitive Golgi tendon organs (Hiebert and Pearson, 1999). The reinforcing action of afferent feedback on the activity in leg extensor muscles has also been described in humans with partial or complete spinal cord injuries (Dietz, 1998; Dietz and Duysens, 2000; Harkema et al., 1997). In these patients the level of activity in leg extensor muscles is strongly dependent upon the amount of weight support (controlled by partially supporting the patient in a harness), while the profile of activity is not strongly related to kinematic parameters such as muscle length and rate of muscle length change. Cutaneous receptors can powerfully influence the step cycle when stimulated (Burke, 1999; Drew and Rossignol, 1987; McCrea, 2001; Zehr and Chua, 1999) but the extent to which signals from cutaneous receptors participate in the production of the motor pattern for unimpeded walking is uncertain. Recent studies in normal cats have shown that removing cutaneous input from the paws of the hind legs has little influence on the stepping movements and the associated motor patterns when the animals walk on a smooth horizontal surface (Bouyer and Rossignol, 2003a,b). However, greater disturbances occur when animals walk on slopes, and they are incapable of correctly placing their paws on the rungs of a horizontal ladder (Bouyer and Rossignol, 2003a). This has lead to the conclusion that cutaneous signals are necessary for skilled locomotor activities. In contrast to the relatively minor effects produced in normal animals, removal of cutaneous inputs from the paws in chronic spinal cats completely abolishes the capacity for these animals to step with their hind legs on a moving treadmill in a manner that adequately supports the weight of the hindquarters (Bouyer and Rossignol, 2003b). The necessity for appropriate signals from cutaneous receptors of the paws for stepping in chronic spinal cats alerts us to the possibility that lessons learned from studying sensory regulation of stepping in normal individuals may need substantial revision when considering sensory control of stepping in spinal cord injured patients. One significant feature of the influence of sensory feedback is that it can initiate vigorous locomotor activity in chronic spinal cats and rats. In animals that have been trained to step with their hind legs on a treadmill, merely moving the treadmill belt is sufficient to initiate stepping, and stepping is usually maintained so long as the belt is moving. This fact must be kept in mind when assessing potential mechanisms underlying functional improvement in locomotion following treatments that promote the regeneration of damaged axons. For example, in chronic spinal animals sensory signals from the hind legs evoked when the hindquarters are dragged over the ground by the forelegs may in some cases be sufficient to activate central pattern generating networks (thus eliciting rhythmic, locomotor movements of the hind legs) even in the complete absence of any direct activation of these networks by regenerated axons. Similarly, improved trunk function rostral to the injury site may also lead to afferent signals capable of evoking stepping movements of the hind legs (Pearson, 2001). Although less is known about the afferent regulation of stepping in humans compared to quadrupeds, knowledge coming from animal studies has, in some instances, provided a rationale basis for the mechanistic explanation of data from human studies (Harkema et al., 1997; Dietz, 1998; Duysens et al., 2000; Harkema, 2001). However, at this stage it would be premature to conclude that afferent control of stepping is more-or-less similar in humans and quadrupeds. It may turn out that there are essential differences related to different needs during quadrupedal and bipedal walking, and the fact that spinal central pattern generating networks may be less important in controlling stepping in humans (see Section 2.1). 3. Enhancement of functional recovery of walking by training With the potential application of strategies to repair the injured spinal cord to restore walking some way into the future (see Section 4), the only alternatives at this time are rehabilitation therapy in combination with drug treatments and/or functional electrical stimulation (FES). Within the past decade there have been a number of major developments in approaches to the rehabilitation of patients with spinal cord injury. One of the most promising is the use of weight-supported training on a treadmill to improve locomotor function in patients with partial spinal cord injury (reviewed in Harkema, 2001). The introduction of this

7 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) technique was based firmly on animal research that showed that following the complete transection of the spinal cord in cats, stepping movements in the hind legs could be enhanced by daily training on a treadmill (Barbeau and Rossignol, 1987; Lovely et al., 1986). We first review the studies reporting improved locomotor function using treadmill training in spinal cord injured patients, and then go on to consider the possible neuronal mechanisms for the functional improvements derived from animal studies Enhancement in spinal cord injured patients Over the past decade numerous studies have clearly demonstrated that walking in patients with incomplete spinal cord injury can be improved by daily training on a treadmill to elicit patterned afferent activity (see Harkema, 2001 for extensive review). The training consists of partially supporting the patient s weight and manual assistance of leg movements by therapists. As training progresses the support of body weight is gradually reduced and less assistance is required to initiate the swing phase and to step. The duration of training varies depending on the severity of the injury, but typically it lasts for a number of months. Two general conclusions from this work have emerged: (i) The beneficial effects can persist for months or years after completion of the training, and if self-sustained ambulation is achieved, improved walking can be retained by normal daily routines in the absence of a specific training program (Wernig et al., 2000; Wirz et al., 2001). (ii) Effective training requires the mimicking of normal movements of the legs, trunk and arms (often by assistance from therapists). This is considered to produce an appropriate pattern of sensory input for driving adaptive changes in neuronal networks in the spinal cord (Harkema, 2001). In contrast to the beneficial effect of treadmill training in patients with incomplete spinal cord injury, similar training in patients with complete spinal cord injury does not lead to sustained stepping movements of the legs, although it does occasionally lead to an ability to elicit swing movements in the absence of any external assistance. This difference may be due to the involvement of supraspinal systems in improving locomotion in patients with incomplete injury. Of considerable interest, however, is that treadmill training in patients with complete injury can increase the magnitude of the EMG patterns in leg muscles in a manner that cannot be explained simply by the enhancement of stretch reflexes (Dietz et al., 1995, 1998; Wirz et al., 2001). This observation suggests that the mechanisms underlying functional enhancement depends to some extent on the modification of neuronal networks in the spinal cord. The training-induced enhancements of the motor pattern in patients with complete spinal cord injury are lost soon after completion of the locomotion training (Wirz et al., 2001). A number of attempts have been made to facilitate the effects of treadmill-training with drug treatment (Barbeau and Norman, 2003; Dietz et al., 1995; Fung et al., 1990), but to date no therapeutic strategy has emerged for routine use with any group of spinal cord injured patients. Nevertheless, a promising observation in a study on several severely disabled incomplete patients is that the oral administration of Clonidine (an alpha-2 receptor agonist) and cyproheptadine (a 5-HT receptor antagonist given to reduce effects of an injury-induced increase in 5-HT receptors) combined with treadmill training resulted in unassisted stepping on the treadmill (Barbeau and Norman, 2003; Fung et al., 1990). Intrathecal administration of a single dose of Clonidine alone has also been found to improve locomotor function in some severe incomplete patients (Remy-Neris et al., 1999). On the other hand, oral administration of Clonidine does not enable stepping in complete spinal cord injured patients (Barbeau and Norman, 2003; Dietz et al., 1995) or in spinal cord injured patients with reasonably good locomotor function (Barbeau and Norman, 2003). Another strategy for improving locomotor function has been to combine treadmill training with electrical stimulation of muscles (Ladouceur and Barbeau, 2000) or the lumbar cord (Herman et al., 2002). Again, as with drug treatments, encouraging results have been obtained on a small number of patients, but clinical protocols that would routinely benefit large numbers of patients remain to be established. On the other hand, a large number of studies have reported positive results of combining functional electrical stimulation (FES) with extensive overground training (Graupe and Kohn, 1994; Kobetic and Marsolais, 1994; Popovic et al., 2001; Sadowsky, 2001; Stein et al., 1992; Wieler et al., 1999). Unlike treadmill training procedures, FES has proven beneficial to some patients with complete spinal cord injury (Kordylewski and Graupe, 2001). Numerous FES systems have been commercialized (see Popovic et al., 2001 for listing). A very recent development is an attempt to enhance functional improvement in walking by assisting stepping on a treadmill with a robotic device named the Lokomat (Dietz et al., 2002). Use of this device decreases the number of therapists and the physical strain on therapists during in the training procedure. It also allows more controlled and consistent movements of the legs. Based on the experience with therapist-assisted training, it is likely that robot assistance will prove beneficial only in incomplete spinal cord injured patients. However other benefits, such as increased cardiovascular performance and decreased bone loss, will likely accrue in all spinal cord injured patients. Indeed, a recent case study has reported considerable improvements in these factors with daily training on a motor driven bicycle (McDonald et al., 2002). With these promising observations on the effects of training in enhancing walking in humans it is important to establish the underlying mechanisms in order to guide future progress. Significant advances in our knowledge of these

8 114 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) mechanisms have occurred over the past few years from animal studies Enhancement and mechanisms in rodents Although it is debatable whether the rat is a suitable animal model for human locomotion (Metz et al., 2000a; Vilensky and O Connor, 1998), it is unlikely that there are fundamental differences in the basic mechanisms for regulating use-dependent plasticity in the spinal cord. Thus considerable effort has been directed at demonstrating use-dependent plasticity in the rat spinal cord, and establishing the underlying mechanisms. Rats generally do not spontaneously develop rhythmic locomotor movements of the hind legs following complete spinal cord transection (Weber and Stelzner, 1977). But as we have discussed earlier, we know that networks capable of generating an appropriate motor pattern for locomotion exist in the spinal cord, since this pattern can be expressed following the application of serotonin either by intrathecal injection or by the implantation of serotonergic neurons (Feraboli-Lohnherr et al., 1999; Gimenez y Ribotta et al., 1998b). The challenge, therefore, is to develop training procedures that will facilitate activity in these networks. The most effective method reported to date is to mimic the pattern of sensory feedback by moving the paralyzed hind legs with a robotic device (de Leon et al., 2002). This device allows loads to be applied to the paws during the stance phase and correctly lift the paws during swing. In many respects this is similar to the assistive movements provided by therapists in training spinal cord injured patients. In animals spinalized within a week after birth, training with the robotic device leads to long periods of sustained stepping on a treadmill without assistance from the device (Timoszyk et al., 2002). Sustained stepping in rats receiving a complete spinal transection as adults and subsequently trained has not been reported. More conventional treadmill-training techniques have proven effective in improving locomotor performance in adult rats with incomplete spinal cord lesions in some studies (Multon et al., 2003; Thota et al., 2001) but not in others (Fouad et al., 2000). Factors such as the extent and location of the lesion, as well the amount of spontaneous locomotor activity in home cages, may establish the extent to which daily training sessions facilitated locomotor behavior and hence explain different results from different groups. The mechanisms underlying the training-dependent improvement in spinal cord injured rats have only just begun to be investigated (see review by Edgerton and Roy, 2002). The most suggestive finding to date is that exercise in normal adult rats significantly increases the level of brain derived growth factor (BDNF) and proteins associated with growth and neuronal plasticity (Gomez-Pinilla et al., 2002). Moreover, inactivation of just one muscle in the hind leg (the soleus) with botulinum toxin reduced the level of BDNF. One interpretation of these findings is that sensory feedback from muscles critically involved in producing locomotor movements is necessary for maintaining an appropriate level of BDNF in the spinal cord, and the additional sensory input associated with exercise induces neurite outgrowth and/or synaptic plasticity via BDNF to produce functional adaptations necessary for producing higher levels of neuronal activity associated with exercise. Whether or not BDNF is elevated by the training procedure using the robotics device remains to be established. In contrast to rats, mice when spinalized as adults readily develop hind leg stepping on a treadmill when trained daily on a treadmill for 14 days (Leblond et al., 2003). The kinematics of the leg movements are reasonably similar to normal, and stepping in the two hind legs alternates. The rate of improvement in stepping was increased by the application of the 5HT agonist quipazine, indicating that serotonergic systems may be involved in this training-dependent enhancement of walking Enhancement and mechanisms in cats A pivotal finding in the field of spinal cord research was that adult spinal cats can be trained to step with their hind legs on a moving treadmill (Barbeau and Rossignol, 1987; Lovely et al., 1986, 1990). This finding led directly to the introduction of treadmill training as a rehabilitation strategy for incomplete spinal cord injured patients, and it unambiguously demonstrated adaptive plasticity in neuronal circuits within the spinal cord. Recent investigations have concentrated on gaining insight into the mechanisms underlying the training-induced improvements in stepping (de Leon et al., 1999; Tillakaratne et al., 2002) and enhancing the training effect by the administration of drugs (Chau et al., 1998a,b, 2002; Rossignol et al., 2001). Because both these areas have been reviewed extensively within the past few years (de Leon et al., 2001; Edgerton et al., 2001; Edgerton and Roy, 2002; Rossignol, 2000; Rossignol et al., 2000, 2002) we have only briefly summarized the main findings in the following discussion. The most significant finding related to the mechanism for the training-induced enhancement of stepping is a reduction in inhibition of pattern generating networks in the spinal cord (de Leon et al., 1999; Tillakaratne et al., 2002). Data supporting this conclusion come from numerous sources. First, administration of strychnine, a glycinergic receptor antagonist, to chronic spinal cats trained for 12 weeks to stand improves stepping for about 45 min but has no effect in animals trained to step (de Leon et al., 1999). Because no weight bearing steps are produced in stand-trained spinal animals without strychnine, these observations strongly indicate that step training reduces glycinergic inhibition of locomotor pattern generating network. Second, a biochemical comparison of inhibitory transmitter systems in standing-trained and step-trained animals has revealed decreased levels of glutamic acid decarboxylase (GAD 67 ), an

9 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) enzyme involved in the synthesis of GABA, in step-trained animals (Tillakaratne et al., 2002). The location of the GAD 67 staining in nonstep-trained animals corresponded to the motor columns of primary knee flexor motoneurons suggesting that step-training facilitates the production of flexor bursts by reducing inhibition of the system generating flexor burst activity. Finally, intrathecal application of bicuculline, a GABA A receptor antagonist improves hind leg stepping in chronic spinal cats (Robinson and Goldberger, 1986). Investigations in chronic spinal dogs (Hart, 1971) and rats (Edgerton et al., 2001) have also provided additional evidence for the notion that an important mechanism underlying improved locomotion with step-training is a reduction of glycinergic inhibition of spinal locomotor networks. Apart from drugs that antagonize inhibitory system, numerous other drugs are known to enhance stepping in cats with complete and incomplete injuries of the spinal cord (Rossignol et al., 2001). In most investigations of this phenomenon only the short-term effects of the drugs have been examined. Thus the important question of whether drug treatments can enhance training effects is largely unanswered. A notable exception, however, is an extensive study on the effects of intrathecal injection of Clonidine on the rate of recovery of stepping in spinal cats (Chau et al., 1998a). Animals with complete spinal cord transection were trained every day after an injection of Clonidine during the first week following the transection. Combining drug treatment with training significantly increased the rate of recovery. Spontaneous, weight-bearing stepping with plantar foot placement was obtained within 1 week, and were retained over several weeks in the absence of Clonidine. Improvements in stepping with training depend on evoking an appropriate pattern of sensory input to modify neuronal systems in the spinal cord. Thus, an important question is how does sensory input produce these modifications? Surprisingly, this issue has received very little attention. For instance, it is completely unknown which groups of sensory afferents are necessary for the training effects to be produced. Although cutaneous input from the paws is essential to evoking stepping movements in spinal cats (Bouyer and Rossignol, 2003a), it has not been established that inputs from these receptors is driving the adaptive changes associated with training. Similarly input from muscle proprioceptors has an important role in regulating the motor pattern in spinal cats (Pearson et al., 1992) but whether input from these afferents are necessary for inducing adaptive changes in the spinal cord during training is unknown. A hint that input from large muscle afferents could be important comes from a recent study in which chemical ablation of these afferents abolished functional recovery from deficits produced by peripheral nerve lesions (Pearson et al., 2003). Apart from the need to establish which groups of afferents are involved in facilitating stepping with training, we also need to know the sites of the adaptive changes in the spinal cord. Numerous possibilities exist, such as enhancement of transmitter release for primary afferents, modification of synaptic transmission between interneurons in the pattern generating network, and changes in the cellular properties of interneurons and motoneurons. A major impediment preventing a quick resolution of this issue is the paucity of information about the cellular and network properties of neurons in the pattern generating network. Although considerable progress is being made on establishing these properties in neonatal rats (Butt et al., 2002a,b; Kullander et al., 2003; Stokke et al., 2002) it is not obvious that modifications of these properties can be easily examined in adult animals in which training effects have been expressed. 4. Enhancement of functional recovery of walking by regeneration of descending axons In the previous sections we have discussed how training, drugs, robotic devices and FES can improve the walking in humans and animals with spinal cord injury. An alternative approach is to restore motor and sensory function by promoting the regeneration and functional reconnection of damaged axons in the spinal cord. This objective has spawned an enormous amount of research activity over the past decade, but although major advances in understanding the mechanisms regulating regeneration of neurons in the spinal cord have been made, there has been no significant breakthrough in establishing a reliable procedure for enhancing motor function and no general consensus on which procedure(s) might be most effective (David and Lacroix, 2003; Edgerton and Roy, 2002; Fawcett, 2002; Fouad et al., 2001; Houle and Tessler, 2003; Schwab, 2002; Selzer, 2003). Nevertheless, many studies have reported improved function after some form of treatment aimed at promoting growth and regeneration of neurons. Virtually all these investigations have been performed on rats, and monitoring changes in the walking behavior has been a common method to assess the effectiveness of the treatment. In this section we will first give a brief overview on approaches used to repair the injured spinal cord and the methods to assess locomotor function in spinal cord injured rats. We then review recent investigations reporting improved walking following a variety of treatments designs to promote growth and regeneration of damaged axons in the spinal cord. One focus of this discussion is an assessment whether any of these studies have demonstrated functional reconnections of regenerated axons Strategies to repair the injured spinal cord While regeneration of severed CNS axons in the adult mammalian spinal cord does not occur under normal conditions, it has been known for some time that CNS neurons will regenerate when provided with a permissive environment for growth, such as a peripheral nerve graft (David and Aguayo, 1981; Tello, 1911). The identification of the factors in the CNS environment that prevent regeneration

10 116 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) Table 1 Treatments designed to promote regeneration in the injured spinal cord and improved motor behavior Treatment Specifics Author and Journal Lesion type Behavior Recovery Bridging and transplants Fetal spinal cord graft, Coumans et al., 2001 Complete lesion Locomotor tests ++ neurotrophins Nerve grafts and afgf Cheng et al., 1996 Complete lesion Locomotor tests ++ Neural progenitor cells Ogawa et al., 2002 Contusion Forelimb use + Olfactory ensheathing glia Ramon-Cueto et al., 2000 Complete lesion Climbing ++ Olfactory ensheathing glia Li et al., 2003 Incomplete lesion Breathing/climbing ++ Olfactory ensheathing glia Lu et al., 2002 Complete lesion Open field locomotion ++ Schwann cells Xu et al., 1997 Complete lesion n.a. n.a. Schwann cells Takami et al., 2002 Contusion Open field locomotion + Stem cell graft McDonald et al., 1999 Contusion Open field locomotion + Polymer scaffold/stem cells Teng et al., 2002 Incomplete lesion Open field locomotion ++ Neurotrophic factors NT-3 Grill et al., 1997a Incomplete lesion Locomotor tests + Fibroblasts expressing BDNF Liu et al., 1999 Incomplete lesion Forelimb use + NT-3/IN-1 Schnell et al., 1994 bfgf Rabchevsky et al., 2000 Contusion Open field locomotion ++ BDNF, NT-4/5 Kobayashi et al., 1997 Incomplete lesion n.a. n.a. BDNF Jakeman et al., 1998 Contusion Locomotor tests + Neutralizing inhibitory environment Modifying signalling pathways (+) Significant; (++) highly significant. IN-1 Bregman et al., 1995 Incomplete lesion Locomotor tests + IN-1 Merkler et al., 2001 Incomplete lesion Locomotor tests ++ Chondroitinase ABC Bradbury et al., 2002 Incomplete lesion Forelimb use, e-phys + Nogo-66 receptor antagonist GrandPre et al., 2002 Incomplete lesion Open field locomotion ++ Vaccination Huang et al., 1999 Incomplete lesion Placing + Stimulated macrophages Rapalino et al., 1998 Complete lesion Open field locomotion ++ Inactivate Rho pathway Dergham et al., 2002 Dorsal hemisection Open field locomotion + Inactivare Rho pathway Fournier et al., 2003 Incomplete lesion Open field locomotion 0 camp Qiu et al., 2002 Incomplete lesion n.a. n.a. has received considerable attention and it is now quite clear that many factors contribute of inhibiting axonal regeneration (reviewed in (David and Lacroix, 2003; Schwab and Bartholdi, 1996; Steeves and Tetzlaff, 1998). Some of the most important are (i) mechanical barriers formed by developing cavities and dense scar tissue, (ii) insufficient neurotrophic support for cell survival and axonal growth, and (iii) inhibitory molecules associated with scar tissue and CNS myelin. To overcome these impediments, and thereby encourage axonal sprouting and regeneration, various approaches for treating spinal cord injury have been implemented either separately or in combination. A summary of promising experimental treatments is given in the following subsections and Table 1. Recent review articles by Horner and Gage (2000), Fouad et al. (2001), Edgerton and Roy (2002) and David and Lacroix (2003) provide more in-depth discussions of current treatment strategies Bridging the lesion site Following the example of David and Aguayo (1981) various permissive substrates have been explored to bridge lesion sites in the spinal cord and to promote the growth of transected axons. These substrates include Schwann cells (the glial cells of the peripheral nervous system) (Paino and Bunge, 1991; Xu et al., 1997), olfactory ensheathing glia (OEGs, the glial cells of the olfactory bulb) (Li et al., 2003, 1998; Ramon-Cueto et al., 2000; Ramon-Cueto et al., 1998), and fetal neuronal tissue or stem cells (Hofstetter et al., 2002; McDonald et al., 1999; Stokes and Reier, 1992). Cellular grafts not only offer regenerating neurons a growth permissive substrate they also reduce cavitation, a factor promoting secondary damage (Xu et al., 1997) Administration of neurotrophic factors To promote the repair of the injured spinal cord neurotrophic factors such as BDNF and NT-3 have been applied via mini-osmotic pumps (Kobayashi et al., 1997; Ramer et al., 2000; Schnell et al., 1994), via modified Schwann cells (Menei et al., 1998) or fibroblasts (Grill et al., 1997b), and via viral vectors (Romero et al., 2001; Zhou et al., 2003). This resulted in many cases in an enhanced axonal survival rate (Hammond et al., 1999; Shibayama et al., 1998), increased sprouting (Schnell et al., 1994) and regeneration (Bregman et al., 1997; Grill et al., 1997a; Kobayashi et al., 1997) of descending tracts in parallel with improved locomotor recovery (Grill et al., 1997a; Namiki et al., 2000). Application of neurotrophic factors has frequently been used in combination with other approaches such as bridges of Schwann (Bamber et al., 2001) or fetal cells (Coumans et al., 2001), and in conjunction with the IN-1 antibody to neutralize the myelin associated inhibitor for neurite growth Nogo-A (von Meyenburg et al., 1998).

11 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) Blocking inhibitory molecules in the growth environment A major factor preventing axonal regeneration in the central nervous system is the existence of growth inhibiting molecules in the cellular environment surrounding the axons (Schwab and Bartholdi, 1996). Central nervous system myelin has been identified as being especially inhibitory for neuronal growth in vitro and in vivo (reviewed in Schwab, 1996; Spencer et al., 2003) and currently three myelin-associated inhibitory proteins have been found, namely myelin associated growth protein (MAG; McKerracher et al., 1994), Nogo-A (Chen et al., 2000; GrandPre et al., 2000) and oligodendrocyte-myelin glycoprotein (Wang et al., 2002; Kottis et al., 2002). Various approaches have been described to neutralize Nogo-A, including the application of the IN-1 antibody, (Bregman et al., 1995; Merkler et al., 2001), the infusion of the IN-1 fragment (Brosamle et al., 2000) and the blocking of the Nogo receptor (GrandPre et al., 2002). Other approaches to minimizing the inhibitory effect of the injured spinal cord include auto-vaccination against myelin (Huang et al., 1999) and the injection of activated macrophages to impose an appropriate inflammatory response in order to clear the growth inhibiting debris, and thus to create a permissive growth environment (Rapalino et al., 1998). In some cases, myelin has been removed altogether (Keirstead et al., 1995; Vanek et al., 1998). These treatment approaches reported increased sprouting and the occurrence of axonal regeneration in parallel with functional recovery (Bregman et al., 1995; GrandPre et al., 2002; Rapalino et al., 1998). Inhibitory molecules associated with the glial scar that develops at the lesion site have also been identified as a major obstacle for regenerating axons (reviewed in Fawcett and Asher, 1999). Chondroitin sulfate proteoglycans are one class of these inhibitors. The digestion of chondroitin sulfate proteoglycans with chondroitinase ABC increases regeneration in vitro (Zuo et al., 1998) and in vivo (Bradbury et al., 2002), the latter resulting in improved grasping movements after cervical spinal cord injury. Rather than neutralizing the inhibitory environment of the adult CNS by focusing on myelin and glial scars, some studies have started to focus on modifying the neuronal response to inhibitory signals. In this way, growth cone collapse is avoided and inhibitory signals are circumvented. One promising approach is to inactivate the Rho signaling pathway. This pathway is involved in the regulation of the cytoskeleton and motility and plays an important role in axonal growth inhibition (Dergham et al., 2002; Fournier et al., 2003). Another research focus is on increasing the neuronal intracellular levels of camp. The level of camp has been shown to determine whether neurons will be repelled or attracted by myelin specific proteins such as MAG (Song et al., 1998). The approach to increase camp in neurons has been reported to circumvent the growth cone collapse induced by myelin associated inhibitors such as MAG and Nogo (Cai et al., 2001) Assessing walking behavior Analysis of walking behavior is the most common strategy for assessing functional recovery following spinal cord injury since it allows a fairly straightforward and fast assessment of changes in function. The current standard is to assess open field locomotion in rats and mice by using the BBB score, which was named according to its creators Basso, Beattie and Breshnahan (Basso et al., 1995). This score was originally developed to quantify the functional outcome of contusion injuries in rats, but it is currently used for assessing the locomotor outcome following different lesion paradigms from partial to complete transections. The BBB score ranges from 0 (minimum = no movement of the hindlimbs) to 21 (maximum = normal overground locomotion) points that are distributed according to criteria such as joint movements, weight support, forelimb-hindlimb co-ordination, foot rotation, toe clearance and tail position. Although this test clearly provides a fast and transparent method for describing the walking performance, it has a number of limitations: (i) it is based on qualitative behavioral observations, (ii) it is nonlinear because points in the score represent more or less discrete aspects of behavior, (iii) improvements in locomotion do not necessarily follow the progression of the score, and (iv) it does not provide any information on possible underlying mechanisms of the recovery. To obtain quantitative information on the timing of motor activity associated with rhythmic movements of individual legs, and the relative timing of movements in different legs, more sophisticated tests than the BBB score are necessary. Alternative testing strategies for evaluating the locomotor capacity of spinal cord injury rats have been discussed in a few studies (Kunkel-Bagden et al., 1993; Metz et al., 2000b; Muir and Webb, 2000). The two standard approaches are the kinematic analysis of limb and body movements and the recording of the patterns of muscle activity (Merkler et al., 2001; Ribotta et al., 2000). These approaches allow a precise analysis of changes in the trajectory of the step cycle and the analysis of changes in the muscle activation patterns. These techniques enable the identification of compensatory strategies and subtle changes in the locomotor pattern. However, as with the BBB score, kinematic and EMG analyses provide no direct information as the cellular mechanisms that underlie any improvements in walking. Locomotor recovery following mild lesions of the spinal cord involving mainly the dorsal spinal tracts (cortico- and rubrospinal) is difficult to assess using open field locomotor scores because ablation of these tracts results only in subtle changes in open field locomotion (Loy et al., 2002b; Schucht et al., 2002; Webb and Muir, 2003). Thus more refined tests (in addition to the BBB score) are required to quantify deficits in locomotion and to assess functional recovery. These include walking on a grid (Bresnahan et al., 1987; Metz et al., 2000b), an inclined plane (Bresnahan et al., 1987), narrow beams (Medinaceli et al., 1982), and using ground reaction force patterns (Webb and

12 118 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) Muir, 2002) and footprint analysis (Kunkel-Bagden et al., 1993) Improved walking following treatments to promote regeneration Many studies have now associated improved walking with anatomical indications of axonal regeneration or sprouting of injured and/or spared axons (see Table 1). In the following discussion we review some of the most prominent of these studies. Although sprouting occurring at different levels of the spinal cord and brainstem can never be excluded as a mechanism contributing to functional recovery, we will focus on the possible role of axons regenerating past the site of injury in the spinal cord. This does not mean that axonal sprouting should be seen as less beneficial than regeneration. On the contrary, since most spinal cord injuries in humans are anatomically incomplete it is currently believed that rearrangements and sprouting of spared fibers systems might play a decisive role in the treatment of patients. To simplify the discussion, the following sections are divided into two, one dealing with reports of improved walking following complete and the second following incomplete injuries of the spinal cord Anatomically complete spinal cord injury It is very encouraging that improved locomotion has now been reported in rodents receiving various experimental treatments following complete transactions of the spinal cord (see Table 1). A well-known study is by Cheng et al. (1996). They reported improved walking after treating a complete transection with a combination of a specific bridging technique and the use of fibrin glue containing acidic fibroblast growth factor (afgf). The treated rats were found to develop partial weight-supported four-limbed stepping and movements were noted in all three joints of the hind legs. This represents a major recovery in locomotor function. In another widely publicized study by Rapalino et al. (1998) adult rats with complete thoracic lesions were treated by the application of activated macrophages to stimulate tissue repair. The observed open field locomotor recovery reached a BBB score of 9 (plantar placement of the paw with weight support in stance only) in the treated rats but remained around 1.5 (up to slight movements in two joints) in controls. Coumans et al. (2001) demonstrated that a delayed treatment using a combination of fetal spinal cord transplants and neurotrophic factors (NT-3 and/or BDNF) after a complete thoracic transection promoted functional recovery. The authors used a variety of behavioral tests including treadmill walking with weight support using a harness and kinematic analysis, stair climbing, runway locomotion, and a set of anatomical approaches to link the regeneration to the observed functional recovery. The treated rats were reported to exhibit plantar foot placement and weight supported stepping, which also represents a major step in recovering locomotion. A very different method for demonstrating locomotor recovery was chosen by Ramon-Cueto et al. (2000). This group reported that in rats with complete spinal cord injury functional recovery followed the injection of olfactory ensheathing cells (OEGs) into the spinal cord at the injury site. All treated rats were reported to have regained voluntary hindlimb movements and body weight support when climbing up on an inclined grid. One important observation that was not included in the original publication was the absence of recovery in open field locomotion (Ramon Cueto, conference presentations). Although all of these studies described regeneration of descending axons past the site of transection, the extent to which direct reconnection of regenerated axons to neurons caudal to the lesion was responsible for improved walking in the treated animals is unclear. No evidence for functional reconnection of regenerated axons was presented in any of the studies. Alternative possibilities for improved recovery of the walking pattern following complete lesions of the spinal cord are increased excitability of the pattern generating networks and sensory pathways caudal to the lesion due to neurotrophic actions of factors produced by the treatment (Pearson, 2001) and increased excitability of spinal networks by non-specific release of neuromodulatory agents from regenerated axons, e.g., 5-HT (Ribotta et al., 2000). Nevertheless, the involvement of regenerated axons in the recovery of walking has been demonstrated in some investigations by re-lesioning of regenerated fibers and noting a loss of functional gains (Rapalino et al., 1998, Coumans et al., 2001). An appropriate approach for demonstrating the functional influences of regenerated axons is to electrically stimulate brain structures sending axons to the lumbar spinal cord and recording of evoked potentials in muscles of the hindlimb. This approach was chosen by Rapalino et al. (1998) to strengthen their claim of functional reconnection of the corticospinal tract. However, since the corticospinal tract is not involved in the initiation and maintenance of walking in rats, it remains unclear whether the recovery of locomotion they reported was achieved by regenerating axons influencing activity of pattern generating networks in the lumbar spinal cord. In summary there are numerous reports of locomotor recovery following complete spinal cord injuries in rats but no study has demonstrated that the recovery is due to influences of regenerated axons normally belonging to pathways involved in controlling central pattern generating networks (e.g., reticulo-spinal pathways). Moreover, it is disappointing that the results of most of the prominent studies (Cheng et al., 1996; Rapalino et al., 1998; Ramon-Cueto et al., 2000) have not yet been confirmed in published reports. This absence of confirmation has led to considerable uncertainty about which procedures have the most potential for enhancing regeneration and functional recovery Incomplete spinal cord injury Judging whether an experimental procedure improves walking following incomplete spinal cord injuries is more

13 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) difficult because there is always a degree of spontaneous recovery. Moreover the inevitable degree of variation in the lesion size, the occurrence of injury induced sprouting at various levels of the CNS (including sites rostral to the lesion), and the possibility that recovery can be due to spared fibers, all complicates the assessment of what mechanisms may be involved. Nevertheless, there have been reports that demonstrate improved walking in incomplete lesioned rats following various treatments to enhance regeneration, and suggestions that this improvement is due to functional influences of regenerated axons (Bregman et al., 1995; GrandPre et al., 2002; McDonald et al., 1999). A general problem of studies using incomplete lesions is that the regenerating axon are associated with pathways that are not normally involved in initiating and controlling open-field locomotion. For example many studies have assessed regeneration of axons in the corticospinal tract (CST) and then reported in parallel recovery of locomotor function thus implying that the improved recovery is due to regeneration of descending axons. As the role of the CST in open-field locomotion is very limited (Muir and Whishaw, 1999) the causal relationship between CST regeneration and locomotor recovery is unlikely. The well publicized study from Bregman et al., 1995, for example reported that application of the IN-1 antibody to neutralize the myelin associated inhibitor Nogo-A resulted in neuronal sprouting and regeneration of the CST in parallel with recovery in the placing test and stride length. Later work confirmed the recovery of walking (Merkler et al., 2001), however, evidence to support the claim that regeneration was involved in the locomotor recovery after these incomplete lesions was not presented. Testing the placing response was used to demonstrate the reestablishment of the CST. However, this placing also occurs in decerebrated rats and is thus not sufficient to prove functional reconnections (Woolf, 1984; Fouad and Bennett, unpublished). In further studies the Schwab group (Raineteau et al., 2002; Raineteau et al., 2001; Thallmair et al., 1998; Z Graggen et al., 1998) demonstrated that anatomical plasticity of the injured CST and the uninjured rubrospinal tract is strongly enhanced by the IN-1 treatment, and thus plasticity in other tracts might have contributed to the recovery of locomotor function in the studies described above. Interestingly, this treatment was reported to enhance sprouting even in the uninjured CNS (Buffo et al., 2000), indicating that injuries of the CNS are not a prerequisite to experimentally enhances axonal sprouting and that sprouting can occur at various levels after a treatment, independently of whether they are injured or not. It has to be pointed out again, that enhanced axonal sprouting does not lessen the impact of these studies; it just deviates from the original idea that the functional recovery was due to axonal regeneration. Another study reporting improved locomotion following inactivation of Nogo-A was by (GrandPre et al., 2002). They found that blocking the Nogo-66 receptor with an antagonist (NEP1-40) resulted in sprouting and regeneration of the CST and a concomitant recovery of open field locomotion in rats with dorsal hemisection. The rats recovered on average from around 12 points in the BBB score (frequent to consistent weight support and no forelimb hind limb coordination) to 15.5 (consistent plantar stepping with weight support and consistent forelimb hind limb coordination but no toe clearance). Although this represents a major improvement in the recovery of locomotion, this functional outcome has to be regarded with caution as no comparisons of the lesions between the treated and untreated groups were published. Some studies have only addressed functional outcome and not considered the basis for observed improvements in walking. McDonald et al. (1999), for example, reported improved open-field locomotion after incomplete contusion injury and embryonic stem cell grafts in adult rats. Implantation of cells was performed in two matched groups of spinal cord injured rats 9 days after injury. This treatment moderately improved the open-field locomotion performance of the rats. On average the rats gained two points in the BBB score from 8 to 10 points. This represents an improvement in locomotion from sweeping with no weight support to occasional weight supported steps. While the treatment has some benefits it would be of value to elucidate the underlying mechanisms for this recovery, thus allowing more rational applications of this method. In summary, promising studies of improved walking following incomplete lesions have been published but none demonstrated that regenerated neurons were involved in the functional improvement. Many studies using incomplete spinal cord injuries show that a certain degree of sprouting and regeneration is correlated with recovery of recovery of walking, but the evidence for a causal relationship does not exist Criteria for demonstrating functional regeneration Currently there is no agreed upon set of criteria that need to be satisfied for a convincing demonstration of functional regeneration of descending axons. Below we present five criteria we regard as necessary to fully substantiate a claim that functional recovery is due to reconnection of regenerated axons. Each criterion on its own has one or more shortcomings, and it is unlikely that all criteria can be addressed in one experiment. Combining as many as possible will allow a strong claim for functional reconnection of regenerated axons in the spinal cord. Criterion 1: Provide evidence that recovery is not due to sparing. The assertions that recovery is due to repair (the reconnection of ablated axons) must be accompanied by evidence that new or strengthened connections formed by spared axons are not responsible for functional improvement (Weidner et al., 2001). For complete transections of the spinal cord, this criterion can easily be satisfied because anatomical confirmation of the lesion completeness can exclude sparing. However, for incomplete spinal cord lesions and especially contusion injuries, this criterion is difficult to satisfy. There will be always spared fibers, even when the main projection of a tract has been ablated. The corticospinal

14 120 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) tract in rats is a good example. Although the main projection (around 90%) is located in the dorsal funiculus, there are fibers projecting in the ventral and lateral funiculus (Brosamle and Schwab, 1997; Weidner et al., 2001). A complete ablation of the CST would be only possible at the level of the brainstem, which is not considered a spinal cord injury. Thus only complete transections of the spinal cord will allow the unequivocal conclusion that recovery following spinal cord injury is not due to spared axons. Criterion 2: Provide anatomical proof of regeneration. Recently several criteria have been suggested to demonstrate axonal regeneration (Steward et al., 2003). They can be summarized as (i) processes of regenerating axons start at the point where the axons were severed, and either enter a lesion zone (thus, encountering either scar or grafted tissue) or travel through a CNS region they normally do not, (ii) processes of regenerating axons show a morphology consistent with growth, i.e., a growth cone, (iii) recovery due to putative regeneration should occur at the time when regenerating axons form functional connections, and (iv) regenerated axons typically have an unusual morphology (e.g., tortuous course and highly branched) especially when growing through scar tissue and gray matter. Criterion 3: Demonstrate recovery of a behavior related to the normal function of the lesioned tract system that has been demonstrated to regenerate. In the case of lesions of the cortico- or rubrospinal tract and the demonstration of treatment induced regeneration of these tracts, fine locomotor skills (ladder walking, beam walking, grasping, etc.) should show improvement (Kunkel-Bagden et al., 1993; Metz et al., 2000b; Muir and Webb, 2000). Similarly, recovery of open field locomotion should be correlated with regeneration of the reticulo- and vestibulospinal tracts (Schucht et al., 2002). Criterion 4: Demonstrate that re-lesioning the regenerated tract abolishes functional gains. Re-lesions appear to be an uncomplicated approach to confirm the role of regenerated neurons, and this approach is certainly valid for complete lesions. However, following incomplete lesions, re-lesions rostral or caudal to the original lesion are highly unlikely to ablate exactly the same fibers as in the first surgery, thus making this strategy of little value. Re-lesions are also not a possible option after contusion or compression injuries as these lesions damage mainly gray matter and white matter to various degrees that cannot be reproduced. Criterion 5: Show that regenerated axons from functional synaptic connections to neurons located at appropriate sites caudal to the injury. An electrophysiological approach is the only method than can unequivocally demonstrate functional reconnection of regenerated axons. Possible strategies are ranging from intracellular recordings of synaptic potentials to evoked potentials in muscles. A functionally recovered pathway demonstrated by one or more of these strategies should be related to the behavior tested. In the case of walking, it would be appropriate to study (stimulate) the reticular formation and to demonstrate input to the spinal pattern generating networks. 5. Summary Restoring motor, sensory and autonomic function following spinal cord injury has become a major endeavor of the neuroscience community over the past decade. The path towards the discovery of effective procedures, especially those involving regeneration of damaged neurons, has been very uneven (Pearson, 2003a). Often initially promising discoveries have either not been reproduced or failed to develop into generally accepted procedures for restoring function. Nevertheless, considerable progress has been made in understanding the many factors involved in promoting and retarding regeneration of neurons in the spinal cord, thus raising the hope that effective treatments will be developed in the near future. Some of the most important findings are: 1. the demonstration that axons in the spinal cord are able to regenerate when provided with a permissive substrate (David and Aguayo, 1981; Schwab and Thoenen, 1985); 2. the use of permissive substrates (e.g., peripheral nerve grafts, Schwann cells, fetal tissue, stem cells, OEGs) for bridging the damaged region in the spinal cord offering a growth permissive environment for neurons, using various cell types including stem cells (Cheng et al., 1996; Coumans et al., 2001; McDonald et al., 1999; Menei et al., 1998; Ramon-Cueto et al., 2000; Xu et al., 1997); 3. the facilitation of axonal sprouting and enhanced neuronal survival by the application of growth factors (Grill et al., 1997a; Kobayashi et al., 1997; Schnell et al., 1994; Xu et al., 1995); 4. identification and cloning of growth inhibitory molecules and their receptors and promotion of axonal growth by their inactivation (Chen et al., 2000; GrandPre et al., 2002; GrandPre et al., 2000; Kottis et al., 2002; McKerracher et al., 1994; Mukhopadhyay et al., 1994; Niederost et al., 1999; Schnell and Schwab, 1990; Snow et al., 1990, Wang et al., 2002); 5. modification of intracellular signaling pathways that are involved in the regulation of growth cone motility and collapse promote axonal sprouting and regeneration (Cai et al., 2001; Dergham et al., 2002; Fournier et al., 2003; Qiu et al., 2002); 6. the capacity for injured axons to form functionally effective pathways either directly or indirectly (Raineteau et al., 2001; Rapalino et al., 1998); 7. the immune system can be manipulated to neutralize inhibitors for axonal growth and promote axonal regeneration (Hauben et al., 2001; Huang et al., 1999; Rapalino et al., 1998). On the basis of one or more of these finding, a small number of clinical trials have been reported to be in progress (Pearson, 2003a). Despite these important advances, it is a surprising fact that no investigation has convincingly demonstrated that improvements in motor function following procedures promoting regeneration (Table 1) can be attributed with cer-

15 K. Fouad, K. Pearson / Progress in Neurobiology 73 (2004) tainty to functional reconnection of regenerated axons to spinal neuronal networks. This is not to say, however, that in all instances functional regeneration did not occur. It is conceivable that functional regeneration might have been achieved and the experimental design was insufficient to demonstrate its occurrence. A number of criteria must be satisfied before a claim for functional regeneration can be made (see Section 4.3) and no study to date has done this satisfactorily for walking. Ultimately electrophysiological approaches are required to make a convincing case for the involvement of regenerated fibers in functional recovery. So until these approaches are used more consistently, claims of treatments leading to reconnection of regenerating axons will rely on indirect evidence and must be treated with caution. Some alternative explanations for functional improvement are (1) non-specific effects of transmitters released from regenerated axons in the absence of the formation of functional synaptic connections, (2) sprouting of undamaged axons rostral and/or caudal to the lesion, (3) release of chemicals with neuromodulatory action by the implanted tissue on interneuronal or other pathways in the lumbar cord, (4) treatment induced reduction of secondary damage. In this review we have focused on recent advances in enhancing walking following spinal cord injury principally because a large number of investigations have reported improved locomotor function following procedures to promote growth and regeneration of damaged axons in the spinal cord (Table 1). In addition, introduction of new rehabilitation procedures, most notably training on a treadmill with body weight support, has proven effective in improving walking in for patients with partial spinal cord injury (Section 3.1). Animal studies have also demonstrated the effectiveness of training in improving walking, and begun to reveal some of the underlying neuronal mechanisms (Sections 3.2 and 3.3). One of the most encouraging outcomes of these recent investigations is the recognition that neuronal networks in the spinal cord can be modified by use in a functionally meaningful manner. The adaptive capacity of spinal networks will likely prove to be an essential component of any strategy designed to improve walking in humans by promoting regeneration of damaged axons. Thus successful therapies for improving walking will undoubtedly consist of multiple approaches: minimization of secondary damage, enhancing neuronal survival, facilitating axonal regeneration through the injury site and into sites caudal to the injury, and training to orchestrate activity in new and old neuronal circuits in a functionally meaningful manner. Acknowledgements We thank Drs. T. Gordon, J. Misiaszek and J. 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