© 2004 by The Society for Integrative and Comparative Biology
Adaptive Mechanisms of Spinal Locomotion in Cats1
1 Centre de Recherche en Sciences Neurologiques, Faculté de médecine, Université de Montréal,Montréal, Québec, H3C 3J7, Canada
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 SYNOPSIS INTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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This paper reviews some aspects of locomotor plasticity after spinalisation and after peripheral nerve lesions. Adult cats can recover spontaneous hindlimb locomotion on a treadmill several days or weeks after a complete section of the spinal cord at T13. The kinematics as well as the electromyographic activity are compared in the same animal before and after the spinal section to highlight the resemblance of locomotor characteristics in the two conditions. To study further the mechanisms of spinal plasticity potentially underlying such locomotor recovery, we also summarize the locomotor adaptation of cats submitted to various types of peripheral nerve section of either ankle flexor or extensor muscles or after denervation of the hindpaws' cutaneous inputs. It is argued that, even in the spinal state, cats have the ability to compensate for such lesions of the peripheral nervous system suggesting that the spinal cord has a significant potential for adaptive plasticity that could be used in rehabilitation strategies to restore locomotion after spinal cord injury.
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INTRODUCTION |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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This short paper reviews some of the work performed by our group and others on the theme of spinal locomotor plasticity. We will first give some evidence that the recovery of locomotion after spinalisation is enhanced by locomotor training and drugs. Then, we will also give more direct evidence that the spinal cord has some adaptive capacities after peripheral nerve lesions, suggesting an important degree of spinal plasticity which is a critical concept for locomotor rehabilitation after spinal injury.
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SPINAL LOCOMOTION |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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Bilateral and coordinated walking movements of the hindlimbs can be observed in most animal species after a complete chronic section of the spinal cord in the lower thoracic region (Grillner, 1981
; Rossignol, 1996, 2000; Rossignol et al., 1996, 2000; Delcomyn, 1980). The cat has a particularly well-developed capacity for spinal locomotion. Two to three weeks after a complete section of the spinal cord at T13, cats can make plantigrade contact and sustain the weight of their hindquarters (Barbeau and Rossignol, 1987; Bélanger et al., 1996). They can adapt their locomotion to the varying speeds of the treadmill and, if the progression of one leg is perturbed by the contact with an obstacle, the limb can generate a coordinated hyperflexion to bring the foot up and around the obstacle (Forssberg et al., 1975).
However, there are also some obvious deficits in spinal locomotion, such as a lack of voluntary control, an absence of sustained coordination between the fore- and the hindlimbs when all four paws are placed on the treadmill belt, and a quasi-total absence of balance control. In fact, even when the animals can sustain the weight of the hindquarters, balance must be supplied by holding the tail to stabilize the hindquarters. Other defects tend to vary from cat to cat, such as foot drag in the initial part of the swing phase, irregularities in stepping frequency, exaggerated adduction of the hindlimbs and sometimes incomplete weight support (Bé langer et al., 1996). Nevertheless, despite these defects, spinal locomotion in the cat is a robust, reproducible and impressive phenomenon.
These observations suggest the existence, in the spinal cord, of neural circuits capable of generating the spinal locomotor pattern on their own in the absence of supraspinal inputs. Further experiments have shown that this spinal locomotor pattern is innate, as hindlimb stepping can be expressed even if kittens are spinalized before they have started to step (Grillner, 1973; Forssberg et al., 1980a, b). In addition, a detailed locomotor pattern can also be observed in curarized spinal cats injected with l-DOPA with recording of muscle nerve (Grillner and Zangger, 1979). Therefore, the spinal cord can generate a locomotor pattern in the absence of descending inputs and of movement-related sensory feedback, thereby suggesting that the spinal locomotor pattern is also central, a concept which was coined by the expression "central pattern generator" or CPG.
The spontaneous (not drug-induced) recovery of spinal locomotion may occur at any time, from a few days to a few weeks after the lesion. A few days only after a low thoracic spinalisation, strong manual stimulation of the perineum or the base of the tail elicits small alternate rhythmic movements of the otherwise flaccid hindlimbs when they are placed on a treadmill while the forelimbs stand on a stationary platform. Flexion movements occur mainly at the hips with the feet dragging on the dorsum and with very little knee and ankle flexion so that the hindlimbs move more or less rhythmically and are then being passively extended at the hip. The animals are unable to sustain the weight of their hindquarters at this very early stage. Some cats may have a rapid progression in the first 10 days, whereas other cats may need 2–3 weeks, or even more, of daily treadmill training to express a full pattern of spinal locomotion. Once this plateau has been reached, the hindlimbs can then follow the treadmill belt up to speeds of 0.8 m/s without perineal stimulation. The paws contact the belt on the plantar surface and the force is usually adequate to sustain the weight of the hindquarters. There is often a pronounced adductor tonus so that a separator has to be placed between the hindlimbs, to prevent them from impeding each other (Bélanger et al., 1996; Rossignol et al., 2002).
In summary, an elaborate locomotor pattern is still expressed in the hindlimbs after complete spinalisation. The observed specific defects can be attributed mainly to the loss of normal control provided by the descending pathways (cortex, brainstem and propriospinal), as revealed by partial central lesion studies (Rossignol et al., 1999; Jiang and Drew, 1996; Brustein and Rossignol, 1998). Furthermore, this pattern is not static but can be modified by external influences, such as training or pharmacological agents, and can be adapted to changes in the sensory-motor plant. We will now summarize some of the work which suggests that, indeed, the spinal cord has some remarkable degree of plasticity.
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LOCOMOTOR TRAINING |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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The importance of locomotor training to facilitate the expression of the spinal locomotor pattern has been documented for quite some time (Shurrager and Dykman, 1951
; Shurrager, 1955), especially in young animals which have, in general, greater locomotor recovery capabilities (Bregman and Goldberger, 1983; Howland et al., 1995a, b). The intensity of training on the treadmill has been shown to have important effects on the recovery of locomotion (Smith et al., 1982; Bregman and Goldberger, 1983; Robinson and Goldberger, 1986), therefore suggesting that external factors could indeed modify or improve the expression of the genetically-determined program. The training effect is also striking in young spinal rabbits, which can be trained to express preferentially an alternate or an in-phase coupling of the hindlimbs (Viala et al., 1986). These two modes of coupling are not as such learned because they can co-exist, but one mode can be trained to predominate over the other by using a specially-designed apparatus favoring one of the modes of coupling.
Adult cats also have the ability to express hindlimb locomotion after complete spinalisation (Sherrington, 1910; McCouch, 1947; Kozak and Westerman, 1966; Afelt, 1970, 1974; Ten Cate, 1962; Dykman and Shurrager, 1956). While the animal maintains its forequarters on a stationary platform above the treadmill, the hindfeet are placed on the belt and the animal is trained to walk at different speeds and to support gradually more and more weight (Barbeau and Rossignol, 1987, 1994; Bélanger et al., 1996). All our adult spinal cats have been able to walk after spinalisation at T13 (Barbeau and Rossignol, 1987; Bélanger et al., 1996; Chau et al., 1998a; Rossignol et al., 2000). This has also been the experience of others (Edgerton et al., 1983; Lovely, et al., 1985; Lovely et al., 1986; Smith et al., 1982). We trained each animal for 30–60 minutes per session every day or every other day, for several weeks, allowing the animal to support independently as much weight as possible and as soon as possible. This is done by using perineal stimulation and gauging how much of the hindquarters weight is to be supported by holding the tail. Also, the paws are manually positioned on the treadmill to favor plantar foot contact strategies.
Figure 1 compares the kinematics and average EMG activity in the same cat before spinalisation and after 38 days of regular treadmill training. It can be seen that the cycle length is generally shorter after spinalisation (compare Fig. 1A and Fig. 1D) for the same walking speed (0.3 m/s) and that the feet tend to drag on the belt in the initial part of the swing phase. The angular excursion of the various hindlimb joints after spinalisation is very similar indeed to that in the intact state although there is an increase in variability. In the intact state, the knee flexor/hip extensor muscle Semitendinosus (St) has a short burst of activity, whereas the hip flexor/knee extensor Sartorius (Srt) is delayed relative to St and has a single burst in flexion. The ankle extensor Gastrocnemius Lateralis (GL) typically starts abruptly, whereas the activity in the knee extensor Vastus Lateralis (VL) usually builds up gradually. The EMG pattern in the spinal state is also quite similar. The EMG discharges are more clonic after spinalisation and the activation delay between St and Srt is present on the ipsilateral side but not on the contralateral side. This may explain why spinal cats tend to drag their feet at the onset of swing, as it appears that hip flexion may start at the same time as knee flexion, whereas normally, knee flexion first clears the foot before the hip flexes. This specific defect might be related to the section of the corticospinal and rubrospinal pathways, as cats with lesions restricted to the dorsolateral quadrants have a quadrupedal locomotor pattern, but show a similar paw drag at the onset of swing (Jiang and Drew, 1996; Rossignol et al., 1999). Srt often has a second burst in the extension phase and is sometimes prominent as in this example and maybe related to the recruitment of that bifunctional muscle to assist weight support. Finally, there is nice symmetrical activation of flexor and extensor muscles on both sides.
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The effect of early training after spinalisation was studied using pharmacological stimulation. Clonidine, an alpha-2 adrenergic agonist, can induce locomotion with plantar foot contact and large amplitude movements for 4–6 hours when injected i.v. or intrathecally (Forssberg and Grillner, 1973
; Barbeau et al., 1987; Chau et al., 1998b). We have made use of this permissive time window caused by the injection of Clonidine (either i.p. or i.t.) to train cats every day during the first week post-spinalisation (Barbeau et al., 1993; Chau et al., 1998a). This intensive early locomotor training regimen would have been impossible without the drug, as spinal cats only have weak leg movements without weight support during the first week post-spinalisation. After only a week of training, these cats could express spontaneous locomotion with plantar foot placement and weight support of the hindquarters, even in the absence of clonidine. Their performance remained good for several weeks thereafter.
Taken together, these results provide further indications that the quality and rate of recovery can be influenced by external factors. Edgerton and his colleagues (de Leon et al., 1998a, b, 1999; Edgerton et al., 1991, 1997) have suggested that the effect of training is exerted mainly through neural mechanisms and not peripheral muscular mechanisms and showed that cats trained specifically to walk will walk better than stand, whereas cats trained to stand still will stand better than walk. Recent evidence (Côté et al., 2003) suggest that long-term treadmill training may actually change the properties of load pathways as studied with intracellular methods during "fictive" locomotion.
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SPINAL PLASTICITY AND LOCOMOTION |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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The above examples of training-induced spinal plasticity somewhat contrasts with the view that the spinal cord might be hardwired. The question of the extent to which the genetically-determined spinal pattern generator is hardwired, and consequently not very adaptable, has been studied using other approaches such as tendon transfers, conditioning of reflexes, and adaptive capacity after peripheral nerve lesions.
Tendon transfers
Can the central nervous system learn to change the timing of activation of muscles in order to generate proper locomotion? This can be studied by transposing the innervation of a muscle to its antagonist, or by transposing one of its tendons to the opposite side of a joint, such that the mechanical action of the muscle is reversed (reviewed in Sperry, 1945). This was investigated with combined EMG and kinematic recordings during locomotion (Forssberg and Svartengren, 1983) with the transposition of the proximal portion of the lower tendon of the medial gastrocnemius muscle (MG) with the distal part of the cut tibialis anterior (TA) tendon. Even after 3 years, one cat still showed locomotor deficits and never changed the timing of activation of MG from extension to flexion. The authors concluded that the locomotor system was therefore "hardwired." A similar conclusion was reached by Sperry (1940, 1941, 1942) who had shown that, if rats are forced to use only the transposed muscles (by cutting muscle nerves to all other muscles acting around the same joint), there is basically no compensation. The general view at that point was, therefore, that central programming was fixed, and could hardly be influenced by changes in sensory feedback.
However, other experiments suggest that there are some plastic changes in the spinal cord after tendon transfers. It was observed (Eccles et al., 1960) that changes could occur even in the simplest connections (the monosynaptic EPSPs) between afferents and motoneurones, long after antagonist nerve crossing. Others (Luff and Webb, 1985) crossed Soleus and EDL muscle nerves and showed that the phase of activity of these muscles during locomotion became variable after crossing, which they attributed to the combination of a lack of proprioceptive information (see also Cope et al., 1994) and/or to some degree of central remodeling. Other experiments (Loeb, 1999) on tendon transfers of distal muscles performed in kittens also showed that there was some important adaptation of the muscle activity during locomotion and fast paw shake, as well as in some reflexes, especially of cutaneous origin. Thus, even in the very demanding situation of tendon transfers, there are indications of some adaptability.
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MODIFICATIONS OF SPINAL REFLEXES |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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Other experiments have suggested that the spinal cord can somehow "memorize" changes in reflex amplitude, an indication of spinal plasticity. The work of Durkovic (Durkovic, 1996
; Durkovic and Damianopoulos, 1986; Durkovic, 1983; Durkovic, 1975) indicates that there could be long-term facilitation of cutaneous reflexes in acute spinal cats. Using the Saphenous nerve as a conditioning stimulus and Superficial Peroneal nerve as a test stimulus, it was shown that the response from the Saphenous nerve was persistently increased for more than 2 hours. Another set of experiments was performed by Wolpaw and his colleagues(Wolpaw and Tennissen, 2001) using operant conditioning in monkeys and rats. They have demonstrated that the H-reflex can be up-regulated or down-regulated and that this H-reflex modulation persists after spinalisation, again indicating a spinal imprint of the conditioning developed while the animal was intact. |
ADAPTATION OF SPINAL LOCOMOTION TO NEURECTOMIES |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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In a series of experiments carried out several years ago (Carrier et al., 1997
), we neurectomized ankle flexors (TA and EDL) on one side in otherwise intact cats. Figure 2 compares the kinematics of locomotion before and after such a neurectomy on the left side. The kinematics of the recovered locomotion was very similar to control after only a few days, except for ankle flexion which was diminished (Fig. 2B). There were some consistent increases in hip and knee flexor amplitude (not shown). However, after spinalisation (Fig. 2C), stepping became asymmetrical and marked by large dysfunctional knee and hip hyperflexions during swing on the denervated side, leading to a maladaptive withdrawal of the foot upwards, while the other side performed almost normal locomotor movements. These hyperflexions during locomotion were even more marked after the injection of clonidine. As detailed above, spinal cats usually recover a smooth and symmetrical locomotion. These denervated cats had almost completely normal kinematics before spinalisation, even though they were neurectomized. The abnormality of the spinal locomotor pattern in cats that have already compensated for a neurectomy performed before spinalisation suggests that compensation involved changes in the spinal cord itself. These changes, although apparently maladaptive, become apparent only when the spinal cord is disconnected entirely from its normal interaction with supraspinal inputs. To show that these changes were not only a reaction of the spinal cat to a peripheral nerve lesion, we performed a similar neurectomy in another cat after spinalisation and expression of locomotion (Fig. 2D). For the entire testing period, the cat did not recover ankle flexion, but did not either display the abnormal hyperflexions reported in cats denervated before spinalisation. These results, therefore, suggest that the asymmetrical hyperflexions described above in cats neurectomized before spinalisation result from modifications that have taken place at several levels in the central nervous system, including in the spinal cord. The fact that these asymmetric movements continued to be expressed for a prolonged period of time after spinalisation shows that compensation has created a long-term imprint in the spinal locomotor network of the adult spinal cat.
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Whereas the previous study dealt with flexor muscles of the ankle, in another experimental series, we lesioned an ankle extensor nerve (LGS) on one side in three spinal cats chronically-implanted with electromyographic electrodes (Bouyer et al., 2001
). After the neurectomy, there was a marked yield at the ankle during the first few days (see Fig. 3A and C) and a large increase in activity in the agonist muscle Medial Gastrocnemius (MG) as seen in Figure 2B. A return to an almost normal ankle movement occurred within a week (see Fig. 3C) and was accompanied by a persistent but smaller change in the activity of the MG muscle (Fig. 3B, 8 days vs. pre neurectomy). These changes occurred too rapidly to be caused by hypertrophy in the MG muscle that could originate from the increased load imposed on this muscle by the denervation of its synergist (Noble et al., 1984; Roy et al., 1991) and therefore have to be of central origin. The fact that spinal cats could compensate and somehow recover a practically normal kinematic pattern suggests that there is indeed a great deal of plasticity in the spinal cord, even in the absence of supraspinal inputs. It must be noted that this by no means implies that supraspinal systems are not important in normal cats when adapting to a similar lesion, nor does it imply that the mechanisms used by spinal cats are the same as those used by intact cats. The point is, however, that the spinal cord has the capacity to adapt extensively to major changes imposed in the sensory-motor plant by peripheral nerve lesions. Are these changes produced by changes in the CPG output, or by changes in the gain of some cutaneous or proprioceptive reflexes that will compensate for the absence of major ankle extensor muscles? Such questions are currently under investigation.
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In a third series of experiments, we removed the cutaneous inputs from both hindpaws in otherwise intact cats. This neurectomy caused little damage to the motor apparatus, as it only involved cutting motor axons to some intrinsic toe muscles (Bouyer and Rossignol, 2003a
). After 24–48 hr, the cats walked quasi-normally on the treadmill but, at the same time, were unable to walk on a horizontal ladder. There was a minor but consistent increase in knee flexor muscle bursts (amplitude and duration) during treadmill walking. After complete locomotor adaptation, cats were spinalised at T13. We observed that they were no longer capable of plantigrade walking even after several weeks of locomotor training (Bouyer and Rossignol, 2003b). The cats simply dragged their paws on the dorsum during swing and supported weight on the dorsum during stance. The EMG pattern, especially of EDL, was quite perturbed since it now discharged during stance rather than during swing. In a complementary experiment on another cat, we observed that after a partial skin denervation performed after spinalisation, adaptation and recovery of the normal positioning of the paw occurred. Indeed, when the cutaneous denervation is progressive, the early deficits related to the removal of a nerve are compensated within a few days, even in the spinal state. Figure 4A shows a spinal cat walking with the Saphenous, Sural, and Deep Peroneal nerves cut many days before. The cat walked almost as a "normal" spinal cat. However, after subsequently cutting the Superficial Peroneal (SP) nerve, the toes doubled under the paw during swing and remained in this inappropriate position during stance (Fig. 4B). However, after 8 days of locomotor training (Fig. 4C), the cat recovered plantar paw placement during stance. After the last cutaneous nerve (Tibial) was cut (Fig. 4D), the cat could no longer place the paw on the plantar surface, and behaved like other completely-denervated cats. These findings, therefore, suggest that the animal, even in the spinal state, is capable of achieving some functional compensation after peripheral lesions and thus modify its locomotor pattern.
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CONCLUDING REMARKS |
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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In summary, the above observations suggest that the characteristics of spinal locomotion can be influenced by external factors, such as training or peripheral nerve lesions and, therefore, that there is an important potential for adaptive plasticity in the spinal cord. It will be crucial to understand how these spinal changes are implemented, if we hope to use this potential spinal plasticity in sensori-motor programs to train humans after spinal cord injuries (Rossignol and Barbeau, 1995
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FOOTNOTES |
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1 From the Symposium Recent Developments in Neurobiology presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 4–8 January 2003, at Toronto, Canada.
2 E-mail: serge.rossignol{at}umontreal.ca
3 Present address: Centre interdisciplinaire de recherche en réadaptation, et intégration sociale (CIRRIS), IRDPQ-Site François-Charon, 525, boulevard Wilfrid-Hamel, bureau B-77, Québec (Qué bec) G1M 2S8, Canada; E-mail: Laurent.Bouyer{at}rea.ulaval.ca
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SYNOPSISINTRODUCTIONSPINAL LOCOMOTIONLOCOMOTOR TRAININGSPINAL PLASTICITY AND LOCOMOTIONMODIFICATIONS OF SPINAL REFLEXESADAPTATION OF SPINAL LOCOMOTION...CONCLUDING REMARKSREFERENCES |
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