Locomotor performance and adaptation after partial or complete spinal cord lesions in the cat.
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Animals↗
Biomedical subjects
S Rossignol
Publications and source records attributed to S Rossignol.
Tapping into spinal circuits to restore motor function.
Motivated by the challenge of improving neuroprosthetic devices, the authors review current knowledge relating to harnessing the potential of spinal neural circuits, such as reflexes and pattern generators. If such spinal interneuronal circuits could be activated, they could provide the coordinated control of many muscles that is so complex to implement with a device that aims to address each participating muscle individually. The authors' goal is to identify candidate spinal circuits and areas of research that might open opportunities to effect control of human limbs through electrical activation of such circuits. David McCrea's discussion of the ways in which hindlimb reflexes in the cat modify motor activity may help in developing optimal strategies for functional neuromuscular stimulation (FNS), by using knowledge of how reflex actions can adapt to different conditions. Michael O'Donovan's discussion of the development of rhythmogenic networks in the chick embryo may provide clues to methods of generating rhythmic activity in the adult spinal cord. Serge Rossignol examines the spinal pattern generator for locomotion in cats, its trigger mechanisms, modulation and adaptation, and suggests how this knowledge can help guide therapeutic approaches in humans. Hugues Barbeau applies the work of Rossignol and others to locomotor training in human subjects who have suffered spinal cord injury (SCI) with incomplete motor function loss (IMFL). Michel Lemay and Warren Grill discuss some of the technical challenges that must be addressed by engineers to implement a neuroprosthesis using electrical stimulation of the spinal cord, particularly the control issues that would have to be resolved.
Adaptation, Physiological↗
Recovery of locomotion after ventral and ventrolateral spinal lesions in the cat. II. Effects of noradrenergic and serotoninergic drugs.
The effects of serotoninergic and noradrenergic drugs (applied intrathecally) on treadmill locomotion were evaluated in two adult cats subjected to a ventral and ventrolateral spinal lesion (T13). Despite the extensive spinal lesion, severely damaging important descending pathways such as the reticulo- and vestibulospinal tracts, both cats recovered quadrupedal voluntary locomotion. As detailed in a previous paper, the locomotor recovery occurred in three stages defined as early period, when the animal could not walk with its hindlimbs, recovery period, when progressive improvement occurred, and plateau period, when a more stable locomotor performance was observed. At this latter stage, the cats suffered from postural and locomotor deficits, such as poor lateral stability, irregular stepping of the hindlimbs, and inconsistent homolateral fore- and hindlimb coupling. The present study aimed at evaluating the potential of serotoninergic and/or noradrenergic drugs to improve the locomotor abilities in the early and late stages. Both cats were implanted chronically with an intrathecal cannula and electromyographic (EMG) electrodes, which allowed determination, under similar recording conditions, of the locomotor performance pre- and postlesion and comparisons of the effects of different drugs. EMG and kinematic analyses showed that norepinephrine (NE) injected in early and plateau periods improved the regularity of the hindlimb stepping and stabilized the interlimb coupling, permitting to maintain constant locomotion for longer periods of time. Methoxamine, the alpha1-agonist (tested only at the plateau period), had similar effects. In contrast, the alpha2-agonist, clonidine, deteriorated walking. Serotoninergic drugs, such as the neurotransmitter itself, serotonin (5HT), the precursor 5-hydroxytryptophan (5HTP), and the agonist quipazine improved the locomotion by increasing regularity of the hindlimb stepping and by increasing the step cycle duration. In contrast, the 5HT1A agonist 8-hydroxy-dipropylaminotetralin (DPAT) caused foot drag in one of the cats, resulting in frequent stumbling. Injection of combination of methoxamine and quipazine resulted in maintained, regular stepping with smooth movements and good lateral stability. Our results show that the effects of drugs can be integrated to the residual voluntary locomotion and improve some of its postural aspects. However, this work shows clearly that the effects of drugs (such as clonidine) may depend on whether or not the spinal lesion is complete. In a clinical context, this may suggest that different classes of drugs could be used in patients with different types of spinal cord injuries. Possible mechanisms underlying the effect of noradrenergic and serotoninergic drugs on the locomotion after partial spinal lesions are discussed.
5-Hydroxytryptophan↗
Pharmacological activation and modulation of the central pattern generator for locomotion in the cat.
Pharmacological agents have been shown to be capable of inducing a pattern of rhythmic activity recorded in muscle nerves or motoneurons of paralyzed spinal cats that closely resembles the locomotor pattern seen in intact cats. Further work, using intraperitoneal or intrathecal injections, suggests that different neurotransmitters may be involved in various aspects of locomotor control, e.g., initiation and modulation of the pattern. Although precursors, agonists or the neurotransmitters themselves of several systems have been investigated (noradrenergic, dopaminergic, serotonergic, glutamatergic), the noradrenergic system seems the most efficient in triggering locomotion in complete spinal cats, with the alpha-2 agonists (clonidine, tizanidine, oxymetazoline) being more potent than the alpha-1 agonist, methoxamine. Moreover, the potency of the drugs may depend on the time of application after the spinal lesion. In chronic spinal cats capable of spontaneous walking on hindlimbs on the treadmill, all neurotransmitters appear to exert distinct recognizable effects on the locomotor pattern. More recent work also suggests that the effects of drugs may differ significantly depending on the type of spinal lesion. For instance, clonidine further reduces the level of weight support during quadrupedal locomotion of cats with lesions of the ventral-ventrolateral funiculi, possibly due to an interference of clonidine with essential compensatory mechanisms used by these animals to walk. Such considerations as the type of drugs, type of lesions, and the time after the lesion will be important for future studies in spinal cord injured patients.
5-Hydroxytryptophan↗
The contribution of cutaneous inputs to locomotion in the intact and the spinal cat.
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Action Potentials↗
Differential effects of the noradrenergic agonist clonidine on the locomotion of intact, partially and completely spinalized adult cats.
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Action Potentials↗
Kinematic analysis of recovered locomotor movements of the hindlimbs in paraplegic rats transplanted with monoaminergic embryonic neurons.
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Animals↗
Early locomotor training with clonidine in spinal cats.
Clonidine, a noradrenergic alpha-2 agonist, can initiate locomotion early after spinalization in cats. Because this effect lasts 4-6 h, we have injected clonidine daily, intraperitoneally or intrathecally, and intensively trained five spinal cats to perform hindlimb walking on a treadmill starting at day 3 and continuing until 10 days posttransection. Each day, clonidine was injected to induce locomotor activity and cats were trained to walk with as much weight support as possible and at different speeds during multiple (1-5) locomotor training sessions, each lasting from 10 to 20 min, until the effects of clonidine wore off. Electromyographic (EMG) activity synchronized to video images of the hindlimbs were recorded before and after each clonidine injection. The results showed, first, a day-to-day change of the locomotor pattern induced by clonidine from the 3rd to the 11th day including an increase in the duration of the step cycle, an increase in the duration of extensor EMG activity, and an increase in total angular excursion of the hip, knee, and ankle joints. Second, after 6-11 days of this regimen, there was an emergence of a coordinated locomotor pattern with weight support of the hindquarters that was visible even before that day's clonidine injection. The results suggested that daily injection of clonidine followed by early and daily interactive locomotor training can enhance the recovery of locomotion in spinal cats.
Animals↗
Effects of intrathecal alpha1- and alpha2-noradrenergic agonists and norepinephrine on locomotion in chronic spinal cats.
Noradrenergic drugs, acting on alpha adrenoceptors, have been found to play an important role in the initiation and modulation of locomotor pattern in adult cats after spinal cord transection. There are at least two subtypes of alpha adrenoceptors, alpha1 and alpha2 adrenoceptors. The aim of this study was to investigate the effects of selective alpha1 and alpha2 agonists in the initiation and modulation of locomotion in adult chronic cats in the early and late stages after complete transection at T13. Five cats, chronically implanted with an intrathecal cannula and electromyographic (EMG) electrodes were used in this study. Noradrenergic drugs including alpha2 agonists (clonidine, tizanidine, and oxymetazoline) and an antagonist, yohimbine, one alpha1 agonist (methoxamine), and a blocker, prazosin, as well as norepinephrine were injected intrathecally. EMG activity synchronized to video images of the hindlimbs were recorded before and after each drug injection. The results show differential effects of alpha1 and alpha2 agonists in the initiation of locomotion in early spinal cats (i.e., in the first week or so when there is no spontaneous locomotion) and in the modulation of locomotion and cutaneous reflexes in the late-spinal cats (i.e., when cats have recovered spontaneous locomotion). In early spinal cats, all three alpha2 agonists were found to initiate locomotion, although their action had a different time course. The alpha1 agonist methoxamine induced bouts of nice locomotor activity in three spinal cats some hours after injection but only induced sustained locomotion in one cat in which the effects were blocked by the alpha1 antagonist prazosin. In late spinal cats, although alpha2 agonists markedly increased the cycle duration and flexor muscle burst duration and decreased the weight support or extensor activity (effects blocked by an alpha2 antagonist, yohimbine), alpha1 agonist increased the weight support and primarily the extensor activity of the hindlimbs without markedly changing the timing of the step cycle. Although alpha2 agonists, especially clonidine, markedly reduced the cutaneous excitability and augmented the foot drag, the alpha1 agonist was found to increase the cutaneous reflex excitability. This is in line with previously reported differential effects of activation of the two receptors on motoneuron excitability and reflex transmission. Noradrenaline, the neurotransmitter itself, increased the cycle duration and at the same time retained the cutaneous excitability, thus exerting both alpha1 and alpha2 effects. This work therefore suggests that different subclasses of noradrenergic drugs could be used to more specifically target aspects of locomotor deficits in patients after spinal injury or diseases.
Adrenergic alpha-1 Receptor Agonists↗
Recovery of locomotion after ventral and ventrolateral spinal lesions in the cat. I. Deficits and adaptive mechanisms.
The recovery of treadmill locomotion of eight adult cats, subjected to chronic ventral and ventrolateral spinal lesions at low thoracic levels (T11 or T13), preserving at least one dorsolateral funiculus and the dorsal columns, was documented daily using electromyographic (EMG) and kinematic methods. The data show that all cats eventually recovered quadrupedal voluntary locomotion despite extensive damage to important pathways (such as the reticulospinal and the vestibulospinal) as verified by injection of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) caudal to the site of lesion. Initially (in the early period after the spinal lesion), all the cats suffered from pronounced locomotor and postural deficits, and they could not support their hindquarters or walk with their hindlimbs. Gradually, during the recovery period, they regained quadrupedal walking, although their locomotion was wobbly and inconsistent, and they suffered from poor lateral stability. EMG and kinematic data analyses showed a tendency for an increase in the variability of the step cycle duration but no major changes in the step cycle structure or in the intralimb coupling of the joints. However, the homolateral fore- and hindlimb coupling was highly perturbed in cats with the largest lesions. Although the general alternating pattern of extensor and flexors was maintained, there were various changes in the duration and amplitude of the EMG bursts as well as a lack of amplitude modulation during walking uphill or downhill on the treadmill. In cats with larger lesions, the forelimbs also seem to take a greater propulsive role than usual as revealed by a consistent increase of the activity of the triceps. In cats with smaller lesions, these deficits were transient, but, for the most extensively lesioned cats, they were pronounced and lasted long term postlesion even after reaching a more or less stable locomotor behavior (plateau period). It is concluded that recovery of quadrupedal locomotion is possible even after a massive lesion to ventral and ventrolateral quadrants, severing the vestibulospinal pathway and causing severe, although incomplete, damage to the reticulospinal tract. The quick recovery in the less lesioned cats can be attributed to remaining pathways normally implicated in locomotor function. However, in the most extensively lesioned cats, the long period of recovery and the pronounced deficits during the plateau period may indicate that the compensation, attributed to remaining reticulospinal pathways, is not sufficient and that other pathways in the dorsolateral funiculi, such as the corticospinal, can sustain and adapt, up to a certain extent, the voluntary quadrupedal walking.
Animals↗
Locomotion of the hindlimbs after neurectomy of ankle flexors in intact and spinal cats: model for the study of locomotor plasticity.
To study the potential plasticity of locomotor networks in the spinal cord, an important issue for locomotor rehabilitation after spinal injuries, we have investigated the locomotor performance of cats before and after a unilateral denervation of the ankle flexors tibialis anterior (TA) and extensor digitorum longus (EDL) both in cats with intact spinal cord and after spinalization. The effects of the inactivation of the ankle flexors were studied in three cats with intact spinal cord during periods of 4-7 wk. Cats adapted their locomotor performance very rapidly within a few days so that the locomotor behavior appeared to be unchanged practically. However, kinematic analyses of video records often revealed small but consistent increase in knee and/or hip flexion. These changes were accompanied by some increase in the amplitude of knee and hip flexor muscle activity. Cats maintained a regular and symmetrical walking pattern over the treadmill for several minutes. Two of these cats then were spinalized at T13 and studied for approximately 1 mo afterward. Whereas normally cats regain a regular and symmetrical locomotor pattern after spinalization, these cats had a disorganized and asymmetrical locomotor pattern with a predominance of knee flexion and absence of plantar foot contact of the denervated limb. Another cat first was spinalized and allowed to recuperate a regular symmetrical locomotor performance. Then it also was submitted to the same unilateral ankle flexor inactivation and studied for approximately 50 days. The cat maintained a well-organized symmetrical gait although there was almost no ankle flexion on the denervated side. There was no exaggerated knee hyperflexion and gait asymmetry as seen in the two previous cats spinalized only after they had adapted to the denervation of ankle flexors. It is concluded that, after muscle denervation, locomotor adaptation is achieved through changes occurring at different levels. Because cats spinalized after adaptation to the neurectomy had an asymmetrical locomotor pattern dominated by hyperflexion, it is suggested that the spinal circuitry has been modified during the adaptive process, presumably through the action of corrective supraspinal inputs. Indeed spinal cats do not normally display such abnormal hyperflexions, and neither did the one cat denervated after spinalization. On the other hand, because the modified locomotor pattern in the spinal state is not functional and contains only some aspects of the compensatory response seen before spinalization, it is suggested that the complete functional adaptation observed in intact cats after peripheral nerve lesions may depend on changes occurring at the spinal and the supraspinal levels.
Animals↗
Responses of medullary reticulospinal neurones to stimulation of cutaneous limb nerves during locomotion in intact cats.
The present study was designed to determine whether the transmission of cutaneous afferent information from the limbs to the medullary reticular formation is phasically modulated during locomotion. Experiments were carried out in three chronically prepared, intact cats in which nerve cuff electrodes were placed, bilaterally, on the superficial radial and the superficial peroneal nerves. Thirty-seven reticulospinal neurones (RSNs) were identified by stimulation of their axons in the lumbar spinal cord (L2); 29 of 37 of these were recorded with the cat at rest, 28 of 37 during locomotion and 20 of 37 both at rest and during locomotion. Low-threshold stimulation of the cutaneous nerves evoked excitatory responses in the majority of RSNs both at rest and during locomotion. In the 28 of 37 RSNs recorded during locomotion, it was possible to record the evoked response to stimulation of all four limb nerves, giving a total of 184 tested cases [RSNs tested x number of nerves stimulated x phase of stimulation (swing or stance)]. The responses of most RSNs to cutaneous stimulation were modulated in a phase-dependent manner during locomotion. The maximal responses in most, but not all, cases were obtained during the swing phase of the limb that was stimulated and were largely independent of the discharge pattern of the cell. We interpret this result as indicating that the efficacy of transmission of the afferent information is determined more by the excitability of the spinal relay neurones than by the level of excitability of the RSNs in the brainstem. It is suggested that the base discharge pattern of RSNs might be largely determined by their central afferent input, while peripheral afferent inputs would primarily serve to modify the RSN discharge pattern in response to perturbations.
Afferent Pathways↗
A comparison of treadmill locomotion in adult cats before and after spinal transection.
1. The aim of this study was to document the kinematics and the electromyographic activity recorded from several muscles during treadmill locomotion in the same cat (N = 4), before and after spinalization by using a chronic implantation method. Because identical experimental and control conditions were used, it was possible to establish similarities and differences in the timing and amplitude of the muscular activity and kinematics under the intact and spinal conditions in the same animal. The data presented in this paper were collected when the cats had fully recuperated a stable locomotor pattern, walking at a constant speed of approximately 0.4 m/s. 2. The adult spinal cats retained many of the general locomotor features and electromyographic (EMG) characteristics seen before transection. However, there were also important differences. 3. There was a reduction in the step length that was principally due to the forward placement of the paw at the onset of the stance. Similarly, there was a decrease in the step cycle duration which was attributed to a reduction of both the stance and swing phases. 4. The overall angular excursions of the hip, knee, and ankle were generally similar, although joints were sometimes more flexed at all phases of the step cycle. In contrast, the overall excursions of the metatarsophalangeal joints was much greater in all four cats after spinalization due to a paw drag during the initial portion of the swing phase that exaggerated the plantarflexion. 5. There was an increase in the EMG amplitude of the flexor muscles at two of three joints (i.e., hip, knee, and ankle) in each cat after spinalization. The change in the EMG amplitude of the extensors did not appear to be as consistent as that observed in the flexor muscles. When looking at each cat individually, the postspinalization extensor activity decreased at two of three joints in two cats, whereas the opposite was true for the other two cats. 6. There was a delay in the onset of the knee flexor (semitendinosus) activity while the ankle dorsiflexor (tibialis anterior) activity started earlier with respect to the beginning of the swing phase. The onset of hip flexors was somewhat more variable. This change in the timing of flexor activity was most probably responsible for the paw drag at the onset of the swing phase. 7. The present results reveal that despite the few differences, the spinal cord and the hindlimbs afferents are capable of generating very good locomotor patterns with almost normal kinematics and EMG characteristics.
Animals↗
Locomotor capacities after complete and partial lesions of the spinal cord.
This paper first reviews some of the observations made on the locomotor capabilities of several animal species with a special emphasis on cats and including primates and man after complete spinal lesions. We show that animals can perform well-coordinated walking movements of the hindlimbs when they are placed on a treadmill belt and this locomotion is also adaptable to speed and perturbations. Cats with partial spinal lesions of the ventral and ventrolateral parts of the cord can perform voluntary quadrupedal locomotion overground or on the treadmill albeit with deficits in weight support and interlimb coordination. We also show that some drugs such as clonidine (an alpha-2 noradrenergic agonist) can be used to trigger locomotion in early-spinal cats and discuss the effects of various neurotransmitter systems on the expression of the locomotor pattern in both complete and partial spinal cats. It is concluded that a pharmacological approach could be used, in combination with other approaches, such as locomotor training and functional electrical stimulation, to improve locomotor functions after spinal cord injuries in humans.
Animals↗
Visuomotor regulation of locomotion.
Vision is obviously important for the control of goal-directed locomotion. This profound influence can be best revealed by interfering with the visual pathways or by altering the visual inputs normally expected to occur during locomotion. For instance, the use of reversed optic flow or reversing prisms can induce significant locomotor changes or lead to powerful illusions, such as the sensation of backward walking while actually walking forward. To better understand the many ways by which visual inputs could actually influence locomotion, an overview of some of the background concepts on the generation, initiation, and control of locomotion is given and, when pertinent, mechanisms by which vision could interact with locomotion at different control levels of the central nervous system are postulated.
Animals↗
Spinal pattern generation.
Recent research in the field of spinal pattern generation has concentrated on three main areas: the effects of various transmitters on spinal rhythmic patterns in reduced preparations (neonatal rats, chick embryos, tadpole embryos, lampreys); the changes in membrane properties of different elements of the generating circuits; and the interactions between central generating mechanisms and afferent inputs. The important message is that new properties of neural membranes, as well as new reflex responses, have been identified that could not have been predicted in the absence of such rhythmic activity.
Afferent Pathways↗
Enhancement of locomotor recovery following spinal cord injury.
Recent advances have been made in new experimental approaches to enhance locomotor recovery in spinal cord-injured subjects. Research in adult animals whose spinal cords have been transected (spinal animals) has focused particularly on locomotor recovery and the use of pharmacological tools to trigger and modulate the locomotor pattern. This provides a rational basis for the rehabilitation and pharmacotherapy of locomotion in spinal cord-injured patients. Findings in the field of locomotor training, locomotor pharmacotherapy, and functional electrical stimulation are reviewed. It is argued that a combination of the various approaches will provide an optimal base for functional locomotor recovery.
Animals↗
Microstimulation of the medullary reticular formation during fictive locomotion.
1. The present study was designed to determine the effects of microstimulation of the medullary reticular formation (MRF) on the locomotor activity of the cat in the absence of phasic afferent feedback from the limbs. To this end, both short (33 ms) and long (200 ms) trains of stimuli (trains of 0.2-ms pulses at 330 Hz, 35 microA) were applied at 43 loci in the MRF (P:6-12 mm; L:0.5-1.5 mm), and in 3 loci in the medial longitudinal fasciculus (P7.5, L < 0.5 mm) during fictive locomotion in the decerebrate and paralyzed cat. The locomotor pattern was monitored by recording the activity of representative flexor and extensor muscle nerves from each of the four limbs. 2. Short trains of stimuli evoked transient excitatory and/or inhibitory responses in extensor and flexor nerves of each limb that were incorporated into the locomotor pattern. In the majority of sites, excitatory responses were obtained in the motor nerves to both flexor and extensor muscles of the fore- and hindlimbs. The exception to this rule was the ipsilateral triceps, in which the predominant response was inhibitory. The amplitude of these responses was dependent on the time of the locomotor cycle at which the stimulus was delivered, and it was always maximum during the period of activity of the respective nerve. 3. The shortest latency response in the nerves to different muscles of the forelimb averaged between 5.6 and 7.3 ms; for the hindlimbs the values were between 6.9 and 9.3 ms. 4. Changing the depth at which the stimulation was applied in any one trajectory usually produced changes only in the amplitude of the evoked responses but occasionally also caused a change in the sign of these responses, especially in the most ventral regions of the MRF. 5. At 72% of the loci (31/43), short trains of stimulation also changed the duration of the activity in the recorded nerves. These changes were often (20/31 loci) sufficiently strong to alter the duration of the overall locomotor cycle. If one considers only the largest changes produced at each locus, stimulation during the period of ipsilateral extensor activity produced an average reduction in the ipsilateral locomotor cycle duration of 12.8 +/- 8.8% (mean +/- SD), whereas stimulation when the ipsilateral flexor nerve was active produced an average increase in locomotor cycle duration of 27.1 +/- 20.8%. 6. Long trains of stimuli produced similar but larger effects than the shorter trains and always reset the locomotor rhythm.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗