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The Journal of Neurophysiology Vol. 80 No. 3 September 1998, pp. 1245-1267
Copyright ©1998 by the American Physiological Society
Centre de recherche en Sciences Neurologiques, Faculté de Médecine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Brustein, Edna and Serge Rossignol. Recovery of locomotion after ventral and ventrolateral spinal lesions in the cat. I. Deficits and adaptive mechanisms. J. Neurophysiol. 80: 1245-1267, 1998. 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.
It is of major clinical importance to identify and understand the adaptive locomotor capacities of the nervous system after spinal cord injuries if one is to design and implement rehabilitation strategies for locomotion (Barbeau and Rossignol 1994 General experimental protocol
Experiments were carried out on eight adult cats (2.5-4.8 kg) that were trained to walk on a treadmill at different speeds (0.2-0.7 m/s) and with different inclines (10° uphill and downhill). When the cats could consistently maintain regular locomotion for periods of ~20 min, they were chronically implanted with electrodes to record EMG activity from fore- and hindlimb muscles. After recovery from surgery, 7-12 control experiments were made over a 1- to 6-wk period to determine the control (intact) EMG and kinematic values. Thereafter, the cats were submitted to the ventral-ventrolateral spinal lesion at thoracic level (T11 or T13), and their locomotor recovery was followed and documented daily. No special training program was applied, and the recordings on the treadmill started when the cat could walk voluntarily with all four limbs at a minimal treadmill speed of 0.1 m/s. When the cats did not show any further locomotor improvement (48-343 days postlesion, depending on the extent of the lesion), WGA-HRP was injected caudal to the site of the spinal lesion (L2). Then, 3 days later, the cats were perfused and the spinal cord, i.e., the site of HRP injection, and the site of lesion were taken for histological processing, as well as the brain stem and the motor cortices. All the surgical procedures and experimental protocols were reviewed and approved by the University Ethics Committee.
Surgical procedures
EMG IMPLANTATION.
The bipolar EMG electrodes were chronically implanted under sterile conditions. First, the cats were premedicated with acepromazine maleate (Atravet, 0.1 mg/kg sc), Atropine (0.05 mg/kg sc), and Penicillin G (40,000 IU/kg im) and then anesthetized with pentobarbital sodium (Somnotol, 35 mg/kg iv). Two 15-pin connectors (TRW Electronic Components Group, Elk Grove Village, IL) were fixed to the skull, and 14 pairs of Teflon-coated stainless steel wires (AS633, Cooner Wire, Chatsworth, CA), soldered to the connector pins, were directed subcutaneously to different muscles acting around the fore- and hindlimb joints. The portion of the wire that was inserted into the muscle belly was exposed for 1-2 mm and then fixed in situ by a silk thread. The EMG electrodes were implanted in the following muscles, listed according to their main function: in the hindlimbs, the hip flexors, iliopsoas (Ip) and sartorius (Srt); the knee flexor, semitendinosus (St); the ankle flexor, tibialis anterior (TA); the knee extensor, vastus lateralis (VL); and the ankle extensors, gastrocnemius medialis (GM) and lateralis (GL); in the forelimbs: the elbow flexor, cleidobrachialis (ClB), and the elbow extensor (lateral head), triceps brachii (TriL).
VENTRAL AND VENTROLATERAL SPINAL LESIONS.
After the 7-12 control experiments (after the EMG implantation) the ventral and ventrolateral spinal lesion was performed. The procedure was done under general anesthesia as described above. A low thoracic vertebra was exposed, T11 for cats EB1-6 and T13 for cats EB7-8, and two small openings were drilled through the vertebral pedicles to approach the spinal cord laterally on both sides. After making a small incision in the dura, a microknife and/or a small forceps were inserted through the openings to lesion the ventral half of the spinal cord while leaving the dorsal portion intact and protected by the overlying laminae. Afterward, the incision was closed in anatomic layers. The postoperative cares were the same as after the EMG implantation. It must be noted that all cats, in contrast to the complete spinal cats whose bladder had to be expressed manually (Bélanger et al. 1996 Recordings and data analysis
EMG activity and the video images used for kinematics analyses were recorded simultaneously and were synchronized using a SMPTE time code (time-code generator Skotel TCG-80N and time-code reader TCR-80N).
EMG.
The amplified and filtered (100 Hz to 3 kHz) signals were recorded on an analog VHS tape recorder (Vetter 4000A PCM Recording Adaptor with cutoff frequency of 1.25 kHz) and later played back and printed out using an electrostatic polygraph (Gould ES-2000). Walking sections, representing the locomotor capacities of the cat at that day, were chosen for detailed analysis and were then digitized at 1 kHz using an AT/486 computer. Custom-made programs were used to determine each burst onset and offset and then to calculate their duration and amplitude. The amplitude was calculated as the integral of the rectified burst of EMG activity divided by the burst duration. Then it was averaged and presented as percent of the control values.
KINEMATICS.
All the walking sections selected for EMG analysis were also used for limb movement analysis as well as for defining the interlimb coupling. Six reflective markers (3 M reflective tape) were placed over the skin of the following bony landmarks: the rostral tip of the iliac crest, the femoral head, the knee joint, the lateral malleolus, the metatarsophalangeal (MTP) joint and the tip of the third toe.
Histological analysis
HISTOLOGICAL EVALUATION OF THE SPINAL SITE OF LESION.
The damage of the spinal lesion was evaluated by inspecting, under light microscope, the physical damage and the extent of cellular and fibrous necrosis in consecutive cross sections of spinal cord stained with Kluver-Barrera (cats EB6-EB8, 8 µm thick, 1 in 50 saved) or with Cresyl violet methods (EB1-EB5, 40 µm thick, 1 in 5 saved). Whereas with the first method myelinated axons can more easily be identified, in the latter it is very well possible under the microscope to identify regions of intact axons that appear as regular densely packed profiles in areas of the white matter. Following these observations the total extent of the damage was reconstructed, and its severity in each region was indicated using different graphic patterns as illustrated in Fig. 1.
WGA-HRP LABELING AND CELL DISTRIBUTION ANALYSIS.
The method of WGA-HRP injection and the related histological procedure have been described earlier (Jiang and Drew 1996
Evaluation of the extent of spinal lesions
To facilitate the description of the results, we have defined two groups of cats; EB1-EB4 and EB5-EB8. This grouping was based both on the extent of the spinal lesion (evaluated histologically) and on the cat's locomotor capacities during the recovery period and the plateau period when they were already walking at their best .
General remarks on the recovery of locomotion
Surprisingly, all the cats eventually recovered voluntary quadrupedal locomotion overground and on the treadmill. However, early after the lesion, the cats could not walk or even support their hindquarters and strolled around using their forelimbs only. For the group of cats, EB1-EB4, with relatively moderate lesions, this period was limited to 1-3 days. However, for the group of cats EB5-EB8, with most extensive lesions, it extended over >3 wk. Afterward, during the recovery period, the cats gradually regained some weight support of the hindquarters and the ability to stand and walk voluntarily with no external help. Yet, they all suffered from poor lateral stability and often fell on one side resulting in a wobbly, inconsistent walking for a few steps at a time. It is interesting to note, however, that the cats did not have problems negotiating obstacles placed in their way overground, or on a treadmill.
Intralimb coupling
The calculated joint angular displacement of the first step cycles illustrated in Fig. 3 for cat EB5 (representing the most lesioned group), from an intact and plateau period (88 days postlesion) trials, is presented in Fig. 6, A and B, respectively, with the averaged angle-angle plots (Fig. 6, C and D). The related raw EMGs are presented in Fig. 7. Notice that after the lesion, the cat's step cycle is shorter (see as well Fig. 4), resulting in a greater number of steps for the same period of time. Some changes were observed in the magnitude of the angular excursion traces. For example, before the lesion, the hip excursion ranged, on the average, between 99 ± 1° and 130 ± 1.5° (mean ± SE), whereas 88 days postlesion, it was reduced (84 ± 4.1° to 105 ± 3.7°). Such changes were observed as well for the knee, ankle, and MTP joints and resulted in a general down displacement of the related angle-angle plots. Despite the excursion changes described above, the joint coupling is largely preserved. The only coupling change, which was specific to this cat, was observed for the knee relative to the ankle. A somewhat earlier extension of the knee relative to the ankle at the end of the swing results in an eight shape angle-angle plot.
Interlimb coupling
It was demonstrated that the step cycle duration on the left and on the right hindlimbs is the same and varies together in the most extensively lesioned cats (see Fig. 4). Not only was the cycle duration the same, but, in addition, the lesion did not affect the alternating coupling pattern between the hindlimbs. This is demonstrated by the raw EMGs of the left and the right VL and the related footfalls illustrated for cat EB5 in Fig. 8, A, E, and I. In this example, the averaged phase difference between the right and left VL burst onset in the intact situation is maintained at 0.52, whereas for the recovery period and the plateau period it is 0.49 and 0.48, respectively. One should notice, however, that the individual phase onset values vary considerably after the lesion. This is easily seen from the consecutive phase values of the RVL burst onset (
EMG activity
Comparison of the raw EMG activity, before and after the lesion (see Figs. 7-9), shows that generally the alternating activity between extensors and flexors of the same limb (see RSt and RGM of cat EB5 in Fig. 7 and LSt and LVL of cat EB7 in Fig. 9E) is maintained as well as the alternating activity between muscles of contralateral limbs such as RVL and LVL or RTriL and LTriL (see Fig. 8, A, E, and I). However, various changes were observed in the amplitude and burst duration of the hindlimb muscles after the lesion. These differed from one cat to another as well as with time postlesion. Two examples are given in Table 4 to demonstrate the variability of the pattern. The first example is taken from cat EB2, which represents the moderately lesioned cat group (EB1-EB4) in which the changes were mostly restricted to the recovery period. The second example is taken from cat EB6 and mostly demonstrates the changes after a more extensive lesion (EB5-EB8), which are sustained and observed also during the plateau period.
Recovery of locomotion as a function of the extent of the spinal lesion
Recovery of locomotion in adult chronic cats was reported to depend on the integrity of the ventral and ventrolateral spinal quadrants (Afelt 1974 Recovery of weight support and lateral stability
In line with the observations of others (Bem et al. 1995 Initiation of locomotion
The involvement of pathways descending in the ventral and ventrolateral quadrants in the initiation of locomotion by MLR and PLR stimulation was studied in acute decerebrate cats that were subjected to different spinal cord lesions at C2-C3 or the brain stem (Noga et al. 1991 Step cycle structure and intralimb coupling
The voluntary and quadrupedal walking was, however, inconsistent as described by the variability of the hindlimbs step cycle duration (Fig. 4), as well from the increased CV and SD values of EMGs amplitude and duration summarized in Table 4. This variability may reflect both the poor lateral stability of the cats as well as the step-to-step adaptations to avoid falling and maintain stepping.
Interlimb coupling
One of the most important deficits observed postlesion was a step-by-step inconsistent coupling between the homolateral fore- and hindlimb, calculated from the onset of EMG activity in the related extensors (Fig. 8) (see as well English 1979 EMG activity
Various changes were observed in the amplitude and duration of the EMG activity as demonstrated in Table 4. The EMG activity of the most lesioned cats were more affected and showed, in general, a pronounced and sustained increase in amplitude and as well a reduction in their duration, which together permitted the cat to produce quick steps at the same length, to maintain the imposed treadmill speed. Another possibility is that the increase in the EMG's amplitude results from permanent changes in the motor units population such as that observed after complete spinal lesion (Cope et al. 1986 Conclusions
Sparing the ventral and ventrolateral funiculi was shown by Windle et al. (1958)
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
). After a complete spinal transection at the low thoracic level, adult cats can walk with the hindlimbs on a moving treadmill, with weight support of the hindquarters and proper plantar foot placement. This indicates that the spinal cord, together with peripheral afferents, but in isolation from descending supraspinal inputs, can generate hindlimb locomotion (Barbeau and Rossignol 1987; Bélanger et al. 1996; Grillner 1981; Rossignol 1996; Rossignol et al. 1996). With the addition of an intensive training program and/or injection of noradrenergic agonists, these locomotor capacities can be expressed earlier and better (Barbeau et al. 1993; Barbeau and Rossignol 1987, 1991; Chau et al. 1998). However, the hindlimbs' locomotion remain limited; it is not initiated voluntarily and it cannot obviously be expressed in coordination with the forelimbs. In addition, there are often deficits such as paw drag during the swing (Bélanger et al. 1996).
), there is a need for a better understanding of such conditions. The work of colleagues (Jiang and Drew 1996) has already shown that lesions limited to the dorsolateral pathways result in prolonged steps, paw drag, and an inability to step properly over obstacles, but, otherwise, there are only transient deficits in posture and interlimb coupling, suggesting that ventral and ventrolateral pathways are capable of controlling quadrupedal voluntary locomotion.
; Eidelberg 1981; Eidelberg et al. 1981; Windle et al. 1958) have suggested that pathways in the ventral and ventrolateral quadrants are essential for the recovery of voluntary quadrupedal locomotion (for more detailed review see Rossignol et al. 1996). These conclusions are, however, mainly based on spinal lesions, sparing only small patches of tissue in the ventral and the ventrolateral quadrants that were found to be sufficient to sustain locomotion. Similarly, in the acute decerebrate cat (Noga et al. 1991; Steeves and Jordan 1980) it was demonstrated that initiation of locomotion by stimulation of the mesencephalic locomotor region (MLR) depends on the integrity of ventrolateral tracts containing the reticulospinal pathways. However, there are now mounting evidence in the cat (Gorska et al. 1990, 1993a,b), in the monkey (Vilensky et al. 1992), as well as in human (Nathan 1994) that long-term recovery of voluntary locomotion is possible despite extensive lesions of the ventral and lateral quadrants, even if there are major locomotor deficits such as disrupted interlimb coupling (Gorska et al. 1993a).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
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FIG. 1.
Extent of the spinal lesions for all 8 cats: the histology of all the cats is displayed in 4 sets of columns. On the left, photomicrographs of the cross-sections taken from the spinal site of lesion, stained with cresyl violet or with Kluver-Barrera, to demonstrate the maximal extent of the lesion. To the right of the photomicrographs, a schematic reconstruction of the site of lesion, evaluated using light microscope. For cats EB1-EB5, the total extent of the lesion is projected on a spinal cord section taken more rostrally, after inspecting several consecutive sections, whereas for cats EB6-EB8 the schemes illustrate the maximal site of lesion to emphasize the deformation of the spinal cord. The various textures identify the extent of damage. Intact: myelinated axons (or axonal profiles) appeared normal under the microscope; Severe damage: absent or highly fibrotic tissue; Moderate damage: some myelinated axons (or axonal profiles) of normal appearance within fibrotic and gliotic tissue; Syrinx: cyst. L = left; R = right. The next 2 adjacent columns illustrate sagittal brain stem sections (left and right) and summarize the total values of horseradish peroxidase (HRP)-labeled cells (percent of control) found in the lateral vestibular nucleus (LVN), pontine reticular formation (PRF), and medullary reticular formation (MRF) for each cat when available (see Table 1).
), controlled their micturition and did not need manual voiding.
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TABLE 3.
The average percent of time spent on 2, 3, or 4 supporting limbs in 7 of the cats, in the intact state, during recovery and plateau-periods
). Briefly, after a recording period of 48-343 days, when the cat showed no more locomotor improvement, WGA-HRP (2%) was pressure injected, a few segments caudal to the site of the spinal lesion, usually at L2. The penetrations were done in two parallel frontal planes that permitted the whole cross-section of the spinal cord to be covered with the WGA-HRP solution (total of 20-30 µl). Three days later, the cat was perfused with 2 l of phosphate-buffered saline 0.9%, 2 l fixative (glutaraldehyde 1.25%, paraformaldehyde 1%, sucrose 1% in phosphate buffer at pH 7.4), and 1 l buffered sucrose solution 4%. The whole brain was removed, the brain stem and motor cortices were cut sagitally (40 µm), and every third section (1/3) was taken for precipitating the HRP reaction products using the tetramethylbenzidine (TMB) method (Mesulam 1978). The reaction was carried as well on cross sections (1/5 saved) taken from the site of injection to verify that it was completely covered with HRP reaction products. Then the HRP-labeled cells in the red nucleus and the lateral vestibular nucleus were counted in all the sections. Moreover, in the motor cortex and the reticular formation the location of the labeled cells was digitized as well (adapted from Matsuyama and Drew 1997). Briefly, the contours of histological sections were traced using a pantograph and then digitized using Autocad. The digitized sections were centered and oriented according to anatomic coordinates (Berman 1968) using a custom-made software. The digitization of the cells position, directly onto the computer image, extended in the brain stem from the midline to 2.5 mm on each side and was done on alternating sections (every 240 µm). Then the cells were divided into two major groups according to stereotaxic coordinates (adapted from Matsuyama and Drew 1997). The first group (A0 to P6) corresponds to the pontine reticular formation (PRF), which includes the nucleus reticularis pontis oralis and nucleus reticularis pontis caudalis, whereas the second group (P6 to P11), corresponds to the medullary reticular formation (MRF), which encompassed the nucleus reticularis gigantocellularis and the nucleus reticularis magnocellularis. For the motor cortex, digitization was done in all the sections (every 120 µm) up to 10 mm from the midline (Jiang and Drew 1996). The values were compared with data from three intact cats (1-tail Student's t-test), after verification of the normality of the distribution of the intact values using Kolomogorov-Smirnov test for goodness of fit with Lilliefors correction (Stephens 1986; Zar 1996). Missing values, resulting from technical problems in processing the perfused tissue, were identified in Table 1 as "not available" (NA).
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TABLE 1.
HRP cell counts
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
; Kuypers 1981; Kuypers and Maisky 1975, 1977). Most of the MRF axons descend in the ventrolateral funiculi; however, they are found as well in the dorsolateral funiculi (Kuypers and Maisky 1977; Petras 1967).
). The HRP analysis is not available for cat EB5, which died unexpectedly. However, based on the physical damage at the site of the spinal lesion and its locomotor capacities during the recovery and the plateau periods, it was included in the second group.
; Kuypers 1981). The number of HRP-labeled cells in the LVN decreased remarkably to 0-33% of the intact values. In cat EB2 we have found only 13 and 10% of labeled cells in the right and left LVN, respectively. In cat EB7, however, 0.5% labeled cells were identified in the right LVN whereas only 0.1% were counted in the left LVN. The very low number of labeled cells in LVN corresponds to a real disruption of this pathway and was not related to a methodological artifact, because the spinal cord cross-section at the site of injection was completely filled with HRP reaction products, and there is a considerable number of heavily labeled cells in the PRF, whose axons descend in adjacent spinal cord areas.
; Kuypers 1981), the HRP labeling in the red nucleus and motor cortex were taken as markers of the integrity of the contralateral DLF. In all cats, both the rubrospinal and the corticospinal pathways were somewhat affected by the lesion, as indicated in Table 1. For example, 1,486 HRP-labeled cells were counted in the right red nucleus of cat EB2, whereas on the left, 1,420 labeled cells were found. These values correspond to 63 and 60% of the intact values. In cat EB6, which had a very extensive lesion (including extensive damage to the right DLF) 2,013 labeled cells were found in the left cortex corresponding to 66% of the intact values. However, on the right cortex 4,155 cells were counted, i.e., to 136% of the control values. Such a phenomenon, of pronounced increase in the number of labeled cells was also observed in the right motor cortex of cat EB7, which showed an even more outstanding increase to 192% of control values. The increase in the total number of labeled cells in the cortex of EB6 and EB7 was also accompanied by changes in the distribution of the cells. In the normal cat (Brustein et al. 1997; Jiang and Drew 1996) the maximal number of cells is found around the lip of the caudal bank of the cruciate sulcus and more laterally as well on the rostral bank. In cat EB7, however, in addition to the normal cell distribution, labeling appeared as well more laterally around the fundus of the cruciate sulcus and, in cat EB6, labeling appeared more medially on the rostral bank.
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FIG. 2.
Recovery of treadmill locomotion following spinal lesion for each one of the 8 cats; graph illustrates the maximal treadmill speed each cat could attain and maintain at least for a few step cycles, as a function of days post spinal lesion.
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FIG. 3.
Stick figures of locomotion pre- and postlesion: the consecutive stick figure diagrams illustrate several steps over a period of 5 s (0.4 m/s), of the right hindlimb of cat EB5 to compare the walking before lesion (intact), short term postlesion (day 36) and long term postlesion (day 88). Each consecutive stick figure is displaced from the preceding one by 3 mm. The vertical bar indicates the length of the tibia (11 cm).
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FIG. 4.
Step cycles before and after lesions: the graphs of the average step cycle duration (mean ± SD), as a function of time after the spinal lesion are illustrated for cats EB2, EB3, EB6, and EB7. The shaded area represents the cycle duration ±SD of 3 control (Intact) experiments. The number of steps used for the calculations varied between 68 and 127 in the control experiments and between 5 and 40 following the lesion, depending on the cat's walking deficits. L = left, R = right; *, results of t-test between the mean step cycle duration pre- and postlesion; 
, results of variance ratio test between the variance pre- and postlesion ( and *, P < 0.05; and **, P < 0.01).
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FIG. 7.
Raw electromyographs (EMGs) before and after the lesion: comparison of the raw EMGs before (A) and after the lesion (B) taken from cat EB5. Both are related to the kinematic data shown in Figs. 3 and 6. The heavy vertical lines are aligned on the St burst onset, whereas the dashed lines are aligned on the onset of RGM, to illustrate relations between phase onset of activity in flexors and extensors, respectively. In the duty cycle traces, the heavy line represents the stance, whereas the down and up arrows represent foot contact and lift, respectively. R, right; St, semitendinosus; Srt, sartorius; VL, vastus lateralis; GM, gastrocnemius medialis.
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FIG. 5.
Correlation of swing and stance duration with the step cycle duration: linear regression relations between the stance or the swing and the step cycle duration in the intact cat and short term or long term postlesion, illustrated for the most lesioned cats: cat EB5 (A, D, and G), cat EB6 (B, E, and H), and cat EB7 (C, F, and I). The ranges of speeds, slope values, and correlation coefficients are summarized in Table 2.
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TABLE 2.
Results of the regression analysis between the cycle duration and the swing or the stance (see Fig. 4)
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FIG. 6.
Representative kinematic data recorded from the right hindlimb of cat EB5 in the intact state and 88 days post spinal lesion. The angular excursions (A and B) are related to the 1st step cycles illustrated in the stick diagram of Fig. 3. Notice that before the lesion (intact), the cat makes 3 steps, whereas after the lesion it makes 4 shorter steps for the same time interval. In the duty cycle traces the heavy line represents the stance whereas the down and up arrows represent foot contact and lift, respectively. The angle-angle plots in C (intact) and D (88 day postlesion) are the means of the whole step sequence, n = 9 (intact), n = 11 (postlesion). Arrows around the plots indicate the direction of the movements in various subdivisions of the step cycle as defined by Phillipson (1905): flexion (F) and 1st extension phase (E1) in swing and the 2nd (E2) and the 3rd (E3) in the stance.
) graphed in Fig. 8F.
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FIG. 8.
Interlimb coupling in cat EB5: comparison of interlimb coupling between the right hindlimb and the right forelimb of cat EB5; Intact, 36 and 88 days postlesion. A, E, and I: representative raw EMGs and footfalls taken from the walking sequences used to calculate the phase of bursts onsets in B, F, and J, the cycle duration in C, G, and K, and the cumulative phase difference in D, H, and L, for each one of the individual consecutive step cycles. Tri, triceps brachii.
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FIG. 9.
Interlimb coupling in cat EB7: comparison of interlimb coupling between the left fore- and hindlimb of cat EB7 in the intact state and 51 days postlesion. A and B: individual values of left VL and TriL cycle duration in consecutive step cycles (as in Fig. 8, C, G, and K). C and D: cumulative phase difference for the same sequence as in A and B. E: raw EMGs and footfalls (51 days postlesion), from which the cumulative values in D were calculated, illustrate the different number of steps (indicated on the footfalls) done by the fore- and the hindlimbs.
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FIG. 10.
Footfall diagrams: representative averaged and normalized footfall diagrams taken from cat EB6 at intact, 77 and 141 days postlesion. Filled horizontal rectangles represent the stance of each one of the limbs; left (L) and right (R) hindlimb (H) and forelimb (F), respectively: LH, RH, LF, and RF. Vertical lines divide the step cycle according to the number of supporting limbs, illustrated as well, in the bottom figurines in which the circles represent whether the limb is in contact with the treadmill (filled) or not (open). The total percent of the time the cat is supported by (2), (3), or (4) limbs is given by the stack bar diagram to the right.
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TABLE 4.
Amplitude and duration of the hindlimb muscles (0.4 m/s)
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TABLE 5.
TriL amplitude at 0.4 m/s
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FIG. 11.
EMG modulation during inclined walking on a treadmill (cat EB5): the averaged, integrated, and normalized EMG amplitude calculated for cat EB5 during walking on inclined treadmill (10°) before the lesion (intact) and as a function of days postlesion, to illustrate the changes in EMG modulation in right hindlimb and forelimb extensors (VL and TriL, respectively) as well in the flexors Srt and CLB. The number of step cycles used for averaging ranged between 18 and 23 for the control experiments (indicated on the abscissa by their experiment number: e2, e5, etc.) whereas, after the lesion, 7-30 steps were used depending on the cat's walking capacities with time after lesion.
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FIG. 12.
EMGs modulation during walking on inclined treadmill (cat EB3): the averaged, integrated, and normalized EMG amplitude calculated for cat EB3 during walking on an inclined treadmill (10°), before the lesion (intact) and as a function of days post spinal lesion, to illustrate the changes in EMG modulation in the left hindlimb and forelimb extensors (VL and TriL, respectively). The number of step cycles used for averaging ranged between 35 and 40 for the control experiments (indicated on the abscissa by their experiment number: e3, e4, etc.), whereas after the lesion, 15-25 steps were used.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Eidelberg 1981; Windle et al. 1958). However, our experiments as well as those of others (Bem et al. 1995; Gorska et al. 1993a,b) show that cats with extensive lesions severing the ventral and ventrolateral quadrants, which eliminate the vestibulo- and severely damage the reticulospinal pathways (see cats EB6 and EB7), but generally preserve pathways in the dorsolateral funiculus such as the corticospinal pathway, can recover quadrupedal voluntary locomotion. Our approach thus permitted to establish that voluntary quadrupedal locomotion is still possible after severe damage to the ventral and ventrolateral pathways, provided important ascending and descending tracts in the dorsolateral quadrants are present. This approach and conclusion are in contrast to that of others (Afelt 1974; Eidelberg et al. 1981; Windle et al. 1958) who concluded that even minimal patches of intact tissue in the ventral quadrants in absence of all the other pathways was essential for hindlimb locomotion. Some of the lesions described in their studies have some similarities to ours. For example, Eidelberg et al. (1981) describe two cats in which only the dorsal columns were left intact and the HRP labeling was confined mainly to the nucleus gracilis; both these cats behaved as complete spinal cats. Afelt (1974) describes a cat in which a patch of tissue remained in the medial DLF. This cat also behaved as a complete spinal cat. However, the extent of the lesion was evaluated only under light microscope and was not assessed by the HRP method. Thus it is possible that the number of functional axons in the patch was much smaller than could be evaluated, which could explain the spinal behavior of the cat.
and Bem et al. (1995) reported recovery of locomotion in cats with intact tissue only in the dorsal columns. This is in contrast to the above-mentioned study of Eidelberg. We believe, in light of our HRP experiments, as well as on Eidelberg's comments (Eidelberg et al. 1981), that examining the site of lesion with light microscope only may not be sufficient to estimate the surviving axons, especially in a highly necrotic and deformed tissue as we have found for cat EB6 on the right PRF (see Fig. 1 and Table 1). Therefore it is probable that more axons have survived elsewhere in the preparation of Gorska et al. (1993a) and Bem et al. (1995), which could explain their recovery.
; Gorska et al. 1993a), we report a correlation between time of recovery of quadrupedal voluntary locomotion and the extent of the spinal lesion. Cats with extensive lesions started walking after 10 days and up to 1 mo postlesion (see Fig. 2). Before that, as we have reported, the cats dragged their hindquarters and suffered from poor weight support and lateral stability. However, Gorska et al. (1993a) and Bem et al. (1995) observed poor lateral stability mainly during the period of recovery. The only cats that showed these long-term deficits (5-6 mo) were the ones described to have only the most dorsal parts of the DLF and the dorsal columns intact. Our cats, however, even the ones classified as less extensively lesioned (EB1-EB4), exhibited swaying of the hindquarters also long term postlesion when they were walking at their best. This difference cannot be attributed to a difference overground versus treadmill locomotion, because our cats showed the same deficits daily overground, as documented in preliminary observations of ground reaction forces (Brustein et al. 1995). It is interesting to note that the progressive recovery of weight support and walking was also observed after lesions sparing only the ventral quadrants (Afelt 1974; Eidelberg et al. 1981) and after lesions restricted to the DLF (Jiang and Drew 1996). However, these were transient, and independent walking over the treadmill at speeds of 0.35 m/s was reported in the latter paper, as soon as 3 days postlesion.
; Mori et al. 1992). In addition, the decrease in weight support may also result from destruction of the vestibulospinal tract, which normally provides strong excitatory drive to extensors (Orlovsky 1972b). The quick recovery of weight support (2-3 days) in cats EB1-EB4, despite the elimination of most of the vestibulospinal pathway, could be due to the spared reticulospinal axons that may be sufficient to maintain the control of muscle tone after the lesion. However, in more extensively lesioned cats, such as EB7, in which a much smaller number of reticulospinal axons have survived, the time needed for recovery (up to 3 wk) may suggest that this low number of neurons (~20%) is not sufficient to maintain normal function (Sabel 1997) even after allowing for a long-term reorganization.
; Guertin et al. 1995; Pratt et al. 1994). However, this by itself may not be enough. Prentice and Drew (1996) suggest the existence of two alternative pathways for postural control during locomotion. One is active during unobstructed walking and the other function during gait modifications such as stepping over an obstacle. It is interesting to note that our cats showed no problems in executing a visuomotor task such as stepping over obstacles (unpublished observations), indicating that these skills were not affected. Implication of the motor cortex during execution of skilled locomotor tasks and gait modifications was shown by many (Armstrong 1986; Beloozerova and Sirota 1993; Drew 1991a; Widajewicz et al. 1994). It is possible that, when the regulation of posture (during level walking) through the reticular formation is insufficient, alternative pathways such as the one active during skilled gait modifications may take over and together with enhancement of segmental reflexes can reestablish some of the postural functions during locomotion, although this is not sufficient for the recovery of lateral stability (Brustein et al. 1995).
; Steeves and Jordan 1980). It was found that lesions to the ventrolateral funiculi abolish MLR initiation of locomotion, whereas any lesion in the dorsal half of the spinal cord had no effect. These findings suggested that MLR initiation of locomotion is conveyed through ventrolateral pathways (for reviews of brain stem centers involved in initiation of locomotor, see Armstrong 1986; Jordan 1991; Rossignol 1996). The inability of MLR stimulation to initiate locomotion after ventrolateral lesions observed in the acute experiments could actually correspond to the situation seen here in the early days postlesion in which no hindlimb locomotion was observed even up to several weeks after the largest lesions, as illustrated in Fig. 2. However, the chronic lesioned cats recover the ability to initiate voluntary locomotion. In the less lesioned cats that recover quickly, the spared reticulospinal axons may be sufficient to regain this function, as suggested before (see Recovery of weight support and lateral stability). However, for the most lesioned cats that started walking after >3 wk post spinal lesion, the participation of alternative pathways in the DLF cannot be excluded. After an extended dorsal hemisection, it was found that stimulation of the pontine locomotor region (PLR) could still evoke locomotion, although a high strength of stimulation was needed, suggesting that normally the PLR exerts its effects at least in part through the dorsolateral pathways (Noga et al. 1991). Such an indirect polysynaptic dorsolateral pathway was proposed by Shik to be involved in initiation of locomotion (Kazennikov et al. 1985; Shik 1983). The locomotion evoked by stimulation along this pathway cannot be differentiated from the one evoked through other locomotor regions, and it is thought to result from the convergence of inputs from the cortex and the reticular formation (Beresovskii 1990).
) results for three of their cats. However, in one cat with bilateral lesions to the DLF, and in cats after lesions to the lateral funiculi (Gorska et al. 1993b), the step cycle duration of the hindlimbs increased, and the stance varied less with the walking speed, much like the swing in intact cats. This discrepancy may result from a difference in the extent and location of the lesions or from a difference between overground and treadmill locomotion. However, this does not resolve the above differences, as even the complete spinal cat maintains normal relations between the step cycle duration and the swing or the stance (Barbeau and Rossignol 1987; Bélanger et al. 1996).
) as well as in cats subjected to lesions restricted to the DLF (Jiang and Drew 1996). However, in these cats the St activity is delayed relative to the lift, and in the complete spinal cat it is accompanied by an earlier onset of TA and a paw drag. Although TA recordings were not available in our cats, the observed St-Srt relations was not accompanied by a paw drag at any time. In this case a tighter Srt-St bursting relation may be beneficial for the cat, assuring a synchronous strong flexion of both the hip and knee at the beginning of the swing, that the hindlimb is cleared of the walking surface to avoid stumbling.
for the intact cat). The larger the lesion, the more severe were the deviations of the fore- hindlimb coupling from the stable intact pattern. The deviations could be classified into three major classes in line with the observations of others (Bem et al. 1995), during overground locomotion. In the first class, the phase differences between the fore- and the hindlimbs vary in the limit of one step cycle, and the step cycle duration in the homolateral fore- and hindlimbs is maintained the same all along the stepping sequence. In the second class, the fore- and the hindlimb of the same side are walking at a slightly different frequency as illustrated by an up to 300-ms difference in their step cycle duration. This uncoupling results in a continuous phase drift between the two girdles. The third type is an in-phase coupling of the homolateral fore- and hindlimb, a walking pattern that is rarely seen for a trained cat walking at a moderate or high speed (English 1979; Hildebrand 1976). The first type of perturbation was observed in cats EB5 and EB6, whereas the second was observed for the most lesioned cat, EB7. All cats adopt the third, in-phase walking pattern except the most lesioned cat, EB7. In cats EB1-EB4 and EB8, this occurs during the recovery period, whereas for cats EB5 and EB6, it appears during the plateau period. Adopting homolateral in-phase walking allows the possibility to increase the period during which all limbs are on the ground to support the weight of the animal, which may contribute to the improvement in walking stability after the lesion and is therefore a compensatory mechanism (Blaszczyk and Loeb 1993; Hildebrand 1976).
observed such coupling changes during overground locomotion in cats with different ventral and lateral spinal lesions, using kinematics events for the analyses. However, the interpretation of the results is not the same as ours, and the homolateral in-phase coupling is related by these authors to be a source of destabilizing oscillations in the walking rhythm. However, if this was the case, our cats could not maintain up to 30 consecutive steps, most of them in in-phase coupling, during the plateau period. The values of cumulative phase difference (see Fig. 8, D, H, and I) support our interpretation. One can see that when the cat uses homolateral in-phase coupling (Fig. 8I) these values stabilize around 0, and only 3 step cycles out of the 30 show extreme deviation, suggesting the return of a more stable coupling pattern.
) and treadmill locomotion (Eidelberg 1981) and also after lesions restricted to the DLF (Jiang and Drew 1996), after damage to long propriospinal neurons (English 1989; see, however, Kato et al. 1984) and to the ventral spinocerebellar pathway. No changes were observed after lesions to the dorsal spinocerebellar tract (English 1985), or to the dorsal columns (Gorska et al. 1993b; Jiang and Drew 1996; see, however, English 1980). Thus the fore- and hindlimb coupling pattern is suggested to result from the contribution of many converging inputs, peripheral, segmental, propriospinal and supraspinal on to the stepping generators (English and Lennard 1982; Miller and Van der Meche 1976; Rossignol 1996; Rossignol et al. 1993). This is in line, therefore, with the suggestion of others (Jiang and Drew 1996), that the deficits in interlimb coupling are related to the extent of the spinal lesion and not necessarily to a specific damage to one pathway.
suggested that supraspinal descending tracts are involved in conveying information adjusting the timing of activity in the fore- and hindlimb. One of the most prominent candidates is the reticulospinal tract. Reticulospinal neurons not only are active and modulated during locomotion (Orlovsky 1970), but single-unit recordings in the intact cat (Drew et al. 1986; Drew and Rossignol 1990a) and in the fictive locomotion preparation (Perreault et al. 1993) have shown that reticulospinal neurons discharge in correlation with the activity of flexors or extensors of more than one limb. Furthermore, microstimulation of these neurons at rest evoked compound movements including one limb or more as well as the neck (Drew and Rossignol 1990a,b). The responses were organized reciprocally between limbs of the same girdle and were simultaneous, as well in the forelimb. During locomotion, the evoked responses, excitatory or inhibitory, were organized with respect to the step cycle and in the thalamic cat (Drew and Rossignol 1984) and in the fictive preparation (Perreault et al. 1994) or the intact cat (Drew 1991b) caused changes in the amplitude as well in the duration of the muscle or in the related nerve activity up to resetting the existent locomotor rhythm. It was therefore suggested that the signal coming from a single reticulospinal neuron could be carried by one axon to more than one muscle in more than one limb to reinforce, on a step-by-step basis, the ongoing locomotor rhythm or even reset it. Taken together, these observations suggest implications of the reticulospinal pathways in the control of the coordination between the limbs (Drew 1991b; Rossignol et al. 1993).
have tested the effect of damage to the caudal pole of the nucleus pontis oralis and to the rostral pole of the nucleus reticularis pontis caudalis on the fore- and hindlimb coupling. They reported a transient effect on the interlimb coordination. The transitory effect is probably due to the limited extent of the lesion, because we have noted that permanent perturbations in the interlimb coupling is associated only with damage to most of the reticulospinal neurons in the pontine and medullary reticular formation nuclei.
; Edgerton et al. 1983). However, these changes are associated with muscle atrophy, which was not apparent here.
for the intact cat) is absent for the most lesioned cats, whereas for the less extensively lesioned animals, the loss of modulation is transient and the cats recover it with time. The lack of AM of the hindlimb extensors can be attributed to the absence or reduction of inputs from vestibulo- and reticulospinal pathways, as well as to damage of ascending pathways such as the ventral spinocerebellar tract, which could lead to a reduction or alteration in descending inputs. The vestibulospinal pathway exerts strong excitatory influence on extensor motoneurons during locomotion (Orlovsky 1972b), whereas the reticulospinal pathways may also exert powerful excitatory effects on the extensor muscles when evoked in the appropriate phase of the step cycle (Drew and Rossignol 1984; Perreault et al. 1994), although its effects have often been associated with flexors (Orlovsky 1970, 1972a). Elimination of these inputs may result in a more restricted firing rate and modulation pattern of the individual motoneuron, which will limit the muscle force production.
. They recorded vestibulo- and reticulospinal neurons in chronic cats during walking over a tilted treadmill. The vestibulospinal neurons showed increased depth of discharge modulation during inclined locomotion as well as changes in peak discharge. The latter effects, together with an increase in discharge, were observed as well for reticulospinal neurons. Thus, in the case of the most extensively lesioned cats in which both the reticulo- and vestibulospinal pathways are severely damaged, such a modulation is absent, and there is no recovery, whereas, in the less lesioned cats long term postlesion, the larger number of surviving reticulospinal axons are probably sufficient to maintain that function. When the EMG modulation is absent for the hindlimb muscles, we observed a more pronounced modulation in Tri amplitude, which is sustained for the extensively lesioned cats and transient for the less lesioned cats. Together this implies that the observed increase in TriL modulation can be interpreted as an adaptive mechanism that is applied as needed. Thus the cat, by exerting control over the forelimbs muscles, can compensate for the deficits in the hindlimb muscle activation. Preliminary data obtained using force platform suggest that the forelimbs contribute to propulsion in these cats (Brustein et al. 1995).
, Afelt (1974), and Eidelberg (1981) to be sufficient for recovery of locomotion. Our results, as well as those of others (Bem et al. 1995; Gorska 1993a,b), show that quadrupedal voluntary locomotion is possible also after extensive lesions to the ventral and ventrolateral pathways, yet sparing pathways in the DLF. However, the cats suffer from major locomotor and postural deficits. Immediately after the lesion and for a few weeks, the most lesioned cats could not support or walk with their hindlimbs, indicating the importance of the ventral and ventrolateral pathways to the normal locomotion, which probably depends heavily on their inputs for initiation of locomotion and for maintaining posture. The time for recovery of weight support and walking in the most extensive lesioned cats also implies some reorganization in the spared pathways, suggesting that they may not be the main contributor or be directly involved in the normal control of these aspects of the locomotion in the intact cat. The deficits observed during the plateau period indicate, however, that DLF pathways, including the residual population of reticulospinal neurons, can be sufficient to provide the necessary drive to initiate locomotion as well as for some locomotor-related postural adjustments. Although the activity in these pathways is sufficient to maintain the intralimb coupling, they are not sufficient to maintain the interlimb coordination or modulate the EMG amplitude during locomotion on an inclined treadmill, nor to maintain lateral stability. These functions are probably normally executed mainly by the brain stem pathways such as the reticulo- and vestibulospinal. The "functional taking over" after partial lesions was suggested by Alstermark et al. (1987) for the recovery of food reaching in cats, by Vilensky et al. (1992) in the monkey as well as in human (Nathan 1994). The basis for such reorganization is suggested to be due to plastic changes such as sprouting (Aoki et al. 1988; Goldberger and Murray 1978; Jiang and Drew 1996; Kimura et al. 1994; Kozlowski et al. 1996). We have observed such changes in the motor cortex of cats EB6-EB8, which show up to a twofold increase in the number of labeled cells, as well as appearance of labeled cells in regions other than those related to the hindlimbs (Brustein et al. 1996). The suggested innervation of the lumbar spinal cord by axons of cells originating in more rostral levels may explain some of the return of locomotor function. We cannot, however, exclude reorganization at the spinal level as well (Carrier et al. 1997). These findings have a special clinical interest because they suggest that some spared axons in the spinal cord may be sufficient to initiate stepping and some postural adjustments. It would therefore seen important to maintain and improve these residual functions, for instance, by drug application, as will be described in a forthcoming paper.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge the contribution of J. Provencher and F. Lebel for assistance during surgeries, experiments, analyses, and preparation of the illustrations; P. Drapeau and G. Messier for programming; J. Lavoie, F. Cantin, and N. De Sylva for histological assistance; C. Gauthier and D. Cyr for illustrations and photographs; and C. Gagner for electronic support. We thank Dr. S. Tardif for statistical advice. We acknowledge reviewer No. 1 for constructive comments on this manuscript. We especially thank Dr. T. Drew for helpful comments on the manuscript.
This work was supported by the Canadian Neuroscience Network and a Group grant from the Medical Research of Canada. E. Brustein was supported by fellowships from the Canadian Neuroscience Network and the Groupe de recherche sur le système nerveux central (GRSNC).
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FOOTNOTES |
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Address for reprint requests: S. Rossignol, Centre de recherche en Sciences Neurologiques, Université de Montréal, PO Box 6128, station Centre-Ville, Montreal, Quebec H3C 3J7, Canada.
Received 3 October 1997; accepted in final form 14 May 1998.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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