Re-expression of Locomotor Function After Partial Spinal
Cord Injury
S. Rossignol, G. Barrière, O. Alluin and A. Frigon
Physiology 24:127-139, 2009. ;doi: 10.1152/physiol.00042.2008
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Re-expression of Locomotor Function
After Partial Spinal Cord Injury

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pattern generator (CPG). In this review, we propose that the spinal CPG also plays

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generally regain hindlimb locomotion on a treadmill because the spinal cord below
the lesion can express locomotion through a neural circuitry termed the central

S. Rossignol,1,2 G. Barrière,1,2
O. Alluin,1,2 and A. Frigon1
1

Department of Physiology, Groupe de Recherche sur leSystème Nerveux Central, Faculty of Medicine,
Université de Montréal, Montreal, Canada; and2Multidisciplinary Team in Locomotor Rehabilitation after
Spinal Cord Injury,
Canadian Institutes of Health Research (CIHR)
serge.rossignol@umontreal.ca

a crucial role in the locomotor recovery after incomplete spinal cord injury.
The consequences of spinal lesions are well known,
namely paralysis, sensory and motor impairments, aswell as autonomic dysfunctions (37). However, basic
mechanisms leading to such deficits remain elusive,
and a better understanding is required to design more
effective treatments to promote partial or full recoveryof these functions. Because of space limitations, we
review here only some of the basic mechanisms that
may underlie locomotor recovery after incomplete
spinal cord injury (SCI) in quadrupedal mammals,
particularly cats, rats, and mice, since this type oflesion is the most frequent in humans.
FIGURE 1 illustrates schematically our current understanding of the control mechanisms of locomotion.
Fundamental to the understanding of locomotion is theconcept of a spinal central pattern generator (CPG) (60,107). The CPG is defined as a spinal network of neurons
capable of generating a rhythmic pattern consisting ofalternating activity between flexor and extensor
motoneurons on the same side with reciprocal activation of homologous motoneurons in the other limb of
the same girdle. In general, during walking or trotting,this network ensures that flexor motoneurons on one
side are active with contralateral extensors and viceversa for extensor motoneurons. However, this pattern is
not a simple alternation between flexors and extensors
because each muscle has, more or less, its own bursting
signature (see panel between the two joints). For instance,
the knee flexor, semitendinosus (St in FIGURE 1) has two
small bursts per step cycle, whereas knee (vastus lateralis; VL in FIGURE 1) and ankle (gastrocnemius
lateralis; GL in FIGURE 1) extensors discharge approximately synchronously but with different discharge profiles. Other types of locomotion, such as gallop, requireco-activation of homonymous muscles on both sides.
Strictly speaking, the term CPG should only apply toactivity generated in completely spinalized (i.e., total
spinal section that removes all descending pathways
from the brain stem and telencephalon) and paralysed(e.g., curarization) animals, a condition that abolishes allphasic sensory inputs associated with limb movement(61, 102). In such a preparation, rhythmic activity,
evoked by injecting the noradrenaline precursor l-dihydroxyphenylalanine (L-DOPA), is recorded from peripheral muscle nerves and is termed “fictive locomotion.”

This rhythmic activity can only be of spinal central origin
because it is generated without any descending or phasic afferent inputs.
In real-life contexts, CPG activity must be turned on
and off and biased on one side or another toaccomplish various goals such as starting, turning,
accelerating, decelerating, and stopping. This isachieved partly by various descending pathways(more on this later), but some phylogenetically old
structures, such as the reticular formation, which project abundantly to the spinal cord, play a particular rolein initiating locomotion (68, 120). Indeed, electricalstimulation of a circumscribed brain stem region
called the mesencephalic locomotor region (MLR),
which more or less coincides with the nucleus
cuneiformis ventral to the inferior colliculus, caninduce locomotion of all four limbs in decerebrate animals (i.e., cortex and basal ganglia removed). Various
gait patterns, such as walk, trot, and gallop, can beevoked with increasing stimulation intensity.
Other descending pathways may be more important for the ongoing control of locomotion. For
instance, the motor cortex is essential for various
adaptive functions associated with locomotion, suchas gait modification when encountering an obstacle(41). Similarly, the vestibular system is implicated in
postural adjustments during locomotion (92, 93).
Other descending pathways release specific neurotransmitters, which are synthesized by cells in welldefined brain stem nuclei (e.g., noradrenaline in thelocus coeruleus and serotonin in the raphe and parapyramidal nuclei). These neurotransmitters exert
powerful effects on the spinal circuitry and canchange characteristics of the locomotor pattern (107).
After incomplete SCI, although the focus is generally on damaged or spared motor descending tracts,major ascending sensory pathways are also severed bypartial SCI. Sensory inputs from the limbs also play a
crucial role in structuring the step cycle so that it isadapted to the ever-changing environment. For
instance, proprioceptive afferents fine tune the amplitude and timing of muscle discharge, thus defining thesubstructure of the step cycle, whereas exteroceptive
inputs, such as cutaneous afferents, are involved incorrect placement of the limbs or in overcoming

1548-9213/09 8.00 ©2009 Int. Union Physiol. Sci./Am. Physiol. Soc.

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Partial Spinal Lesions
General methodological approaches
Producing partial spinal lesions. Multiple methods for
producing partial spinal lesions exist, which can cause
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problems in interpretation because different pathways
can be severed to varying extents. One can distinguishbetween three large classes of methods: surgical, compressive, or neurotoxic.
With surgical approaches, a laminectomy is made,and after opening the dura matter a section of the spinal
cord is made in the transverse plane at the desired vertebral level. This approach is particularly useful for
lesioning tracts located dorsally (e.g., dorsal columns,
corticospinal, rubrospinal) (67) or for unilateral hemisections (8, 63, 65, 79). Ventral pathways can beaccessed without damaging dorsal pathways through apedicellectomy on either side of the vertebrae (18) or
through a laminectomy with a lateral approach (55).
For compressions, several devices can be used to
impact the cord from the dorsal aspect by dropping calibrated weights from different heights or with impactors(see later). Other approaches use a clip with two semicircular arms to compress the cord for a desired lengthof time with a calibrated force. Contusions can be more
reproducible than surgical transections because themechanical devices used (impactors, weight drops,
clips) can be precisely calibrated (17, 48, 69, 70, 132).
Other methods to produce partial lesions of the cord
include Rose Bengal toxicity (129) or demyelination
using immunological methods (85, 86). Althoughthese methods may produce more focused lesions,valuable in assessing the role of specific pathways,
they do not produce the mechanical damages typicalof compression or surgical injuries in which the initiallesion may progress significantly as a result of various
secondary mechanisms such as neurotoxicity (125).
It is important to document the extent of the lesion
as thoroughly as possible (18). Although lesions are
generally assessed using histological methods (35, 59),
new approaches using magnetic resonance imaging(MRI) can also evaluate damages to the spinal cord
noninvasively in vivo. This is a great asset when dealing with chronic spinal lesions because one can get afairly good approximation of lesion extent before theterminal histological evaluation. Diffusion weighted
imaging (DWI), best known as diffusion tensor imaging (DTI), evaluates diffusion of water molecules
through the spinal cord and the isotropy/anisotropy of
diffusion along white matter tracts. By connecting themain eigenvectors of successive voxels, the tensors
delineate the white matter continuity in various partsof the spinal cord from various seed points in different
quadrants, a process called tractography (25). The
problem with DTI is that it represents the main vector
of diffusion. Other related methods (HARDI for highangular resolution diffusion imaging) such as Q-ball
imaging could identify the course of fiber tracts in different directions (26), a potentially very useful feature
to detect reconfiguration of pathways around the SCI.
Functional MRI (fMRI) could also be used eventually
to detect functional changes in the spinal cord following injury. However, the BOLD (blood oxygenationlevel detection
for various r
response is bwhich is delay
activity. Other
different princ

Evaluating

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obstacles in their paths. The importance of sensory
inputs in the expression of locomotion cannot be
overstated and has been the subject of a few previous
reviews (50, 51, 113).
Although this review mainly deals with partial
lesions, it is important to know that, after a complete
spinal transection, most quadruped mammals will
recover some degree of locomotor function in the limbs
below the lesion (33, 108, 110, 111). Cats (112), rats (52),and mice (83) can re-express hindlimb locomotion provided the spinal cord below the complete lesion is properly stimulated, either pharmacologically or throughlocomotor training. After a complete spinalization, therecovery of hindlimb locomotion evidently results fromthe re-expression of the spinal CPG, which is facilitatedby afferent inputs. In well trained chronic spinal animals, it is possible to record a fictive locomotor patternwith a tonic perineal stimulation without drug application (102), again showing the prominence of a central
spinal CPG that has been rendered autonomous by previous locomotor training.
Therefore, locomotion is controlled at multiple levelsof the central nervous system, and a subtle and intricate
balance is established between these levels of control.
This then leads to the question of how an optimal equilibrium is re-established when this exquisite balance isperturbed following lesions of the spinal cord. After partial lesions, both supraspinal and spinal mechanisms
could participate in the recovery of locomotion.
Traditionally, although the role played by remnant
descending inputs has been emphasized, the intrinsic
spinal network is now receiving more attention (8).
Theoretically, remnant descending pathways could
take over functions of the damaged spinal cord, relegating spinal mechanisms to a secondary role. An alternative is that remnant descending pathways promote
reorganization of the spinal circuitry so that the spinal
CPG plays a primary role in the recovery of locomotion
after partial lesions. Although both supraspinal andspinal mechanisms are most likely involved, it is important to dissociate their respective contributions to promote different rehabilitation strategies.
In this review, we will first discuss various means of
producing and evaluating partial spinal lesions in animalmodels as well as some of the methodology used toassess locomotion and its recovery. We will discussdifferent types of partial spinal lesions, focusing on remnant locomotor capacities and deficits specific to abolishing certain pathways. Finally, we will discuss recent
studies that highlight some of the important spinal
mechanisms putatively involved in locomotor recovery
and their clinical implications.

Evaluating loc
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Other methods
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an distinguishsurgical, com-level detection) signal in the cord is still problematicfor various reasons (27), namely that the BOLD
response is based on the hemodynamic response,
which is delayed by several seconds relative to neuralactivity. Other methods may also be applied based on
different principles (123).

Evaluating Locomotor Performance
Evaluating locomotor performance is crucial to assessthe degree and quality of locomotor recovery after SCI.
Some methods are useful to give an overall assessment oflocomotor behavior, such as the BBB score (21 points
score). The BBB assesses various aspects of locomotion
such as foot placement, weight bearing, and interlimb
coordination (11). This method, however, more or lessassumes a linear recovery of locomotion, which might
not be realistic. For instance, depending on lesion extent,
forelimb-hindlimb coordination can be permanently
lost, resulting in a maximal score of 12 that will not reflect
further improvements of hindlimb locomotor capacities(3, 108). However there is a correlation between the sizeof the lesion produced by a contusion and sensorimotor
deficits that may follow a high-order polynomial (77).
Other methods evaluate some skilled aspects of locomotion, such as the ability to place the foot on a horizontal
ladder or the capacity of animals to grip a turning rod(Rotarod). These methods are useful to evaluate the voluntary control of locomotion of all four limbs (49, 80, 94).
Finally, the most objective and accurate method toevaluate the locomotor pattern is by using chronic
electromyography recordings combined with synchronized video recordings of movementjs (14).
Although more cumbersome and resource intensive,
this method permits a powerful quantitative comparison between locomotion observed before and after a
spinal lesion, as well as its evolution over time (8)(see FIGURE 2).

ventral to the dorsal column in the rat. Although paststudies showed that lesioning the dorsal/dorsolateralspinal cord produce only transient deficits in overground or treadmill locomotion (46, 57), moredetailed analyses demonstrated that, even during“simple” locomotion, persistent deficits arise (67, 73,
96). In cats, early after a bilateral dorsal/dorsolaterallesion at T13, the most consistent deficits are dragging
of the hindpaw along the treadmill belt at swing onset
due to impaired intralimb coupling between hip andknee joints at the stance-to-swing transition (67). In
cats and rats, dorsal/dorsolateral spinal lesions

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tomy is made,on of the spinal
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nilateral hemihways can beways through artebrae (18) or
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69, 70, 132).
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86). Although
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Specific partial spinal lesions
Lesions of specific quadrants will first be detailed
with respect to their consequences on locomotion,emphasizing remaining capabilities and deficits. We
will then review unilateral hemisection studies,
which lesion simultaneously dorsal and ventral
quadrants on one side and compressive lesions,which incompletely damage several spinal tracts.
FIGURE 3 summarizes the location of the main
descending pathways in the spinal cord of the cat, as
determined from previous work (64, 105).
Dorsal-dorsolateral lesions. Following unilateralor bilateral lesions to the dorsal-/dorsolateral spinal
cord, which contains ascending sensory pathways
and descending motor pathways, such as the corticospinal (CST) and rubrospinal (RST) tracts (81),animals can eventually recover a voluntary
quadrupedal locomotion. It should be recalled that
the CST in cats is dorsolateral, whereas it is just

FIGURE 1. General scheme of locomotor control (107)At the center, the spinal cord contains a network of interneurons capable of generating
the basic locomotor pattern of flexor (St-Semitendinosus; Srt, Sartorius) and extensor
motoneurons (VL, vastus lateralis; GL, gastrocnemius lateralis) on both sides (L, left; R,
right) (the spinal central patten generator or CPG) (60). Various descending pathways
act directly on the spinal cord or through the reticular formation to initiate or modulate
the locomotor pattern for goal-directed behaviors. These supraspinal inputs are carriedthrough the dorsolateral funiculus (DLF) or the ventrolateral funiculus (VLF).
Neurotransmitters such noradrenaline (NE), serotonine (5-HT), dopamine (DA), or glutamate may also affect the properties of the CPG. Afferent inputs from the skin and muscles (cell bodies in the dorsal root ganglia or DRG) also contribute to the step-by-step
adjustments of the cycle (113).

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impair the coordination between the fore- andhindlimbs (i.e., interlimb coordination) but not the
coupling between homologous limb pairs (47, 56, 67).
The main component of the CST does not appear
to be critical for the control of locomotion in cats or
rats because unilateral or bilateral lesions of the CSTat the pyramidal level do not produce long-lasting
deficits in overground or treadmill locomotion (46,97). On the other hand, sectioning other dorsal/dorsolateral pathways, such as the RST and ascending
sensory pathways (ASPs), produces persistent
deficits during overground and skilled locomotionin the rat. For example, a unilateral dorsolateralfuniculus (DLF), dorsal funiculus (DF), or

combined DLF/DF lesion at C3 produces clear persistent ipsilateral (i.e., ipsilateral to lesion) forelimband hindlimb deficits during overground locomotion, mainly in the ability to generate ground reaction forces (130). Skilled locomotion, assessed by ahorizontal ladder walking test, is also impaired withincreased paw placement errors in the fore- andhindlimbs. Deficits are similar to those observed
following unilateral ablation of the red nucleus (98),indicating an important role of the RST in regulating
flexor and extensor activity during overground andskilled locomotion. Large lesions of the dorsal
spinal cord in rats will even abolish the capacity forskilled locomotion (73).
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FIGURE 2. General methodology for the study of locomotion in cats with spinal lesions
Initially, the animal is placed with its forelimbs standing on a stationary platform while its hindlimbs walk on the treadmill (arrows within the belt indicate the direction of movement). Later on, cats can walk freely on the treadmill with all
four limbs. Pairs of EMG wires are implanted into various muscles (only 1 pair is represented here), and an intrathecal
cannula is inserted through the atlanto-occipital ligament down to ~L4. The multi-pin EMG connector, as well as thecannula inlet, are cemented to the skull. Reflective markers are placed at various points on the limb, and the angle
measurements are taken in the indicated orientations. For each video field (16.7 ms between fields), the coordinates of
the reflective markers are obtained, and the hindlimb movement is reconstructed as indicated in the kinematic model(MTP = metatarsophalangeal joint). From such data, the swing and stance phases of each cycle can be reconstructed asshown below. Note that, to prevent overlap of the stick figures, each one is displaced by an amount equal to the displacement of the foot along the horizontal axis. The foot contact and foot lift are also measured to determine cycle
length and duration and also to synchronize EMG events when needed. The digital (SMPTE) time code (top right) isused to synchronize video and EMG recordings. The spinal lesions are made at T13, unless otherwise specified.

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Deficits stem
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Deficits stemming from DLF and/or DF lesions do
not solely stem from RST damage. Ascending sensory pathways in the DF are important in regulatingmuscle activity during locomotion because selective
DF lesions that spare the main CST and RST produce
deficits similar to DLF lesions (73). Moreover,ascending sensory pathways appear particularly
important for functional recovery after RST damage
because abolishing these pathways in the DF after
bilateral DLF lesions severely impaired recovered
skilled locomotion (73).
What emerges from these studies is that descending
and ascending pathways in the dorsal/dorsolateralspinal cord are normally involved in overground locomotion and become increasingly important during
skilled locomotion. The RST appears relatively more
important for hindlimb locomotion in quadrupedmammals than the CST because RST lesions produce
long-lasting deficits, whereas, following selective
lesions of the main component of the CST in cats (46)and rats (97), animals make a full recovery. Although
there is no direct evidence, locomotor recovery following CST lesions could be due to “functional substitution” by the RST (67), whereas the CST appears
limited in substituting for the RST.
Therefore, lesions of the dorsal/dorsolateral produce initial deficits that gradually recover, particularly during treadmill or overground locomotion, andsome deficits that persist, which are more apparent
during skilled locomotion. Both descending andascending pathways appear to participate in locomotor recovery.
Ventral-ventrolateral. Ventral spinal lesions haveattracted considerable interest because some of themain descending pathways, such as reticulospinal andvestibulospinal pathways are located ventrally. Given
that stimulation of the MLR activates reticulospinal
pathways (100, 101, 119), it is natural to presume thatlesions of these pathways through ventral spinal lesions
will result in severe paralysis. Several lesion studies were
performed in rats and cats (1, 54, 55). In the rat, locomotion can be re-instated, provided that part of the ventral
pathways remains. However, in the cat, althoughcomplete ventral lesions (performed through a pedicellectomy) result in the abolition of voluntary hindlimb
locomotion for 3–4 wk, locomotion does return, albeit
with some deficits, such as fore-/hindlimb coordinationand some weight-support deficits leading to occasional
stumbling (18, 19). However, the intralimb locomotor
pattern of the hindlimbs is well preserved. Cats also
develop a strategy whereby weight support is largely
shifted toward the forelimbs, contrary to the case in normal cats. The development of such compensatory strategies is important in the context of locomotor recovery.
Similar compensatory strategies involving cervical segments are also found in humans with SCI (58).
Besides its role in triggering locomotion, the reticulospinal pathways are also implicated in the

step-by-step control of locomotion. Given their widespread projections, these cells may participate in thecoordination between limbs as well as in weight support directly or as an integrative relay between the cortex and spinal cord (39, 42, 43, 71, 72, 103, 104, 116).
Similarly, vestibulospinal pathways affected by theselesions normally have an important role in posturalcontrol during locomotion (92, 93).
Hemisections. In contrast to bilateral lesions of thedorsal/dorsolateral or ventral/ventrolateral spinal
cord, unilateral hemisections completely damage
ventral and dorsal tracts on one side only, with primarily incomplete damage on the other side.
Following such lesions in rodents, cats, and monkeys,
treadmill and overground locomotion resumes withindays or weeks, depending on the extent and level ofthe lesion (8, 15, 30, 31, 62, 63, 74, 75, 78, 115, 124).
Lesion extent and the amount of locomotor training
are the most important factors governing locomotor
recovery and performance (e.g., maximal walking
speed and endurance) (77). For instance, we recently
showed in cats hemisected at the thoracic level thatthe smaller the lesion the faster the locomotor recovery (8). In the same study, we showed that untrainedcats eventually re-expressed a quadruped locomotion
but with lesser capacities compared with trained animals with similar lesions.
In cats, during the first few days after hemisection,
the hindlimb ipsilateral to the lesion exhibits flaccid
paresis and drags on the treadmill. At this stage, animals walk tripedally and need assistance forhindquarter support and body equilibrium duringlocomotion (8, 63). Within 2 wk, cats recover

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on the treaddmill with alln intrathecal
well as thethe angle
coordinates ofmatic model
constructed as
al to the dismine cycle
op right) is
ecified.

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FIGURE 3. Descending pathways in the cat as determined fromthe work of Refs. 64, 105

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hindquarter support, and use of the affected hindlimb
progresses from a passive crutch with minimal limb
excursion to an active locomotor pattern (63, 78). The
hindlimb on the lesioned side exhibits an increased
swing phase duration and reduced support time that is
not observed on the contralateral side. Increased
swing duration is, however, marked by a limited limb
excursion that results in foot contact behind or justbelow the hip joint. During swing, an important paw
drag is commonly observed and stance is performedon the dorsum of the hindpaw. The swing-to-stancetransition on the lesioned side is marked by excessive
abduction of the hindlimb and is initiated with a more
extended hip position compared with the intact side(8, 63, 78). Interlimb coordination between fore- andhindlimbs is also affected (8, 15, 63, 78). With large
lesions, an uncoupling of the fore- and hindlimbs isobserved and the cycle frequency is respectively
increased and decreased in the fore- and hindlimbs.
With smaller lesions, coupling is preserved, but aIntact0,8 m/sHemispinal 18 days
0.8 m/s

l St

l GM
r GM
l TA
r TA
l HL
r HL
l FL
r FL
1s

1s

Foot contact

130

Foot contact

Hip

Joint excursion (degrees)

70
140

Knee

100
170

Ankle

110
270

160

MTP

0

0.5

1

1.5

2

0

0.5

Phase of the step cycle

1

1.5

2

Phase of the step cycle

5 cm

Swing

StanceSwing

StanceFIGURE 4. Recovery of quadrupedal locomotion following a unilateral dorsal/dorsolateral low thoracic lesion in a cat
Left: a sequence of treadmill locomotion before spinalization (i.e., in the intact state) at 0.8 m/s. Top: the EMGs wererecorded in both hindlimbs and are presented with stance phase duty cycles (black bars) in the four limbs. Middle:
mean angular excursions of the hip, knee, ankle and metatarsophalangeal (MTP) joints of the left hindlimb. Bottom:
stick diagrams represent stance and swing phase extracted from the same sequence as the EMGs. Right: EMGs, mean
angular excursion, and stick diagrams obtained in the same cat, at the same treadmill speed, 18 days following a unilateral dorsal/dorsolateral lesion of the spinal cord at a low thoracic level (T11). It is worth noting that this cat wastrained daily following the lesion, which resulted in a similar pattern of locomotor activity compared with the intact
state. l, Left; r, right; St, semitendinosus; GM, medial gastrocnemius; TA, tibialis anterior; HL, hindlimb; FL, forelimb.

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REVIEWS

wing-to-stanced by excessive
ed with a more
he intact side
ween fore- and8). With large
d hindlimbs iss respectively
nd hindlimbs.
served, but a2cel low tho-e EMGs werebs. Middle:
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and occasional weight support during stepping), compared with the same injury at L3–L4 (88). Contusion at
T13–L2 could damage key elements of the spinal CPG for
hindlimb locomotion thought to be localized at L1–L2 inthe rat (16, 22, 89). In a recent study, the effects of training
on electrophysiological properties were studied in different groups of rats 1 mo after compression of the thoracic
spinal cord (12). Stimulation of the ventrolateral funiculus at C5 generated extracellular field potentials at L3,
and it was shown that neuronal conductivity was severely impaired in untrained rats compared with trained rats,
although in both injured groups it remained much belowthat of uninjured controls. These data indicate that training can restore some of the connectivity between cervicaland lumbar levels. The authors attributed a role of brainderived neurotrophic factor (BDNF) because trained
injured rats showed elevated levels of BDNF comparedwith the untrained group (12). Others have also demonstrated increased levels of BDNF in monkeys after partial
spinal lesions (134). Electrophysiological changes wereassociated with a decreased capability to lift and advancethe hindlimbs (28), producing an increased stance phaseduration (12). Forelimb stance duration was also
increased after contusion at L2 (29), which suggests a
strategy to adapt forelimb velocity with impaired
hindlimb movements.
With contusion injuries, lesion severity and consequently locomotor deficits can be graded according to
the distance travelled by the impact device (77, 87). For
example, in mice, forelimb-hindlimb coordination
deficits appear after low-intensity contusion (i.e., 0.3mm distance of impact over 23-ms period), which
disappear within 2 wk post-injury, although foot placement, assessed by a grid walking test, remains
deficient (87). A moderate thoracic contusion (i.e., 0.5mm distance of impact over 23-ms period) produces
immediate hindlimb paralysis followed by gradual
recovery of plantar stepping, although poor forelimbhindlimb coordination remains. Moreover, mice withmoderate contusions exhibit persistent paw drag, paw
rotation, and loss of coordination between fore- andhindlimbs. With severe contusion (i.e., 0.8-mm distance of impact over 23-ms period), mice show flaccid
paralysis during the first week post-injury and gradually recover small joint movements, but voluntary locomotion with full weight support does not recover (87).
After contusion injury, locomotor training (99, 127,
128) and afferent inputs from the periphery appear toplay an important role in the recovery process (122).
Therefore, locomotor capabilities after spinal contusion depend on lesion severity and activity-dependent processes, such as locomotor training (99, 122).

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pacing activity, in which locomotor movements ofhomolateral limbs are synchronized, is often
observed. This is often seen with spinal lesions andmight correspond to a tripod gait, providing a morestable pattern of locomotion (18).
Over time and/or with training, the affected
hindlimb exhibits less paw drag during swing, plantar
paw placement during stance develops, and the animal can adapt its locomotor pattern to increasing
treadmill speed. As a result, a symmetrical gait withproper left/right alternation is restored. However, forelimb/hindlimb coordination remains modified. In catswith small lesions, a 1:1 coupling is most often preserved, but homolateral limbs tend to walk in phase(pacing pattern), whereas in cats with larger lesions acomplete uncoupling is maintained over time, the step
cycle frequency being different at both girdles.
Moreover, skilled locomotion, such as ladder or grid
walking is also impaired following spinal hemisection(62, 63, 124). For instance, precise placement of thehindpaw on the rungs of a ladder is durably altered on
the side of the lesion, and during overground locomotion the affected hindlimb cannot anticipate encountered obstacles (40).
Therefore, substantial recovery of hindlimb locomotion is observed following lateral hemisection of
the spinal cord. Initial and persistent deficits aremostly observed on the side of the lesion and reflect
deficits associated with ventral (transiently impaired
body equilibrium) and dorsal lesions (impaired
skilled locomotion).
FIGURE 4 illustrates the pattern of EMG discharge
and the kinematics before and 18 days after a spinal
hemilesion on the left side. The similarity of the locomotor pattern is striking, although the post-lesional
pattern is somewhat more variable (see standard deviation in angular joint displacements).
Spinal contusions. The majority of SCIs in humans
results from an impact to the vertebral column, which
produces contusions of the spinal cord. In animals,
contusion models have helped our understanding of
biological mechanisms involved in the secondary
injury that follows the initial SCI (121, 132). Contrary
to transection models, contusive lesions are diffuse(24) and generally result in a central cavitation rimedby spared white matter (94, 106). Generally, locomotor
recovery correlates with the cavitation volume andlesion severity (106). The extent of spinal white matterdamage, depending on the intensity of the injury, isstrongly related with the number, localization, andamount of damaged spinal tracts and thus with locomotor deficits (84, 90, 117). On the other hand, thequantity of gray matter lost after contusion poorly correlates with locomotor deficits (88).
The contusion level has a direct bearing on locomotor recovery. For instance, in rats, a contusion at T13L2 results in greater loss of locomotor function, asassessed by the BBB scale (i.e., absence of coordination

Compensatory Mechanisms Leading
to the Re-expression of Locomotion
The above summary on partial spinal lesions emphasizes how lesions of various pathways can induce

PHYSIOLOGY • Volume 24 • April 2009 • www.physiologyonline.org

133

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Sprouting and regeneration
Work aimed at blocking molecules (e.g., anti-NOGO,
anti-Rho) that hinder regeneration shows fiber growththrough or around the spinal lesion. However, thesefibers, which may partly originate from regenerating
damaged or sprouting undamaged fibers, only reach a
few millimeters below the lesion (7). On the other
hand, 5-HT fibers can grow for longer distances and,as such, change the local excitability of the spinal circuitry below the lesion. Moreover, what is unclear iswhether increased sprouting and/or regeneration
leads to improved functional outcomes or maladaptive changes within the spinal cord.
It was shown that, following lesions of descending
pathways, new circuits could be formed by sproutingof remaining descending fibers that eventually reachthe spinal cord via new routes, including
134

PHYSIOLOGY • Volume 24 • April 2009 • www.physiologyonline.org

propriospinal neurons (7). This is the case after
lesioning the CST, in which collaterals reach cellbodies at the origin of other descending pathways(rubrospinal, reticulospinal, propriospinal). This
raises the important issue as to whether this represents a new circuitry or the strengthening of an existing circuitry. Recent work in the in vitro neonatal rat
preparation (32, 133) has shown, using a combination of serial hemisections and pharmacologicalstimulation, that propriospinal neurons can not onlytransmit command signals from the brain stem toinitiate rhythmic locomotor-like activity in the lumbar cord but that they may also be sufficient. Similar
conclusions were reached in the mouse (31) and in
the rat (59). In a similar vein, Kato, using double
hemisections in the cat (74), showed that, followinginterruption of descending pathways through staggered hemilesions at different levels, animals stillregained voluntary locomotion, suggesting thatdescending commands reach the lumbar spinal cord
through a system of interconnecting propriospinal
neurons that form a link from the brain stem to thelumbar cord. This overall scheme of activation of the
spinal locomotor CPG by brain stem stimulation waspreviously proposed (118).
A number of observations from our laboratory andothers suggest that this propriospinal circuitry may
be distributed over a certain number of spinal segments but that premotoneuronal thoraco-lumbar
segments exert a powerful effect on the lumbar circuitry. In the neonatal rat, it was suggested that low
thoracic and upper lumbar segments are critical forthe expression of locomotion evoked through chemical simulation (22). These regions also correspond toregions of higher excitability for rhythmogenesis in
the rat (76). Furthermore, excitotoxic destruction ofinterneurons at L2 in the rat abolishes locomotion.
Inactivation of L3–L4 segments using the noradrenergic blocker yohimbine completely blocked locomotion in completely spinal cats (91). Similarly,
electrical microstimulation of the spinal cord can
induce locomotion in completely spinal cats, provided the integrity of these midlumbar spinal segments
is preserved (9, 10). Chronic spinal cats that recovered locomotion after a first complete section at T13
will be unable to walk after a second section at caudal
L3–L4 even after weeks of trying to train the animals
to walk. This is not a consequence of abolishing all
motononeuron activity since other rhythmic patterns
can be evoked such as fast paw shakes (82). Veryrecent data also suggest, using injections along the
spinal cord, that spontaneous decerebrate locomotion in the cat is abolished by inactivating L3–L4 segments specifically (34). None of the other segments
rostral to L3–L4 could block locomotion, although
the simultaneous inactivation of several segments
eventually abolished locomotion. These data suggestthat propriospinal interneurons mainly locatedDownloaded from http://physiologyonline.physiology.org/ by guest on August 28, 2012variable deficits that affect step length, step frequency,
interlimb or intralimb joint coupling, foot drag, or
deficits in weight support. What is remarkable is how
the CNS optimizes locomotion through the action ofremnant structures.
Following partial spinal lesions, the voluntary recovery of locomotion undoubtedly reflects changes in sensorimotor interactions within and between the spinal
CPG, descending supraspinal and propriospinal inputs,
as well as peripheral sensory feedback (109). In cats,
after partial or complete spinal lesions, the re-expression of locomotion is facilitated with treadmill locomotor training and by stimulating the skin of the perineal
region (5, 8). Whereas perineal stimulation provides amore or less tonic cutaneous input, locomotor training
provides phasic cutaneous and proprioceptive feedback that is consistent with normal locomotion. Thesesensory cues are thought to promote reorganization of
the spinal locomotor CPG so that it can operate more
efficiently with diminished influences from supraspinal
structures (44, 113). Descending motor pathways arealso altered following incomplete SCI and, throughactivity-dependent processes, can induce changes
within spinal sensorimotor pathways (23, 126).
Compensatory changes within the central nervous system after incomplete SCI no doubt involve several
mechanisms, such as sprouting, regeneration, andfunctional synaptic modifications.
Thus, although there are some specific deficits dueto the inactivation of specific functional pathways, animals can in most instances eventually regain a functional locomotor pattern, enabling them to movearound even in the open field. Several mechanisms
probably participate in the functional recovery of locomotion, and none are mutually exclusive. We will
review some of these mechanisms and propose thatphysiological, and most likely anatomical, plasticity at
the spinal level below the injury participates in an
important manner in the re-expression of locomotion
after partial SCI.

above L4 (thusegments) are
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abolishing all
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kes (82). Veryons along thebrate locomong L3–L4 segher segments
ion, althougheral segments
e data suggest
ainly locatedabove L4 (thus mainly hindlimb premotoneuronalsegments) are essential for locomotion. The interest
here is of course that, if some segments of the spinal
cord have an important role in rhythmogenesis, thentargeting these regions with various types of stimulation may prove to be a useful strategy because it
would limit the problem to a more circumscribedarea of the cord (see also Ref. 52).
How spinal locomotor circuits are activated bydescending commands is of course at the heart of the
problem with regard to the re-expression of locomotion after partial SCI. Lesion studies reported above
suggest that, whatever the lesion, animals can usually
re-express locomotion with time, albeit with somespecific motor deficits. Therefore, it is important todistinguish clearly how the spinal locomotor rhythm
is generated from how it is controlled. Indeed, animals may walk with some interlimb coordination
deficits, weight support weakness, or foot drag, butthey will walk. The bulk of the evidence suggests thatmultiple pathways can access the spinal network necessary for expressing locomotion. This is also the conclusion of studies indicating that the relationshipbetween the amount of spared white matter and locomotor recovery is not linear but follows some higher
harmonic function (77).
How should one envisage the role of these new orreconfigured pathways? One tacit hypothesis is thatthese plastic neuroanatomical changes lead to a “takeover” by descending pathways of lost spinal function.
This could be achieved either by new anatomical circuits or by physiological alteration of synaptic strengthof existing pathways. However, another interpretation
posits that the role of remnant descending pathways
after partial SCI is to regain access to and reorganize
the spinal CPG so that it is optimized to perform in theabsence of descending pathways. In such a model, theamount of spared white matter may not be so relevant
because hindlimb locomotion is then primarily generated by the CPG. This interpretation requires showingthat here is a change in the behavior of the CPG after apartial spinal lesion, which is discussed next.

The role of the spinal CPG
In experiments of spinal hemisection (T10–T11) incats (8), it was found that cats trained to walk on thetreadmill for several weeks until they regained goodquadrupedal walking could also walk bipedally withthe hindlimbs within hours of a complete spinal section at T13. FIGURE 5 summarizes the results of theseexperiments. This is a striking result because, normally, complete spinal cats require weeks to regain proper
hindlimb locomotion after a complete spinal section.
Our interpretation is that the spinal cord was dramatically changed during the period of locomotor recovery
after the partial lesion, undoubtedly through interactions between spinal sensorimotor mechanisms andremaining descending pathways. Therefore, after apartial lesion, the expression of locomotion probably
results from a combination of plastic changes (physiological and/or anatomical) within descending pathways, as well as important changes within the spinal
cord. Instead of taking over lost spinal functions, remnant descending pathways or regenerating pathways
could direct the reorganization of the spinal circuitry
so that it can function optimally and with a greaterlevel of independence so that, after the complete section, the full pattern of hindlimb locomotion can be
expressed by an already autonomous CPG. We are currently evaluating the nature of these changes at the
spinal level and the importance of the delay between
the partial and complete spinal lesions in the dual
lesion paradigm, as well as the importance of locomotor training in inducing these changes at the spinallevel. As an example, our laboratory’s previous workon complete spinal cats clearly showed an upregulation of several receptors (i.e., 5-HT1A, alpha-1, andalpha-noradrenergic receptors) (53). Similar mechanisms could also occur after partial lesions and lead tochanges in the spinal circuitry. For instance, changes
in neuronal properties may occur with chronic exposure to serotoninergic stimulation (2).
The main conclusion of this brief review of multiple
types of lesions is that there are several ways throughwhich the CNS and peripheral afferent inputs canaccess the spinal locomotor circuitry. This apparent
redundancy points to the fact that the rhythm is generated at the spinal level and that various degrees ofcontrol levels can modulate this spinal circuitry
through multiple pathways. The removal of certain
pathways produces specific locomotor deficits, but the
spinal circuitry and other intact pathways are still able
to optimize remnant locomotor functions.

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he case afterals reach celling pathways
spinal). Thiser this repreng of an existo neonatal rat
g a combinaarmacologicals can not only
brain stem toty in the lumicient. Similarse (31) and inusing double
hat, following
through staganimals still
ggesting thatar spinal cord
propriospinaln stem to thetivation of themulation was

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Clinical implications
What are the clinical implications of these concepts?
First of all, the evidence is that, in several vertebrates,
including mammals such as the cat, the rat, and themouse, an elaborate circuitry exists in the spinal cord
capable of generating the basic locomotor pattern.
Some aspects of these basic mechanisms should beconserved in humans and integrated with evolutionary
bipedality and greater corticalization. Studies inhumans indeed suggest the existence of such a basic
spinal circuitry (20, 21, 95, 114, 131). This work showsthat involuntary rhythmic activity can be generated at
the spinal level in patients with complete or incomplete SCI either spontaneously or through spinal stimulation. According to the preceding strict definition ofa CPG, more evidence is required to irrefutably provethe concept of central pattern generation in humans(complete spinalization and neurochemical paralysis).
If the basic control design of locomotion in humans is
consistent with millions of years of evolutionary biology, then our attitude toward management of humans
with SCI should somehow reflect this understanding.

PHYSIOLOGY • Volume 24 • April 2009 • www.physiologyonline.org

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Recherche sur
had a postdoc
Team as well as
du Québec. O.
Multidisciplinar
Groupe de Rec
Frigon was fEngineering Re
CDRF postdoct

cological stimulation (6) could be helpful, at least initially, in activating and maintaining remnant spinal locomotor functions. These methods, by removing some initial balance and weight support constraints, may altogether improve and maintain spinal locomotor functions
so that any new contacts by reorganized descending
pathways may find an optimally functioning spinal cord.
It should also be expected, as has been clearly shown(66), that new strategies can be added to compensate for
specific deficits, which reflect specific spinal lesions, andthat locomotor recovery, after incomplete SCI, may result
from activating the basic spinal circuitry together withmore specific compensatory mechanisms. 
S. Rossignol holds a Canada Research Chair on the
Spinal Cord and is director of the Multidisciplinary Teamon Locomotor Rehabilitation after SCI (Strategic Initiative
Canadian Institute for Healh Research). He holds funds
from the CIHR and The Christopher and Dana Reeve
Foundation (CDRF) and is currently on sabbatical at La
Pitié-Salpétrière in Paris and funded by the Institut deReferences

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Locomotor control mechanisms at various levels of
the CNS are plastic, as shown by lesions studies, andthey are probably amenable to some degree of modifications that could be induced by appropriate interventions. Ongoing clinical trials in humans, using
anti-NOGO and anti-Rho, offer tremendous potential tofacilitate fiber regrowth. Newly formed or regenerated
pathways can, in turn, reach the spinal cord and reestablish contact through short or long propriospinal
pathways. Moreover, specific training, such as treadmill
locomotor training, maintains optimal function within
local spinal circuits capable of generating locomotion
and should be viewed as a prerequisite for new connections to function appropriately. Work in various laboratories have indicated beneficial effects of locomotor
training in humans or of locomotor activity in general (4,13, 36, 38, 45), either through the dedication of therapists, through the use of robotic devices, or by spontaneous self locomotor training. In that context, pharma-

1.

Afelt Z. Func
the spinal c393–407, 19

2.

Antri M, Barof locomoto
combined
receptors wi
162–167, 20

3.

Antri M, Ors
ic spinal rat:
nist. Eur J N

4.

Barbeau H,
emerging coviduals with
2006.

5.

Barbeau H,
ic spinalizati

6.

Barbeau H, R
following sp
1994.

7.

Bareyre FM,
TC, Weinma
taneously fo
Neurosci 7:8.

Barrière G, L
role of the slocomotion
3976–3987,

9.

Barthélemy
locomotor aelectrical micats. J Neur

10. Barthélemy
mechanisms
ulation and
Neurophysio

11. Basso DM, B
locomotor r
Neurotraum

12. Beaumont E
improves therons and loc
Neurosci Re

13. Behrman AL
spinal cord
688–700, 20

14. Belanger M,of treadmilltransection.

15. Bem T, Gors
terns of fore
motion in cBrain Res 10

FIGURE 5. General description of the dual lesion paradigm
A: locomotion of the left hindlimb is displayed using stick figures reconstructed from light reflecting dots placed on thelimb as shown at top. The figure illustrates two experimental streams. In stream 1, a cat was spinalized at T13 and wasparalyzed (2 days). The hindlimbs only dragged on the belt without locomotor movements. After a period of locomotor
training (see vertical bar at left), the cat walked bilaterally, as shown at 21 days. In stream 2, another cat was partiallylesioned at T10–T11 on the left side, trained daily (see vertical bar at left) and could walk voluntarily on the treadmill
with all four limbs (18 days). One day after the complete spinal section at T13, the animal could walk immediately, andfurther training still improved the gait up to 21 days. B: the three conditions of cats as intact, after a partial spinal
lesion, and after the complete spinal lesion. C: drawing of a spinal cord, indicating the level of the partial lesions(T10–T11) and the complete spinal section (T13–L1), as well as the localization of the spinal locomotor CPG.

136

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16. Bertrand S,
bar segment
spinal cord
2002.

17. Black P, Mark
Gillespie J, F
Dynamic loa

18. Brustein E, R
and ventrola
tive mechan

at least initialnt spinal locooving some iniints, may altomotor functions
ed descending
ng spinal cord.
clearly shown
ompensate fornal lesions, andSCI, may result
together with.

placed on the
T13 and was
d of locomotor
was partiallyhe treadmill
mediately, andial spinal
lesions
PG.

Recherche sur la Moelle et l’Encéphale (IRME). G. Barriere
had a postdoctoral fellowship from the Multidisciplinary
Team as well as from the Fonds de la Recherche en Santédu Québec. O. Alluin has a postdoctoral fellowship of theMultidisciplinary Team through a partner grant from theGroupe de Recherche sur le Système Nerveux Central. A.
Frigon was funded by the Natural Sciences andEngineering Research Council of Canada and now holds a
CDRF postdoctoral fellowship.

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Chair on the
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