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Plasticity of connections underlying locomotor recovery after
central and/or peripheral lesions in the adult mammals
Serge Rossignol
Phil. Trans. R. Soc. B 2006 361, 1647-1671
doi: 10.1098/rstb.2006.1889

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Phil. Trans. R. Soc. B (2006) 361, 1647–1671
doi:10.1098/rstb.2006.1889
Published online 4 August 2006

Plasticity of connections underlying locomotor
recovery after central and/or peripheral lesions
in the adult mammals
Serge Rossignol*
Department of Physiology, Centre for Research in Neurological Sciences, Faculty of Medicine, Université deMontréal, PO Box 6128, Station Centre-Ville, Montréal, Québec, Canada H3C 3J7This review discusses some aspects of plasticity of connections after spinal injury in adult animalmodels as a basis for functional recovery of locomotion. After reviewing some pitfalls that must be
avoided when claiming functional recovery and the importance of a conceptual framework for thecontrol of locomotion, locomotor recovery after spinal lesions, mainly in cats, is summarized. It is
concluded that recovery is partly due to plastic changes within the existing spinal locomotor
networks. Locomotor training appears to change the excitability of simple reflex pathways as well as
more complex circuitry. The spinal cord possesses an intrinsic capacity to adapt to lesions of central
tracts or peripheral nerves but, as a rule, adaptation to lesions entails changes at both spinal andsupraspinal levels. A brief summary of the spinal capacity of the rat, mouse and human to express
spinal locomotor patterns is given, indicating that the concepts derived mainly from work in the cat
extend to other adult mammals. It is hoped that some of the issues presented will help to evaluate how
plasticity of existing connections may combine with and potentiate treatments designed to promote
regeneration to optimize remaining motor functions.
Keywords: locomotion; pharmacology; spinal sections; plasticity; reflexes; training

1. INTRODUCTION
This review summarizes multiple observations related
to the functional recovery of locomotion after spinal
injury, especially in animal models and humans withspinal cord injuries, and discusses putative mechanismsof this recovery. Functional recovery of locomotion
after central nervous system lesions in the adultsuggests that the properties of circuits and cells
normally implicated in the generation and control oflocomotion have been modified to optimize its
re-expression through a reduced circuitry. However,
we are generally still far from establishing how new
anatomical connections made by regenerating axons or
sprouting from undamaged pathways or how plasticchanges in the transmission within existing circuits
correlate with functional recovery of locomotion.
Nevertheless, it is worthwhile to report and discuss
experiments demonstrating such recovery becausesome of the conclusions reached can be helpful inevaluating the recovery of function in paradigms aimed
at fostering regeneration or axonal sprouting.
(a) Miraculous locomotor recoveries(i) False resurrections versus miraculous functional
locomotor recovery
In an excellent paper addressing issues of anatomical
regeneration (Steward et al. 2003), the authors
provided several anatomical guidelines to distinguish,
in spinal lesion studies, true regenerating axons from*serge.rossignol@umontreal.ca
One contribution of 13 to a Theme Issue ‘The regenerating brain’.

spared axons. Indeed, there are several possible pitfalls
to avoid before claiming that true regeneration has
occurred. This is even more important since some ofthese pitfalls may obfuscate the claim of functional
recovery in the same studies. As detailed later, theneural controls of locomotion are widely distributedand partial recovery of function does not necessarily
imply regeneration or the acquisition of new function.
Therefore, distinguishing recovery of function due toregeneration from the re-expression of partial remnant
function is as important as differentiating true anatomical regeneration from sprouting.
(ii) Preparations
Choice of preparation is important when studying therecovery of locomotion. It is often argued that lesions
best approximating clinical situations in humans
should be studied in animals (i.e. contusion). While
this argument is entirely valid when assessing potential
therapeutic approaches to spinal lesion, it might blurthe issue on the mechanisms of recovery themselves.
Indeed, when studying the recovery of locomotion in
the hindlimbs after a spinal lesion, it is crucial to beaware that the spinal cord caudal to the injury has
autonomous intrinsic capabilities to generate locomotor movements, when sensory afferents are stimulated or pharmacological agents are applied. This will
be detailed later for various species. Using complete
surgical section of the cord might not be the mostclinically relevant preparation but it is the only one thatcan clearly identify these intrinsic spinal capabilities
that must be taken into account when claiming thereturn of function after partial spinal cord injuries.

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S. Rossignol Plasticity of connections in adult mammals

Although it is not always feasible to make a second
spinal section to assess that the recovered function isdependent on regenerating or sprouting axons, it
should be strongly encouraged. In some studies,such second complete spinal lesions were performedin spinal rats implanted with 5-hydroxytryptamine(5-HT; serotonin) cells below the transection todemonstrate that locomotor recovery was entirely due
to spinal mechanisms and not potential re-growth ofaxons through the spinal lesion (Ribotta et al. 2000).
The level of the complete spinal section is importantbecause some segments of the spinal cord are crucial
for the expression of locomotion. In the rat, upper
lumbar segments are important for locomotion either
because they essentially contribute to pattern generation (Cazalets 2000; Bertrand & Cazalets 2003) or are
more excitable and prone to generate locomotion when
activated (Kjaerulff & Kiehn 1996). Similar findings in
the cat indicate that midlumbar segments (L3–L4)
have profound effects on locomotion since restrictedchemical activation or inhibition of these segments
induces or inhibits locomotion (Marcoux & Rossignol
2000). Furthermore, spinal cats cannot walk after alesion at caudal L4, which remains rostral to the main
hindlimb motor neuron pools (Langlet et al. 2005).
The notion that all spinal segments are notequivalent applies not only to the organization ofcellular elements but also to the distribution of multiple
transmitter receptors at different spinal levels. For
example, 5-HT receptors of various subtypes are
distributed non-uniformly along the thoraco-lumbar
cord so that the presence or absence of locomotor
response to drugs may entirely depend on the level ofthe cord accessible to the drugs (damaged or undamaged; Schmidt & Jordan 2000). This point was
important in the earlier mentioned studies on 5-HT
cell grafts in adult spinal rats (Gimenez y Ribotta et al.
2000) since only those grafts that re-innervatedappropriate levels (namely L2 in the rat) induced
locomotor recovery.
(iii) Scales and other measurements
Various techniques can be used to assess the recovery of
locomotion after lesion. In rats, the Basso, Beattie andBresnahan (BBB) scale (Basso et al. 1995) evaluates
several aspects of locomotion on a 22-point scale(including the 0 level) of open-field locomotion. Such ascale has obviously been very useful to screen animals
with partial spinal lesions and correlate the recovery offunction with the amount of spinal damage after spinal
contusion utilizing mechanical devices or controlledweight drops (Basso et al. 1996; Young 2002).
However, it is based on qualitative assessment and its
linear scale does not account for the nonlinearity oflocomotor recovery. Moreover, the lowest and highest
scores are not necessarily used (the worst and the best
performances), which may distort statistics (see,however, the correction suggested by the originatorsof this scale; Ferguson et al. 2004).
However, as detailed elsewhere (Antri et al. 2002,
2003), the BBB score is severely limited when dealing
with animal models with complete spinal section. Indeed,
after such complete section, there are no neuralmechanisms for fore- and hindlimb coordination. This
Phil. Trans. R. Soc. B (2006)means that on the BBB scale the maximum attainable
score is 11 since this is the highest possible score
without fore- and hindlimb coordination. However, in
the absence of such coordination, the quality oflocomotor movements produced by the spinal cord
below the lesion still evidently improves. Thus, thisamelioration cannot be reflected with the BBB scale.
This led some researchers (Antri et al. 2002, 2003) touse a modified 23-point scale whereas scores above 11
reflect improvements in body weight support, plantar
foot contact and left–right coordination of the hindlimb
locomotor movements.
Another concern with the BBB scale is the relianceon visual observation for fore- and hindlimb coordination over 4–5 cycles. The definition of coordination
for this scale is a one-to-one correspondence between
steps of the fore- and hindlimbs. Two independent
oscillators at the same frequency can be ‘coordinated’,
although they are not coupled. Fore- and hindlimb
oscillators, which have evolved biologically to operate
at close frequencies because they are usually coupled,
will oscillate at their natural frequency if allowed tooscillate independently of each other and may appear
coupled even though they are not. Such apparent
coordination is well exemplified by studies in the cat inwhich extensive but partial lesions of the cord
were performed at the last thoracic segment (T13;
Brustein & Rossignol 1998). In such animals, fore- andhindlimb coordination could be maintained for several
cycles, but precise measurements indicated a gradualshift of one limb pair with the other since both walked
at a slightly different mean frequency. A casual
observation over 4–5 cycles would miss this. Similarfindings were reported for stepping in spinal mice
(Leblond et al. 2003).
Therefore, it is most advisable to use electromyographic (EMG) recordings and kinematic measurements (Bélanger et al. 1996; Brustein & Rossignol
1998; Ribotta et al. 2000; Merkler et al. 2001; Leblond
et al. 2003) to better characterize changes observed
over several cycles after different types of lesions andexperimental manipulations designed to improve
recovery of locomotion. These quantitative methods
ensure, for instance, that real and not apparent
interlimb coordination has been regained or the joint
movement and muscle activation have been restored
close to normal. Obviously, when skilled locomotor
movement must be assessed other methods, as
reviewed by others (Basso 2004; Fouad & Pearson
2004), should also be complementary.
(b) Conceptual framework of locomotor control
The conceptual framework of the organization andcontrol of locomotion is also a key to the interpretationof locomotor recovery after spinal lesion. It has been
known for a long time (Sherrington 1910) that spinal
animals have the potential to generate well-organizedbilateral locomotor movements of the hindlimbs asreviewed elsewhere (Delcomyn 1980; Grillner 1981;
Rossignol 1996; Rossignol et al. 1996; Rossignol et al.
2002). Although not much is yet known concerningneural elements of the spinal circuitry, we know for afact that it can operate in isolation from supraspinal
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Plasticity of connections in adult mammals
(a)

(b)

forebrain

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forebrain

brain stem

brain stem

CPG

CPG

F

F
E

spinalcord

S. Rossignol

E

IN

IN

IN

IN

F

E

F

E

Figure 1. General scheme of the normal control of locomotion. (a) In this simplified scheme, essential elements of the control oflocomotion are represented. At the core and within the spinal cord is a network of interneurons capable on its own to generate
locomotion (central pattern generator, CPG). For the sake of simplification, the CPG has only two main phases: F (flexion) andE (extension). This CPG is presumed to project to groups of interneurons (IN), which in turn contact various pools of flexor (F)and extensor (E) motor neurons innervating flexor and extensor muscles, represented here in a human leg. Afferent feedback isrepresented generically by a single type of afferent originating from the muscles and should be interpreted to mean various
proprioceptive afferents as well as cutaneous afferents. These afferents form intraspinal circuits (monosynaptic, disynaptic,
trisynaptic and polysynaptic) that can reach the motor neurons, the interneurons or the CPG. Similarly, descending inputs fromthe forebrain or the brainstem can modify locomotion through actions on the motor neurons, interneurons or the CPG either
directly or through the brainstem descending pathways. All these descending pathways are lumped for the sake of simplicity andinclude pathways with fast conduction (corticospinal, rubrospinal, reticulospinal and vestibulospinal) as well as slowly
conducting and neurochemically defined pathways originating from the brainstem and releasing for instance noradrenaline orserotonin. (b) In this scheme, all the descending pathways are cut and degenerate (dashed lines). In this situation, the control oflocomotion must rely on internal changes of connectivity within the spinal cord (nor represented) and on an increased
importance of sensory pathways from the periphery represented here as thicker lines that can reach the cord and influence
locomotion by acting at several sites (motor neurons, interneurons or CPG).

elegantly demonstrated using ‘fictive locomotion’ inwhich spinal rhythms are recorded with peripheral
nerve or ventral root discharges in the absence of any
overt movement or phasic afferent inputs as a result of
the curarization (Grillner & Zangger 1975, 1979). Thisis a key concept having far reaching consequences forthe interpretation of animal paradigms to study
locomotor recovery after spinal lesions (Grillner
2002). The concept of central pattern generationsuggests that the basic locomotor pattern is generated
within the spinal cord and that descending commands
as well as sensory information interact with thiscircuitry to initiate, stop or modulate its characteristics(frequency, output amplitude and coordination; seefigure 1a). This basic spinal circuitry is geneticallydetermined since kittens spinalized prior to having
actually walked develop walking capabilities of thehindlimbs (Grillner 1973; Forssberg et al. 1980a,b).
Phil. Trans. R. Soc. B (2006)

Therefore, locomotion is a genetically determinedspinal circuitry with which afferent feedback anddescending inputs interact. Thus, eliminating someafferent feedbacks (e.g. nerve sections, deafferentation)or sectioning descending pathways with surgical ormechanical methods removes inputs to the spinal
locomotor generating circuits but does not affect themain spinal circuitry, which is normally involved in thegeneration of rhythmicity. After such lesions, however,a new equilibrium must be achieved between controllers to optimize the remaining locomotor capabilities. This reorganization suggests a great deal ofplasticity in the connectivity of pathways controlling
locomotor functions.
This sturdy but flexible design is important to ensurethat locomotion, a basic essential function in animals, isoptimized despite various types of central or peripheral
nerve injuries that deprive it of some controls.

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However, it raises the complexity for the experimenter
wanting to show that a given treatment improves
locomotor function after spinal cord injury (SCI).
Indeed, what is due to the treatment and what resultsfrom spontaneous recovery of an intrinsic spinal
function? The usual argument is that if control
untreated animals do not show the same improvement
then the latter is due to the treatment. With
regeneration, this becomes problematic since partial
regeneration of a given pathway might be accompaniedby sprouting in undamaged pathways and the creationof new circuits that may reach spinal circuitry via
reticulospinal, rubrospinal or propriospinal pathways(Raineteau et al. 2002; Steward et al. 2003; Bareyre
et al. 2004) or even to neurochemically defined
pathways that may change the overall excitability ofthe spinal circuitry. Therefore, the functional improvement resulting from a given treatment may in part bedue to changes in undamaged pathways or the intrinsic
spinal circuitry.
The latter point is important since amelioration of
locomotion might not be due to a point-to-point
reconnection between descending pathways and thespinal circuitry but rather to a generalized effect that
may increase the overall excitability of the circuit. As
will be seen later, intravenous, epidural or intrathecal
injections of some neurotransmitter agonists can excite
spinal locomotor circuits even in the absence of any
descending connections. This is true even in chronic
animals in which the terminals of aminergic descending
pathways remaining below the lesion have disappeared.
The implication here is that re-growth of descending
pathways that can increase neurotransmitter release(e.g. 5-HT) can lead to some recovery of function even
without a point-to-point re-growth of descending fibres
with specific neural elements. Indeed, such neurotransmitter release could re-establish essential membrane properties crucial for rhythmicity. This
constitutes the basis for studies using chronic drug
administration to maintain or regain membrane
properties involved in rhythm generation (Antri et al.
2002, 2003; Orsal et al. 2002).
It was felt necessary to address these generalconsiderations in the introduction to better evaluate
the experimental observations made in animal preparations and in humans with various types of spinal
lesions. Because of the main theme of this review, more
observations from animal experiments will be reported
to highlight the plasticity of connections. In thiscontext, the expression ‘plasticity of connections’ wastaken to include changes in locomotor behaviour,
modifications of reflexes or modulation of pharmacological responsiveness, which must implicate theplasticity of some connections.

2. FUNCTIONAL LOCOMOTOR RECOVERY
AFTER SPINAL LESIONS(a) Studies in animals(i) CatSpontaneous recovery
Complete spinal section. After a complete section at T13,
cats gradually recover hindlimb locomotion over atreadmill. Although initially well studied in kittens
Phil. Trans. R. Soc. B (2006)(Grillner 1973; Forssberg et al. 1980a,b), this recovery
is also prominent in the adult cat (Barbeau & Rossignol
1987; Bélanger et al. 1996; de Leon et al. 1998a,b;
Rossignol et al. 2000, 2002) suggesting a great deal ofplasticity even as adult. Figure 1b illustrates how, after acomplete spinal section in the adult cat, intrinsic spinal
mechanisms (CPG) coupled to increased sensory feedback may cooperate in the re-expression of locomotion.
Two to three days after spinalization, the cat isplaced with its forelimb standing on an immobile
platform above the treadmill while the hindlimbs areheld over the moving treadmill belt. At this very earlystage, the experimenter has to hold the hindquarters of
the animal. Pinching the perineum or the base of thetail (sometimes the abdomen), some small alternate
steps of the hindlimbs can be observed especially inmore proximal joints (hip and knee movements) but
the animal is incapable of plantar foot placement andwalks on the dorsum of the foot. After 2–3 weeks ofdaily training on the treadmill, cats can walk withhindquarter weight support while making plantar footcontacts and generating much larger steps where thefoot is placed in front of a line projecting from the hip
joint to the ground. Perineal stimulation is no longer
needed, but the animal must be prevented from fallingon the side by holding the tail since all vestibulospinal
and reticulospinal control of equilibrium has been lost.
In figure 2, kinematic measurements (angulardisplacement and stick figures) and EMG dischargeof several muscles recorded in the same chronicallyimplanted cat before (figure 2a), early (figure 2b at
8 days) and late (figure 2c at 21 days) after spinalization
are illustrated. Even when the spontaneous locomotor
pattern has recovered, step cycles remain generally
shorter than prior to spinalization (compare stick
figures in figure 1a,c). In most cases, there is somedegree of foot drag at the onset of the swing phase,
which can occupy up to one-third of the swing phase.
There are striking similarities between the EMG
discharges of the same cat before and after spinalization
although raw EMG recordings are frequently more‘choppy’ since there is often an underlying clonus. The
characteristic muscular discharge envelope, such as thegradual onset of the knee extensor (VL) and the abrupt
onset of the ankle extensor (GL), is preserved.
Discharge amplitude in extensor muscles may beoverall reduced which probably corresponds todecreased weight support. Diminished weight support
probably results from the loss of reticulospinal andvestibulospinal pathways. Indeed, similar deficits areobserved with partial spinal lesions of ventral andventrolateral spinal pathways as will be discussed later(Brustein & Rossignol 1998).
Timing characteristics between flexor muscles atdifferent joints are often (but not always) altered in the
spinal cat. For instance, in the intact cat, there is adelay between the initial burst of the knee flexor
semitendinosus (St) and the burst of the hip flexor
sartorius (Srt; see figure 2a, right). After spinalization(see figure 2c, right), the St and Srt muscles often start
discharging at the same time, which may explain theobserved foot drag. Indeed, knee flexors usually
withdraw the foot before the hip flexors bring thelimb forward. Since hip, knee and ankle flexions areDownloaded from rstb.royalsocietypublishing.org on September 4, 2012

Plasticity of connections in adult mammals

S. Rossignol

1651

intactleft contact
150 0.3 m s–1

(a)
cat B
stance

swing

hip
knee
ankle

mtp

LSt

80
160 hip80
150 kneeLSrt

80 angle
250
mtp
170

RSt

LVL
LGL
RSrt
RVL

C16t3071s

0.2 m s–1(b)stancejoint angle (degrees)

150
swing

swing

5 cm

5 cm

stance

LSt

80
160
80
150

LSrt

80
250

RSt

LVL
LGL
RSrt
RVL

170

0.3 m s–1

120

(c)

lesion T13
8 days

C16t602

21 days
LSt

90
110
80
170

LSrt

110
240

RSt

LVL
LGL
RSrt
RVL

170
0

0.5
1.0
1.5
phase of step cycle

C16t802

2.0

Figure 2. Comparison of treadmill locomotion of a cat in the intact condition and at two different days after a T13 spinal section.
(a) Locomotor pattern in the intact state. (b) Locomotor pattern 8 days after spinalization. (c) Recovery of locomotion after
21 days of treadmill training. Left column: stick figures reconstructed from a video sequence of one-step cycle generated from aframe-by-frame video analysis displaying the swing and the stance phase separately. The orientations of joint measurements are
given. Note that the calibration of the x-axis is twice that of the y-axis (see calibration in (c), left part of the figure). Middle column:
angular excursion of the four joints (hip, knee, ankle and metatarsophalangeal (mtp)) averaged over 10 cycles. Paw contact(down arrow); paw lift (up arrow); stance phase (horizontal line). Flexion always corresponds to downward deflections of theangular traces. The treadmill speed is indicated in metres per second (m sK1) and is 0.3 m sK1 except for (b), which is at
0.2 m sK1 but the cat was not walking. Right column: raw EMG activity of the flexor and extensor muscles of the left (L) and right(R) hindlimb during locomotion. LSt, left semitendinosus; LSrt, left sartorius; LVL, left vastus lateralis; LGL, left
gastrocnemius lateralis; RSt, right semitendinosus; RSrt, right sartorius; RVL, right vastus lateralis; and RGL,
right gastrocnemius lateralis. The scale bar equals 1 s and applies to all EMG traces. Modified with permission from Langlet
et al. (2005).

initiated more or less at the same time, the foot moves
forward on the treadmill belt before it is lifted. Suchspecific deficits in the timing of hindlimb flexors may
result from damage to corticospinal pathways since
they are also seen after lesions of the dorsolateral tracts
in the cat ( Jiang & Drew 1996).
Incomplete spinal sections. In the context of locomotor
plasticity, it is of great interest to perform restrictedlesions of the spinal cord to study early deficits, which
are related mainly to the destruction of some pathways
and then to assess the time course and extent oflocomotor compensation that results from the action ofremnant pathways. The results of lesions of major
tracts on the recovery of locomotion will be briefly
reviewed and the reader is referred to previous reviews
for more complete details (Grillner 1981; Armstrong
1986, 1988; Rossignol 1996; Grillner et al. 1997;
Jordan 1998; Drew et al. 2004). It will be seen that noneof the spinal quadrants, and, therefore, none of thedescending pathways plays an indispensable role in thePhil. Trans. R. Soc. B (2006)

basic generation of locomotion in the cat, althoughsevere deficits may be observed as a result of deficientsupraspinal controls.
Ventrolateral pathways. It is generally believed that
locomotion is initiated via the activation of themesencephalic locomotor region (MLR; Shik et al.
1966; Orlovsky & Shik 1976), which activates reticulospinal cells projecting down to the spinal cord and thus
the central pattern generator (CPG) (see figure 1a).
Various diencephalic and telencephalic structures
project directly to the MLR and reticular formation(Grillner et al. 1997; Jordan 1998). Besides initiating
locomotion, the reticular formation also plays a majorrole in the control of locomotion and associated posture(Shimamura et al. 1982; Drew et al. 1986; Mori 1987;
Drew & Rossignol 1990a,b; Drew 1991; Perreault et al.
1993, 1994; Kably & Drew 1998a,b; Matsuyama &Drew 2000a,b; Prentice & Drew 2001; Drew et al. 2004;
Matsuyama et al. 2004a,b). Thus, it should be expectedthat a lesion affecting reticulospinal pathways should

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S. Rossignol Plasticity of connections in adult mammals

greatly impact locomotion. Although it is difficult tocompletely section the reticulospinal pathways, theconsequences of major damage can be observed using
ventral and ventrolateral lesions of the cord.
Based on the literature cited earlier, it was initiallysuggested that medial and mediolateral pathways were
essential for locomotion (Eidelberg 1981). For locomotion to recover, a small part of a ventrolateral
quadrant had to be spared (Afelt 1974; Eidelberg et al.
1981a,b; Contamin 1983). However, other experiments suggested that cats (Gorska et al. 1990, 1993a,b;
Zmyslowski et al. 1993; Bem et al. 1995; Brustein &Rossignol 1999; Rossignol et al. 1999) and monkeys(Vilensky et al. 1992) could walk with the hindlimbs
even after large lesions of these pathways at the lastthoracic segment (T13). Similarly, humans who had asurgical section of ventral pathways for intractable pain
retained walking ability (Nathan 1994).
In cats chronically implanted with EMG electrodes,
ventral/ventrolateral pathways were sectioned bilaterally (Brustein & Rossignol 1998, 1999). With small
lesions, cats could walk voluntarily at speeds of up to
0.7 m sK1 with all four limbs, 1–3 days after the lesion.
However, with large lesions, which spared only part ofthe dorsal columns and various amounts of thedorsolateral quadrant, cats initially behaved ascomplete spinal cats. In open field, the forelimbs
propelled the body but they dragged their hindquarters
around over ground for a period of 3–6 weeks. With
regular treadmill training, all cats regained voluntary
locomotion of all the four limbs, although with thelargest lesions, animals could not walk faster than
0.4 m sK1. Hindlimb coupling remained stable ataround 50% of the cycle. These cats walked with amore crouched position denoting a reduction in weightsupport ability. The hindlimb–forelimb coordination
was at times unstable and cats often adopted a pacing
gait, i.e. the fore- and hindlimbs on one side were inswing or in stance at the same time and alternated withthe contralateral limbs. The fore- and hindlimb could
even walk at slightly different mean frequencies leading
to occasional stumbling. Precise measurements of theforelimb–hindlimb coupling showed a gradual drift
over several cycles that led to stumbling. When walking
up-slope there was an increase in the amplitude of theforelimb elbow extensors to compensate for increased
load. The amplitude of extensor burst in the hindlimbs
did not compensate during up-slope walking due to thelack of supraspinal compensatory signals. On force
platforms, the forelimbs became propulsive in contrast
to the normal situation where the hindlimbs arepropulsive. Despite some walking instability on thetreadmill, it is remarkable that at this stage cats could
voluntarily stand up, walk around and overcome
natural obstacles on the ground or treadmill.
Horseradish peroxidase (HRP) was injected below
the spinal lesion at the conclusion of the experiment toevaluate the number and location of spinally projecting
cells. In the pontine reticular and medullary reticularformations, labelled cells accounted for 5–48% ofnormal values depending on the size of the spinal
lesion. Vestibulospinal neurons were virtually wiped
out. Counts of rubrospinal cells were either normal orsomewhat decreased since some lesions may havePhil. Trans. R. Soc. B (2006)

encroached rubrospinal axons. The remaining reticulospinal and rubrospinal cells may have participated in
the recovery of locomotion. Although propriospinal
neurons were not studied, they could be strategicallyplaced to participate in such compensation as
suggested by others ( Jordan & Schmidt 2002; Bareyre
et al. 2004). However, preliminary evidence suggeststhat the number of HRP-labelled cells was higher in the
motor cortex of lesioned cats compared with control
cats and their distribution was somewhat more lateral(Rossignol et al. 1999), suggesting that a significant
compensation from corticospinal pathways may
contribute to locomotor recovery.
Dorsolateral pathways. Cats can walk over groundafter large lesions of the dorsolateral white matter(Gorska et al. 1993b; Zmyslowski et al. 1993; Bem
et al. 1995). In more quantitative studies of treadmill
locomotion after lesions of the dorsolateral funiculus,
which included the dorsal columns ( Jiang & Drew
1996), it was shown that voluntary quadrupedal
locomotion is impaired for 3–10 days. Cats adopted
a more crouched posture during walking for a periodof 2–3 weeks and step-cycle duration was increased
due to a prolongation of stance, which is contrary tocats with ventrolateral lesions where step cycles ofindividual hindlimbs close to normal were observed.
On the contrary, cats with dorsolateral lesions hadchanges in intra-cycle characteristics. For instance,
there was simultaneous onset of the knee flexor St
with the hip flexor Srt. As mentioned earlier, there
normally exists a delay between the two with St
discharging before Srt, which potentially underscorespersistent foot drag. Contrary to ventrolaterallesions, cats with dorsolateral lesions are unable tovoluntarily modify their gait to step over an obstacle
on a treadmill (Drew et al. 1996). Finally, in catswith dorsolateral lesions, both fore- and hindlimbs
participate in compensating for treadmill slopes.
Hemisections. Hemisections of the cord have beenstudied in various animal preparations, but there are anumber of inconsistent reports on the deficits andrecovery of locomotion. Nevertheless, there is anagreement that the hindlimb ipsilateral to the lesion
gradually recovers locomotion within approximately
one month (Eidelberg et al. 1986; Basso et al. 1994;
Kuhtz-Buschbeck et al. 1996). Remaining deficits
following this period are not consistent among authors.
In one study using precise kinematic measures(Kuhtz-Buschbeck et al. 1996), the permanent deficit
is a shortening of stance and a prolongation of swing on
the side of the lesion leading to some asymmetrical gait.
A reduction in stance is compatible with an inability tosupport weight (as seen in the complete spinal cat).
The slowing of the swing phase might in turn be related
to the lesion of the corticospinal tract (CST), although
the timing abnormalities seem to differ compared withdorsolateral tract lesions (Jiang & Drew 1996). There isalso a variable degree of spasticity manifested as a
reduced yield during the E2 phase of locomotion(Kuhtz-Buschbeck et al. 1996). Although the role ofdescending intact tracts were considered important for
the recovery of locomotion after hemisection, sprouting
of afferents was proposed as a major player in thisrecovery (Basso et al. 1994). However, other workDownloaded from rstb.royalsocietypublishing.org on September 4, 2012

Plasticity of connections in adult mammals
suggests that afferent fibre sprouting caudal to thelesion does not greatly differ between the lesioned andintact sides (Nacimiento et al. 1993).
Pharmacology
Previous sections indicated a functional locomotor
recovery resulting from a reorganization of pathways atseveral levels. However, the plasticity in connections
can also stem from changes in responsiveness topharmacological agents and/or changes in the densityof various neurotransmitter receptors.
Neurotransmitter agonists. Early work using thenoradrenaline precursor 3,4-dihydroxy- L-phenylalanine (L-DOPA) in acute spinal cats ( Jankowska
et al. 1967a,b) led to the concept of a central patterngenerator for locomotion (Grillner & Zangger 1979).
Indeed, after an i.v. injection of L -DOPA, thecharacteristic discharge pattern recorded in flexor andextensor nerves (electroneurograms) during fictive
locomotion shared many similarities with EMG
patterns recorded in the walking cat. Therefore,
specific chemicals can trigger the activity in an extant
autonomous spinal circuitry since cats were bothspinalized and curarized. As mentioned earlier (seefigure 1a), this central pattern generator concept iscentral to our understanding of locomotor control.
This seminal work was followed by other studies
attempting to determine which receptors of which
neurotransmitter systems activate the CPG with theaim of applying such pharmacological tools in the
rehabilitation of locomotion after spinal injury inanimals and particularly humans.
First, agonists of different subtypes of adrenergic
receptors were used. The a-2 noradrenergic
agonist, clonidine, was first used in acute spinal cats
(Forssberg & Grillner 1973) and it was found that a welldeveloped bilateral hindlimb walking pattern could be
evoked within minutes of the clonidine injection inabout one-third of cats. It is important to realize thatwith appropriate neurochemical stimulation, even after
acute spinalization, cats can walk with the hindlimbs.
Therefore, recovery of spontaneous locomotion inchronic spinal cats must then represent plastic changes
in the pathways leading to the activation of this extant
spinal pattern generator more than in the CPG itself.
Following this work, we have found that, in adultspinal cats chronically implanted with EMG electrodes, only the a-2 adrenergic agonists, such as clonidine,
injected intraperitoneally (Barbeau et al. 1987a), or
similar agonists (tizanidine, oxymethazoline) injected
intrathecally (Chau et al. 1998b) induce locomotion
shortly after spinalization. Later on, when cats haveregained spontaneous locomotion, these noradrenergic
agonists still exert potent effects on the locomotor
pattern by increasing EMG burst duration and overall
step length. There are, however, smaller changes in the
burst amplitude. In the present context of plasticity ofconnection, it is worth mentioning that the effects ofclonidine differ, whether the cats have an intact spinal
cord, a complete or a partial spinal lesion (Rossignol
et al. 1998, 2001). Whereas in the intact state
intrathecal injection of clonidine has little effect, it
has, in the same cat but early after spinal section the
striking effect of evoking locomotion (Giroux et al.
Phil. Trans. R. Soc. B (2006)

S. Rossignol

16532001). Furthermore, in cats with a large ventral andventrolateral lesion, an intrathecal clonidine injection
can altogether stop voluntary quadrupedal locomotion(Brustein & Rossignol 1999). Therefore, the state ofreceptivity of receptors as well as the presence of preand postsynaptic receptors in various neural elements
may differ in different models of spinal lesion, and thiswill determine the effects of the drugs. This isimportant when assessing drugs in humans since theextent of the lesion is not known most of the time
(Remy-Neris et al. 1999).
Serotonergic agonists such as quipazine, 5-methoxy-N,
N-dimethyltryptamine or the precursor 5-hydroxytryptophan do not initiate locomotion in acute spinal cats
(Barbeau & Rossignol 1990). As will be seen later, thisis a major difference between cats and rodents. The
reason for the inability of 5-HT agonists in evoking
locomotion might be related to the level of the spinal
section as suggested by others (Schmidt & Jordan
2000) on the basis of the segmental distribution of
5-HT receptor subunits important for locomotion.
Therefore, the level of section may be important inevaluating the effects of stimulation by certain drugs
since the receptors on which they are acting as well as
their state of responsiveness may differ in different
preparations (intact cord, complete or incomplete
spinal section). Although 5-HT agonists do not initiate
locomotion in spinal cats, they increase the output
amplitude of activity of hindlimb muscles (especiallyextensors) and paraxial muscles (Barbeau & Rossignol
1990). In cats with ventrolateral spinal lesions,
5-HT agonists increased weight support as well as
the endurance of the cats to walk uninterruptedly(Brustein & Rossignol 1999). Importantly, thesepharmacological effects were well integrated in anotherwise voluntarily generated locomotor pattern,suggesting that voluntary commands could make bestuse of the increased spinal excitability provided by thepharmacological stimulation.
Shortly after spinal section in cats, intrathecal
injections of N-methyl-D-aspartate (NMDA), contrary
to in vitro neonatal rats or lampreys and in contrast
with decerebrate cats (Douglas et al. 1993), does not
induce locomotion but generates tremor and toe
fanning (Chau et al. 2002; Giroux et al. 2003).
However, when injected intrathecally in spinal catsthat just started to generate small steps (around
6–7 days), NMDA could boost emergent locomotor
patterns for several hours (Chau et al. 2002). NMDA
had little effects per se on the spontaneously recovered
locomotor pattern several weeks after spinalization.
Neurotransmitter antagonists. The use of various
neurotransmitter antagonists is of interest not only toblock the effects of previously described effects ofagonists in the spinal cat but also in determining therole that certain receptors may play in the spontaneously
generated locomotor pattern in the intact or spinal cat.
Yohimbine, an a-2 adrenergic blocker, reverses theeffect of clonidine on the initiation of locomotion or theclonidine-induced change in the step cycle (Barbeau
et al. 1987a; Giroux et al. 2001). However, yohimbine
has no effect in the chronic spinal cat walking on atreadmill. Although this might appear obvious since
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1654

S. Rossignol Plasticity of connections in adult mammals

spinalization, it is important to block these receptors toshow that residual noradrenaline and other moleculesthat could potentially activate these receptors are
not responsible for the ability of the cat to walk.
However, yohimbine induces, in the intact cat, an
important incoordination of the fore- and hindlimbs
and an inability to adequately control the trunkand hindquarters that can often walk sideways relative
to the forelimbs (Giroux et al. 2001) suggesting thatin normal locomotion, noradrenergic neurotransmission is important for interlimb coordination(McDearmid et al. 1997).
Since 5-HT does not induce locomotion in the cat,less evidence is available on 5-HT blockers. However,
one study showed that cyproheptadine greatly reduces
the enhanced muscular output induced by 5-HT
agonists in spinal cats (Barbeau & Rossignol 1990,
1991). No data were obtained yet on intact cats.
Aminophosphonopentanoic acid (AP-5), an NMDA
blocker, was shown to influence locomotion in the intact
cat by reducing its weight support. However, the cat had
no difficulty in compensating for this deficit and could
continue walking on the treadmill. In the very same cats,
which had received AP-5 in the intact state without
effect, the same drug completely blocked the spontaneously generated locomotion after spinal transection(Giroux et al. 2003). This suggests that NMDA
receptors play a crucial role in generating spinal
locomotion and that minor effects observed in the intact
cat after AP-5 injection probably result from compensation by other neurotransmitters released by intact
descending pathways, which are absent in the spinal cat.
Thus, in the weeks after spinalization, one of the
major changes that occur is a basic transformation of
the central spinal circuitry which normally operates
through a balance of various neuromodulators(including monoamines) to a more restricted set oftransmitters/modulators acting on glutamatergic
receptors. Furthermore, the key role played by afferent
inputs in spinal locomotion (see later) may be related totheir ability to release neurotransmitters capable ofactivating the locomotor spinal circuitry.
Evolution of receptors after spinalization. In an attempt
to study the plastic changes in the cord after spinalization, the distribution of a1-, a2-noradrenergic andserotonin1A (5-HT1A) receptors was studied in the
spinal cords of normal cats as well as in cats spinalized at
T13 a few weeks or months earlier (Giroux et al. 1999).
Binding densities of a-1 and a-2 receptors significantly
increased in the lumbar segments at 15–30 days after
spinalization. At longer survival times (three or moremonths), binding densities returned to near control
values. The 5-HT1A receptors also followed the sameprofile of upregulation and returned to control values.
The marked upregulation of various monoaminergic
receptors observed after spinal section is therefore aclear example of the plasticity of connections occurringin the adult. However, although the timing appears
appropriate, the links between these receptor changes
and recovery of locomotor capabilities have not yet been
established. This might explain why larger doses ofclonidine are usually needed to induce locomotion in
the acute stage of spinalization. When receptors are
upregulated, smaller doses of clonidine are efficacious.
Phil. Trans. R. Soc. B (2006)

However, even after several months, clonidine is still
very effective at very low doses suggesting that otherintracellular mechanisms that may increase receptor
coupling with intracellular events become importantwith time (Reader et al. 2001).
Preliminary work on a-amino-5-hydroxy-3-methyl4-isoxazole propionic acid (AMPA) receptors shows an
upregulation but, contrary to aminergic receptors, itappears that this upregulation is maintained (Chauet al. 2001), consistent with the fact that glutamatergic
receptors are important, for long-term maintenance ofspinal locomotion.
Preliminary work has been done to determine thesegmental and laminar distribution of various types ofreceptors (Rossignol et al. 2002). There are indications
that the upregulation differs according to segments(being highest in the midlumbar segments; Rossignol
et al. 2002) but this must be confirmed because it has
implications for determining the importance of thelevel of spinal transection for locomotor recovery.
Level of spinal section
The level of spinalization in the recovery of locomotion
is important on several counts. A better understandingof spinal levels implicated in the generation of
locomotion might be extremely useful in optimizing
strategies when using spinal electrical stimulation,
pharmacological stimulation through intrathecal
delivery systems or through grafts of cells releasing
biogenic amines. In the context of plasticity ofconnections, it might also suggest how intersegmental
reconnections are important for the re-expression of
locomotion.
Our initial work using intrathecal delivery of drugs
indicated that application of drugs at rostral segmentsof the spinal cord in cats (at around L4) were very
effective in triggering or modulating locomotion (Chauet al. 1998a,b; Giroux et al. 2001). Further work
showed that, in cats spinalized one week earlier, an
intraspinal injection of clonidine or yohimbine,
restricted to the L4 segment, initiated or blocked thespinal locomotion, respectively (Marcoux & Rossignol
2000). It should be recalled that this spinal level in thecat is rostral to the main hindlimb motor neuron pools(Vanderhorst & Holstege 1997). In such experiments,
it was also shown that a lesion at caudal L4 abolished all
spinal locomotion even after i.v. injections of clonidine.
It was unclear whether this constituted a second spinal
shock or a disconnection of specific spinal segments
critical for locomotion. Indeed, previous work byothers suggested that neural elements in these segments are critical for locomotion (Shefchyk et al. 1990;
Jankowska & Edgley 1993; Davies & Edgley 1994;
Jankowska et al. 2003).
A series of experiments was performed on catsspinalized at T13 and trained to recover locomotion of
the hindlimbs on the treadmill. Thereafter, each cat
was submitted to a second complete spinal section andtheir locomotor ability was re-assessed over several
weeks or months (Langlet et al. 2005). A second
spinalization at L2 or rostral L3 did not significantly
alter the ability of the cats to walk (see figure 3),
eliminating the hypothesis that a second spinal shock is
responsible for the effects seen after a second lesion atDownloaded from rstb.royalsocietypublishing.org on September 4, 2012

Plasticity of connections in adult mammals(a) cat C
stance0.3 m s120
swing

first lesion T13
17 days–1

S. Rossignol

1655

LSt

90
120
90
140

LSrt

110
230

RSt

LVL
LGL
RSrt
RVL

180

c17t808second lesion caudal L2
2 days(b)

0.3 m s–1

110
swing

5 cm

5 cm

stance

LSt

80
110
90
140

LSrt

100
200

RSt

LVL
LGL

170
0

0.5
1.0
1.5
phase of step cycle

2.0

RSrt
RVL

c17t1001

Figure 3. Comparison of recovery of locomotion after a second spinal lesion at the caudal part of L2 segment. Stick diagrams,
angular displacement and raw EMG traces of hindlimb flexor and extensor muscles are as displayed in figure 3. (a) Recovery of
locomotion after a first transection at T13 after 17 days of training. (b) Locomotor performance 2 days after the second lesion at
the caudal L2 level in the same cat. Modified with permission from Langlet et al. (2005).

L4 reported earlier. However, when the second chronic
lesion was at caudal L3 or L4 (see figure 4), locomotion
was completely abolished and could not be reinstatedeven after 3–4 weeks of locomotor training. Although
locomotion was not expressed, it was remarkable tofind that other rhythmic activities, such as fast paw
shake, were not only present but also enhanced(figure 4, bottom right). Therefore, the spinal cord
below the lesion has the capacity to generate rhythmic
activity but not locomotion. This also indicated thatmotor neurons of recorded muscles were undamagedby the lesion and other neural elements important fortriggering locomotion are located at or above L4. We do
not yet know which interneuronal system plays such a
crucial role, but it is probable that interneurons
identified in these regions are important (Edgley et al.
1988; Shefchyk et al. 1990). It is also conceivable thatpropriospinal interneurons in the rostral cord (Shik1997; Jordan & Schmidt 2002), after section, become‘leaders’ to coordinate spinal locomotion, which may
underlie plastic changes in connectivity. Such interneuronal plasticity remains to be characterized, butother work ( Jordan & Schmidt 2002) has shown usingc-fos labelling, after intensive locomotion in decerebrate cats, that cholinergic propriospinal interneurons
are numerous, which suggests the possibility of plasticchanges in interneuronal populations.
Finally, midlumbar segments may be important inevoking locomotion by other means. It was recently
shown that intraspinal electrical microstimulation
applied at different spinal levels could initiate locomotion in one-week spinal cats (Barthélemy et al.
2005). After inactivating these midlumbar segments
by yohimbine or performing a second lesion at caudal
L4, locomotion could no longer be evoked byintraspinal microstimulation (Barthélemy et al. 2002;
Rossignol et al. 2002). Whether or not these segments
are essential for evoking locomotion via brainstem
Phil. Trans. R. Soc. B (2006)

stimulation is still under study (Leblond & Rossignol
2003).
Role of sensory inputs in locomotion
The role of sensory afferents in locomotion is importantand increasingly so for locomotor recovery after spinal
lesion. The recovery of spinal locomotion probably
depends on proper stimulation of afferent inputs bylocomotor training. Training leads to specific motor
improvements (Edgerton et al. 1997) and accelerates
the recovery of spinal locomotion when provided early
after a spinal lesion under proper pharmacologicalstimulation (Chau et al. 1998a; Rossignol et al. 2001).
Within the context of this review, it is only possible
to give a general overview of the role of afferents duringlocomotion and how transmission in reflex pathways
may be changed after a spinal lesion, thus giving an
indication that even the simplest reflexes undergo
plastic changes after spinal lesion even in the adult.
For a broader review on the topic of sensorimotor
interactions during locomotion, the reader is referred
to a recent review (Rossignol et al. 2006). At the onset,
however, it should be stated that dorsal rhizotomy in
the acute decerebrate cat (Grillner & Zangger 1984) or
chronic dorsal rhizotomy (Wetzel et al. 1976; Goldberger 1977) does not prevent locomotion, althoughobviously it precludes adaptation of the pattern to theexternal environment. Similarly, after neurochemicalparalysis, which abolishes all phasic sensory inputs,
neurochemical activation by DOPA (Grillner &Zangger 1979) or other noradrenergic agents(Pearson & Rossignol 1991) or by brainstem stimulation ( Jordan et al. 1979) can induce locomotion.
Finally, pyridoxine intoxication, which removes large
diameter sensory afferents, does not prevent the longterm recovery of locomotion despite an initial inability
to walk (Pearson et al. 2003). In real life, of course,
sensory inputs have important adaptive roles.

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1656

S. Rossignol Plasticity of connections in adult mammals
first lesion T13
35 days

(a)
Cat E

LSt
LSrt
LVL
LGL
RSt
RSrt

Cl3t161

RVL
(b)

1s

second lesion caudal L3
6 days
LSt
LSrt
LVL
LGL
RSt
RSrt

Cl3t1701

RVL(c)

20 days

LSt
LSrt
LVL
LGL
RSt
RSrt
Cl3t12001

RVL
0.3 m s–1
FPS

Figure 4. Abolition of locomotion after a second spinal transaction at caudal L3. Figurines drawn from the video recordings
show the hindlimb position. (a) Spinal locomotion after 35 days of training following a first transection at T13. (b) Absence of
locomotion 6 days after a second lesion at caudal L3. Only tonic activity of the flexors (St and Srt) was observed. (c) Absence of
locomotion following 20 days of training after the caudal L3 lesion. Some small movements of flexion and extension wereobserved but no locomotion. Note the presence of spontaneous fast paw shakes (FPS), a rhythmic pattern which has a much
faster frequency than locomotion. Modified with permission from Langlet et al. (2005).

Proprioceptive afferents (groups Ia, Ib and II)
appear to regulate in part the duration of various
sub-phases of the step cycle (step frequency and speed)
as well as the discharge amplitude of muscles.
For instance, protracting the hip joint or the shoulder
joint generally lengthens the step cycle and stops
walking if it reaches the maximum limit (Pearson &Rossignol 1991; Saltiel & Rossignol 2004a).
A retraction has the opposite effect and speeds up thecycle. Phasic protraction of the shoulder during fictive
or real locomotion (Rossignol et al. 1993; Saltiel &Rossignol 2004b) or imposed protraction of thehindlimb during swing (Lam & Pearson 2001; McVea
et al. 2005) shortens the swing phase during real
locomotion whereas protraction during the stancephase of fictive locomotion prolongs swing. This
indicates very well that although fictive locomotor
rhythms can be evoked in spinalized and curarizedanimals, when present, proprioceptive afferent feedback participates in the regulation of the step cycle.
Similarly, the amplitude of muscle discharge can be
regulated by proprioceptive afferent feedback. It has
Phil. Trans. R. Soc. B (2006)

been proposed that 40–60% (Donelan & Pearson
2004a) of the amplitude of ankle extensor discharge
depends on afferent feedback. Thus, during unloadinga human subject walking on a treadmill, there is a major
reduction in EMG amplitude (Harkema et al. 1997;
Dietz & Colombo 1998; Dietz & Duysens 2000). If theankle extensors are unloaded during stance bymechanically extending the ankle through an externalankle brace, a 50% decrease in EMG amplitude of theankle extensor muscle ensues (Sinkjaer et al. 2000). In
cats, elegant experiments have been performed toevaluate unloading during locomotion, in particular‘foot-in-the hole’ experiments in which cats suddenly
make one step through a trap (Gorassini et al. 1994) orwalk on a peg, which is lower than expected (Donelan &Pearson 2004b). In all these cases, where sensory
feedback is reduced presumably because of a decreasein ankle extensor load, there is a short latency reduction
in ankle extensor muscle activity.
Cutaneous inputs, on the other hand, appear to havea major role in positioning the foot during locomotion.
In humans (Zehr et al. 1998a,b; Zehr & Stein 1999),

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S. Rossignol

Plasticity of connections in adult mammals

Phil. Trans. R. Soc. B (2006)(b) monosynaptic excitation
sham
trainedLGS Mn
1 mv

(a)
E

CDP
Pl (1p 1.8T)
1 ms

3(c) disynaptic IB inhibition

2
1
IB

IA

1 mv

LGS MnExt MnCDPPl (6p 1.8T)

10 ms

stim
(d) polysynaptic excitation
MG Mn

1 mv

cats (Rossignol et al. 1988, 2006; Rossignol 1996;
Bouyer & Rossignol 2003a) and rats (Schouenborg
2003), an exquisite number of reflexes are used tocorrectly place the foot after electrical or mechanicalstimulation. Given the multisynaptic nature of
cutaneous pathways, it can be expected that theseare highly plastic and considerably modified after
spinal lesions.
Changes in reflex pathways after chronic spinalization.
After chronic spinal hemisection (Hultborn & Malmsten
1983a,b) or complete spinal section (Hochman &McCrea 1994a), the spasticity observed has been
attributed to changes in reflex pathways although precise
underlying mechanisms are unclear and appear to differ
in various motor neuron pools and even in various typesof motor neurons (Hochman & McCrea 1994c). In theanaesthetized cat, six weeks after complete cord section,homonymous monosynaptic Ia EPSPs in lateral gastrocnemius (LG) can almost double, whereas in other ankle
extensors, changes in amplitude are non-existent or
minimal. Heteronymous excitatory post-synaptic
potentials (EPSPs) are also markedly increased not onlyin LG but also in medial gastrocnemius (MG),suggesting that these changes are not due to changes inmembrane properties of motor neurons since homonymous EPSPs in MG motor neurons are unchanged. The
rise time and half width of these EPSPs are also
diminished and these changes cannot be wholly attributed to the minimal changes in membrane
properties seen in motor neurons after spinalization(Hochman & McCrea 1994b) and must therefore be
attributed to changes in other control mechanisms suchas presynaptic inhibition or to changes in the efficacy ofsome synapses close to the soma. However, it was more
recently shown in rats which develop tail spasticity after alow sacral spinal section that plateau potentials return inmotor neurons and might in part be responsible for the
spasticity and increase in some reflex responses (Bennett
et al. 2004; Li et al. 2004; Heckmann et al. 2005).
Changes in other pathways have been documented
after spinalization in animals and humans such as
an increase in recurrent inhibition (Hultborn &Malmsten 1983b; Shefner et al. 1992) and a decrease
in reciprocal inhibition (Xia & Rymer 2005). Flexion
responses following spinalization are increased(Sherrington 1910).
Changes in reflex pathways after locomotor training.
Interesting studies were performed in spinal cats thatwere either trained or not (shams) on a treadmill todetermine if training influenced transmission in reflex
pathways. Monosynaptic excitation, disynaptic inhibition and polysynaptic excitation were studied in aterminal experiment in trained and sham chronic spinal
cats (Côté et al. 2003). The changes were firstquantified at rest in the absence of fictive locomotion.
It was found that locomotor training significantly
decreased monosynaptic excitation and disynaptic
inhibition evoked by 1b afferent stimulation. Disynaptic inhibition could even be reversed by clonidine to apolysynaptic excitation even without locomotion.
During fictive locomotion, similar changes wereobserved. Figure 5 gives a summary of these changes
in various pathways.

1657

CDP
LGS (6p 1.8T)

10 ms

Figure 5. Evaluation of the effect of locomotor training onload pathways. (a) Spinal proprioceptive pathways understudy. A schematic of three sensory pathways transmitting
inputs from muscle group I afferents to ExtMn is shown to
the left: the monosynaptic (stretch reflex) pathway (fromgroup Ia afferents originating in muscle spindles ofextensors), the disynaptic inhibitory pathway (from group
Ib afferents of extensors originating in Golgi-tendon organs
plus some group Ia fibres) and the polysynaptic excitatory
pathway (from groups Ib and Ia afferents of extensors). In
the acute spinal cat, this latter pathway shares interneurons
with the network generating the excitatory locomotor drivein extensors (box E). Sample records of motor neuronalpostsynaptic potentials used for measurements are on theright. (b) The amplitude of monosynaptic EPSPs wasmeasured at a latency of 1.4 ms (rising phase in thisexample, i.e. just before the onset of possible disynaptic
components). Note that compared to the sham (green),
the monosynaptic reflex is decreased after locomotor
training (black). (c) The disynaptic Ib inhibition was
evoked by a short train of stimuli (six pulses, 1.4–2.0 T,
200–300 Hz), and the inhibitory post-synaptic potential(IPSP) amplitude was measured at the maximal negative
deflection in the intracellular trace. Note that there were
often monosynaptic EPSPs (six positive humps) overriding
the inhibitory trough (dotted line). It is clear that
locomotor training reduces the maximal disynaptic inhibition. Afferent volley was monitored by recording the cord
dorsum potential (CDP). (d ) Polysynaptic excitation was
evoked by a similar short train of stimuli, and theamplitude was measured at the maximal positive deflection(dotted line) underlying monosynaptic EPSPs. Modified
with permission from Côté et al. (2003).

It is believed that observed changes could reduce
spasticity (reduction in 1a afferent transmission) andincrease the recruitment of extensor motor neurons(ExtMn) for the recovery of weight-bearing locomotion. Again these changes are not due to alterations
in membrane properties of the motor neurons since nocorrelation could be established between the changes

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S. Rossignol Plasticity of connections in adult mammals
(i)
MG Mn

CCS-MG

1 mv

sham
R2

trainedCDP
CCS (1p2T)

10 ms

(ii)
MG Mn

MPL-MG
46%
*
89%
1 *
R2
0
R3
R1
–1
sham
–2
*
trained
–3
54%

2
1
0
–1
–2
–3
–4

1 mv

sham

trainedstim
CDP
MPL (1p 2T)

10 ms

(iii)
MG Mn
trained

SP-MG

10 ms

1 mv

R3

R1

sham
trained
61%
**

10
8
6
4
2
0

R2
R1

R3

Mn

R1

(b)

47%
**

amplitude (mv)R3

amplitude (mv)

(c)

(a)

amplitude (mv)

1658

R2
R1: early excitation
R2: middle inhibition
R3: late excitation

sham
CDP
SP (1p 2T)

R2
R3

R1
*

sham
trained67%
10 ms

Figure 6. Evaluation of the effect of locomotor training on cutaneous pathways. (a) Hypothetical cutaneous pathways leading to
responses of various latencies (R1, R2 and R3) are illustrated. (b) Type of responses to cutaneous stimulation recorded in motor
neurons. Representative averaged post-synaptic potential patterns (nZ62) evoked by cutaneous afferents (caudal cutaneous
sural (CCS), medial plantar (MPL) or superficial peroneal (SP)) recorded in extensor or flexor/bifunctional motor neurons areshown. The initial depolarization is referred to as R1 (early excitation), the subsequent hyperpolarization as R2 (middle
inhibition) and the following depolarization as R3 (late excitation). (c) Training specifically modified transmission fromcutaneous afferents to the MG motor pool. Left: PSPs (nR40) evoked by stimulation of (i) CCS, (ii) MPL and (iii) SP afferents
recorded in MG motor neurons with similar AHPs (range 70–91 ms) in a sham (grey) and a trained cat (black). Right:,
histograms of the mean amplitude of responses evoked by (i) CCS, (ii) MPL and (iii) SP afferents recorded in all MG motor
neurons in shams (grey) and trained cats (black). Six of the nine pathways tested in MG motor neurons were modified bytraining. Significant differences are indicated as follows: p!0.05; p!0.01. Overall, training (i) decreased both CCS-MG-R1(by 47%) and CCS-MG-R3 (by 61%) amplitudes, (ii) increased MPL-MG-R1 amplitude (by 89%), decreased MPL-MG-R2(by 54%) and MPL-MG-R3 (by 46%) amplitudes and (iii) decreased SP-MG-R2 amplitude (by 67%). Mn, motor neuron.
Modified with permission from Côté & Gossard (2004).

observed and the after-hyperpolarization (AHP) of
motor neurons, which reflects the membrane time
constant and input resistance. The changes are rather
attributed to excitability changes of interneurons
receiving group I inputs to explain the reduced
autogenic inhibition and to increases in the output ofpresynaptic interneurons on group Ia afferent terminals, which can reduce monosynaptic excitation.
Interestingly, reflexes evoked by so-called flexor
reflex afferents (FRAs) generated crossed activation of
flexor motor neurons rather than ExtMn, suggesting animportant reorganization of specific reflex pathways orat least a significant change in bias since both crossed
extensor and crossed flexor pathways exist (Safyants
1970; Rossignol & Gauthier 1980; Gauthier &Rossignol 1981).
Furthermore, cutaneous pathways show reduced
excitability specifically from foot pads (from the medial
plantar nerve) after locomotor training (Côté &Phil. Trans. R. Soc. B (2006)

Gossard 2003), again suggesting that training
diminishes hyperreflexia from the foot pads after
spinalization. Figure 6 schematically illustrates thepathways involved, the various responses observed
and the changes after locomotor training.
The relationship between the changes in proprioceptive and cutaneous pathways induced by locomotor training and the actual improvement oflocomotor performance is an important question
and may justify major efforts in attempting tonormalize the gain of reflex pathways after SCI inorder to achieve the best possible locomotor
performance.
Plastic changes after neurectomies. The functional
recovery of locomotion after spinal lesions suggests
changes occurring within the spinal cord to optimize
the remaining circuitry controlling locomotion. The
above reflex changes occurring during locomotor
training suggest a great deal of plasticity in the spinal

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Plasticity of connections in adult mammals
cord after lesion and the possibility of influencing thisplasticity. In the last decade or so, we have performed
various experiments to demonstrate spinal plasticity,i.e. a functional compensation achieved solely by the
spinal cord in absence of descending inputs. Whereas
studies on locomotion demonstrate some type ofplasticity, the fact that there exists a spinal patterngenerator (Grillner & Zangger 1979) and spinal kittens
can express locomotion even if the spinalization has
occurred before having had the chance to walk clearlysuggests a largely hardwired spinal pattern generator(Forssberg & Svartengren 1983). Thus, the expressionof locomotion after spinalization is not the result oflearning a new pattern but the result of re-expressing a
spinal component of the overall locomotor program.
That specific training can promote aspects of thismotor control (bias on alternation or bias on posturalcontrol; Hodgson et al. 1994) reveals that the patterngenerator, although hardwired, can still be modulatedby biasing some of its components and this training canhave long-term effects (de Leon et al. 1999).
To demonstrate spinal plasticity more directly, we
studied how cats adapt their locomotor pattern after anerve section either in the intact state or after
spinalization and we have compared the compensation
occurring in both states in the same cat. To this end wehave severed muscle nerves and cutaneous nerves of
the hindlimbs.
Muscle nerve section. Although sectioning a peripheral muscle nerve removes both sensory and motor
functions for that particular muscle, such sections areuseful in evaluating the capacity of cats in the intact or
spinal state to adapt its locomotor pattern when specificmuscles are removed. Nerves to ankle flexors (tibialis
anterior, TA and extensor digitorum longus, EDL)
were cut in one leg while cats had an otherwise intact
spinal cord and had been chronically implanted with
EMG electrodes (Carrier et al. 1997). Remarkably,
following such a neurectomy, locomotor movements
were very similar to control after only a few days. There
was obviously some reduction in the ankle flexion andthe amplitude of hip and knee flexor EMGs wereincreased to compensate for the reduced ankle flexion.
When the cats had recovered a stable symmetricallocomotion they were spinalized, and walking became
asymmetric and included increased hip flexions duringswing on the denervated side, which were largely
dysfunctional. However, when the neurectomy was
performed in a spinal cat that had already recovered
locomotion, there was a reduced ankle flexion but noabnormal dysfunctional hyperflexions as observed
when the neurectomy was performed before spinalization. It can thus be concluded that the removal of amuscle usually active during locomotion results inplastic changes occurring both at the spinal andsupraspinal levels. The spinal cord alone does notseem capable in this case to compensate functionallybut there are undoubtedly changes occurring in thecord manifested as hyperflexions. How supraspinal andspinal changes combine to produce an almost normal
locomotion when the neurectomy is performed before
spinalization is still being investigated.
Similarly, others have developed a model of muscle
neurectomy of the gastrocnemius lateralis–soleus
Phil. Trans. R. Soc. B (2006)

S. Rossignol

1659(GLS; Whelan et al. 1995; Pearson et al. 1999; Pearson
2000). Such a neurectomy produces a marked yield at
the ankle but 5 days after, agonist muscles such as MG
and plantaris compensate for the removal of GLS byincreasing their discharge amplitude leading to acompensation of the yield. We used the same model
for collaborative experiments (Bouyer et al. 2001) inwhich the GLS nerve was sectioned on one side in threechronic spinal cats after they had regained normal
spinal locomotion (see above). Similarly to the intact
state, a significant ankle yield was observed during
stance for the first few days, and the GM burst ofactivity markedly increased. The yield almost
completely recovered within a week and GM activity
remained elevated. The mechanisms of such compensation in spinal cats still have to be elucidated but surely
the observations clearly indicate a functional compensation in the spinal state suggesting important spinal
capacity for adaptation presumably supported bychanges in synaptic transmission in various pathways.
Cutaneous nerve section. Although it is generally
believed that removal of cutaneous inputs by nerve
section or anaesthesia does not prevent locomotion(Sherrington 1910; Engberg 1964; Forssberg et al.
1977; Duysens & Stein 1978; Prochazka et al. 1978),recent experiments on denervation of the foot pads
have brought another perspective on the contributionof cutaneous inputs to locomotion (Bouyer & Rossignol
1998, 2001, 2003a,b; Rossignol et al. 2002). The fivecutaneous nerves of the hindfeet were cut in otherwise
intact cats. Within 2 days, these cats walked almost
normally on the treadmill. The only detectable change
was a somewhat faster swing with increased discharge
amplitude of the knee and ankle flexor muscles (seefigure 7). However, when placed on a horizontal
ladder, soon after the foot denervation and for up toseven weeks, cats were unable to place their feetcorrectly on the rungs. A strategy was developed by
the cats to grip the rungs and, when this capacity wasachieved, the cats were then spinalized at T13.
After spinalization, cats could generate alternate
walking movements of the hindlimbs but were unable
to place the feet on the plantar surface, which they
performed very well before spinalization even though
their hindfeet had been denervated. It should also be
pointed out that although ‘normal’ spinal cats (i.e. with
intact cutaneous denervation) tend to drag their feet in
the initial swing, this drag disappears (Barbeau &Rossignol 1987; Bélanger et al. 1996). We concluded
from this work that on the one hand, cutaneous sensory
inputs are very important for the recovery and expressionof spinal locomotion. On the other hand, the functional
adaptation seen after denervation in the intact state
probably depends largely on supraspinal compensations
since a major foot placement deficit is present after
spinalization. Recent work on this model (Bouyer et al.
2000; Bretzner & Drew 2005a) clearly indicates that the
motor cortex participates actively in this compensation.
Indeed, after denervation responses to intracortical
microstimulation is increased even 40 days after
denervation and may contribute in setting the discharge
amplitude of certain muscles such as hindlimb flexors tooffset the sensory denervation (see figure 8). Also, a lesionDownloaded from rstb.royalsocietypublishing.org on September 4, 2012

1660

S. Rossignol Plasticity of connections in adult mammals(b)

before neurectomy
swing

2 days afterswing

stancestance(c)41 days afterswing

stance

5 cm

(a)

5 cm

joint angle (degrees)

(d )

(e)
150 hip
90
150
knee
90
150 ankle
90
270
170 MTP
0500
time (ms)

1000

0

500
time (ms)

1000

(f)

intactpost-neurectomy
(g)

Srt

Srt

St

St

VL

VL

EDL

EDL

LG

LG

MG

MG

EDB

EDB
0

500
time (ms)

1000

0

500
time (ms)1000

Figure 7. Cutaneous neurectomy of the hind feet in the cat. (a–c) Stick figure reconstructions of left hindlimb movements from aframe-by-frame video analysis of cat walking on the treadmill at 0.5 m sK1. (a) Control, (b) 2 days, and (c) 41 days after
complete denervation of both hindfeet. Horizontal and vertical scales are 5 cm. (d and e) Mean angular excursions at each of four
limb joints. Thickness of lines represents 1 s.d. In (d ), control (grey line) and 2 days postdenervation (black line) aresuperimposed. Dashed lines represent divisions of step cycle according to Philippson (1905) for control walking situation. In (e),superimposition is between control (grey line) and 41 days postdenervation (black line). Synchronization is on foot contact.
Arrow highlights increased knee flexion. ( f and g) Rectified averaged EMG activity of the main muscles recorded simultaneouslywith kinematics shown in (d ) and (e). In ( f ), control EMG activity (grey area) and 2 days postdenervation (black line) aresuperimposed. In ( g), superimposition is between control (grey area) and 41 days postdenervation (black line). Srt, sartorius
anterior; St, semitendinosus; VL, vastus lateralis; EDL, extensor digitorum longus; LG, lateral gastrocnemius; MG, medial
gastrocnemius; EDB, extensor digitorum brevis. Reproduced by permission from Bouyer & Rossignol (2003a).

of the motor cortex may disrupt the compensation seen
after neurectomy (Bouyer et al. 2000).
Does this mean that all the plastic changes occur
exclusively in descending pathways? Two experimentssuggest that this is probably not the case. The first
concerns one cat that had been completely denervatedexcept for a tiny cutaneous branch originating from thedeep peroneal nerve. This spinal cat could indeed regain
a correct foot placement during locomotion, which
disappeared after anaesthesia of the receptive field ofthat nerve or after cutting that last remaining nerve. The
implication here is that the spinal cat adapted its
locomotion based on considerably reduced cutaneous
sensory input, suggesting an important reorganization
at the spinal level itself. To address the question of spinal
plasticity further, we performed a progressive cutaneous
denervation of one hindfoot in a cat that had beenspinalized before and had recovered locomotion. It was
fascinating to see that this spinal animal could adapt its
locomotion after each individual nerve section until all
cutaneous nerves were cut in that hindfoot, a time atwhich the cat lost the ability to place the foot on theplantar surface as was the case in other cats (Bouyer &Rossignol 2003b). These experiments clearly show that
Phil. Trans. R. Soc. B (2006)

when an animal must adapt its locomotion after loss of
cutaneous information that plastic changes in supraspinal and spinal connections occur.
(ii) Rat
Earlier sections dealt with work performed on the cat.
Similar work was done on rodents but only somehighlights will be given as they pertain to the main topic
of this review. In fact, several other chapters in this issue
deal with various types of lesioned descending
pathways (CST) or spinal lesions (weight drops(Young 2002), surgical overhemisections (Bregman1998)) in rats and the recovery of function.
The interest of partial spinal lesions is to study
plastic changes leading to functional recovery. Probably
the best type of work of this kind is exemplified by
Bareyre et al. (2004) showing the development of new
circuits using propriospinal neurons as relay neurons tore-establish function.
Although rats spinalized early after birth can recover
locomotion (de Leon et al. 2002), adult rats do notrecover spontaneous treadmill walking after a midthoracic spinalization in contrast to the situation in
adult cats. However, adult chronic spinal rats can walk

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Plasticity of connections in adult mammals
10 days before
denervation

2 days after
denervation

40 days after
denervation

N = 41 phase 0.14

N = 43 phase 0.15

N = 25 phase 0.14

N = 13 phase 0.58

N = 15 phase 0.58

N = 14 phase 0.58

(a)

S. Rossignol

1661

LSrt

LSt

LTA

LEDB

LVL

(b)
LSrt

LSt

LTA

LEDB

LVL
–50

0

50 100 150 200 –50(ms)

050 100 150 200 –50(ms)

050 100 150 200(ms)

Figure 8. Increased corticospinal efficacy after a unilateral complete cutaneous denervation of the foot. (a) Average of EMG
responses evoked during the swing phase at a current strength of 35 mA before and after denervation from a microwire implantedin the motor cortex. For the St and TA, the figure identifies both short (black) and longer (grey) latency responses. (b) Average
EMG responses, evoked by the same microwire at the same current strength during the stance phase. Note that the scale used todisplay a given EMG is constant in all traces. Note the significant increase in the muscle responses evoked by the cortical
microwires even 40 days after the cutaneous denervation. Reproduced with permission from Bretzner & Drew (2005a).

on a treadmill with the hindlimbs using different
forms of stimulation thus demonstrating theimportant capacity of the cord to generate locomotionin the rat. For example, serotonergic stimulation(Feraboli-Lohnherr et al. 1999) induces a locomotor
pattern and chronic treatment with serotonergic
agonists maintains this ability (Antri et al. 2002,
2003; Orsal et al. 2002). Recently, electrical stimulation of the dorsal columns together with 5-HT
stimulation was shown to induce locomotion on atreadmill in adult spinal rats (Ichiyama et al. 2005).
Perhaps the most relevant work in the context of thisissue is the work on transplant of mesencephalicembryonic 5-HT cells below a chronic spinal lesion
performed in adult rats (Feraboli-Lohnherr et al. 1997;
Ribotta et al. 2000). This showed that 5-HT cells,
implanted after a spinal section, re-establish contacts
with target neurons in various parts of the cord andfacilitate the expression of a well-coordinated locomotor pattern. Importantly, even following a second
spinal transaction at T8, the locomotor capability
Phil. Trans. R. Soc. B (2006)

remains showing that the locomotor capability was
not due to regeneration of axons through the lesion
which could have been favoured by the graft but rather
by the sublesional graft itself which acted as more orless a biological pump of 5-HT that raised theexcitability of relevant spinal circuits (see figure 9).
Interestingly, the grafts had to innervate the upper
lumbar levels (L1–L2), which, in the rat, are crucial
levels for the expression of locomotion (Cazalets et al.
1995; Cazalets 2000; see earlier for critical levels in thecat at L4). Indeed, cell grafts that did not projectterminals to at least L1 did not induce locomotion.
Therefore, grafts at T9 (the spinalization is at T8) did
not induce locomotion whereas grafts at T11 did.
Therefore, the rat spinal cord possesses thenecessary circuitry to generate spinal locomotion
but electrical or pharmacological stimulation, namely
the serotonergic system, is required for locomotion.
In that context, it is often reported that with partial
lesions, there is often a regeneration of 5-HT whichmight explain part of the functional recovery sinceDownloaded from rstb.royalsocietypublishing.org on September 4, 2012

1662

S. Rossignol Plasticity of connections in adult mammals
intact(a)swing

stancejoint angle (degrees)

(b)

(d)

spinal T11-transplantedswing
stance(e)stancestance

swing

swing

140

90

hip

50
110

knee

100
120

50
120

ankle

60
170

50
240

mtp

50
240

180

180
100 ms

100 ms( f ) N =6

N =6

(c)
LIp
LSt
LVL
LTA
LGM

r6t82

r1t32
RTA

RSt
0

1.0
phase of step cycle

2.0

0

1.0
phase of step cycle

2.0

Figure 9. Comparison of rhythmic locomotor activity in an intact rat (a–c) and nine weeks after transplantation of embryonicraphe-cells from E14 embryos (d–f ). (a and d ) Reconstruction, as stick diagrams, of treadmill locomotor movements duringswing and stance phases. Each stick figure is displaced from the previous by an amount equivalent to the foot displacement toavoid overlap of all the figures. (b and e) Variations of mean angle joints (thick lines) and their standard deviations (thin lines)
from six consecutive step cycles, in (from top to bottom) hip, knee, ankle and metatarsophalangeal (mtp) joints. The same
normalized step cycle is displayed twice to facilitate viewing the events at around the trigger point (foot contact of the limb facing
the camera, down-going arrow). The foot lifts of the same limb are also indicated by up-going arrows. Angular excursions ofvarious joints are averaged for six cycles and synchronized on foot contact. (c and f ) Corresponding synchronized EMG activity
in various muscles of ipsi (i) or contralateral (co) hindlimbs. Ip, iliopsoas (hip flexor); St, semitendinosus (knee flexor and hip
extensor); VL, vastus lateralis (knee extensor); TA, tibialis anterior (ankle flexor); and GM, gastrocnemius medialis (ankle
extensor). Note the discharges of LIP, LSt and LTA during the swing phase and of LVL and LGM during stance. The
contralateral St (coSt) also discharges during the ipsilateral stance indicating a good alternation between limbs. Reproducedwith permission from (Gimenez y Ribotta et al. 2000).

release of 5-HT by these axons might be sufficient tofacilitate the spinal circuitry for locomotion (Coumans
et al. 2001).
(iii) Mouse
The adult spinal mouse is capable of hindlimb
locomotion on a treadmill (Leblond et al. 2003) or of
fictive spinal rhythms ( Jiang et al. 1999). We haveshown that the locomotor pattern can be surprisingly
consistent and apparent coupling between the fore- andhindlimbs can at times be misleading but easily
Phil. Trans. R. Soc. B (2006)

detected by analysing the timing of coupling. Pharmacological work has also indicated that 5-HT agonists
induce locomotion shortly after spinalization and canevoke important modulatory effects on the patternwhen animals have recovered spontaneous locomotor
function (Guertin et al. 2002; Leblond et al. 2002;
Guertin 2004, 2005).
In models of functional recovery after partial lesions,transplants or other types of stimulation, it is very
important to account for the existence of this capacityof adult mice to generate elaborate rhythmic alternate

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Plasticity of connections in adult mammals
(a)

(d )

intact1663

spinal T8- quipazine
stance
swing

swing

1 cm

stanceS. Rossignol

stance1 cm
stance

swing

(b)

swing

(e)

joint angle (degrees)

130 hip60
110 knee

60
130

ankle

40
(c)

(f)
N =15

N=15

LTA
LVL
RTA
RVL
0

1.0
phase of step cycle

2.0

0

1.0
phase of step cycle

2.0

Figure 10. Comparison of locomotion in an intact mouse and a spinal mouse injected with quipazine. Kinematics and EMGs
during treadmill locomotion (0.2 m sK1) in a mouse before and 15 days after a complete section of the spinal cord at T8 level.
Since this mouse was not specifically trained, quipazine (2 mg kgK1) was given to trigger a good pattern of locomotion after
spinalization. (a and d ) Stick diagrams representing the left hindlimb during a complete step cycle (stance and swing) (a) beforeand (d ) after spinalization. The horizontal arrows indicate the direction of the movement (stance and swing). (b and e) Angularexcursions of three joints averaged over 15 cycles (b) before and (e) after spinalization. All angle measurements weresynchronized with the left foot contact; flexions correspond to downward deflections of the traces. Downward arrows indicate
foot contact and upward arrows indicate foot lift (repeated for two cycles). (c and f ) EMG recordings of two flexor muscles: theleft and right tibialis anterior (LTA and RTA) and two extensor muscles: left and right vastus lateralis (LVL and RVL) averaged
over the same 15 cycles are rectified and normalized (c) before and ( f ) after spinalization.

locomotor pattern of the hindlimbs with sensory
stimulation, even though it might be seen as aconfounding issue to evaluate the real impact of agiven treatment.
The possibility of recording kinematic and EMG(Leblond et al. 2003; Fong et al. 2005; Pearson et al.
2005; see figure 10) data in mice will be of great interestin view of the ongoing genetic characterization of spinal
cells that might be involved in locomotion (Kiehn &Kullander 2004). Thus, it might be feasible in the
future to study the connectivity of genetically identified
cells in normal and spinal mice and better identify theplastic changes occurring in well-defined cells.

2004), it would appear that the framework provided byanimal work has been useful in conceptualizing
experiments in humans and developing locomotor
training strategies based on the plasticity observed inanimal experiments. The field of locomotor recovery inhumans after SCI has been reviewed several times(Barbeau et al. 1998, 1999, 2002; Barbeau & Fung
2001) and only some highlights will be reported here as
they apply to the plasticity of connections in the adult.
Some reviews are particularly useful to relate animal
work and the clinical conditions (Barbeau & Rossignol
1994; Rossignol 2000; Harkema 2001; Dietz &Harkema 2004).

(b) Studies in humans
Despite doubts expressed about the adequacy ofanimal models in the study of spinal injuries (Dobkin(i) Locomotion after spinal cord injury in human subjects
There are a number of indications that the spinal
cord of humans is also endowed with intrinsic

Phil. Trans. R. Soc. B (2006)

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1664

S. Rossignol Plasticity of connections in adult mammals(a)after training

before training

TA

Sol

0.5 mV
50 ms

MEP p-p(mV)(b)

1000 TA

VL

1000
500
500
0

Bkd EMG(mV)

1500 VL

0

40
20
0

30 40 50 60 70 80
MSO (%)

20 30 40 50 60 70
MSO (%)

30 40 50 60 70 80
MSO (%)

Figure 11. Change in motor evoked potentials by transcranial magnetic stimulation (TMS) in SCI patients trained on atreadmill. (a) Antagonist MEPs (four superimposed raw EMG traces) of the SOL muscle (bottom traces) to TMS while thesubject (7M) produced a background contraction of the target (agonist) TA muscle (top traces). Before training (left graphs),
motor-evoked potentials (MEPs) were not evoked in the electrically silent SOL muscle. After training (right graphs), the MEP in
the facilitated TA muscle increased and a MEP emerged in the SOL muscle with a similar latency to that of the TA muscle(40 ms TA versus 41 ms SOL). Arrows mark the time of the 80% MSO (maximum stimulator output) stimulation. (b)Representative recruitment curves from three different subjects before (solid circles, solid lines) and after (open circles, dottedlines) treadmill training. Top graphs: recruitment curves from the TA (subject 5M, left graph) and VL muscles (subject 4M,
middle graph; subject 1M, right graph). In all three examples, the recruitment curves after training rested above the recruitment
curves before training, especially at intermediate and high stimulation intensities. The slope of the steep portion of the sigmoidline fit to the recruitment curve also increased after training although MEPthresh did not change in most cases. Bottom graphs:
the mean background EMG after training (dotted horizontal line) was similar to the background EMG before training(solid horizontal lines). Data points represent trial meanGs.d. Modified and reproduced with permission from Thomas &Gorassini (2005).

capabilities to generate rhythmic movements (Kuhn
1950). With stimulation of FRAs, long latency andlong duration discharges were described in SCI
subjects as well as rhythmic myoclonic-like patterns(Bussel et al. 1988; Bussel et al. 1992). With epiduralelectrical stimulation (Dimitrijevic et al. 1998),
rhythmic patterns could be evoked in complete SCI
subjects. Whether there is in humans a central
pattern generator for locomotion would require
recording of such a pattern after a complete section
and after curarization as was done in several species(see above) and also in non-human primates(Fedirchuk et al. 1998).
In humans, the term functionally complete SCI
refers to the inability of the subjects to produce
voluntary movements or to feel sensory stimuli.
However, this might be somewhat misleading since
the absence of voluntary movement does not per semean that the spinal cord is anatomically completely
sectioned and, therefore, all the phenomena observed
after injury are due to the action of the spinal cord.
However, it is likely that spinal or subcortical areas
Phil. Trans. R. Soc. B (2006)

contribute to the involuntary expression of such
locomotor pattern. One spectacular case was reported(Calancie et al. 1994) of a functionally complete SCI
subject who could generate involuntarily fairly elaborate alternating locomotor movements of the lower
limbs when reclined and with the hip extended. This
lasted for a prolonged period but subsided indicatingthat some other descending control must have takenover to suppress these unwanted movements.
It was shown that in clinically complete SCI
subjects, a locomotor pattern could be generated bypassive manual entrainment (Dietz 1995; Dietz et al.
1994, 1995) and the pattern expressed was more
complete in patients with higher lesions (Dietz et al.
1999). These patterns are interpreted to result frominteractions between a spinal cord locomotor generator
and sensory afferent feedback, namely the activation ofload afferents (Dietz et al. 1995; Harkema et al. 1997).
On the other hand, it was shown that functionallycomplete spinal cord subjects could recruit more
muscles and at a higher level of activity when walking
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Plasticity of connections in adult mammals
produce voluntary movements (Maegele et al. 2002).
This suggests that remnant voluntary control coupledwith enhanced sensory inputs can combine to shape thelocomotor pattern as is the case in animals.
(ii) Locomotor training
Patients with partial spinal cord lesions can walk albeit
with some deficits (Pepin et al. 2003a,b). Animal andhuman experiments suggesting a potential for an
involuntary rhythmogenesis at the spinal cord/brainstemlevel has encouraged the promotion of locomotor
training on a treadmill with body weight support,
robotics or muscle stimulation with remarkable results(Barbeau et al. 1987b; Colombo et al. 1998; Wernig
et al. 1999; Behrman & Harkema 2000; Edgerton et al.
2001; Barbeau et al. 2002; Wirz et al. 2005). Thus,
patients who were wheel-chair bound could transfer
the benefit of their treadmill locomotor training to daily
life situations.
(iii) Changes in ascending and descending pathways
after lesions
This is a very large topic in itself and only very recent
work on aspects relevant to the present theme isdiscussed.
A recent report on patients with a chronic cervicallesion of more than six months describes the emergenceof interlimb reflexes coupling cervical and lumbosacral
segments (Calancie et al. 2005). The relevance in thepresent context is that these interlimb reflexes are notapparent within the first six months but graduallydevelop, suggesting an ongoing plasticity of connections even in the adult after spinal injury.
Another very significant piece of work (Thomas &Gorassini 2005) has shown that functional locomotor
improvement after 3–5 months of locomotor training inhumans with SCI is accompanied by a significant change
in motor potentials evoked by transcranial magnetic
stimulation (TMS; see figure 11). Thus, it can beconcluded that the overall transmission in the corticospinal pathway is enhanced by locomotor training andmay, at least in part, be responsible for the functionalamelioration. This could be achieved at different levels asshown for the changes occurring after neurectomies(Bretzner & Drew 2005a,b). In the present case, however,a change in intracortical excitability was also observed
suggesting intracortical modifications of excitability
resulting from locomotor training.
3. CONCLUDING REMARKSThis review has attempted to summarize some aspectsof a very large topic dealing with plasticity ofconnections after spinal injury in adult mammals.
The issue of locomotor recovery in animal models wasaddressed and the point was made that recovery ispartly due to plasticity within existing spinal locomotor
networks. Locomotor training appears to change theexcitability of simple reflex pathways as well as more
complex circuitry. Some work was reported demonstrating the potential intrinsic plasticity of the spinal
cord in adapting to lesions (central or peripheral) but,usually, adaptation to lesions entails changes both atspinal and supraspinal levels. Finally, a very brief
Phil. Trans. R. Soc. B (2006)

S. Rossignol

1665

overview of human work was given to indicate at leastthat the principles regulating the recovery of locomotor
functions in humans are probably very similar to thoseobserved in animal experiments.
It is comforting to think that the nervous system,
even at the adult stage, is plastic enough to optimize
internal motor sequences after lesion, that this canfurther be optimized by various types of stimulation(pharmacological, electrical) and prepares the terrain
for further success in axonal regeneration to add
voluntary and more refined controls of the expressionof locomotion after spinal lesion.
I wish to acknowledge Daniel Cyr, Janyne Provencher andHugues Leblond for their help with illustrations. I would also
like to thank former students, postdoctoral fellows orcollaborators whose work is partly illustrated here
(C. Langlet, L. Bouyer, D. Orsal and H. Leblond). Special
thanks to Drs J.-P. Gossard, T. Drew and M. Gorassini forproviding modified figures from their published work.
A special thanks to Alain Frigon for revising the text. Finally,
many thanks are addressed to the Canadian Institute of
Health Research for continuous support over the years
through individual grants, group grants and a Canada
Research Chair on the Spinal Cord and a grant from the
Canadian Foundation for Innovation.

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