Acta Physiol 2007, 189, 171180

REVIEW

The spinal pathophysiology of spasticity from a basic

science point of view
J. B. Nielsen,1,2 C. Crone2,3 and H. Hultborn2
1 Department of Exercise and Sport Science, University of Copenhagen, Copenhagen N, Denmark
2 Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen N, Denmark
3 Clinic of Neurophysiology, Copenhagen University Hospital (Rigshospitalet), Copenhagen , Denmark

Received 7 July 2006,

accepted 21 August 2006
Correspondence: J. B. Nielsen,
Department of Exercise and Sport
Science & Department of Medical
Physiology, Panum Institute,
University of Copenhagen,
Blegdamsvej 3, 2200 Copenhagen
N, Denmark. E-mail: j.b.nielsen@
mfi.ku.dk

Abstract
Spasticity is a term, which was introduced to describe the velocity-sensitive
increased resistance of a limb to manipulation in subjects with lesions of
descending motor pathways. This distinguishes spasticity from the changes in
passive muscle properties, which are often seen in these patients, but are not
velocity-sensitive. Increased excitability of the stretch reflex is thus a central
component of the definition of spasticity. This review describes changes in
cellular properties and transmission in a number of spinal reflex pathways,
which may explain the increased stretch reflex excitability. The review
focuses mainly on results derived from the use of non-invasive electrophysiological techniques, which have been developed during the past 2030
years to investigate spinal neuronal networks in human subjects, but work
from animal models is also considered. The reflex hyperexcitability develops
over several months following the primary lesion and involves adaptation in
the spinal neuronal circuitries caudal to the lesion. In animal models, changes
in cellular properties (such as plateau potentials) have been reported, but
the relevance of these changes to human spasticity has not been clarified. In
humans, numerous studies have suggested that reduction of spinal inhibitory
mechanisms (in particular that of disynaptic reciprocal inhibition) is involved. The inter-subject variability of these mechanisms and the lack of
objective quantitative measures of spasticity have impeded disclosure of a
clear causal relationship between the alterations in the inhibitory mechanisms and the stretch reflex hyperexcitability. Techniques which make such a
quantitative measure possible as well as longitudinal studies where development of reflex excitability and changes in the inhibitory mechanisms are
followed over time are in great demand.
Keywords motoneurones, pathophysiology, spasticity, spinal cord.

Spasticity is a common disorder in patients with injury

of the brain and spinal cord. The prevalence is reported
to be around 85% of patients with multiple sclerosis
(Rizzo et al. 2004), 6578% of patients with spinal
cord injury (Maynard et al. 1990), but only around
35% in stroke patients with persistent hemiplegia
(Sommerfeld et al. 2004).

Significant scientific interest has been devoted to

spasticity over the past 1015 years, as it provides an
example of plastic changes occurring distal to a central
lesion. Knowledge about the mechanisms responsible
for these plastic changes may be of importance in
relation to rehabilitation of function following central
motor lesions and understanding the pathophysiology

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J B Nielsen et al.

of spasticity may provide important clues to its treatment. In this review we will discuss current views on the
pathophysiology of spasticity and point to some future
directions of research.

What is spasticity?
The definition of spasticity has been discussed over the
years since the term was introduced. One of the most
cited definitions is that of Lance (1980), in which it is
stated that: Spasticity is a motor disorder characterized
by a velocity-dependent increase in tonic stretch reflexes
(muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one
component of the upper motor neurone syndrome. This
definition is well in line with the description of
hypertonia and rigidity by Sherrington (1898) in decerebrate animals, which has been the basis of much of the
subsequent experimental work in animals as well as in
humans. A strict definition is essential for research
concerned with the possible spinal mechanisms involved
in the pathophysiology of spasticity, which will be the
topic of most of this review and it is therefore also this
definition, which will be used here. However, the
definition has been challenged in recent years for two
different reasons. First, many different clinical signs are
referred to as spasticity, such as increased muscle tone,
clonus, spasms and hyperreflexia, but it is clear that
these symptoms can exist independently of each other
and do not necessarily share a common pathophysiology. Lances definition of spasticity includes only the
increased velocity dependent stretch reflexes and hyperactive tendon jerks and is thus narrower than some of
the clinical uses of the term, but it does have the
advantage of being more precise. Some authors have
decided to use the more clinically relevant definition,
which also includes clonus, spasms and hyperreflexia
(Skold et al. 1999, Dietz 2000), whereas others have
decided to use the more strict definition which focuses
on hypertonia (Bohannon 1993, Kita & Goodkin
2000). It may be relevant to use different definitions
depending on which kind of scientific question is asked,
but it is of paramount importance that the definition of
spasticity which is used, is clearly stated in each case in
order to avoid confusion. Secondly, several studies have
shown that many subjects who have been found to be
spastic by clinical examination turn out not to have any
signs of hyperreflexia (Sinkjr et al. 1993, SchindlerIvens & Shields 2004). The increased muscle tone in
such subjects rather seems to be caused by structural
changes in the muscles related to contractures (Dietz
et al. 1981; Sinkjr et al. 1993, see review by Gracies
2005a,b). It has therefore been argued that spasticity
may also be explained by changes in muscle properties
and not only by hyperreflexia and alterations of the

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central processing of sensory input in the spinal cord

(Dietz et al. 1981, Gracies 2005a,b). The most likely
explanation why several studies have failed to find any
hyperreflexia in patients, who were deemed clinically to
be spastic, is thus that it is very difficult to distinguish
clinically between the increased hypertonia caused by
the passive muscular changes and the active stretch
reflex mediated changes. This distinction requires that
it is possible to determine to what an extent the muscle
resistance, which is perceived by the examiner, is
velocity dependent (which would be a sign of spasticity), or not (which would rather suggest muscular
changes). Especially for the heavy lower limb this may
be difficult. This problem may also explain the relatively
low inter-rater reliability of the Ashworth test of
spasticity, which relies on the ability of the examiner
to determine the velocity-dependent muscle resistance
(Haas et al. 1996, Blackburn et al. 2002, Platz et al.
2005). These problems of determining spasticity independently of muscle resistance changes, emphasize the
need of developing more optimal techniques for spasticity evaluation (Burridge et al. 2005; and see later).
In our opinion it is thus important to reserve the term
spasticity to conditions related to an alteration of
central processing of sensory input and to exclude
structural changes in the muscles. In the following we
will thus discuss the electrophysiological changes which
have been found in animals and humans with spasticity.

Pathophysiological CNS-changes in spasticity

Granted that velocity dependent increase of muscle
resistance and hyperreflexia are central in the pathophysiology of spasticity, it has been a logical step to
investigate which alterations in spinal reflex transmission could be responsible for the increased stretch reflex
activity. Figure 1 gives an overview of the spinal reflex
circuits, that could, theoretically, be involved in the
development of spasticity and which have been investigated over the past 3040 years. The monosynaptic Ia
excitation certainly contributes to the major excitation
underlying the dynamic and tonic components of the
stretch reflex. However, many spinal reflex pathways
may increase or decrease the effect of this monosynaptic
excitation: Excitation and inhibition from muscle spindle group II afferents (not indicated in Fig. 1); autogenetic inhibition from Golgi tendon organs (via Ib
afferents); recurrent inhibition (via motor axon collaterals and Renshaw cells); presynaptic inhibition of Ia
afferent terminals; and reciprocal inhibition from muscle spindle Ia afferents from the antagonist muscles. The
changes in reflex transmission in these pathways may
depend both on an altered supraspinal drive (if any
remains), and on secondary changes at cellular level in
the spinal cord below the lesion. Among these

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Acta Physiol 2007, 189, 171180

Figure 1 Diagram of various spinal pathways which may

contribute to the development of spasticity.

secondary changes are morphological plasticity like

collateral sprouting from remaining/surviving neurones as a result of partial denervation (Raisman
1969, Raineteau & Schwab 2001, Bareyre et al.
2004), as well as denervation supersensitivity of
partially denervated neurones (Stavraky 1961). These
are aspects investigated in animal models, but not in
spastic patients, and they will not be covered in this
short review. Here we will focus on aspects where the
work on animal models can be more directly related to
the research on spastic patients.

Changes in motoneuronal properties following

spinal lesions, with special reference to
plateau potentials
The classical view of the mammalian spinal motoneurone held that the cell membrane was essentially passive
in areas of synaptic contact, allowing a linear summation of synaptic inputs and passive transmission to the
spike-initiating region. During the last 20 years research
has shown that several active membrane properties
further shape the motoneuronal output (Rekling et al.
2000, Powers & Binder 2001, Heckman et al. 2003,
Hultborn et al. 2004, Heckmann et al. 2005). In the
present context voltage-dependent, persistent inward
Ca2+ and Na+-currents are of particular relevance, as
they amplify and prolong the response of motoneurones
to synaptic excitation. These inward currents can
produce prolonged depolarizations (plateau potentials)

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Spasticity

when opposing outward currents are reduced or the

Ca2+ channels are facilitated by, e.g. serotonergic and
noradrenergic innervation of the motoneurones. When
a graded depolarizing current is injected through an
intracellular electrode into a motoneurone of a decerebrate cat, a critical threshold (plateau threshold) is
reached. Above this threshold, further depolarization
will trigger a regenerative activation of a sustained
inward current. In the decerebrate cat (with tonic
descending serotonergic drive) the plateau potentials
are easily evoked. However, following an acute spinal
transection they cannot be evoked unless the persistent
inward current is specifically increased by, for example,
monoaminergic agonists.
As in humans, large spinal lesions in cats lead to an
immediate depression of spinal reflex activity and a
subsequent development of a spastic syndrome (Bailey
et al. 1980). In a few cases, it was possible to demonstrate that plateau potentials can again be induced in the
chronic spinal state without adding any neurotransmitter precursors or agonists (see Hultborn et al. 2004).
This suggested that plateau properties, returning long
after the spinal injury, can play a role in the pathophysiology of spasticity. More recently, Bennett et al.
(1999, 2001) developed a rat preparation in which a
very low chronic spinal lesion causes pronounced
hyperreflexia of the tail without interfering with normal
hindlimb or bladder function. Because the sacrocaudal
spinal cord is very thin, it was possible to study the tail
motoneurones in an in vitro preparation, and then
compare the intrinsic properties of tail motoneurones
after an acute transection and after chronic lesions
when the rats had developed spasticity and hyperreflexia. Plateau properties were regularly seen in the
chronic test state, but never in the acute control
situation (Bennett et al. 2001). Clearly, these observations have opened new horizons for further investigation of the cellular mechanisms underlying spasticity.
Although these observations were made in motoneurones it is likely that similar plastic changes occur also
at interneuronal level although this has not been shown.
Little is known about a possible contribution of
plateau potentials to the development of spasticity in
human subjects because of the difficulty in demonstrating the existence of such intrinsic membrane properties
in the intact organism. However, Nickolls et al. (2004)
found that muscle stimulation, which provided an
excitatory sensory drive to the spinal motoneurones,
did not induce plateau-like behaviour of motor unit
activity in patients with spinal cord injury as easily as in
healthy subjects, but nevertheless argued that plateau
potentials might contribute to the clinical manifestations of the patients, such as spasticity. From observations of motor unit behaviour during spasms in spinal
cord injured patients, Gorassini et al. (2004) inferred

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J B Nielsen et al.

that motor units required significantly less synaptic

drive in order to be de-recruited at the end of spasms as
compared to the synaptic drive required to recruit them
in the beginning of the spasm. From this they argued
that plateau potentials were activated during the spasm
and appeared to contribute to the occurrence of the
spasms. To what an extent this observation relates to
the development of spasticity with the restricted definition that we are using in this review is unclear.

Increased fusimotor drive?

Increased fusimotor drive leading to increased sensitivity of the muscle spindles to muscle stretch was a
popular theory some 2030 years ago. Evidence to
support such a mechanism came from experiments in
animals with decerebrate rigidity (see Granit 1970). In
human subjects, it was found during the 1960s and
1970s that stretch reflexes, which are influenced by the
sensitivity of the muscle spindles, tended to be more
increased in spastic patients than the H-reflex which is
evoked by electrical stimulation of the peripheral nerve
and is therefore not influenced by the sensitivity of the
muscle spindles (Ashby & Verrier 1976). However,
subsequent studies have demonstrated that H-reflexes
and stretch reflexes differ in many other ways than their
sensitivity to changes in fusimotor drive and a
comparison of the two reflexes therefore cannot be
used to make any conclusions regarding changes in
muscle spindle sensitivity (Burke et al. 1983, 1984,
Morita et al. 1998). Microneurography studies have
also failed to demonstrate any changes in the discharge
of muscle spindle afferents in spastic patients making it
unlikely that any significant changes in fusimotor drive
exists (Hagbarth et al. 1973, Wilson et al. 1999a,b).
The hypothesis that increased fusimotor drive is
involved in the pathophysiology of spasticity has
consequently been abandoned.

Increased transmitter release from muscle

spindle afferents?
Several researchers in the 1960s and 1970s were
inspired by the demonstration of presynaptic inhibition
of primary afferents in the cat spinal cord by John
Eccles and others (see review by Rudomin & Schmidt
1999) and sought to find techniques for studying
presynaptic inhibition in human subjects. One of these
techniques was to vibrate the Achilles tendon and
record the resulting depression of the soleus H-reflex
(Burke & Ashby 1972, Ashby et al. 1974). In the cat
presynaptic inhibition of Ia afferents is evoked by
activation of muscle spindle afferents from flexor
muscles and is distributed widely (Rudomin & Schmidt
1999). It was therefore reasonable to assume that the

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depression of the H-reflex during vibration of the

Achilles tendon was caused by this mechanism. As this
vibratory inhibition was subsequently found to be
decreased in spastic patients and to vary with signs of
reflex hyperexcitability following stroke or spinal cord
injury (Ashby et al. 1974, Ashby & Verrier 1975,
1976), it quickly became generally accepted that
spasticity involved reduced presynaptic inhibition of
the Ia afferents. This was further substantiated by the
finding that diazepam, which among its many effects
increases presynaptic inhibition, reduced spasticity in
parallel with increased vibratory inhibition (Verrier
et al. 1975, Delwaide 1985). However, later studies
have demonstrated that this interpretation is in all
likelihood false. First, the ankle plantarflexors are a
weak source of presynaptic inhibition of Ia afferents and
this mechanism is thus unlikely to produce the very
strong depression of the soleus H-reflex which is seen
during Achilles vibration (Hultborn et al. 1996). Secondly, activation of Ia afferents from the plantarflexors
has been shown to evoke a strong and long-lasting
reduction in the transmitter release from the activated
afferents (Crone & Nielsen 1989, Hultborn et al.
1996). This post-activation depression lasts for more
than 10 s and is restricted to previously activated
afferents, whereas presynaptic inhibition lasts for only
300400 ms and is widely distributed to other Ia
afferents also (Hultborn et al. 1996). It was originally
described already by Eccles & Curtis (1960), who
noticed that the size of the Ia EPSP was frequency
dependent, with a relative facilitation at short intervals,
and with a depression with longer intervals. Most of the
physiological firing frequency range of the Ia afferents
falls within the range where the depression is dominant.
The depression of the monosynaptic Ia EPSP results
primarily from mechanisms operating within the presynaptic terminals (Lev-Tov & Pinco 1992, Pinco &
Lev-Tov 1993, Li & Burke 2001) and is likely to involve
two independent pools of readily releasable transmitter
(Li & Burke 2001). Importantly, the post-activation
depression is also reduced in spastic patients (Nielsen
et al. 1993, 1995a) and the temporal changes in the
depression in the months following spinal cord injury
mimics that of the changes of the vibratory inhibition
(Schindler-Ivens & Shields 2000). Reduced post-activation depression has also been demonstrated in the upper
limb of spastic patients and seems generally to be well
correlated to hyperreflexia and spasticity (Aymard et al.
2000).
Experiments in rats following spinal lesions also
indicate that the low frequency depression is much
reduced (Thompson et al. 1992; note that these authors
interpreted this as a reduction of GABA-ergic presynaptic inhibition). It is not known how a spinal lesion
could affect Ia terminals, but an impressive array of

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Acta Physiol 2007, 189, 171180

mechanisms have been identified that contribute to this

short-term synaptic plasticity (both the initial facilitation and the following depression; recently reviewed by
Zucker & Regehr 2002).
Did this mean that presynaptic inhibition was not
reduced in spastic patients after all? The answer to this
question required development of a more optimal
technique for evaluation of presynaptic inhibition than
the vibratory inhibition. Such a technique was introduced by Hultborn et al. (1987). It rests on the
measurement of the size of heteronymous monosynaptic
facilitation of the soleus H-reflex evoked by stimulation
of the femoral nerve. Any change in presynaptic
inhibition of Ia afferents must be assumed to cause a
change in the Ia monosynaptic EPSPs and thus cause a
change in the size of the facilitation. Using this
technique Nielsen et al. (1995b) demonstrated that
presynaptic inhibition was reduced in spastic patients
with multiple sclerosis. A similar finding was made for
patients with spinal cord injury, but not for hemiplegic
stroke patients (Faist et al. 1994). Presynaptic inhibition
thus seems to be reduced in some spastic patients, but
not in all, and the role of presynaptic inhibition in
spasticity needs to be assessed more carefully in future
studies.

Changes in inhibition of motoneurones?

Several different inhibitory pathways contribute to the
control of the activity of the spinal motoneurones in
relation to voluntary movement. Here three of these
pathways, which have been suggested to play a role in
the pathophysiology of spasticity will be mentioned.

Disynaptic reciprocal Ia inhibition

Among the various segmental reflex pathways which
exert inhibition of spinal motoneurones most interest
has been devoted to the disynaptic reciprocal Ia
inhibitory pathway. This pathway is involved in ensuring that antagonist muscles remain relaxed when the
agonist muscles are activated during voluntary movements (Crone & Nielsen 1994). Evidence that the
interneurones interposed in the pathway from ankle
dorsiflexors to plantarflexors are tonically active in
healthy subjects at rest have been provided (Nielsen
et al. 1995a) and the pathway thus contributes to
maintaining the excitability of soleus motoneurones low
in resting subjects. Reduced reciprocal inhibition may
therefore contribute to the development of hyperreflexia
and spasticity. Reduced reciprocal inhibition of ankle
plantarflexor motoneurones has also been found in
spastic patients with multiple sclerosis (Crone et al.
1994), stroke (Crone et al. 2006), spinal cord injury
(Crone et al. 2006) and hereditary spastic paraparesis

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Spasticity

(Crone et al. 2004). Evidence of reduced reciprocal

inhibition between wrist muscles in stroke patients has
also been provided (Nakashima et al. 1989), but as
inhibition at the wrist level is likely to be mediated by Ib
inhibitory interneurones, it is unclear how this finding
should be interpreted. Reciprocal inhibition from ankle
plantarflexors to dorsiflexors has in contrast been found
to be increased in spastic patients (Yanagisawa et al.
1976, Mailis & Ashby 1990). As dorsiflexor muscles
seldom show any spasticity this does not invalidate the
general impression from the available data that reduced
reciprocal inhibition seems to be closely related to the
clinical manifestation of spasticity in the involved
muscles. The finding that no correlation between the
degree of spasticity (assessed by the Ashworth scale) and
the degree of reduced reciprocal inhibition has been
shown (Crone et al. 1994) is not surprising given the
already mentioned problems in grading spasticity clinically. Reduced reciprocal inhibition is thus a strong
candidate for playing a major role in the pathophysiology of spasticity.

Recurrent inhibition
Recurrent inhibition is mediated by Renshaw cells,
which are located in the ventral horn of the spinal cord,
where they receive excitatory collaterals from the motor
axons and project back to the motoneurones as well as
Ia inhibitory interneurones (Baldissera et al. 1981).
Recurrent inhibition is not easy to study in human
subjects, but Pierrot-Deseilligny & Bussel (1975) have
developed a complex H-reflex technique by which this
is possible. The basis of the technique is to use a
previous reflex discharge to activate the Renshaw cells
and study the effect of this activation on a subsequently
evoked test reflex. With this technique it has been
demonstrated that recurrent inhibition at rest appears
to be normal in most patients with spasticity (Katz &
Pierrot-Deseilligny 1982, 1999), but an impaired
modulation of the inhibition has been observed in
spastic patients during voluntary movement (Katz &
Pierrot-Deseilligny 1982). In some patients with both
supraspinal as well as traumatic spinal lesions increased
recurrent inhibition may be seen (Katz & PierrotDeseilligny 1982, Shefner et al. 1992), which obviously
plays no role in the development of spasticity. Only in
patients with progressive paraparesis or ALS is a
reduction found at rest and it is doubtful that this
reduction contributes to the spasticity observed in these
patients (Mazzocchio & Rossi 1989, Raynor & Shefner
1994). Changes in recurrent inhibition thus probably
plays no major role in the pathophysiology of spasticity,
but further studies are needed in order to elucidate if
this mechanism plays a role in the functional disability
of these patients.

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Autogenetic Ib inhibition
Autogenetic Ib inhibition was described originally in the
cat spinal cord in the 1950s (Laporte & Lloyd 1952).
The inhibition is caused by activation of Ib afferents
coming from Golgi tendon organs and is mediated by
segmental inhibitory interneurones projecting to the
motoneurones of the same muscle. Ib inhibition may
also be demonstrated in human subjects by stimulating
the branch from the tibial nerve which innervates the
medial gastrocnemius muscle and measuring the subsequent depression of the soleus H-reflex (PierrotDeseilligny et al. 1979). Whereas this inhibition is
easily demonstrated in healthy subjects, Delwaide &
Olivier (1988) failed to produce any inhibition on the
paretic side in six of six hemiplegic patients, but instead
observed a facilitatory effect in many subjects. This may
relate to the pronounced facilitatory effect on the soleus
H-reflex following stimulation of the peroneal nerve,
which was observed by Crone et al. (2006) in their
longitudinal study of patients with hemiplegia. One
possible explanation of the occurrence of this facilitation, which paralleled the development of hyperreflexia,
is increased excitability of excitatory Ib afferent pathways, similar to those described in the cat spinal cord
(Gossard et al. 1994, McCrea et al. 1995). Furthermore
it has been argued that reciprocal inhibition at wrist
level is mediated by Ib inhibitory pathways (Wargon
et al. 2001). If so, the observation that reciprocal
inhibition at the wrist level is reduced in hemiplegic
patients (Nakashima et al. 1989) may provide further
evidence that alteration of Ib inhibition/excitation plays
a role in the pathophysiology of spasticity. It thus seems
likely that changes in the balance between inhibitory
and excitatory Ib pathways play an important role in
the development of spasticity and further studies in this
area are certainly needed.

How do we improve the understanding of the

pathophysiology of spasticity?
In studies on the pathophysiology of spasticity it is often
investigated whether the severity of spasticity and the
magnitude of change in a given parameter are positively
correlated with each other. If such a correlation is not
found, which has been the case in the majority of
studies, it is sometimes argued that the measured
mechanism probably has no causal role in spasticity,
but may be an epiphenomenon. We would like to argue
against this interpretation. First there is a general
problem that correlation in itself can never be used as
a proof of causality. However, it is even more important
that both the evaluation of the severity of spasticity and
the measurement of possible pathophysiological mechanisms are far from optimal with the techniques

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currently available. As already mentioned a detailed

quantification of spasticity is difficult to obtain clinically and the available Ashworth scale appears not to
provide a very accurate and reproducible measure of the
severity of spasticity (Haas et al. 1996, Blackburn et al.
2002, Platz et al. 2005). In our opinion, a correlation
between change in activity in any of the mechanisms
that have been implicated in the pathophysiology of
spasticity and the severity of spasticity should not be
ruled out until more optimal techniques for evaluation
of spasticity have been developed. Biomechanical dynamometers, which permit standardized muscle stretches
at sufficiently high velocities to elicit stretch reflex
activity, seem promising as a basis for such a technique
(Knutsson & Martensson 1976, Burridge et al. 2005).
It may, however, still be a problem that the techniques for measuring alterations of the various potentially pathophysiological mechanisms are not sensitive
and/or stable enough. There is considerable variability
in all the measures even within a healthy population and
it seems doubtful that we obtain a true measure of the
various mechanisms with the currently available techniques. One example is that disynaptic reciprocal
inhibition is absent in many healthy subjects, although
they of course are not spastic (Crone & Nielsen 1994)
and it thus seems likely that we are not obtaining a true
and relevant measure of reciprocal inhibition. Again
development of new techniques and new approaches to
the problem appear necessary.
This leaves us with the problem that different
mechanisms (reciprocal inhibition, presynaptic inhibition, post-activation depression) have been shown to be
altered in spastic patients, but based on the available
data and the currently available techniques we cannot
determine their possible causal role. One way of
determining a causal relationship is to perform longitudinal studies of the development of spasticity and
changes in the various mechanisms following a CNS
lesion. This approach would over-come the inherent
variability of the measured parameters between subjects, but it is very time consuming and difficult to
recruit patients to the study. For these reasons there are
only very few published longitudinal studies, which
include only a small numbers of subjects (Okuma & Lee
1996, Crone et al. 2006). An international collaboration between laboratories with the necessary expertise,
know-how and technology is required in order to
perform this type of studies in a sufficiently large
population of patients.
Even with data from longitudinal studies available we
may still be faced with the problem that spasticity may
not be caused by a single mechanism, but rather by an
intricate chain of alterations in different inter-dependent
networks. Postsynaptic inhibition for instance is pivotal
in switching off plateau potentials in motoneurones

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Acta Physiol 2007, 189, 171180

under normal physiological conditions (Bennett et al.

1998, Hultborn et al. 2003). Reduced reciprocal inhibition could thus probably also have a consequence for the
behaviour of the channels responsible for persistent
inward currents in the motoneurones. Alterations in
persistent inward currents may likewise have a consequence for the response of the motoneurones to reciprocal inhibition. Similarly, changes in the properties of
Ca++channels following activation of a synapse which
leads to post-activation depression must be assumed also
to influence presynaptic inhibition of the terminal
(Enriquez-Denton et al. 2002). Changes in the level of
post-activation depression may thus also influence the
level of presynaptic inhibition and vice versa. In order to
understand the pathophysiology of spasticity we may
thus have to incorporate a better understanding of the
spinal networks which regulate the activity of the spinal
motoneurones. Although much has been achieved
towards this end over the past 30 years we still have
very far to go. The difficulty of solving this problem does
not become less by the fact that individual patients have
lesions affecting different pathways to a different extent
and that the subsequent adaptations in the spinal
networks, as a reaction to the primary lesion or therapeutic intervention, may vary considerably. Understanding these adaptations is a tremendous task for the future,
but with considerable importance for the future treatment of patients following brain and spinal cord injury.

What is the functional significance of

spasticity?
An essential question that has been addressed in several
studies in various ways is whether spasticity has any
significance for the voluntary movements performed by
the patients. There is certainly no need to treat
spasticity, if it has no functional significance and is
only a minor problem for the patient. It has been
pointed out that stretch reflexes appear not to be
pathologically enhanced during voluntary activation of
a muscle (Dietz et al. 1991, Toft et al. 1993). This is not
surprising given the normal regulation of the stretch
reflex during voluntary movement in healthy subjects.
During voluntary movement reciprocal inhibition of the
activated motoneurones is reduced (Crone et al. 1985,
Iles 1986), as is presynaptic inhibition of the Ia afferents
(Hultborn et al. 1987) and post-activation depression
(Hultborn & Nielsen 1998). Such changes (as well as
increased motoneuronal excitability) are responsible for
the increase of the stretch reflex during voluntary
activation of the involved muscle. In spastic patients
these mechanisms are reduced already at rest and are
not modulated during voluntary movement (Morita
et al. 2001). The increase in the stretch reflex seen
during voluntary activation, is therefore less pro-

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nounced in spastic patients than in healthy subjects

and there is thus relatively little difference between the
size of the stretch reflexes measured during voluntary
movement in these patients and healthy subjects. Based
on this observation it has been argued that spasticity
may have little functional consequence during movement and that treatment therefore should be restricted
(Dietz et al. 1991, Toft et al. 1993). However, it should
be pointed out that the functional significance of
spasticity does not solely relate to the active muscle,
but also to the antagonist muscles which are supposed
to remain relaxed during many movements. Hyperactive stretch reflexes may be elicited easily in an
antagonistic spastic muscle and thus impede the initiation or execution of agonist movement (el-Abd et al.
1993). It has also been pointed out that many subjects
in fact may use their spasticity to stand and even to walk
(Dietz 2001). The basis for this is that sensory feedback
is normally integrated with supraspinal signals in
interneurones and motoneurones and that spinal networks contribute to the motor activity during these
tasks. Reduction of the sensory feedback by the current
available antispastic therapy (i.e. diazepam, baclofen,
tizanidine) may thus not only reduce spasticity, but will
inevitably also influence the ability of the patients to
perform voluntary movements. From this point of view
it is evident that antispastic therapy should be given
with care in patients with only mild to moderate
spasticity and reasonably preserved functionality.

Conclusion and future directions of research

As already mentioned there is a significant need for
development of new techniques for assessment of
spasticity in order to make a quantitative comparison
of the severity of spasticity and pathophysiological
changes in defined spinal motor mechanisms possible.
With such techniques at hand a logical next step would
be to perform longitudinal studies of changes in
spasticity and the specific motor mechanisms following
brain and spinal cord injury. In all likelihood a full
understanding of the pathophysiology of spasticity will
require measurement of several mechanisms and an
understanding of the interaction of these parameters in
the altered spinal network in patients with different
lesions along the neuroaxis. Gaining a more detailed
understanding of the intricate mechanisms underlying
the development of spasticity will increase the possibilities of developing more optimal and differentiated
methods of neurorehabilitation.
Preparation of this article was supported, in part, by the
Danish Medical Research Council and the Ludvig and Sara
Elsass Foundation. I would also like to thank Lisbeth Causse
for her secretarial assistance.

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J B Nielsen et al.

References
el-Abd, M.A., Ibrahim, I.K. & Dietz, V. 1993. Impaired activation pattern in antagonistic elbow muscles of patients with
spastic hemiparesis: contribution to movement disorder.
Electromyogr Clin Neurophysiol 33, 247255.
Ashby, P. & Verrier, M. 1975. Neurophysiological changes
following spinal cord lesions in man. Can J Neurol Sci 2,
91100.
Ashby, P. & Verrier, M. 1976. Neurophysiologic changes in
hemiplegia. Possible explanation for the initial disparity between muscle tone and tendon reflexes. Neurology 26,
11451151.
Ashby, P., Verrier, M. & Lightfoot, E. 1974. Segmental reflex
pathways in spinal shock and spinal spasticity in man.
J Neurol Neurosurg Psychiatry 37, 13521360.
Aymard, C., Katz, R., Lafitte, C. et al. 2000. Presynaptic
inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and
patients with hemiplegia. Brain 123, 16881702.
Bailey, C.S., Lieberman, J.S. & Kitchell, R.L. 1980. Response
of muscle spindle primary endings to static stretch in acute
and chronic spinal cats. Am J Vet Res 41, 20302036.
Baldissera, F., Hultborn, H. & Illert, M. 1981. Integration in
spinal neuronal systems. In: V.B. Brooks (ed.) Handbook of
Physiology, Motor Control, pp. 509595. Williams & Wilkins Publishing Company, Baltimore.
Bareyre, F.M., Kerschensteiner, M., Raineteau, O., Mettenleiter, T.C., Weinmann, O. & Schwab, M.E. 2004. The injured spinal cord spontaneously forms a new intraspinal
circuit in adult rats. Nat Neurosci 7, 269277.
Bennett, D.J., Hultborn, H., Fedirchuk, B. & Gorassini, M.
1998. Synaptic activation of plateaus in hindlimb motoneurons of decerebrate cats. J Neurophysiol 80, 20232037.
Bennett, D.J., Gorassini, M., Fouad, K., Sanelli, L., Han, Y. &
Cheng, J. 1999. Spasticity in rats with sacral spinal cord
injury. J Neurotrauma 16, 6984.
Bennett, D.J., Li, Y. & Siu, M. 2001. Plateau potentials in
sacrocaudal motoneurons of chronic spinal rats, recorded in
vitro. J Neurophysiol 86, 19551971.
Blackburn, M., van Vliet, P. & Mockett, S.P. 2002. Reliability
of measurements obtained with the modified Ashworth scale
in the lower extremities of people with stroke. Phys Ther 82,
2534.
Bohannon, R.W. 1993. Tilt table standing for reducing spasticity after spinal cord injury. Arch Phys Med Rehabil 74,
11211122.
Burke, D. & Ashby, P. 1972. Are spinal presynaptic inhibitory mechanisms suppressed in spasticity? J Neurol Sci 15,
321326.
Burke, D., Gandevia, S.C. & McKeon, B. 1983. The afferent
volleys responsible for spinal proprioceptive reflexes in man.
J Physiol 339, 535252.
Burke, D., Gandevia, S.C. & McKeon, B. 1984. Monosynaptic
and oligosynaptic contributions to human ankle jerk and
H-reflex. J Neurophysiol 52, 435448.
Burridge, J.H., Wood, D.E., Hermens, H.J. et al. 2005. Theoretical and methodological considerations in the measurement of spasticity. Disabil Rehabil 27, 6980.

178

Acta Physiol 2007, 189, 171180

Crone, C. & Nielsen, J. 1989. Methodological implications of
the post activation depression of the soleus H-reflex in man.
Exp Brain Res 78, 2832.
Crone, C. & Nielsen, J. 1994. Central control of disynaptic
reciprocal inhibition in humans. Acta Physiol Scand 152,
351363.
Crone, C., Hultborn, H. & Jespersen, B. 1985. Reciprocal Ia
inhibition from the peroneal nerve to soleus motoneurones
with special reference to the size of the test reflex. Exp Brain
Res 59, 418422.
Crone, C., Nielsen, J., Petersen, N., Ballegaard, M. & Hultborn, H. 1994. Disynaptic reciprocal inhibition of ankle
extensors in spastic patients. Brain 117, 11611168.
Crone, C., Petersen, N.T., Nielsen, J.E., Hansen, N.L. &
Nielsen, J.B. 2004. Reciprocal inhibition and corticospinal
transmission in the arm and leg in patients with autosomal
dominant pure spastic paraparesis (ADPSP). Brain 127,
26932702.
Crone, C., Johnsen, L.L., Biering-Sorensen, F. & Nielsen, J.B.
2006. Appearance of reciprocal facilitation of ankle extensors from ankle flexors in patients with stroke or spinal
cord injury. Brain 126, 495507.
Delwaide, P.J. 1985. Electrophysiological analysis of the mode
of action of muscle relaxants in spasticity. Ann Neurol 17,
9095.
Delwaide, P.J. & Olivier, E. 1988. Short-latency autogenic
inhibition (IB inhibition) in human spasticity. J Neurol
Neurosurg Psychiatry 51, 15461550.
Dietz, V. 2000. Spastic movement disorder. Spinal Cord 38,
389393.
Dietz, V. 2001. Gait disorder in spasticity and Parkinsons
disease. Adv Neurol 87, 143154.
Dietz, V., Quintern, J. & Berger, W. 1981. Electrophysiological studies of gait in spasticity and rigidity. Evidence that altered mechanical properties of muscle
contribute to hypertonia. Brain 104, 431449.
Dietz, V., Trippel, M. & Berger, W. 1991. Reflex activity and
muscle tone during elbow movements in patients with
spastic paresis. Ann Neurol 30, 767779.
Eccles, J.C. & Curtis, D.R. 1960. Synaptic action during and
after repetitive stimulation. J Physiol 150, 374398.
Enriquez-Denton, M., Morita, H., Christensen, L.O., Petersen,
N., Sinkjaer, T. & Nielsen, J.B. 2002. Interaction between
peripheral afferent activity and presynaptic inhibition of ia
afferents in the cat. J Neurophysiol 88, 16641674.
Faist, M., Mazevet, D., Dietz, V. & Pierrot-Deseilligny, E.
1994. A quantitative assessment of presynaptic inhibition of
Ia afferents in spastics. Differences in hemiplegics and
paraplegics. Brain 117, 14491455.
Gorassini, M.A., Knash, M.E., Harvey, P.J., Bennett, D.J. &
Yang, J.F. 2004. Role of motoneurons in the generation
of muscle spasms after spinal cord injury. Brain 127,
22472258.
Gossard, J.P., Brownstone, R.M., Barajon, I. & Hultborn, H.
1994. Transmission in a locomotor-related group Ib pathway from hindlimb extensor muscles in the cat. Exp Brain
Res 98, 213228.
Gracies, J.M. 2005a. Pathophysiology of spastic paresis. I:
Paresis and soft tissue changes. Muscle Nerve 31, 535551.

2007 The Authors

Journal compilation 2007 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2006.01652.x

Acta Physiol 2007, 189, 171180

Gracies, J.M. 2005b. Pathophysiology of spastic paresis. II:
Emergence of muscle overactivity. Muscle Nerve 31,
552571.
Granit, R. 1970. The Basis of Motor Control. Academic Press,
London and New York.
Haas, B.M., Bergstrom, E., Jamous, A. & Bennie, A. 1996. The
inter rater reliability of the original and of the modified
Ashworth scale for the assessment of spasticity in patients
with spinal cord injury. Spinal Cord 34, 560564.
Hagbarth, K.E., Wallin, G. & Lofstedt, L. 1973. Muscle
spindle responses to stretch in normal and spastic subjects.
Scand J Rehabil Med 5, 156159.
Heckman, C.J., Lee, R.H. & Brownstone, R.M. 2003. Hyperexcitable dendrites in motoneurons and their neuromodulatory control during motor behavior. Trends Neurosci
26, 688695.
Heckmann, C.J., Gorassini, M.A. & Bennett, D.J. 2005. Persistent inward currents in motoneuron dendrites: implications for motor output. Muscle Nerve 31, 135156.
Hultborn, H. & Nielsen, J.B. 1998. Modulation of transmitter release from Ia afferents by their preceding activity
a post-activation depression. In: P. Rudomin, R. Romo &
L. Mendell (eds) Presynaptic Inhibition and neuronal control mechanisms, pp. 178191. Oxford University Press,
Oxford.
Hultborn, H., Meunier, S., Morin, C. & Pierrot-Deseilligny,
E. 1987. Assessing changes in presynaptic inhibition of I a
fibres: a study in man and the cat. J Physiol 389,
729756.
Hultborn, H., Illert, M., Nielsen, J., Paul, A., Ballegaard, M. &
Wiese, H. 1996. On the mechanism of the post-activation
depression of the H-reflex in human subjects. Exp Brain Res
108, 450462.
Hultborn, H., Denton, M.E., Wienecke, J. & Nielsen, J.B.
2003. Variable amplification of synaptic input to cat spinal
motoneurones by dendritic persistent inward current.
J Physiol 552, 945952.
Hultborn, H., Brownstone, R.B., Toth, T.I. & Gossard, J.P.
2004. Key mechanisms for setting the input-output gain
across the motoneuron pool. Prog Brain Res 143, 7795.
Iles, J.F. 1986. Reciprocal inhibition during agonist and antagonist contraction. Exp Brain Res 62, 212214.
Katz, R. & Pierrot-Deseilligny, E. 1982. Recurrent inhibition
of alpha-motoneurons in patients with upper motor neuron
lesions. Brain 105, 103124.
Katz, R. & Pierrot-Deseilligny, E. 1999. Recurrent inhibition
in humans. Prog Neurobiol 57, 325355.
Kita, M. & Goodkin, D.E. 2000. Drugs used to treat spasticity.
Drugs 59, 487495.
Knutsson, E. & Martensson, A. 1976. Action of dantrolene
sodium in spasticity with low dependence on fusimotor
drive. J Neurol Sci 29, 195212.
Lance, J.W. 1980. Symposium synopsis. In: R.G. Feldman,
R.R. Young & W.W. Koella (eds) Spasticity: Disordered
Motor Control. Symposia Specialists, Miami (1980), pp.
485500. Year Book Medical Publishers, Chicago.
Laporte, Y. & Lloyd, D.P. 1952. Nature and significance of the
reflex connections established by large afferent fibers of
muscular origin. Am J Physiol 169, 609621.

J B Nielsen et al.

Spasticity

Lev-Tov, A. & Pinco, M. 1992. In vitro studies of prolonged

synaptic depression in the neonatal rat spinal cord. J Physiol
447, 149169.
Li, Y. & Burke, R.E. 2001. Short-term synaptic depression in
the neonatal mouse spinal cord: effects of calcium and
temperature. J Neurophysiol 85, 20472062.
Mailis, A. & Ashby, P. 1990. Alterations in group Ia projections to motoneurons following spinal lesions in humans.
J Neurophysiol 64, 637647.
Maynard, F.M., Karunas, R.S. & Waring, W.P. III 1990.
Epidemiology of spasticity following traumatic spinal cord
injury. Arch Phys Med Rehabil 71, 566569.
Mazzocchio, R. & Rossi, A. 1989. Recurrent inhibition in
human spinal spasticity. Ital J Neurol Sci 10, 337347.
McCrea, D.A., Shefchyk, S.J., Stephens, M.J. & Pearson, K.G.
1995. Disynaptic group I excitation of synergist ankle extensor motoneurones during fictive locomotion in the cat.
J Physiol 487, 527539.
Morita, H., Petersen, N., Christensen, L.O., Sinkjaer, T. &
Nielsen, J. 1998. Sensitivity of H-reflexes and stretch reflexes
to presynaptic inhibition in humans. J Neurophysiol 80,
610620.
Morita, H., Crone, C., Christenhuis, D., Petersen, N.T. &
Nielsen, J.B. 2001. Modulation of presynaptic inhibition and
disynaptic reciprocal Ia inhibition during voluntary movement in spasticity. Brain 124, 826837.
Nakashima, K., Rothwell, J.C., Day, B.L., Thompson, P.D.,
Shannon, K. & Marsden, C.D. 1989. Reciprocal inhibition
between forearm muscles in patients with writers cramp and
other occupational cramps, symptomatic hemidystonia and
hemiparesis due to stroke. Brain 112, 681697.
Nickolls, P., Collins, D.F., Gorman, R.B., Burke, D. & Gandevia, S.C. 2004. Forces consistent with plateau-like behaviour of spinal neurons evoked in patients with spinal cord
injuries. Brain 127, 660670.
Nielsen, J., Petersen, N., Ballegaard, M., Biering-Sorensen, F.
& Kiehn, O. 1993. H-reflexes are less depressed following
muscle stretch in spastic spinal cord injured patients than in
healthy subjects. Exp Brain Res 97, 173176.
Nielsen, J., Crone, C., Sinkjaer, T., Toft, E. & Hultborn, H.
1995a. Central control of reciprocal inhibition during fictive
dorsiflexion in man. Exp Brain Res 104, 99106.
Nielsen, J., Petersen, N. & Crone, C. 1995b. Changes in
transmission across synapses of Ia afferents in spastic patients. Brain 118, 9951004.
Okuma, Y. & Lee, R.G. 1996. Reciprocal inhibition in hemiplegia: correlation with clinical features and recovery. Can J
Neurol Sci 23, 1523.
Pierrot-Deseilligny, E. & Burke, D. 2005. The Circuitry of the
Human Spinal Cord. Cambridge University Press, Cambridge, UK.
Pierrot-Deseilligny, E. & Bussel, B. 1975. Evidence for recurrent inhibition by motoneurons in human subjects. Brain
Res 88, 105108.
Pierrot-Deseilligny, E., Katz, R. & Morin, C. 1979. Evidence of
Ib inhibition in human subjects. Brain Res 166, 176179.
Pinco, M. & Lev-Tov, A. 1993. Modulation of monosynaptic
excitation in the neonatal rat spinal cord. J Neurophysiol 70,
11511158.

2007 The Authors

Journal compilation 2007 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2006.01652.x

179

Spasticity

J B Nielsen et al.

Platz, T., Eickhof, C., Nuyens, G. & Vuadens, P. 2005. Clinical scales for the assessment of spasticity, associated phenomena, and function: a systematic review of the literature.
Disabil Rehabil 27, 718.
Powers, R.K. & Binder, M.D. 2001. Input-output functions of
mammalian motoneurons. Rev Physiol Biochem Pharmacol
143, 137263.
Raineteau, O. & Schwab, M.E. 2001. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci
2, 263273.
Raisman, G. 1969. Neuronal plasticity in the septal nuclei of
the adult rat. Brain Res 14, 2548.
Raynor, E.M. & Shefner, J.M. 1994. Recurrent inhibition is
decreased in patients with amyotrophic lateral sclerosis.
Neurology 44, 21482150.
Rekling, J.C., Funk, G.D., Bayliss, D.A., Dong, X.W. &
Feldman, J.L. 2000. Synaptic control of motoneuronal excitability. Physiol Rev 80, 767852.
Rizzo, M.A., Hadjimichael, O.C., Preiningerova, J. & Vollmer,
T.L. 2004. Prevalence and treatment of spasticity reported
by multiple sclerosis patients. Mult Scler 10, 589595.
Rudomin, P. & Schmidt, R.F. 1999. Presynaptic inhibition in
the vertebrate spinal cord revisited. Exp Brain Res 129,
137.
Schindler-Ivens, S. & Shields, R.K. 2000. Low frequency depression of H-reflexes in humans with acute and chronic
spinal-cord injury. Exp Brain Res 133, 233241.
Schindler-Ivens, S.M. & Shields, R.K. 2004. Soleus H-reflex
recruitment is not altered in persons with chronic spinal cord
injury. Arch Phys Med Rehabil 85, 840847.
Shefner, J.M., Berman, S.A., Sarkarati, M. & Young, R.R.
1992. Recurrent inhibition is increased in patients with
spinal cord injury. Neurology 42, 21622168.
Sherrington, C.S. 1898. Decerebrate rigidity, and reflex coordination of movements. J Physiol 22, 319332.
Sinkjaer, T., Toft, E., Larsen, K., Andreassen, S. & Hansen,
H.J. 1993. Non-reflex and reflex mediated ankle joint stiffness in multiple sclerosis patients with spasticity. Muscle
Nerve 16, 6976.

180

Acta Physiol 2007, 189, 171180

Skold, C., Levi, R. & Seiger, A. 1999. Spasticity after traumatic
spinal cord injury: nature, severity, and location. Arch Phys
Med Rehabil 80, 15481557.
Sommerfeld, D.K., Eek, E.U., Svensson, A.K., Holmqvist, L.W.
& von Arbin, M.H. 2004. Spasticity after stroke: its occurrence and association with motor impairments and activity
limitations. Stroke 35, 134139.
Stavraky, G.W. 1961. Supersensitivity Following Lesions of the
Nervous System. An Aspect of the Relativity of Nervous
Integration, pp. 1210. University of Toronto Press, Toronto.
Thompson, F.J., Reier, P.J., Lucas, C.C. & Parmer, R. 1992.
Altered patterns of reflex excitability subsequent to contusion injury of the rat spinal cord. J Neurophysiol 68,
14731486.
Toft, E., Sinkjaer, T., Andreassen, S. & Hansen, H.J. 1993.
Stretch responses to ankle rotation in multiple sclerosis patients with spasticity. Electroencephalogr Clin Neurophysiol
89, 311318.
Vedel, J.P. & Paillard, J. 1966. Interpretation of the phenomena of spasticity and rigidity from new data on the central
controls of fusimotor activity in the cat. Rev Neurol (Paris)
115, 129134.
Verrier, M., MacLeod, S. & Ashby, P. 1975. The effect of
diazepam on presynaptic inhibition in patients with complete and incomplete spinal cord lesions. Can J Neurol Sci 2,
179184.
Wargon, I., Lamy, J.C., Baret, M. et al. 2001. The disynaptic
group I inhibition between wrist flexor and extensor muscles
revisited in humans. Exp Brain Res 168, 203217.
Wilson, L.R., Gandevia, S.C., Inglis, J.T., Gracies, J. & Burke,
D. 1999a. Muscle spindle activity in the affected upper limb
after a unilateral stroke. Brain 122, 20792088.
Wilson, L.R., Gracies, J.M., Burke, D. & Gandevia, S.C.
1999b. Evidence for fusimotor drive in stroke patients based
on muscle spindle thixotropy. Neurosci Lett 264, 109112.
Yanagisawa, N., Tanaka, R. & Ito, Z. 1976. Reciprocal Ia
inhibition in spastic hemiplegia of man. Brain 99, 555574.
Zucker, R.S. & Regehr, W.G. 2002. Short-term synaptic
plasticity. Annu Rev Physiol 64, 355405.

2007 The Authors

Journal compilation 2007 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2006.01652.x