Chapter 2: Pathophysiology of spasticity

By Jens Bo Nielsen, Maria Willerslev-Olsen and Jakob Lorentzen.

This chapter will argue

that proper evaluation of spasticity requires biomechanical and electrophysiological techniques

that spasticity is not caused by pyramidal tract lesion

that spasticity is caused by plastic adaptation in neural networks

that spasticity is not caused by a single mechanism but by a multitude of alterations in spinal motoneurones

and interneurons

that clonus, spasms and spastic dystonia are caused by at least partly different pathophysiological mechanisms

than spasticity

1.0 How to measure spasticity - from clinical evaluation to biomechanical techniques

The clinical evaluation of spasticity currently rests on the eyes and hands of the clinician. Muscle

tone is essentially determined by sensing the resistance to passive movement around a joint with the

patient in an as relaxed position as possible. By making movements at different velocities the

clinician may get a feeling of whether the resistance is present at all velocities or only with the

fastest stretch of the muscles. Sometimes a distinct brief resistance – a catch - may be determined

with quick stretches at specific positions of the joint. Backed up by other signs such as large – and

especially non-symmetrical - tendon jerks and the presence of clonus, the clinician may decide that

the resistance is velocity-dependent and may possibly be related to hyperexcitable stretch reflexes;

i.e. that the muscle resistance is caused by spasticity according to Lance´s definition. In many cases

the determination of the presence of spasticity is relatively straightforward and unproblematic.

However, if the patient is not fully relaxed, if the changes in reflex excitability are not very large or

if other mechanisms also contribute to increased muscle resistance the precise diagnosis may be

difficult. The presence of alterations in the elastic properties of the muscle, connective tissue and/or

tendons especially makes it difficult to perform the evaluation sufficiently fast and powerfully and it

therefore becomes a challenge to determine the presence of spasticity. The presence of involuntary

static muscle activity (spastic dystonia) and an associated inability of the patient to fully relax the

muscle also make the evaluation difficult. Clinical evaluation of spasticity has consequently been

shown to have variable reproducibility within and between raters (Bhimani et al 2011, Biering-

Sorensen et al 2006, Haugh et al 2006, Mutlu et al 2008) and to be very little related to objective

biomechanical measures of spasticity (Lorentzen et al 2010, Willerslev-Olsen et al 2013). The

Ashworth scale was introduced in 1964 (Ashworth 1964) as a simple 5 point scale ranging from

normal muscle tone (0) to rigidity (4) in order to quantify spasticity in multiple sclerosis before and

after treatment. The scale does not distinguish stretch reflex mediated muscle resistance from other

causes of muscle resistance (in particular contractures) and an additional grade (1+) was therefore

introduced in 1987 to designate slight resistance with a clear catch (Bohannon & Smith 1987). This

modified Ashworth Scale (MAS) is now the most commonly used clinical scale, although it is

confounded by the same limitations as the original scale except for the additional grade.

Furthermore, the introduction of this additional grade seems not to have improved the reliability of

the scoring (Bhimani et al 2011, Biering-Sorensen et al 2006) and a conspicuous over-

representation of scores 1-2 suggests that what is scored in most patients is ´some resistance but not

too much´ (Biering-Sorensen et al 2006). The scale has consequently shown low validity in studies

in which it has been related to biomechanical measures of stiffness (Biering-Sorensen et al 2006,

Lorentzen et al 2010, Sehgal & McGuire 1998). It is surprising given these drawbacks that the scale

has become the scale of choice in the clinic rather than the older Tardieu scale. The Tardieu scale

was introduced originally in 1954 (Tardieu et al 1954) and has later been modified to the scale that

is in use today (Haugh et al 2006, Held 1969). The essence of the scale is that the examiner has to

move the examined limb at three different velocities (slow, moderate and as fast as possible) in

order to determine range of movement, presence of passive resistance and the presence of spasticity.

The scoring of spasticity is based on the presence of a catch and clonus. Although the Tardieu scale

theoretically should more adequately distinguish passive and active components of muscle

resistance than the Ashworth scale, it has not gained an as wide use in the clinic as the Ashworth

scale. Part of the reason for this is that the technique is more demanding for the examiner and is

therefore less easy to perform in a similar way for two raters.. The scale also lacks sufficient

dimensionality to cover patients with very severe spasticity that prevents elicitation of stretch

reflexes and clonus. The focus on the presence of clonus is also problematic given the uncertainty

regarding the mechanisms of clonus and its relation to spasticity (see below).

Biomechanical evaluation of spasticity was introduced in 1976 (Knutsson & Martensson 1976)

and various devices and techniques have been developed and tested since then (Mirbagheri et al

2005, Mirbagheri et al 2009, Mirbagheri et al 2004, Sinkjaer 1997, Sinkjaer et al 1992, Sinkjaer &

Magnussen 1994, Sinkjaer et al 1995, Sinkjaer et al 1988, Toft et al 1989b, Toft et al 1989c, Wood

et al 2005). The main advantage of these techniques is that they provide an objective and

quantitative assessment of muscle resistance. With the addition of EMG measurements from the

stretched muscles they may provide an objective and precise way of distinguishing reflex-mediated

from passive muscle resistance (Lorentzen et al 2010, Sinkjaer et al 1993, Toft et al 1989b,

Willerslev-Olsen et al 2013). From this point of view biomechanical evaluation combined with

electrophysiological measures might be considered a ´gold standard´ for spasticity evaluation with

which other measures may be compared. However, the expertise and technology involved is too

demanding for routine clinical use. Hand-held dynamometers and other simplified biomechanical

devices may provide sufficiently reliable and consistent measures, but none of the commercially-

available devices have so far shown sufficiently promising results to be used more widely in the

clinic for spasticity evaluation (Barden et al 2012, Benard et al 2010, Calota et al 2008, Kim et al

2011, Lee et al 2004, Lorentzen et al 2012, Waldman et al 2013). Only few of the existing devices

provide a distinction between reflex-mediated and passive muscle stiffness and there is therefore a

clear need of developing more optimal easy-to-use devices that can help the clinician in the routine

clinical diagnosis.

2.0 The nature of the muscle response to stretch

In order to understand the pathophysiology of spasticity it is useful initially to consider the

responses of a muscle to stretch (Fig. 2). At velocities below the threshold of the stretch reflex the

resistance against the movement is caused solely by the passive elastic properties of the muscle,

connective tissue, tendon and joint (Lorentzen et al 2010, Mirbagheri et al 2005, Mirbagheri et al

2004, Toft et al 1989a, Toft et al 1989b). This resistance is usually called passive stiffness (Toft et

al 1989a, Toft et al 1989b) and appears to be relatively insensitive to the velocity of the stretch

(Lorentzen et al 2010). However, it varies with the position of the joint and thus the degree of

stretch of the muscle (Mirbagheri et al 2005, Mirbagheri et al 2009, Mirbagheri et al 2004). If the

subject is not fully relaxed neural activation of the muscle will result in formation of cross-bridges

between myosin and actin filaments that will impede the stretch and add very significantly to the

stiffness (Fig. 2). This stiffness is usually called intrinsic stiffness to distinguish it from the passive

and reflex-mediated stiffness (Sinkjaer et al 1993), but it should be emphasized that it is caused by

an (extrinsic) neural signal and may be very difficult to distinguish in practice from reflex-mediated

stiffness given the integration between descending motor commands and reflexes (Nielsen 2004).

When stretches above a certain threshold (which is determined individually by the sensitivity of

muscle spindles, transmitter release from central synapses and the excitability of motoneurones) are

applied, a stretch reflex response will be evoked and add to the resistance against the movement

(Fig. 2). This reflex mediated stiffness is at least in theory equivalent to the catch that is assessed as

part of the clinical evaluation of spasticity. The mechanical response evoked by the stretch conceals

that there are at least two separate reflex responses in most muscles (Christensen et al 2000). These

responses may be demonstrated by EMG measurement from the muscle (Toft et al 1989b, Toft et al

1991). The initial (short-latency or M1) response is mediated by the spinal monosynaptic Ia

pathway and is equivalent to the reflex response elicited by a tendon tap (Morita et al 1998). The

response is generally strongly exaggerated in spastic patients (Ibrahim et al 1993, Sinkjaer &

Magnussen 1994, Sinkjaer et al 1993). In lower limb muscles the initial response is followed by a

second (medium-latency or M2) and sometimes a third (long-latency or M3) response (Christensen

et al 2000). The M2 response has been shown in all likelihood to be mediated by gr. II afferents

from the muscle spindles (Christensen et al 2000, Grey et al 2001). Similar to the M1 response it is

generally exaggerated in spastic patients (Sinkjaer & Magnussen 1994, Sinkjaer et al 1993,

Willerslev-Olsen et al 2014). The third response on the other hand is generally reduced or abolished

in spastic patients consistent with the idea that it is mediated by a transcortical pathway which is

involved in the lesion(Christensen et al 2000). Similar mechanisms probably also contribute to the

stretch response observed at longer latency than the M1 response (generally called long-latency or

M2 response) in upper limb muscles, but due to the short difference in conduction time for spinal

and transcortical responses the responses appear to be difficult to separate (Christensen et al 2000).

These later responses in upper limb muscles may therefore be reduced, unchanged or exaggerated in

the individual patient.

Since the mechanical resistance sensed either by a clinical examiner or a biomechanical device is

the sum of these different reflex responses, transmission in all the involved pathways should be

taken into account when considering the cause of an exaggeration of the muscle resistance.

3.0 Is spasticity caused by lesion of the pyramidal tract?

Spasticity is observed following both spinal and cortical lesions and is in the clinic commonly

associated to lesion of the corticospinal tract, but studies in animal suggest that this is wrong. Tower

(1940) was the first to observe in monkeys that selective lesion of the pyramidal tract produced

flaccid paresis without any signs of spasticity (Tower 1940). This was investigated in more detail in

the seminal studies by Lawrence & Kuypers (Lawrence & Kuypers 1968a, Lawrence & Kuypers

1968b). They reported that complete unilateral or bilateral pyramidal tract lesion in monkeys

produced severe reduction in muscle tone, whereas lesion of brainstem tracts left the monkeys with

increased reflex excitability and high muscle tone (Lawrence & Kuypers 1968a, Lawrence &

Kuypers 1968b). These observations have been confirmed in several subsequent studies in both

monkeys and other animals (Aoki et al 1976, Metz et al 1998). The evidence that the pyramidal

tract is not involved in the development of spasticity in animals is thus convincing.

The most convincing evidence from human subjects is that of Nathan (1994) who reported the

effect of surgical incision in the spinal cord to relieve chronic pain. His findings are well in line

with the studies in monkey. In subjects in whom lateral incisions severing the corticospinal tract

were made, no spasticity was observed, whereas this was the case for more ventral lesions which

severed descending tracts from the brain stem (Nathan 1994). Other studies on the topic have only

involved observations from single subjects. Sherman et al. (2000) somewhat confusingly reported

increased biceps brachii tendon jerk without clinical signs of spasticity in a single patient with

selective unilateral lesion of the pyramidal tract (Sherman et al 2000). In all likelihood this finding

says more about the clinical examination than anything else. The same may be the case for the study

of Paulson et al. (1986), who reported development of spasticity in a single patient with selective

lesion of the medullary pyramids (Paulson et al 1986). On balance the human studies thus point in

the same direction as the animal studies in suggesting that spasticity is caused by lesion of brain

stem pathways or their cortical control rather than lesion of the corticospinal tract. The low

occurrence of spasticity in stroke survivors with severe paresis or paralysis as sign of corticospinal

lesion is well in line with this (Wissel et al 2013).

These findings suggest that lesion of the corticospinal tract alone is insufficient to start the range of

spinal adaptations that result in spasticity. Apparently, additional affection of the vast innervation of

spinal motoneurones and interneurons by reticulospinal pathways and other descending tracts from

the brain stem is required in order to set the adaptive changes in motion, but we have little

understanding why this is.

4.0 Spasticity does not appear immediately after lesion but is caused by adaptive changes in

spinal networks

The excitability of spinal circuitries is depressed during a variable period in both animals and

humans following a spinal lesion due to what is called ´spinal shock´ (Ditunno et al 2004). The

mechanisms responsible for spinal shock are not fully clarified but seem to involve loss of

descending excitation, increased spinal inhibition, reduction of persistent inward currents in the

spinal motoneurones due to loss of serotonergic innervation, reduced neuronal metabolism and

retraction of dendrites and synapses (Ditunno et al 2004). The time course of development of

spasticity following spinal lesion is likely related both to the gradual relief of spinal shock and the

gradual development of a hyperexcitable state leading to spasticity. In the clinic spasticity usually

becomes manifest in spinal cord injured subjects 1-12 month after the lesion whereas reflex

hyperexcitability is observed in animals within 1-2 month (Aoki et al 1976, Ditunno et al 2004).

Spinal shock is not observed following stroke or supraspinal lesions in animals and it is therefore

possible to follow the development of spasticity without the interference from spinal shock in such

cases. In the clinic spasticity develops in some patients already within the first month after stroke,

but in the majority of patients spasticity is not manifest until more than 3 month after stroke (Wissel

et al 2013). The importance of this is that spasticity is not caused by simple release of the spinal

circuitries from a tonic supraspinal inhibition, which was believed some years ago (Burke 1988).

This idea ties into another old belief which has also been proven wrong: That spinal reflexes are

primitive reflexes which in humans are only seen in the first year of life, but are then suppressed as

the corticospinal tract develops and achieves functional connections with the spinal circuitries. With

this mindset it follows that in adults reflexes and exaggerated reflexes in particular are seen as

abnormal and require treatment because they are thought of as being caused by the release of a

normal inhibitory descending influence. However, what really happens during development is that

the corticospinal tract and spinal circuitries become functionally integrated and learn to collaborate

to mediate voluntary movements (Clowry 2007, Nielsen 2004).

Moreover, the gradual development of spasticity puts emphasis on plastic changes in the spinal

circuitries below the lesion as adaptations to the loss of descending supraspinal drive (Burke 1988).

5.0 Pathophysiology of exaggerated stretch reflex activity (or increased muscle tone)

It may seem self-evident to point out that the task of a spinal motoneurone is to activate the muscle

fibres that it innervates and thereby contribute to movement. However, this simple notion provides

an intuitive way of understanding the adaptive changes that occur in the spinal networks in response

to lesion of descending motor fibres: When descending excitation of the motoneurone is lost,

regulatory mechanisms that aim to help the motoneurone to restore an efficient output to the muscle

set in. This point has been illustrated in a simplified version in Fig. 2. In the normal situation

sensory input and descending drive both contribute to the activation of the motoneurones.

Following lesion of central motor fibres, the descending drive is reduced and the sensory input is

insufficient to maintain a normal output from the spinal cord to the muscles. As spasticity develops

compensatory plastic mechanisms set in. These involved increased sensory drive, increased

descending drive in surviving motor fibres and alteration of intrinsic mechanisms in the spinal

motoneurones. These changes help to increase the output from the spinal cord to the muscles, albeit

not necessarily to the level before lesion.

In the motoneurone these plastic changes involves up-regulation of membrane channels and

receptors that increase the excitability of the membrane and reduction of the threshold for action

potential generation (Fig. 3a). It also involves sprouting of nearby fibres (descending fibres as well

as sensory afferents and fibres from local interneurons), growth of motoneuronal dendrites and

establishment of new synaptic sites (Fig. 3b). Mechanisms that regulate transmitter release from

sensory afferents (and in all likelihood also central motor fibres), such as presynaptic inhibition,

ensure that the efficiency of the synapses that contribute to the motoneuronal drive is increased

(Fig. 3c). A general up-regulation of excitation and down-regulation of inhibitory influences from

various interneuronal populations on the motoneurones is seen (Fig. 3d). All these mechanisms

work in concert with the common aim to maintain a functional output from the spinal cord to the

muscles. Spasticity thus reflects an adaptive change in the spinal cord aimed at maintaining a

functional output when a significant part of the normal descending excitatory drive to the

motoneurones is lost. It is difficult to see this as a maladaptation. It is essentially a very sensible

adaptation.

5.1 Pathophysiological role of motoneronal changes

The neuronal membrane is packed with receptors and channels that contribute to the regulation of

the excitability of the cell. The number, density, type and state of these receptors and channels is

regulated by a large number of intracellular messenger systems. These mediate changes in the

receptors and channels themselves and regulate gene transcription and production of the proteins

necessary for new receptors. The excitability of the cell is thus in essence a dynamic property which

is continuously regulated according to the immediate and more distant experience of the cell.

Dramatic changes such as loss of a major part of the excitatory drive to the cell therefore have

significant immediate and long-term impact on the trafficking of molecules and molecular signaling

within and between the individual cells.

Voltage dependent Ca2+ and Na+ persistent inward currents (PICs) play a central role in this

regulation of motoneronal (as well as interneuronal) excitability (Heckman et al 2003, Hultborn et

al 2004, Powers & Binder 2001, Rekling et al 2000). Inward currents produce prolonged

depolarizations (plateau potentials) when opposing outward currents are reduced or the Ca2+

channels are facilitated by, e.g. serotonergic and noradrenergic innervation of the motoneurones

(Heckman et al 2003, Hultborn et al 2004, Powers & Binder 2001, Rekling et al 2000). Under

normal circumstances the function of PICs is however much more dynamic and subtle. Although

not fully clarified one important functional role of PICs seems to be to enhance the synaptic effect

of excitatory inputs to the motoneurones. EPSPs in motoneurones produced by pyramidal tract

activation are thus boosted by PICs to an extent that it has been argued that physiological

descending drive to the motoneurones would be insufficient to drive the motoneurones at the firing

frequencies observed during movement without them (Binder 2002, Hultborn et al 2004, Hultborn

et al 2003). It has also been argued that EPSPs generated at dendritic sites distant from the cell

soma would be unable to reach the spike initiation zone without the existence of PICs in the

membrane to increase the gain of the EPSPs (Binder 2002). As already mentioned PICs cannot be

evoked during the period of spinal shock following spinal cord lesions unless specifically increased

by monoaminergic agonists (Ditunno et al 2004, Hultborn et al 2004). However, plateau potentials

may be induced again at least in some cases in the chronic spinal state without adding any

neurotransmitter precursors or agonists (see Hultborn et al. 2004). 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. PICs were

regularly seen in the chronic test state, but never in the acute control situation (Bennett et al 1999,

Bennett et al 2001). This appears to be linked to upregulation of monoaminergic receptors, in

particular 5-HT(2B) and 5-HT(2C) receptors in the motoneuronal membrane (Murray et al 2010,

Murray et al 2011a, Rank et al 2011, Ren et al 2013, Wienecke et al 2010). 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 PICs 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 (Nickolls et al 2004). It is not immediately clear how this should be the

case.

From observations of motor unit behaviour during spasms in spinal cord injured patients,

Gorassini et al. (2004) inferred 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 persistent inward currents were activated

during the spasm and appeared to contribute to the occurrence of the spasms (Gorassini et al 2004).

In line with animal experiments this appears to depend on upregulation of serotonergic receptors

(D'Amico et al 2013a, D'Amico et al 2013b). These findings from both animal and humans are

certainly of relevance for the pathophysiology of spasms, but given the mechanisms involved,

upregulation of PICs is unlikely to be a universal explanation of spasticity. Loss of serotonergic

innervation and subsequent upregulation of 5-HT receptors likely only occurs to any significant

extent following spinal cord injury, but not following supraspinal lesions. This likely also explains

why spasms are rare in spastic patients following stroke. This in turn undermines the idea that PICs

should be causally involved in the pathophysiology of spasticity.

5.2 Sprouting, new synapses

Following lesions in the central nervous system several morphological changes are usually seen

including outgrowth of dendrites, ‘collateral sprouting’ from remaining/surviving neurons as a

result of partial denervation and establishment of new synapses ((Bareyre et al 2004, Fouad et al

2001, Raineteau & Schwab 2001, Raisman 1969, Weidner et al 2001). Such adapations are well

documented for terminations of descending fibres on the spinal motoneurones following especially

spinal cord injury (Fouad et al 2001, Raineteau & Schwab 2001).They probably contribute to

´overactivity´ phenomena such as spastic dystonia (see later) and lack of specificity of voluntary

motor control following central lesions. They may thus contribute to the inability of patients in

performing precise movement, the tendency to perform involuntary associated movements and the

development of ´spastic´ postures involving involuntary excessive activation of postural muscles

during movement. However, to what an extent these mechanisms also contribute to stretch reflex

exaggeration is unclear. Muscle afferents likely also sprout and innervate vacant synaptic sites from

descending fibres on spinal motoneurones, but there is little direct evidence of this.

5.3 Regulation at presynaptic sites: Increasing the input from surviving fibres

Although the majority of interest has naturally been devoted to alterations in transmitter release

from sensory afferents in relation to the development of spasticity it should be emphasized that it is

likely that synapses of surviving descending fibres and spinal interneurons are also upregulated in

order to facilitate activation of the motoneurones following the lesion as already mentioned above.

However, such changes have to the best of our knowledge not been thoroughly investigated.

Presynaptic inhibition elicited by sensory afferents (see below) has been shown not to be distributed

to descending motor fibres (Nielsen & Petersen 1994, Rudomin et al 1991). Post-activation

depression (see below) also does not seem to affect transmission from descending pathways

(Hultborn et al 1996). However, it is unlikely that synapses of the descending fibres as the only

synapses in the nervous system would not be subjected to some kind of regulation and thereby

amenable to plastic adaptive changes following lesion.

5.3.1. Presynaptic inhibition

Presynaptic inhibition of sensory afferent terminals was described originally in the cat spinal cord

by Frank & Fuortes in 1957 (Frank 1957) and subsequently investigated in more detail by John

Eccles and his co-workers ((Eccles et al 1962a, Eccles et al 1963, Eccles et al 1962b) and see

reviews by (Rudomin & Schmidt 1999, Willis 2006). The interneurons responsible for presynaptic

inhibition receive considerable input from a range of sensory afferents of different modality

throughout the leg as well as descending control from the corticospinal tract and brainstem nuclei

(Burke 2012, Jankowska 1992, Rudomin & Schmidt 1999, Willis 2006). The interneurons in turn

project widely in the spinal cord to suppress transmitter release from sensory afferent terminals on

motoneurones by releasing GABA which binds to receptors located on the presynaptic terminals of

the sensory afferents (Burke 2012, Rudomin & Schmidt 1999). Activation of GABA-A receptors

result in opening of Cl channels which causes an outward Cl current and thereby a depolarization of

the terminals (primary afferent depolarization; PAD – although other mechanisms may also

contribute to this phenomenon (Hochman et al 2010). PAD inactivates some of the voltage-sensitive

sodium channels and thereby reduces the amplitude of any subsequent action potentials. As a

consequence fewer voltage sensitive Ca channels are opened and transmitter release from the

terminals is reduced (Burke 2012, Rudomin & Schmidt 1999).

In both human and animal experiments presynaptic inhibition has been found to be strongly

regulated by supraspinal control centres (Burke 2012, Meunier 1999, Rudomin et al 2004). During

voluntary movement including locomotion presynaptic inhibition is turned into a highly focused

modulatory mechanism which shapes the sensory inflow to spinal motoneurones and interneurons

according to the needs of the given task and the central command (Dietz et al 1990, Faist et al

1996). Activation of some muscles may thereby be facilitated by removing presynaptic inhibition of

the sensory afferents, while ensuring that unwanted activation of other muscles (such as

antagonists) does not take place (Crone & Nielsen 1989b, Hultborn et al 1987, Nielsen &

Kagamihara 1993). This regulation of presynaptic inhibition in relation to voluntary movement is of

significance for the functional relevance of spasticity and will be further described in chapter 4.

Following spinal cord lesion in cats presynaptic inhibition of sensory afferents is reduced and this

reduction seems to follow the development of spasticity (Naftchi et al 1979).

In humans presynaptic inhibition of Ia afferents on spinal motoneurones supplying leg muscles has

been found to be reduced in multiple sclerosis and spinal cord injured subjects with spasticity as

compared to a population of able-bodied individuals (Fig. 4; (Faist et al 1994, Nielsen et al 1995b).

This is also the case in cerebral palsy individuals with clinical signs of spasticity (Achache et al

2010). Presynaptic inhibition of Ia afferents from upper limb muscles is also reduced in spastic

stroke survivors (Aymard et al 2000, Lamy et al 2009), but this is not the case for presynaptic

inhibition of Ia afferents from leg muscles (Aymard et al 2000, Faist et al 1994, Lamy et al 2009). It

has therefore been argued that reduced presynaptic inhibition is unlikely to be involved in the

pathophysiology of spasticity, but is more likely an epiphenomenon (Lamy et al 2009), possibly in

relation to the disuse of the limb (Lundbye-Jensen & Nielsen 2008). The observation that there is no

correlation between reduced presynaptic inhibition and the degree of spasticity evaluated by the

Ashworth scale is in line with this (Aymard et al 2000, Lamy et al 2009, Nielsen et al 1995b).

However, as mentioned above the Ashworth scale has been shown to be a poor measure of the

extent of spasticity and this finding may therefore rather be related to short-comings of the clinical

evaluation of spasticity.

The success of GABAergic drugs, such as diazepam and baclofen, in reducing reflexes and

diminishing spasticity (Abbruzzese 2002, Macdonell et al 1989, Verrier et al 1975) should not be

taken as support that presynaptic inhibition plays an important role for the development of

spasticity. Any drug that reduces transmitter release from sensory afferent terminals on spinal

motoneurones or suppress motoneuronal excitability would have a similar effect and contrary to

what is sometimes claimed a specific effect on an important pathophysiological mechanism would

make little difference (Murray et al 2011b).

5.3.2 Post-activation depression

It was originally described by Curtis & Eccles (1960) that Ia EPSPs are frequency dependent, with

a relative facilitation at short intervals, and a depression with longer intervals (Curtis & Eccles

1960). This naturally influences also the size of stretch reflexes and it is therefore not surprising that

a similar pattern of facilitation and suppression of the Soleus H-reflex and stretch reflex may be

demonstrated in humans (Crone & Nielsen 1989a, Grey et al 2008, Hultborn et al 1996, Taborikova

& Sax 1968). Following a single elicitation of a stretch reflex or an H-reflex subsequent reflexes are

strongly depressed for up to 10-15 seconds (Fig. 5). This depression has been called post-activation

depression since it is seen following a previous activation of homonymous Ia afferents and is not (or

only to a limited extent) seen for afferents that have not been activated (Hultborn et al. 1996). It is

therefore assumed that the depression results primarily from mechanisms operating within the

presynaptic terminals (Lev-Tov & Pinco 1992, Li & Burke 2001, Pinco & Lev-Tov 1993). It is

unclear whether similar mechanisms are involved but post-activation depression shares many

features with the short-term homosynaptic plasticity described for synapses in the hippocampus

(Andersson & Hanse 2011).

Post-activation depression is reduced in spastic patients with spinal cord injury (Nielsen et al 1993,

Nielsen et al 1995b), multiple sclerosis (Nielsen et al. 1995; Grey et al. 2008), stroke (Aymard et al

2000, Grey et al 2008, Lamy et al 2009, Schindler-Ivens & Shields 2000) and cerebral palsy

(Achache et al 2010), thus ensuring that transmitter release is not significantly reduced with

discharges of Ia afferents at rates above 0.1 Hz (Fig. 5). This is well within the physiological range

of the firing rate of Ia afferents and normal activity of Ia afferents must therefore be expected to be

influenced by this. It is also within the range of frequencies used during the neurological

examination of spasticity and the reduction in post-activation depression thus directly contributes to

the exaggeration of the stretch reflex and the increased reflex mediated muscle tone determined

during the examination (Grey et al. 2008). In fact, the data from Grey et al. (2008) indicates that if

the neurological examiner made sure to test reflexes and muscle tone at intervals longer than 10 s

no significant reflex alteration as compared to healthy subjects would be detected. It is in other

words only because the neurological examination usually involves multiple attempts at moving the

limb or evoking the reflex, which then causes post-activation depression to be elicited, that reflex

exaggeration is determined in spastic patients. This may also explain the close correlation between

reduced post-activation depression and the clinical assessment of spasticity (Grey et al. 2008; Lamy

et al. 2009; Achache et al. 2010), although the limitations in this assessment should be kept in mind.

Post-activation depression is also the only mechanism which has been shown to be affected in both

the lower and upper limb in spastic subjects regardless of the ethiology of spasticity (Achache et al

2010, Lamy et al 2009). This may indicate a key role of reduced post-activation depression in the

string of events leading to spasticity. The simple regulation of the contribution of sensory inputs to

the activation of the motoneurones that it provides is an attractively simple means of upgrading

sensory input when descending drive is lost. However, it should be pointed out that we still have no

clear understanding of the functional significance of post-activation depression as will be further

discussed in Chapter 4.

It is not known how a spinal lesion could affect Ia terminals, but an impressive array of mechanisms

have been identified that contribute to short-term synaptic plasticity in general (both the initial

facilitation and the following depression; recently reviewed by Zucker & Regehr 2002). Although

post-activation depression appears to be a mechanism intrinsic to the synapses, several studies have

provided evidence that it may be regulated by descending motor commands and is thus a highly

regulated mechanism (Nielsen et al 2007, Raoul et al 2012). It is certainly a possibility that loss of

this descending regulation leads to alterations in the mechanisms responsible for the depression,

possibly secondary to alterations in monoaminergic neurotransmitters and their receptors similar to

what has been described for motoneurones (D'Amico et al 2013b, Murray et al 2011b, Rank et al

2011). It has also been suggested that the reduced post-activation depression may be related to lack

of sensory activity secondary to disuse of the limb (Lundbye-Jensen & Nielsen 2008).

5.4 Transmission in group II pathways

As already mentioned muscle stretch and passive manipulation of a limb as part of clinical and

biomechanical evaluation of spasticity, generates activity also in gr. II pathways that probably

contribute to the muscle resistance sensed during the clinical examination. The interneurons

mediating these effects appear to be primarily located in Rexeds laminae IV and VIII, whereas

another group of interneurons located in Rexeds laminae V-VII integrate input from gr. II afferents

and gr. Ib afferents from Golgi tendon organs (Jankowska & Edgley 2010). Some of these

interneurons are inhibitory whereas others are excitatory and the effect on a given set of spinal

motoneurons by activation of the afferents thus depends heavily on central regulation of the

interneurons (Jankowska 1989, Jankowska & Edgley 2010). Notably, monoaminergic

neurotransmitters effectively suppress transmission in group II pathways and may thereby produce a

selective suppression of the medium-latency (M2) reflex responses in lower limb muscles (Corna et

al 1995, Grey et al 2001)). The antispastic effect of Tizanidine (Kamen et al 2008) may be related to

this selective depression. Most studies have reported exaggerated group II reflexes in spastic

subjects and there is evidence to suggest that transmission in excitatory group II pathways are

released from descending monoaminergic suppression in patients with central motor lesions

(Nardone & Schieppati 2005). However, it is not clarified to what an extent group II interneurons

play a pathophysiological role in spasticity.

5.5 Pathophysiological role of changes in postsynaptic inhibition of motoneurones

Motoneurones are under close inhibitory control from a number of spinal interneuronal populations.

The most well studied are the interneurons mediating reciprocal Ia inhibition, Recurrent inhibition,

Ib autogenetic inhibition and Non-reciprocal gr. I inhibition (Fig. 3).

5.5.1 Disynaptic reciprocal Ia inhibition

It was Charles Sherrington who provided the first evidence of a spinal pathway that could elicit

suppression of antagonist muscles (his reciprocal innervation (Sherrington 1906)), but it was work

by John Eccles which demonstrated the disynaptic nature of the reciprocal Ia inhibitory pathway

(Hultborn 2006). Work by Hans Hultborn in the late 1960s and 1970s clarified the organization of

the interneurons interposed in the pathway and especially the parallel activation of descending

fibres and sensory afferents on common motoneurones and Ia inhibitory interneurons (Hultborn

1976, Hultborn et al 1976a, Hultborn et al 1976b, Hultborn et al 1976c, Hultborn et al 1971,

Hultborn & Udo 1972). This laid the basis for an understanding of the central control of reciprocal

inhibition in relation to voluntary movements in the 1980s and 1990s (Crone et al 1985, Crone et al

1987, Iles 1986, Kagamihara & Tanaka 1985, Nielsen & Kagamihara 1992, Nielsen et al 1992,

Shindo et al 1984, Tanaka 1976). This control is generally impaired in patients with spasticity as

will be further discussed in chapter 4.

For reciprocal inhibition to be of any pathophysiological relevance for spasticity it is essential that

there is evidence that the interneurones interposed at least in the pathway from ankle dorsiflexors to

plantarflexors are tonically active in healthy subjects at rest (Nielsen et al 1995a). The pathway thus

contributes to maintaining the excitability of soleus motoneurones low in resting subjects. The

reduction of reciprocal inhibition between ankle dorsiflexors and plantarflexors which has been

observed in spastic patients with multiple sclerosis (Crone et al 1994), stroke (Bhagchandani &

Schindler-Ivens 2012, Crone et al 2003, Crone et al 2000, Okuma & Lee 1996, Okuma et al 2002,

Okuma et al 1999), spinal cord injury (Crone et al 2003) and hereditary spastic paraparesis (Crone

et al 2004) may therefore potentially contribute to hyperreflexia and increased reflex mediated

muscle tone in the ankle plantarflexors. Achache et al. (2010) reported that reciprocal inhibition was

similar in healthy subjects and adults with CP, but since there was hardly any inhibition in healthy

subjects, a possible reduction of reciprocal inhibition in CP subjects may have gone unnoticed.

Reciprocal inhibition from ankle plantarflexors to dorsiflexors is in contrast usually found to be

increased in spastic patients (Mailis & Ashby 1990, Yanagisawa et al 1976). As dorsiflexor muscles

seldom show any spasticity this may not be too surprising. Reciprocal inhibition has also been

found to be deficient in wrist muscles (Artieda et al 1991), but since newer studies have put doubt

on the origin and nature of the inhibition observed between wrist muscles, the significance of this

finding is unclear (Wargon et al 2006).

It has generally not been possible to find any correlation between reduced reciprocal inhibition and

the degree of spasticity evaluated by the Ashworth scale, but given the lack of reliability of the

Ashworth scale and the small size of reciprocal inhibition in many subjects, this is not surprising.

On the other hand a positive correlation has been found between reduced reciprocal inhibition and

functional deficits in stroke patients and regardless of its pathophysiological role in spasticity,

reciprocal inhibition thus appears to be of clinical importance for at least gait function in spastic

patients (Bhagchandani & Schindler-Ivens 2012, Okuma & Lee 1996).

5.5.2 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 (Fig. 6). 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 (Pierrot-Deseilligny & Bussel 1975). 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 1999, Katz et al 1982). 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 play no major role in the pathophysiology of spasticity.

5.5.3 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 (Pierrot-Deseilligny 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 (Delwaide & Oliver 1988). 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.

(2003) in their study of patients with stroke and spinal cord injury (Crone et al 2003). 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 2006). 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.

5.5.4 Fusimotor drive. Gamma-spasticity

Increased fusimotor drive leading to increased sensitivity of the muscle spindles to muscle stretch

was a popular explanation of spasticity some 20–30 years ago (so-called gamma-spasticity). 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, Burke et al

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, Wilson et al 1999b).

6.0 How is clonus related to spasticity?

Clonus is characterized by rhythmic alternating oscillation at relatively low frequency (3-8 Hz) at

distal joints, in particular the ankle joint, following muscle stretch that is sufficiently fast to elicit a

stretch reflex (or catch). Clonus is primarily seen in spastic patients and exaggerated stretch reflexes

are usually present when clonus is observed (Mukherjee & Chakravarty 2010). Clonus is therefore

also often considered as an integrated part of spasticity as also witnessed by the focus on clonus in

the Tardieu scale (Haugh et al 2006). However, many patients with severe spasticity fail to show

clonus and especially when muscle tone is very pronounced clonus is seldom seen (Mukherjee &

Chakravarty 2010). One possible explanation of this is that at least partly different

pathophysiological mechanisms may be involved in the development of spasticity and clonus.

Clonus has traditionally been thought to be caused by alternating elicitation of stretch reflexes in

antagonist muscles (Hidler & Rymer 1999). The observation that the frequency of clonus depends

on the length of the limb segment in which clonus is observed, is consistent with this idea (Hidler &

Rymer 1999). Furthermore, clonus has been observed to be reset by stimulation of peripheral nerves

and to disappear when sensory afferent activity is blocked by ischemia (Rossi et al 1990).

Modelling studies also show that increased stretch reflex excitability with appropriate conduction

delays may adequately explain the occurrence of clonus (Hidler & Rymer 1999). If this is correct,

inclusion of clonus in the definition of spasticity and its use in the Tardieu scale would be justified.

However, several studies have suggested that other mechanisms may at least contribute to the

occurrence of clonus (Beres-Jones et al 2003, Dimitrijevic et al 1980, Walsh & Wright 1987).

Dimitrijevic et al. (1980), contrary to Rossi et al. (1990), failed to interfere with clonus by sensory

inputs and demonstrated examples where clonus was elicited by cutaneous input rather than muscle

stretch. Walsh & Wright (1987) also failed to interfere with clonus by mechanical loading of the

limb. Beres-Jones et al (2003) observed that EMG patterns in antagonistic ankle joint muscles

during clonus in spinal cord injured subjects were often synchronized and unrelated to mechanical

stretch of the muscles (Beres-Jones et al 2003). These studies, thus, suggest that central oscillator

networks may at least contribute to the occurrence of clonus. Their central idea is that sensory input

to the spinal cord may activate the rhythmic locomotor network in the cord. This network has been

shown to be capable of oscillating for prolonged periods of time following sensory input in animals

and to some extent also in humans (Calancie et al 1994, Dietz et al 1997, Pinter & Dimitrijevic

1999). Due to the contradictory findings in the various studies it seems at least possible that both

mechanisms may be involved, possibly to varying extent in different patients. Regardless of this,

caution should be made when relating clonus too closely to spasticity.

7.0 What causes a spasm?

Spasms are involuntary muscle contractions, which last from seconds to minutes and are usually

provoked by a sensory stimulus, although in some cases no clear sensory stimulus can be

determined. Spasms are differentiated from spasticity by the longer duration and strength of the

contraction, which can sometimes be so severe that it becomes painful. Spasms are also

differentiated from spasticity by being elicited preferentially by cutaneous rather than muscle

afferent inputs. Spasms are mainly seen following spinal cord injury, whereas they are rarely seen

in stroke patients even with very significant exaggeration of stretch reflexes and severe muscle tone

(Malik et al 2014). Spasms are thus clearly distinct pathophysiologically from spasticity. The

occurrence of spasms is closely related to increased withdrawal reflexes following injury and it is

generally accepted that spasms are caused by pathologically increased transmission in flexor reflex

afferent (FRA) circuitries in the spinal cord (Barolat & Maiman 1987). As already discussed,

studies in both animal and human have suggested a significant role of upregulation of 5-HT

receptors, secondary to loss of serotonergic innervation and resulting in increased persistent inward

currents (PICs) in motoneurones and possibly also in interneurons in the FRA circuitries (Bennett et

al 1999, Bennett et al 2001, D'Amico et al 2013b, Gorassini et al 2004, Murray et al 2011a). This

would explain why spasms are mainly seen in spinal cord injured subjects and rarely following

stroke or in cerebral palsy.

8.0 Spastic dystonia is not caused by increased stretch reflex activity

Spastic dystonia is a term that was introduced by Denny-Brown to designate tonic muscle activity

in arm muscles in monkeys following central motor lesion (Denny-Brown 1966). He observed that

the activity persisted when dorsal roots were cut and concluded that stretch reflex activity was not

involved. In humans it is seen in the upper limb where it contributes to the hemiplegic posture

primarily in subjects with stroke or cerebral palsy (Gracies 2005, Sheean 2002, Sheean & McGuire

2009). In humans a dynamic form of spastic dystonia is also seen during standing and gait where

the subject may adopt a posture with plantarflexion at the ankle, pronounced extension at the knee

and associated flexion at the elbow (Gracies 2005, Sheean 2002, Sheean & McGuire 2009). These

features resemble the overflow phenomena observed in patients with extrapyramidal (basal ganglia)

lesions, hence the term dystonia. We have at present no clear indication of what causes spastic

dystonia except for the findings in monkey by Denny-Brown (and which need to be confirmed in

humans). Plastic changes at a spinal level involving upregulation and sprouting of surviving

descending fibres may explain both the tonic and dynamic form, whereas upregulation of PICs in

motoneurones may possibly explain the tonic form (Gorassini et al 2004). However, changes at a

cortical level may also play a role and it should also be kept in mind that stroke often involves other

structures than the descending pathways and that basal ganglia affection is not uncommon in stroke

patients. Spastic dystonia may thus be the end-result of reduced voluntary control of muscles due to

(partial) corticospinal lesion and increased involuntary activation due to basal ganglia lesion.

Concluding remarks

This chapter has emphasized that there is a range of adaptations in spinal circuitries following

lesion of central motor fibres. These adaptations should be seen as an attempt to ensure a functional

output from the spinal cord following loss of some of the normal supraspinal drive to the spinal

motoneurones. We have the possibility of testing part of the circuitries that show adaptation

following lesion by imposing muscle stretch and eliciting a sensory input to the spinal cord. The

increased muscle resistance that we may sense in this way thus provides information of only some

of the adaptations that occur and it is therefore not surprising that spasticity; i.e. hyperactive stretch

reflexes only provide a partial insight into the full range of clinical manifestations of the adaptations

to central lesions. In a broader sense these adaptations are also responsible for such manifestations

as spasms, clonus and spastic dystonia as well as the movement disabilities encountered by patients

following central motor lesions. These may to some extent be related to spasticity but may also be

seen separately. Treatment of patients with central motor lesions should take the different

underlying pathophysiological mechanisms responsible for the various manifestations of spinal cord

adaptations in to account. The realization that sensory feedback is closely integrated with

descending motor commands as a basis of all movements and that spasticity is a reflection of an

upgrading of sensory feedback as a compensation for loss of descending drive, should also warrant

caution when prescribing antispastic medication to patients with some functional ability.

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FIGURES AND LEGENDS

Fig. 1. Objective biomechanical and electrophysiological evaluation of spasticity

Fig. 2. Theoretical changes in sensory and descending input to spinal motoneurones in the

acute and chronic phase following central motor lesion.

Fig. 3. The stretch reflex circuitry and spinal pathophysiological mechanisms in spasticity

Fig. 4 Presynaptic inhibition and spasticity

Fig. 5. Post-activation depression and spasticity

Fig. 6. Disynaptic reciprocal inhibition and spasticity