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Published in final edited form as:
Neurorehabil Neural Repair. 2010 January ; 24(1): 23–33. doi:10.1177/1545968309343213.

Management of Spasticity After Spinal Cord Injury: Current
Techniques and Future Directions
Sherif M. Elbasiouny, PhD1, Daniel Moroz2, Mohamed M. Bakr, MD3, and Vivian K.
Mushahwar, PhD4
1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago,
Illinois, USA
2Centre for Neuroscience, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,

Canada3Children’s Hospital Boston, Boston, Massachusetts, USA

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4Department of Cell Biology and Centre for Neuroscience, Faculty of Medicine and Dentistry,

University of Alberta, Edmonton, Canada

Abstract
Spasticity, resulting in involuntary and sustained contractions of muscles, may evolve in patientswith stroke, cerebral palsy, multiple sclerosis, brain injury, and spinal cord injury (SCI). The
authors critically review the neural mechanisms that may contribute to spasticity after SCI andassess their likely degree of involvement and relative significance to its pathophysiology.
Experimental data from patients and animal models of spasticity as well as computer simulations
are evaluated. The current clinical methods used for the management of spasticity and thepharmacological actions of drugs are discussed in relation to their effects on spinal mechanisms.
Critical assessment of experimental findings indicates that increased excitability of bothmotoneurons and interneurons plays a crucial role in pathophysiology of spasticity. New
interventions, including forms of spinal electrical stimulation to suppress increased neuronal
excitability, may reduce the severity of spasticity and its complications.

Keywords

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spasticity; spasms; spinal cord injury; upper motor neuron syndrome; rehabilitation; neurologicaldisorderIntroduction
Spasticity is one feature of the upper motor neuron syndrome and a major cause of disability
in individuals with a variety of central nervous system diseases (including stroke, cerebral
palsy, and multiple sclerosis) and trauma (such as spinal cord injury [SCI] and brain injury).
Spasticity is usually defined as a velocity-dependent increase in the tonic stretch reflex(muscle tone) with exaggerated tendon jerks, clonus, and spasms, resulting from the© The Author(s) 2009
Corresponding Author: Sherif M. Elbasiouny, Department of Physiology, Feinberg School of Medicine, 303 E. Chicago Ave, Ward
5-194, Northwestern University, Chicago, IL 60611, USA, s-elbasiouny@northwestern.edu.
Declaration of Conflicting Interests
The authors declare that they do not have any conflict of interest.

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hyperexcitability of the stretch reflex.1 Because spasticity results from lesions in the
pyramidal and extrapyramidal pathways,2 its pathophysiology varies depending on the siteof the lesion but commonly develops in the antigravity muscles. For instance, excessive
muscle tone in the upper-extremity flexor muscles is prominent in spasticity following
stroke, with relatively lesser involvement of muscle spasms. On the other hand, excessive
muscle spasms in the lower-extremity extensor muscles are prominent following SCI. It isalso believed that the mechanisms underlying spasticity in stroke and SCI are different.
Neural mechanisms are thought to be the primary contributors to spasticity following SCI,
whereas alterations in muscle contractile properties play a substantial role in spasticity
following stroke. Accordingly, clinicians and researchers consider the classical definition of
spasticity to be narrow and restrictive.3,4
The term spasticity has been increasingly used to refer to several features of the upper motor
neuron syndrome.5 For example, in addition to muscle hypertonus, spasticity following SCI
could also involve hyperreflexia, clonus, clasp-knife responses, long-lasting cutaneousreflexes, and muscle spasms evoked by brief nonnoxious cutaneous stimuli.4 In this article,
we review the mechanisms contributing to these different features of the syndrome of
spasticity after SCI and critically assess their possible involvement and significance to thepathophysiology of spasticity.

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More than 80% of people with SCI have spasticity,6 and many have greater disability from
it. Spasticity develops gradually over several months after injury. Immediately following
SCI, the spinal cord becomes areflexic (spinal shock), a period characterized by loss of
tendon reflexes below the level of the lesion, muscle paralysis, and flaccid muscle tone.
Weeks after injury, various reflexes such as the tendon reflex, the flexor withdrawal reflex,
and the Babinski sign appear.7 The threshold of the flexor reflexes, which are usually
evoked by cutaneous stimulation, decreases over time to a point that brief stimulation of thefoot plantar surface can evoke long-lasting flexor contractions.8 Extensor reflexes, which areusually evoked by proprioceptive stimuli, occur later and episodes of flexor/extensor muscle
co-contraction become pronounced.8 Intense muscle spasms can also be triggered by various
other stimuli such as heat/cold and bladder distention.9 Extensor spasms that cause episodic
lower-extremity rigidity can at times provide assistance in dressing or walking but areusually painful and can be violent enough to expel a person out of a wheelchair. In
individuals with incomplete SCI, spasticity may reduce the functional utility of residual
voluntary motor control, compromising rehabilitation efforts.

Mechanisms Underlying Spasticity
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The pathogenesis of spasticity following SCI in patients remains uncertain. The increased
excitability of the stretch reflex in patients with spasticity directed research efforts toward
investigating the spinal mechanisms modulating the excitability of this reflex (Figure 1) andthe potential alteration in its excitability after SCI. We evaluated several proposedmechanisms and assessed their likelihood of involvement and relative significance in thepathophysiology of spasticity (Table 1). In this assessment, the likelihood of involvement of
a particular mechanism in spasticity was based on 3 criteria: (1) detection of abnormality inthe excitability of the mechanism in both humans and animal models of spasticity; (2)detection of abnormality in the same mechanism under different experimental conditions (ie,rest versus contraction); and (3) consistency in the mechanism’s alteration using multiple
assessment measures. Pathologies present during movement (ie, during muscle contraction
or functional tasks) were deemed to be especially relevant to spasticity because of theresulting movement impairment. A mechanism that is likely involved in spasticity wasconsidered to be significant if an influential role of that mechanism in the manifestation of
spasticity has been established experimentally and clinically.

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Page 3Fusimotor Hyperexcitability

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The common characteristics between human spasticity and animal rigidity induced after
intercollicular decerebration led to the assumption that the same spinal mechanisms
contribute to the exaggeration of the stretch reflex in both conditions. In decerebrate animal
rigidity, the exaggerated stretch reflex was attributed to the hyperactivity of γ-motoneurons
that control the sensitivity of muscle spindles and stretch reflex gain.28 It was therefore
posited that the hyperexcitability of the stretch reflex leading to spasticity after SCI is also
because of an increase in the activity of γ-motoneurons (Figure 1). This hypothesis was
refuted because direct recordings from muscle spindles in individuals with SCI showed noincreases in activity during bouts of spasticity.29 Furthermore, despite the resemblance
between spasticity and decerebrate animal rigidity, critical differences are found in the timecourse of development of each symptom. Spasticity develops weeks after SCI, whereas
decerebrate animal rigidity appears within 1 hour after decerebration.30 The prolonged
duration for the development of spasticity after SCI suggests the contribution of plasticchanges in other spinal pathways to spasticity. Accordingly, fusimotor hyperexcitability is
unlikely to be involved in the pathophysiology of spasticity after SCI.
Axonal Sprouting

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Another mechanism for spasticity was proposed by McCouch et al.15 After SCI, terminals of
the damaged axons on spinal neurons degenerate. By a few weeks postinjury, the remaining
local afferents sprout new synaptic terminals in the vacated space and enhance the efficacyof the spinal connections. The prolongation in the time-to-peak of excitatory postsynaptic
potentials (EPSPs) in spastic individuals supports the sprouting of Ia-afferents and theformation of new synapses on motoneurons.16 This proposed mechanism provides an
explanation for the temporal changes in behavior after SCI and could contribute to spasticity
by strengthening existing spinal circuits and/or increasing synaptic inputs to interneurons.17
It could also explain the disruption in the balance between excitatory and inhibitory inputs tomotoneurons observed during spasticity as described in the following section. Thus, axonal
sprouting is likely to contribute to the pathogenesis of spasticity after SCI. Given that axonal
sprouting could contribute to several spinal mechanisms underlying spasticity, its
significance to the pathophysiology of spasticity is high.
Alterations in Other Spinal Mechanisms
Evidence from experiments in humans and animal models of spasticity demonstrated thatalterations in the excitability of numerous excitatory and inhibitory spinal pathways occur
after SCI (Figure 1). These alterations are discussed below along with the pharmacologicalactions of antispasticity drugs used for management (Figure 2).

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Reduction in postactivation depression—The size of the Hoffmann reflex (H-reflex)
is usually reduced during repetitive stimulation of Ia muscle spindle fibers at stimulus rates
above 0.3 pulses per second. This phenomenon is called postactivation dep ression (PAD)
and results from the reduction in the amount of neurotransmitter release at the Ia–
motoneuron synapse because of repeated activation.31 Reduction in PAD following SCI has
been confirmed in humans as well as in animal models of SCI (Figure 1B).21,22 Therefore, it
is likely that it is involved in the pathophysiology leading to spasticity. However, thesignificance of PAD to spasticity should be considered with caution as PAD was assessed inthese studies only at rest, whereas the level of PAD is dependent on muscle activity (ie, restvs contraction). In healthy individuals, the suppression of the H-reflex through PAD isdiminished during volitional muscle contraction,23,24 and abolished during standing.24
Therefore, in spastic individuals, PAD might also be reduced during functional tasks; thus,
the specific significance of its reduction at rest to spasticity following SCI is uncertain.

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Reduction in presynaptic inhibition—Presynaptic inhibition (PSI) adjusts the strengthof synaptic inputs to neurons by regulating the levels of neurotransmitter release (Figure 1).
PSI is governed by descending drives in a state-dependent manner. Reduction in PSI has
been reported in individuals with spasticity under both rest and muscle contraction
conditions. In spastic individuals with SCI, PSI evoked by muscle or tendon vibration at rest
was reduced,18 indicating an increase in the strength of the excitatory Ia–motoneuron
synapse.19 The reduction in the magnitudes of the H-reflex and tendon jerks, however, could
be a result of concurrent reduction in PAD, which is activated by vibration as well. The
modulation of the H-reflex during muscle contraction was also altered in individuals withspasticity after incomplete SCI; the H-reflex disappeared during standing but was slightly
depressed during walking relative to intact subjects.20 This lack of modulation of reflexes
during walking probably contributes to the stiff gait observed after SCI.30 Thus, reduction in
PSI is likely to be involved in the pathophysiology of spasticity following SCI. However, incontrast to findings in humans, no reduction in PSI was found in animal models of
spasticity.32 Because of the inconsistency in results from humans and animal models, andthe possibility of mixed actions with PAD, reduction in PSI appears to have moderatesignificance to spasticity. Nonetheless, PSI has been the target of many antispastic drugs.
Baclofen (GABAB agonist), the most commonly used agent for the treatment of spasticity,
acts in part by reducing neurotransmitter release from presynaptic terminals through the
reduction of Ca2+ influx (Figure 2).33 Benzodiazepines (GABAA agonists) increase PSI atspinal and supraspinal sites (Figure 2)34 by opening chloride ion channels and inhibiting thepresynaptic terminal.
Reduction in Ia-reciprocal inhibition—The reciprocal activation of antagonisticmuscles during movement is mediated by a disynaptic inhibitory pathway called Iareciprocal inhibition (Figure 1). Alteration in the excitability of Ia-reciprocal inhibition in
individuals with spasticity following SCI was reported, but contradictory results wereobtained regarding the nature of this alteration. For instance, Ia-reciprocal inhibition was
reduced in individuals with spasticity after incomplete SCI; they were unable to suppress the
H-reflex when activating antagonistic muscles and showed abnormal coactivation ofantagonistic muscles during isometric contractions.25 Further more, Crone et al26 found that
Ia-reciprocal inhibition was replaced by reciprocal excitation of antagonistic muscles after
SCI, which facilitated co-contraction of antagonistic muscles during movements.
Conversely, Boorman et al27 found that Ia-reciprocal inhibition was increased in individuals
with spasticity resulting from incomplete SCI. Therefore, alteration in Ia-reciprocal
inhibition is likely to occur in spasticity following SCI, but the nature of alteration and its
significance to the pathophysiology of spasticity is unclear.

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Enhancement in the Excitability of Motoneurons
The enhancement in excitability of motoneurons is most likely involved in thepathophysiology of spasticity following SCI. First, it has been confirmed in spastic
individuals and in animal models of spasticity.10,11,35,36 Second, it was observed during restand muscle contraction. In people with spasticity caused by SCI, an increase in the ratio ofpotentials resulting from electrical stimulation of the sensory and motor axons (Hmax/Mmax)
was observed at rest.12 An increase in the amplitude and persistence of the F-wave (theelectrical potential resulting from antidromic activation of motoneurons) was also apparent,7
further supporting the enhancement of motoneuronal excitability. During muscle spasms,
motor unit recordings indicated an increase in motoneuronal firing rate, causing vigorousmuscle contraction.37 Third, the enhancement in motoneuronal excitability was consistently
observed using multiple assessment measures.7,12,37 The enhancement in motoneuronal
excitability was attributed to alterations in motoneuronal intrinsic properties, such as theactivation of persistent inward currents (PICs) and depolarization of the membrane potential.

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10,11 These alterations have been extensively assessed in a validated chronic spinal rat modelof spasticity,10,11,35 which established the ionic basis of the long-lasting exaggerated

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reflexes and muscle spasms associated with spasticity.
Activation of persistent inward currents—A PIC is a depolarizing current that does
not inactivate with prolonged membrane depolarization. The activation of the motoneuronal
PIC is regulated through the monoaminergic drive from the brainstem. After SCI, the PIC is
no longer under the control of descending drive, leading to uncontrolled and highmotoneuronal firing rates. The long-lasting exaggerated reflexes and muscle spasms seen
during spasticity could be partly because of uncontrolled activation of PICs after injury.38
The activation of PICs transforms the response of motoneurons to brief volleys of Ia-afferent
input from short to long-lasting firing activity.39 Therefore, activation of PICs causes selfsustained firing and maintained increases in motoneuronal excitability.

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In spinal motoneurons, PICs are mediated by 2 types of ion channels with distinctive
properties: the L-type calcium channels40 and persistent sodium channels.35,41 After SCI,
the Ca2+ PIC, which has little time-dependent inactivation, underlies the long-lastingreflexes seen in spasticity,10,42 whereas the Na+ PIC, which becomes partially inactivatedwith time, is responsible for the initiation of the spontaneous firing commonly seen inassociation with a muscle spasm or voluntary contraction.10,42 Motor unit recordings fromspastic individuals after SCI suggest that spasticity in humans involves similar Ca2+ and Na+
ionic mechanisms.42 Furthermore, recent computer models of motoneurons incorporating
Ca2+ and/or Na+ PICs were able to exhibit self-sustained firing, plateau potentials, andsustained depolarization of the membrane potential that were similar to those seen during
spasticity.43,44

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Differential control of spinal neurons by descending drive—The monoaminergic
drive from the brainstem to the spinal cord regulates the excitability of spinal neurons during
different motor tasks. A number of neuromodulators have been shown to influencemotoneurons, such as serotonin (5-HT), norepinephrine (NE), acetylcholine, thyroid
releasing hormone, substance P, and adenosine. 5-HT and NE are the most extensively
studied monoaminergic inputs. The monoaminergic drive has differential effects on theventral and dorsal horns of the spinal cord (Figure 2). In the ventral horn, monoamines haveexcitatory effects on motoneurons and low-threshold muscle afferents (group I).45
Furthermore, 5-HT and NE enhance PIC activation,46 induce membrane depolarization,47
and decrease the amplitude of afterhyperpolarization.48 Collectively, these effects increase
the excitability of the cell. Conversely, monoamines inhibit, through PSI, sensory inputs tomotoneurons49 such as cutaneous50 and high-threshold muscle afferent inputs (groups III
and IV).51 They also suppress inputs to deep dorsal horn interneurons from high-thresholdafferents.52 This differential control by the monoaminergic drive in the spinal cord is
attained through the effect of different monoaminergic receptors. For example,
motoneuronal PIC facilitation is achieved through 5-HT253 and NE α1 receptors,46 whereas
cutaneous and high-threshold muscle afferent inhibition is achieved through 5-HT1b/d andNE α2 receptors.54
This differential control is altered after SCI, a mechanism that contributes to the emergenceof spasticity. Acutely, the loss of the monoaminergic drive reduces the excitability of
motoneurons in the ventral horn but increases the size and duration of the polysynaptic
EPSPs of sensory inputs mediated through the dorsal horn because of loss of inhibition.55
Despite the increase in the excitability of interneuronal pathways, long-lasting reflexes are
not activated during this stage because of the reduced excitability of motoneurons. In thechronic stages of injury, motoneurons become highly sensitive to residual monoamines
available below the level of the lesion. These facilitate the reactivation of the PICs and
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restore the motoneuronal excitability (Figure 2).56 Nonetheless, this reactivation of PICs is
no longer regulated by the brainstem, which leads to uncontrolled motoneuronal firing
evoked by synaptic inputs.10 In this stage, prolonged EPSPs generated by sensory stimuli
can activate the PIC and trigger long-lasting reflexes and muscle spasms.55 Thus, spasticity
does not emerge until motoneurons become hyperexcitable, regardless of the increases ininterneuronal excitability early after SCI. This indicates that the enhancement inmotoneuronal excitability plays a significant role in the pathophysiology of spasticity.
Further support for this supposition is found in the action of the antispastic drug, baclofen,
which partially acts on motoneurons and suppresses their excitability by reducing the Ca2+
PIC57 and shortens the duration of the monosynaptic EPSPs36 (Figure 2).
Enhanced Excitability of Interneurons

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The enhancement in excitability of interneurons is also most likely involved in thepathophysiology of spasticity following SCI. This has been confirmed in humans and inanimal models of spasticity. For example, the magnitude of flexor reflexes mediated bypolysynaptic pathways was increased in individuals with spasticity after SCI.7 Mailis andAshby13 reported an enhancement in the transmission through polysynaptic pathways from
Ia-afferents to motoneurons. Schmit and Benz58 observed extensor spasms in individuals
with SCI, similar to those seen clinically, when they shifted from a sitting to a supine
position. The spasms were triggered by single-leg extensions about the hip. Thus, singlejoint movements can also evoke multijoint responses after SCI.59 These observations
support the contribution of increased excitability of interneuronal circuits to thehyperexcitability of reflexes in spasticity and the importance of hip afferents in triggering
extensor spasms.60 Moreover, an increase in the ratio of excitatory-to-inhibitory inputs tomotoneurons originating predominantly from spinal interneurons was observed during thedevelopment of spasticity.14 Collectively, evidence suggests that the enhancement in the
excitability of interneurons plays a significant role in the pathophysiology of spasticity.
Several antispastic drugs have targeted the interneuronal polysynaptic pathways. Clonidine,an α2-adrenergic receptor agonist, suppresses polysynaptic reflexes11,61 and blocks theprolonged polysynaptic EPSPs that activate the PICs (Figure 2). It also enhances the PSI of
sensory afferents.61 Tizanidine, another α2-adrenergic receptor agonist, acts presynapticallyby reducing the release of excitatory neurotransmitters (glutamate and aspartate) frominterneurons (Figure 2).62

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In conclusion, multiple spinal mechanisms appear to be involved in the pathogenesis of
spasticity after SCI. Therapeutic interventions targeting one or more of these mechanisms
may be especially effective in reducing the severity of spasticity and related motor
disabilities in people with SCI.

Current Treatments of Spasticity
Current clinical management of spasticity involves a wide variety of therapies ranging fromnoninvasive (eg, oral administration of antispastic drugs, physiotherapy) to invasive
procedures (eg, surgical rhizotomy). The type and rate of treatment depend on the levels of
spread (diffuse versus focal) and disability (mild vs severe) caused by spasticity.63 Common
techniques for the management of spasticity and potential new interventions are summarized
below.
Physical Techniques
Increased muscle tone causes spastic muscles to resist stretch and remain shortened for long
durations. Prolonged muscle shortening leads to joint deformation and changes in the
intrinsic properties of soft tissues and muscle fibers, which in turn restrict the range of
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motion63 and diminish the functional use of residual voluntary movements in individuals
with incomplete SCI. These changes contribute a biomechanical component, in addition to
the neural components discussed, to the disability resulting from spasticity. Whereas
antispastic drugs act on the neural component of spasticity, physiotherapy minimizes thebiomechanical side effects. Daily passive muscle stretching assists in reducing muscle tone
and in maintaining joint mobility and range of motion (Figure 2). Orthoses are used to holdthe limb in positions that resist contractures. Exercises are also performed to strengthen the
spastic and synergistic muscles.63 Given the importance of hip afferents in triggering
extensor spasms, careful positioning of the hip during patient manipulation (eg, transfers to/from wheelchairs) assists in minimizing the effects of those reflexes in individuals with SCI.
64

Pharmacological and Surgical Approaches

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Antispastic medications—Because oral medications produce systemic side effects, they
are usually used in patients with diffuse spasticity. The most commonly used antispastic
drugs are baclofen, benzodiazepine, clonidine, and tizanidine. These drugs could be usedalone or in combination to obtain a desired effect and are administered orally or
intrathecally. Because these medications produce nontargeted release of pharmacologicalagents, their major side effect is a general suppression of neuronal activity in individuals
who already have a reduced voluntary drive. The majority of these drugs act by targeting the
motoneuronal and/or interneuronal spinal mechanisms. Dantrolene sodium acts peripherally
on intrafusal and extrafusal muscle fibers by decreasing the release of Ca2+ from thesarcoplasmic reticulum, which may reduce muscle force during contractions (Figure 2).65
Chemical neurolysis—Chemical neurolysis is usually used in individuals with focal
spasticity or in those who want to assess the functional gain of future surgical treatments
prior to the surgical procedure. A peripheral nerve innervating spastic muscles is injectedwith phenol or alcohol solutions (Figure 2), which destroy myelin. The effects of thesesolutions are proportional to their concentrations.63 Aqueous phenol is also used for motor
point injection specifically in spastic muscles through an easy and safe procedure; however,
the effectiveness of the injection diminishes over time and repeated injections are needed.
The common complication is treatment failure resulting from poor localization of the nerve
or an inadequate dose.63

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Botulinum toxin—Botulinum toxin, injected intramuscularly, acts on the neuromuscularjunction to inhibit the release of acetylcholine (Figure 2).66 The toxin causes chemical
denervation of intrafusal and extrafusal muscle fibers, and its effect is reversible.67 The
clinical effect of the toxin appears 24 to 72 hours following administration and lasts 2 to 6
months depending on the dosage. The treatment is effective in reducing pain and muscle
spasm. The major side effect is excessive weakness of the treated muscle.
Surgical techniques—Surgical procedures are commonly used when spasticity cannot be
managed by any of the aforementioned techniques. They involve the ablation of motor
nerves and/or rhizotomy of sensory spinal roots to interrupt the sensory input (Figure 2).68
Ablation of motor nerves is effective when spasticity is focal in muscles innervated by thesame nerve trunk and is usually selective in its suppression of spasticity without causing
excessive muscle weakening. Preserving 25% of the motor fibers is necessary to maintainmuscle tone.63 The main disadvantage of surgical procedures is that they are irreversible.

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Electrical Stimulation

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Various electrical stimulation modalities have been used to reduce the level of spasticity.
These modalities range from surface electrical stimulation of muscles to electricalstimulation of the peripheral and central nerves.
Muscles—Surface electrical stimulation for the reduction of spasticity involves stimulationof the spastic muscles69 and/or their antagonists.70 In the former case, reduction of spasticity
is attributed to stimulation of the cutaneous afferents, which could suppress motoneuronal
excitability by depressing the propriospinal interneurons or induce long-term synaptic
changes in primary afferents in the dorsal horn (Figure 2).71 In the latter case, reduction of
spasticity may be attributed to the activation of the Ia-reciprocal inhibition pathway, which
reduces the amplitude of the motoneuronal PIC and level of motoneuronal excitability(Figure 2).72

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Peripheral nerves—Electrical stimulation of peripheral nerves to block exaggerated
motor activity was examined in animal models (Figure 2). Application of direct current(DC)73 or high-frequency stimulation of various waveforms (sinusoidal and rectangularpulses) induced conduction block in peripheral nerves, which was complete and reversible.
74 Despite their desired properties, electrical stimulation strategies of peripheral nerves lackspecificity because of the fact that primary sensory fibers have larger diameters and lower
extracellular activation thresholds than motor fibers and are more likely to be activated first.
Therefore, this technique would block sensory and motor muscle activity and may preventthe transmission of residual voluntary activation of muscles that might remain after
incomplete SCI.
Epidural—Electrical stimulation of the dorsal columns of the spinal cord throughepidurally placed electrodes may reduce spasticity.75 Epidural stimulation can be effective
in reducing mild spasticity,76 but its efficacy depends on electrode location and stimulation
parameters.75 The clinical effect of epidural stimulation probably results from activation of
inhibitory networks in the spinal cord,75 increasing the level of PSI,77 or activating
inhibitory networks within the dorsal column–brainstem–spinal loop (Figure 2).78 However,
epidural stimulation sometimes lacks long-term efficacy in reducing spasticity, pain, andmuscle spasms after SCI.79

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Intraspinal microstimulation—This technique aims to suppress the intrinsic excitabilityof spinal motoneurons through the application of extracellular current pulses using finemicrowires implanted in the spinal cord (Figure 2).80 As demonstrated by computer
simulations, the applied pulses regulate the membrane potential of the first node of Ranvier
and modulate the increased motoneuronal firing activity after SCI. Various waveforms were
tested in simulations for modulating the motoneuronal firing behavior, including
subthreshold biphasic charge-imbalanced pulses and suprathreshold high-frequency
alternating current (AC) pulses. The effect of these pulses ranged from a graded reduction to
full blockade of the aberrantly high motoneuronal firing rate, respectively. The former
pulses deactivate the Na+ channels at the first node of Ranvier and reduce axonal
conduction, whereas the latter pulses inactivate the Na+ channels at the first node of Ranvier
and block axonal conduction. These pulses are effective even in the presence of increased
sprouting and changes in motoneuronal intrinsic properties encountered after long-term SCI.
80 The proposed pulses could provide a means for reducing spasticity without prohibiting
muscle activation through residual volitional drive. Figure 3 shows preliminary results fromour laboratory demonstrating the effect of these pulses on the level of spasticity measured invivo in the chronic spinal rat model. During the application of these pulses, the tail-resistive
force to stretch (a measure of spasticity) was reduced by nearly 45% (Figure 3E).

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Electrical fields—Electrical fields, in the form of DC or AC applied across the spinal cord
through metal plates, have been shown through computer simulations to provide anothermeans for modulating the firing rate of motoneurons after SCI.81 The electrical fields induce
differential polarization in the various structures of the motoneuron and modulate themagnitude of the dendritic Ca2+ PIC, thereby suppressing their excitability (Figure 2).
Application of electrical fields could alleviate spasticity by reducing the excessively highmotoneuronal firing rates after chronic SCI. These proposed electrical fields could bepractically implemented by passing electrical current between the metal plates usedclinically to provide mechanical support to the spinal column after SCI. Figure 3D shows theeffect of slow AC electrical fields, applied noninvasively in the chronic adult spinal rat
model, on the level of spasticity. The tail-resistive force to stretch was reduced by nearly
14% during the application of the electrical field (Figure 3E).
In sum, available techniques for the clinical management of spasticity might mitigate one or
few of the underlying pathological spinal mechanisms contributing to spasticity. Given themultifactorial origin of spasticity, a successful strategy would most likely require a
combination of interventions to achieve the best clinical outcome.

Conclusion
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Spasticity that leads to spasms, pain, and contractures is a debilitating secondary
complication of SCI. Identification of potential mechanisms and their significance to thepathophysiology of spasticity is critical for the design of rehabilitation programs. The
pathogenesis of spasticity resulting from SCI is multifactorial and extends beyond thestretch reflex. It also depends on the type, site, and duration of injury. The alteration in
excitability of various inhibitory pathways has historically been studied the most, with lessfocus until recently on the alterations in excitability of motoneurons and interneurons
themselves. This latter alteration appears to play critical roles in the manifestation of
spasticity after SCI and could become the target of new pharmacological and clinicaltreatments. The new electrical stimulation interventions suggested by computer simulations
for suppressing motoneuronal excitability seem promising, but more careful studies inanimal models are required to establish the effectiveness of these techniques.

Acknowledgments
Funding

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This work was funded by the National Institute for Neurological Disease and Stroke, National Institutes of Health(NINDS-NIH). S. M. Elbasiouny was supported by an Alberta Heritage Foundation for Medical Research(AHFMR) doctoral scholarship. He is currently supported by the Tim E. Noel fellowship from the Canadian
Institutes of Health Research (CIHR) and the ALS Society of Canada. D. Moroz was supported by an AHFMR
summer studentship. V. K. Mushahwar is an AHFMR Senior Scholar.

References
1. Lance, J. Pathophysiology of spasticity and clinical experience with baclofen. In: Lance, J.;
Feldman, R.; Young, R.; Koella, W., editors. Spasticity: Disordered Motor Control. Yearbook;
Chicago, IL: 1980. p. 185-204.
2. Burke D. Spasticity as an adaptation to pyramidal tract injury. Adv Neurol 1988;47:401–423.
[PubMed: 3278524]
3. Pandyan A, Gregoric M, Barnes M, et al. Spasticity: clinical perceptions, neurological realities andmeaningful measurement. Disabil Rehabil 2005;27:2–6. [PubMed: 15799140]
4. Young RR. Spasticity: a review. Neurology 1994;44:S12–S20. [PubMed: 7970006]
5. Edwards, S. Neurological Physiotherapy: A Problem-Solving Approach. 2nd ed.. Churchill
Livingstone; Edinburgh, NY: 2002.
Neurorehabil Neural Repair. Author manuscript; available in PMC 2010 April 28.

Elbasiouny et al.

Page 10

NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript

6. Levi R, Hultling C, Seiger A. The Stockholm Spinal Cord Injury Study: 2. Associations between
clinical patient characteristics and post-acute medical problems. Paraplegia 1995;33:585–594.
[PubMed: 8848313]
7. Hiersemenzel L-P, Curt A, Dietz V. From spinal shock to spasticity: neuronal adaptations to a spinal
cord injury. Neurology 2000;54:1574–1582. [PubMed: 10762496]
8. Ashby, P.; McCrea, D. Neurophysiology of spinal spasticity. In: Davidoff, RA., editor. Handbook of
the Spinal Cord. Marcel Dekker; New York, NY: 1987. p. 120-143.
9. Little J, Micklesen P, Umlauf R, Britell C. Lower extremity manifestations of spasticity in chronic
spinal cord injury. Am J Phys Med Rehabil 1989;68:32–36. [PubMed: 2917056]
10. Li Y, Gorassini MA, Bennett DJ. Role of persistent sodium and calcium currents in motoneuron
firing and spasticity in chronic spinal rats. J Neurophysiol 2004;91:767–783. [PubMed: 14762149]
11. Li Y, Harvey PJ, Li X, Bennett DJ. Spastic long-lasting reflexes of the chronic spinal rat studied invitro. J Neurophysiol 2004;91:2236–2246. [PubMed: 15069101]
12. Delwaide, PJ. Pathophysiological mechanisms of spasticity at the spinal cord level. In: Thilmann,AF.; Burke, DJ.; Rymer, WZ., editors. Spasticity: Mechanisms and Management. Springer-Verlag;
Heidelberg, Germany: 1993. p. 296-308.
13. Mailis A, Ashby P. Alterations in group Ia projections to motoneurons following spinal lesions inhumans. J Neurophysiol 1990;64:637–647. [PubMed: 2213136]
14. Kitzman P. Changes in vesicular glutamate transporter 2, vesicular GABA transporter andvesicular acetylcholine transporter labeling of sacrocaudal motoneurons in the spastic rat. Exp
Neurol 2006;197:407–419. [PubMed: 16300756]
15. McCouch GP, Austin GM, Liu CN, Liu CY. Sprouting as a cause of spasticity. J Neurophysiol
1958;21:205–216. [PubMed: 13539657]
16. Noguchi T, Homma S, Nakajima Y. Measurements of excitatory postsynaptic potentials in thestretch reflex of normal subjects and spastic patients. J Neurol Neurosurg Psychiatry
1979;42:1100–1105. [PubMed: 533849]
17. Krenz NR, Weaver LC. Sprouting of primary afferent fibers after spinal cord transection in the rat.
Neuroscience 1998;85:443–458. [PubMed: 9622243]
18. Faist M, Mazevet D, Dietz V, Pierrot-Deseilligny E. A quantitative assessment of presynaptic
inhibition of la afferents in spastics: differences in hemiplegics and paraplegics. Brain
1994;117:1449–1455. [PubMed: 7820579]
19. Delwaide, P. Human monosynaptic reflexes and presynaptic inhibition. In: Desmedt, J., editor.
New Developments in Electromyography and Clinical Neurophysiology. Karger; Basel,
Switzerland: 1973. p. 508-522.
20. Yang J, Fung J, Edamura M, Blunt R, Stein R, Barbeau H. H-reflex modulation during walking inspastic paretic subjects. Can J Neurol Sci 1991;18:443–452. [PubMed: 1782608]
21. Nielsen J, Petersen N, Ballegaard M, Biering-Sorensen F, Kiehn O. H-reflexes are less depressedfollowing muscle stretch in spastic spinal cord injured patients than in healthy subjects. Exp Brain
Res 1993;97:173–176. [PubMed: 8131827]
22. Thompson F, Parmer R, Reier P. Alteration in rate modulation of reflexes to lumbar motoneurons
after midthoracic spinal cord injury in the rat: I. Contusion injury. J Neurotrauma 1998;15:495–
508. [PubMed: 9674553]
23. Hultborn, H.; Nielsen, J. Modulation of transmitter release from Ia afferents by their preceding
activity: a “postactivation depression.”. In: Rudomin, P.; Romo, R.; Mendell, LM., editors.
Presynaptic Inhibition and Neural Control. Oxford University Press; New York, NY: 1998. p.
178-191.
24. Stein R, Estabrooks K, McGie S, Roth M, Jones K. Quantifying the effects of voluntary
contraction and inter-stimulus interval on the human soleus H-reflex. Exp Brain Res
2007;182:309–319. [PubMed: 17562030]
25. Boorman GI, Lee RG, Becker WJ, Windhorst UR. Impaired “natural reciprocal inhibition” inpatients with spasticity due to incomplete spinal cord injury. Electroencephalogr Clin
Neurophysiol 1996;101:84–92. [PubMed: 8647026]

Neurorehabil Neural Repair. Author manuscript; available in PMC 2010 April 28.

Elbasiouny et al.

Page 11

NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript

26. Crone C, Johnsen LL, Biering-Sorensen F, Nielsen JB. Appearance of reciprocal facilitation of
ankle extensors from ankle flexors in patients with stroke or spinal cord injury. Brain
2003;126:495–507. [PubMed: 12538415]
27. Boorman G, Hulliger M, Lee RG, Tako K, Tanaka R. Reciprocal Ia inhibition in patients withspinal spasticity. Neurosci Lett 1991;127:57–60. [PubMed: 1881620]
28. Rushworth G. Spasticity and rigidity: an experimental study and review. J Neurol Neurosurg
Psychiatry 1960;23:99–118. [PubMed: 14440257]
29. Hagbarth KE, Wallin G, Lofstedt L. Muscle spindle responses to stretch in normal and spastic
subjects. Scand J Rehabil Med 1973;5:156–159. [PubMed: 4272612]
30. Pierrot-Deseilligny, E.; Burke, D. The pathophysiology of spasticity and Parkinsonian rigidity. In:
Pierrot-Deseilligny, E.; Burke, D., editors. The Circuitry of the Human Spinal Cord: Its Role inMotor Control and Movement Disorders. Cambridge University Press; New York, NY: 2005. p.
556-599.
31. Crone C, Nielsen J. Methodological implications of the post activation depression of the soleus Hreflex in man. Exp Brain Res 1989;78:28–32. [PubMed: 2591515]
32. Hultborn H, Malmsten J. Changes in segmental reflexes following chronic spinal cord hemisectionin the cat: II. Conditioned monosynaptic test reflexes. Acta Physiol Scand 1983;119:423–433.
[PubMed: 6666623]
33. Bussieres N, El Manira A. GABAB receptor activation inhibits N- and P/Q-type calcium channels
in cultured lamprey sensory neurons. Brain Res 1999;847:175–185. [PubMed: 10575086]
34. Schlosser W. Action of diazepam on the spinal cord. Arch Int Pharmacodyn Ther 1971;194:93–
102. [PubMed: 4330851]
35. Li Y, Bennett DJ. Persistent sodium and calcium currents cause plateau potentials in motoneuronsof chronic spinal rats. J Neurophysiol 2003;90:857–869. [PubMed: 12724367]
36. Li Y, Li X, Harvey PJ, Bennett DJ. Effects of baclofen on spinal reflexes and persistent inward
currents in motoneurons of chronic spinal rats with spasticity. J Neurophysiol 2004;92:2694–2703.
[PubMed: 15486423]
37. Thomas CK, Ross BH. Distinct patterns of motor unit behavior during muscle spasms in spinal
cord injured subjects. J Neurophysiol 1997;77:2847–2850. [PubMed: 9163400]
38. Eken T, Hultborn H, Kiehn O. Possible functions of transmitter-controlled plateau potentials inalpha motoneurones. Prog Brain Res 1989;80:257–267. discussion 39-42. [PubMed: 2699366]
39. Hounsgaard J, Hultborn H, Jespersen B, Kiehn O. Intrinsic membrane properties causing a bistablebehaviour of alpha-motoneurones. Exp Brain Res 1984;55:391–394. [PubMed: 6086378]
40. Hounsgaard J, Kiehn O. Ca++ dependent bistability induced by serotonin in spinal motoneurons.
Exp Brain Res 1985;57:422–425. [PubMed: 2578974]
41. Lee RH, Heckman CJ. Essential role of a fast persistent inward current in action potential initiationand control of rhythmic firing. J Neurophysiol 2001;85:472–475. [PubMed: 11152749]
42. Gorassini MA, Knash ME, Harvey PJ, Bennett DJ, Yang JF. Role of motoneurons in thegeneration of muscle spasms after spinal cord injury. Brain 2004;127:2247–2258. [PubMed:
15342360]
43. ElBasiouny SM, Bennett DJ, Mushahwar VK. Simulation of dendritic Cav1.3 channels in cat
lumbar motoneurons: spatial distribution. J Neurophysiol 2005;94:3961–3974. [PubMed:
16120667]
44. ElBasiouny SM, Bennett DJ, Mushahwar VK. Simulation of Ca+2 persistent inward currents inspinal motoneurons: mode of activation and integration of synaptic inputs. J Physiol (Lond)
2006;570:355–374. [PubMed: 16308349]
45. Hammar I, Jankowska E. Modulatory effects of alpha 1-, alpha 2-, and beta-receptor agonists on
feline spinal interneurons with monosynaptic input from group I muscle afferents. J Neurosci
2003;23:332–338. [PubMed: 12514232]
46. Lee RH, Heckman CJ. Enhancement of bistability in spinal motoneurons in vivo by thenoradrenergic alpha 1 agonist methoxamine. J Neurophysiol 1999;81:2164–2174. [PubMed:
10322057]

Neurorehabil Neural Repair. Author manuscript; available in PMC 2010 April 28.

Elbasiouny et al.

Page 12

NIH-PA Author Manuscript
NIH-PA Author Manuscript
NIH-PA Author Manuscript

47. Hsiao CF, Trueblood PR, Levine MS, Chandler SH. Multiple effects of serotonin on membrane
properties of trigeminal motoneurons in vitro. J Neurophysiol 1997;77:2910–2924. [PubMed:
9212246]
48. Berger A, Bayliss D, Viana F. Modulation of neonatal rat hypoglossal motoneuron excitability byserotonin. Neurosci Lett 1992;143:164–168. [PubMed: 1436663]
49. Jacobs BL, Fornal CA. Serotonin and motor activity. Curr Opin Neurobiol 1997;7:820–825.
[PubMed: 9464975]
50. Clarke RW, Eves S, Harris J, Peachey JE, Stuart E. Interactions between cutaneous afferent inputs
to a withdrawal reflex in the decerebrated rabbit and their control by descending and segmental
systems. Neuroscience 2002;112:555–571. [PubMed: 12074898]
51. Cleland CL, Rymer WZ. Neural mechanisms underlying the clasp-knife reflex in the cat: I.
Characteristics of the reflex. J Neurophysiol 1990;64:1303–1318. [PubMed: 2258748]
52. Garraway SM, Hochman S. Modulatory actions of serotonin, norepinephrine, dopamine, andacetylcholine in spinal cord deep dorsal horn neurons. J Neurophysiol 2001;86:2183–2194.
[PubMed: 11698510]
53. Perrier J-F, Hounsgaard J. 5-HT2 receptors promote plateau potentials in turtle spinal motoneurons
by facilitating an l-type calcium current. J Neurophysiol 2003;89:954–959. [PubMed: 12574471]
54. Bras H, Jankowska E, Noga B, Skoog B. Comparison of effects of various types of NA and 5-HT
agonists on transmission from group II muscle afferents in the cat. Eur J Neurosci 1990;2:1029–
1039. [PubMed: 12106064]
55. Bennett DJ, Sanelli L, Cooke CL, Harvey PJ, Gorassini MA. Spastic long-lasting reflexes in theawake rat after sacral spinal cord injury. J Neurophysiol 2004;91:2247–2258. [PubMed:
15069102]
56. Harvey PJ, Li X, Li Y, Bennett DJ. 5-HT2 receptor activation facilitates a persistent sodium
current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord
injury. J Neurophysiol 2006;96:1158–1170. [PubMed: 16707714]
57. Russo RE, Nagy F, Hounsgaard J. Inhibitory control of plateau properties in dorsal horn neuronesin the turtle spinal cord in vitro. J Physiol (Lond) 1998;506:795–808. [PubMed: 9503338]
58. Schmit B, Benz E. Extensor reflexes in human spinal cord injury: activation by hip proprioceptors.
Exp Brain Res 2002;145:520–527. [PubMed: 12172664]
59. Schmit BD, McKenna-Cole A, Rymer WZ. Flexor reflexes in chronic spinal cord injury triggeredby imposed ankle rotation. Muscle Nerve 2000;23:793–803. [PubMed: 10797404]
60. Wu M, Hornby TG, Hilb J, Schmit BD. Extensor spasms triggered by imposed knee extension inchronic human spinal cord injury. Exp Brain Res 2005;162:239–249. [PubMed: 15586272]
61. Schomburg E, Steffens H. The effect of DOPA and clonidine on reflex pathways from group II
muscle afferents to alpha-motoneurones in the cat. Exp Brain Res 1988;71:442–446. [PubMed:
2844579]
62. Davies J, Johnston S, Lovering R. Inhibition by DS 103-282 of D-(3H) aspartate release fromspinal cord slices. Br J Pharmacol 1983;78:2.
63. Barnes, MP.; Johnson, GR. Upper Motor Neurone Syndrome and Spasticity: Clinical Management
and Neurophysiology. Cambridge University Press; Cambridge, UK: 2001.
64. Onushko T, Schmit BD. Reflex response to imposed bilateral hip oscillations in human spinal cord
injury. J Neurophysiol 2007;98:1849–1861. [PubMed: 17652410]
65. Ellis K, Carpenter J. Mechanism of control of skeletal-muscle contraction by dantrolene sodium.
Arch Phys Med Rehabil 1974;55:362–369. [PubMed: 4368898]
66. Burgen A, Dickens F, Zatman L. The action of botulinum toxin on the neuro-muscular junction. J
Physiol 1949;109:10–24. [PubMed: 15394302]
67. Rosales R, Arimura K, Takenaga S, Osame M. Extrafusal and intrafusal muscle effects inexperimental botulinum toxin-A injection. Muscle Nerve 1996;19:488–496. [PubMed: 8622728]
68. McLaughlin JF, Bjornson KF, Astley SJ, et al. Selective dorsal rhizotomy: efficacy and safety in
an investigator-masked randomized clinical trial. Dev Med Child Neurol 1998;40:220–232.
[PubMed: 9593493]

Neurorehabil Neural Repair. Author manuscript; available in PMC 2010 April 28.

Elbasiouny et al.

Page 13

NIH-PA Author Manuscript
NIH-PA Author Manuscript

69. Vodovnik L, Bowman B, Hufford P. Effects of electrical stimulation on spinal spasticity. Scand J
Rehabil Med 1984;16:29–34. [PubMed: 6608787]
70. Alfieri V. Electrical treatment of spasticity: reflex tonic activity in hemiplegic patients and selected
specific electrostimulation. Scand J Rehabil Med 1982;14:177–182. [PubMed: 6983718]
71. Dewald J, Given J, Rymer W. Long-lasting reductions of spasticity induced by skin electricalstimulation. IEEE Trans Rehabil Eng 1996;4:231–242. [PubMed: 8973949]
72. Kuo JJ, Lee RH, Johnson MD, Heckman HM, Heckman C. Active dendritic integration of
inhibitory synaptic inputs in vivo. J Neurophysiol 2003;90:3617–3624. [PubMed: 12944534]
73. Bhadra N, Kilgore KL. Direct current electrical conduction block of peripheral nerve. IEEE Trans
Neural Syst Rehabil Eng 2004;12:313–324. [PubMed: 15473193]
74. Bhadra N, Kilgore KL. High-frequency electrical conduction block of mammalian peripheral
motor nerve. Muscle Nerve 2005;32:782–790. [PubMed: 16124008]
75. Pinter M, Gerstenbrand F, Dimitrijevic M. Epidural electrical stimulation of posterior structures of
the human lumbo-sacral cord: 3. Control of spasticity. Spinal Cord 2000;38:524–531. [PubMed:
11035472]
76. Barolat G, Singh-Sahni K, Staas WJ, Shatin D, Ketcik B, Allen K. Epidural spinal cord stimulationin the management of spasms in spinal cord injury: a prospective study. Stereotact Funct
Neurosurg 1995;64:153–164. [PubMed: 8746504]
77. Hunter JP, Ashby P. Segmental effects of epidural spinal cord stimulation in humans. J Physiol
1994;474:407–419. [PubMed: 8014902]
78. Saade NE, Tabet MS, Atweh SF, Jabbur SJ. Modulation of segmental mechanisms by activation ofa dorsal column brainstem spinal loop. Brain Res 1984;310:180–184. [PubMed: 6478238]
79. Midha M, Schmitt J. Epidural spinal cord stimulation for the control of spasticity in spinal cord
injury patients lacks long-term efficacy and is not cost-effective. Spinal Cord 1998;36:190–192.
[PubMed: 9554020]
80. ElBasiouny SM, Mushahwar VK. Modulation of motoneuronal firing behavior after spinal cord
injury using intraspinal microstimulation current pulses: a modeling study. J Appl Physiol
2007;103:276–286. [PubMed: 17234800]
81. ElBasiouny SM, Mushahwar VK. Suppressing the excitability of spinal motoneurons byextracellularly applied electrical fields: insights from computer simulations. J Appl Physiol
2007;103:1824–1836. [PubMed: 17702836]

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Figure 1.

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Schematic and block diagrams illustrating the main spinal circuits involved in the control of
movement and the alteration in their excitability during spasticity. (A) Excitatoryinterneurons are represented by open circles and excitatory synapses by V-shaped bars.
Inhibitory interneurons and inhibitory synapses are represented by filled circles. Pathways
illustrated are the following: (1) the Ia-afferent fibers from 2 antagonistic muscles, their
excitatory monosynaptic connection with the homonymous motoneuron (orange), and theirinhibitory disynaptic reciprocal connection with the heteronymous motoneuron (blue); (2)the Ia-afferent inputs with their presynaptic inhibitory interneuron (PS, blue synapse); (3)group II afferents with their polysynaptic connections to the α-motoneuron throughpropriospinal neurons (PO, yellow); (4) γ-motoneurons innervating intrafusal muscle fibers(green); and (5) α-motoneurons innervating extrafusal muscle fibers (red). (B) Block
diagram summarizing the alteration in excitability of spinal mechanisms contributing to theexaggerated reflexes in spasticity. Solid arrows indicate increased input and dotted arrows
indicate reduced input after chronic spinal cord injury. PIC, persistent inward current; mn,
motoneuron.

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Figure 2.

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Block diagram illustrating the flow of events following spinal cord injury (SCI). The
differential effect of monoamines on the dorsal and ventral horns is indicated. The site ofaction and nature of effect of the various drugs and interventions used for the managementof spasticity after SCI are illustrated. Red color indicates a positive action, that is, increase,
whereas a blue color indicates a negative action, that is, reduction. A description of theeffect of each treatment method is provided in the text. 5-HT, serotonin; NE,
norepinephrine; e-Stim, electrical stimulation; PICs, persistent inward currents; ISMS,
intraspinal microstimulation

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Figure 3.

Effects of electrical stimulation techniques on the level of spasticity after spinal cord injury(SCI). Spasticity was assessed by measuring the tail-resistive forces through a force
transducer connected to the rat tail, in response to sinusoidal side-to-side tail stretches. (A)Low tail-resistive forces measured from an adult intact rat, that is, no spasticity (control
condition). (B) higher tail-resistive forces measured from an adult rat with chronic SCI at
S2/S3 in response to the same level of sinusoidal tail stretches. (C) Intraspinal
microstimulation (ISMS) current pulses (suprathreshold high-frequency sinusoidal pulses:
120 μA, 5 kHz) delivered through 4 microwires implanted in the sacral cord below thelesion of an adult rat with chronic (3 months) spinal injury; injection of ISMS pulses
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reduced the tail-resistive force in response to tail stretches. (D) AC electrical field (1 Hz,
100 mV/mm) applied along the mediolateral axis of the spinal cord through external metal
plates during tail stretches of a chronic spinal rat (3 months) with spasticity; application of
the electrical field slightly reduced the tail-resistive force. (E) Summary of mean tailresistive forces in response to tail stretches under different conditions (before SCI, 3 weeks
after SCI when spasticity was not fully developed, chronic SCI when spasticity was fully
developed, chronic SCI during the injection of ISMS current pulses, and chronic SCI during
the application of electrical fields). In these experiments, the fields were applied throughexternal plates positioned noninvasively on the outside of the rat. The effectiveness of the
fields is expected to increase substantially when applied through the metal plates/rods used
to stabilize the spine. Data presented as mean ± SD. Asterisks represent the statisticalsignificance level: **P < .01; ***P < .001.

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LikelyLikelyLikelyUnlikely

Reduction in presynaptic inhibition

Reduction in postactivation depression

Reduction in Ia-reciprocal inhibition

Fusimotor hyperexcitability

Most likely

Enhancement in the excitability of interneurons
LikelyMost likely

Enhancement in the excitability of motoneurons

Axonal sprouting

Involvement in Spasticity

Mechanism

None

Unclear

Uncertain

Moderate

High

High

High

Significance for Spasticity

28, 29

25-27

21-24

18-20

15-17

7, 13, 14

7, 10-12

References

The Likelihood of Involvement of the Various Mechanisms Thought to Contribute to Spasticity After Spinal Cord Injury and Their Extent of Significance

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Table 1Elbasiouny et al.
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