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INVITED REVIEW ABSTRACT: Spastic paresis follows chronic disruption of the central exe-cution of volitional command. Motor function in patients with spastic paresisis subjected over time to three fundamental insults, of which the last two areavoidable: (1) the neural insult itself, which causes paresis, i.e., reducedvoluntary motor unit recruitment; (2) the relative immobilization of the pareticbody part, commonly imposed by the current care environment, whichcauses adaptive shortening of the muscles left in a shortened position and

joint contracture; and (3) the chronic disuse of the paretic body part, whichis typically self-imposed in most patients. Chronic disuse causes plasticrearrangements in the higher centers that further reduce the ability to vol-untarily recruit motor units, i.e., that aggravate baseline paresis. Part I of thisreview focuses on the pathophysiology of the first two factors causing motorimpairment in spastic paresis: the vicious cycle of paresis–disuse–paresisand the contracture in soft tissues.

Muscle Nerve 31: 535–551, 2005

PATHOPHYSIOLOGY OF SPASTIC PARESIS.I: PARESIS AND SOFT TISSUE CHANGES

JEAN-MICHEL GRACIES, MD, PhD

Department of Neurology, Mount Sinai Medical Center, One Gustave L Levy Place, Annenberg 2/Box 1052, New York, New York 10029-6574, USA

Accepted 19 November 2004

Disruption of the execution of voluntary motorcommand causes paresis, which in turn commonly leads to relative immobilization and chronic disuseof the paretic body part. The latter two events con-stitute additional insults to the neural–muscular–skeletal structures involved in movement generation.Lesion- and activity-dependent plastic rearrange-ments combine to cause adaptative changes withinthe higher centers, the spinal cord, and the nonneu-ral soft tissues involved in movement (muscles, joints, skin, vessels).

As a consequence of these events, an abnormalsensitivity to muscle stretch develops in the pareticbody part, manifesting in multiple ways in patients with central paresis. A classic feature is an increasedmuscle response to phasic stretch,40,149 which invari-ably follows the rule that the higher the velocity of stretch, the more increased is the reflex.33,230 Thisobservation led to the definition of spasticity as a

velocity-dependent increase in stretch reflex.142 Pa-tients with spasticity form a clinically and physiolog-

ically recognizable population. These patients aredisabled by three main features: (1) paresis, i.e.,reduced voluntary recruitment of skeletal motorunits; (2) soft tissue contracture, in particular mus-cle shortening and joint retraction; and (3) muscleoveractivity, i.e., reduced ability to relax muscle. Thefirst part of this review discusses the pathophysiolog-ical mechanisms that lead to the first two of thesethree disabling factors.

In damage from acute events (such as stroke ortrauma), it is possible to distinguish events accordingto their stage of occurrence following the initiallesion: immediate (seconds), acute (hours anddays), and subacute/chronic (weeks, months, and years). In damage from chronic and progressive con-ditions (such as multiple sclerosis or tumors), imme-diate, acute, and chronic events tend to blend andevolve simultaneously. For the sake of clarity, themechanisms of motor impairment and their timecourse after acute damage to the central motor pathways are reviewed.

IMMEDIATE EFFECTS OF CENTRAL LESION

Paresis. Paralysis or paresis is defined as decreased vol-

untary motor unit recruitment , i.e., inability or difficulty to voluntarily recruit skeletal motor units to generatetorque or movement. An injury to higher centers may disrupt central voluntary motor command at various

Abbreviations: CNS, central nervous system; EMG, electromyogram;EPSP, excitatory postsynaptic potential; MRI, magnetic resonance imaging;MVC, maximal voluntary contractionKey words: contracture; disuse; immobilization; paresis; pathophysiologyCorrespondence to: J.-M. Gracies; e-mail: [email protected]

© 2005 Wiley Periodicals, Inc.Published online 15 February 2005 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20284

Pathophysiology of Spastic Paresis I MUSCLE & NERVE May 2005 535



levels,190 which can be grouped into higher, middle,and lower levels of command (Fig. 1).

The higher level can be subdivided into two func-tional units. The first unit provides the spatial and

temporal representation or guidance of the move-ment, i.e., it generates the kinematic parameters of themovement required: spatial location of origin and endof movement, as well as a kinematic profile includingacceleration, speed, and course. This unit correspondsto activities that have been termed motor imagination,mental representation, movement rehearsal, or spatio-temporal concept.11,103,107,122,123,215,216The mental rep-resentation of movement is assumed to involve thefollowing cortical areas: (1) posterior parietal and

lateral frontal premotor areas for sensory-based, i.e.,externally triggered functions11,103,122,123,215,216; and(2) inferior parietal and prefrontal circuits for well-learned skilled actions or internally-based functions,

i.e., automatic movements.37,92 Patients with mag-netic resonance imaging (MRI)–defined lesions of the lateral prefrontal or posterior parietal cortexmay show apraxia and deficits in motor memo-ry.187,203 These syndromes typically generate theclinical impression of excessive motor hesitation with a sense of ineluctable inaccuracy during theperformance of voluntary movement, and intensepatient frustration. However, these patients are not paretic.37,83

FIGURE 1. Movement generation. The classically opposed types of movement command, voluntary and reflex, are schematized. Thecomponents of each level of voluntary command are indicated with the proposed location of the underlying pathways. Only abnormalities

in the middle and the lower levels of command alter spinal reflexes, and only abnormalities in the lower level of motor command cause

significant paresis. Alterations in spinal reflexes mostly occur through direct pathways from the areas subserving middle and lower levels

of command to the lower motor neurons. Among the altered reflexes, responses to slow muscle stretch are evaluated by tests of

resistance to passive movements (i.e., tone), while responses to fast stretch are obtained through tendon taps. Disruptions of the central

execution of motor command (framed) are the object of this review. CAR, cutaneous abdominal responses; CPR, cutaneous plantar

responses; DTR, deep tendon reflexes.

536 Pathophysiology of Spastic Paresis I MUSCLE & NERVE May 2005



The second unit of the higher level of motorcommand generates the voluntary drive, or motiva-tion to move. It may be argued that lack of motiva-tion to move might clinically represent a pure motorform of abulia, which can be a consequence of fron-tal and bipallidal lesions.248 However, the functionalunit involved in the motivation to move likely in-

volves specific limbic pathways, particularly the me-dial frontal-subcortical (anterior cingulate) circuits, which could interface between deep limbic and neo-cortical functions.128,160,237,265 The involvement of anterior cingulate cortex activation in volition hasbeen supported in simple reaction tasks by the con-sistent observation that anterior cingulate cortex ac-tivity is associated with a gain in reaction speed, at the expense of spatial accuracy.169,171,265 Patients with MRI-defined contusions of the mesial prefron-tal cortex show slow motor performance and havereduced movement-related potentials, but are not

paretic.258

The middle level of motor command corre-sponds to the planning and preparation of the move-ment. This is the actual programming in time andspace of the various muscle contractions and relax-ations required to accomplish the movement in-tended by the higher level’s mental representation,including timing, rapidity of onset, and intensity andduration of each muscle contraction. This level of motor preparation involves the anterior part of thesupplementary motor area,45,146,199 which has recip-rocal connections with the prefrontal cortex16 andthe basal ganglia.121,180 It also involves the cerebel-lum,118,157,253 which adds this preparatory role to itsinvolvement in monitoring the movement during itsexecution and in motor learning.103,120,243 Patients with disturbances of movement preparation typically exhibit acceleration deficits. Examples include ni-grostriatal dysfunction (e.g., Parkinson’s disease), in which insufficient movement acceleration is associ-ated with decreased movement size (hypometria)and slight asymmetrical weakness44; and cerebellardysfunction, in which insufficient movement accel-eration is associated with increased movement size(hypermetria) by insufficient braking due to delayed

antagonist contraction53,259 and with increased reac-tion times.52,53 However, patients with disturbancesof movement preparation are not paretic.44,153

The lower level of central voluntary motor com-mand is the execution of the movement itself, whichis disrupted in patients who go on to develop spasticparesis. Once the movement has been conceived,decided, and planned, the plan is executed centrally by the primary motor area (Brodman area 4), cen-trum semiovale, internal capsule, and corticospinal

tract,103,200 and peripherally by the lower motor neu-ron, neuromuscular junction, and muscle. A lesionin any of the central execution areas disconnects theconcept, will, and program of the movement from itseffectors and disrupts the access of the volitionalcommand to the lower motor neuron. Although dis-turbances at the higher and middle levels may alter

motivation to move, ability to conceive movement inspace, memory of motor skills, movement planning,or movement monitoring, only lesions involving thelower level cause true paresis and are the direct concern of this article. However, additional alter-ations of the middle and higher levels remain of fundamental importance in paresis because they may limit considerably the capacity for training andthe potential for recovery (discussed later).178

Pathophysiology of Paresis. Motor Unit Recruitment

Patterns. Paresis may represent the most disabling

symptom after disruption of the execution of motorcommand.143,173 It may occur regardless of the pres-ervation of higher levels of command and, in partic-ular, of the ability to plan the movement.223 Only afew studies have investigated motor weakness early after the paralyzing insult, i.e., before the emergenceof the later effects of immobilization and disuse, andtheir associated neural and muscular plastic rear-rangements.49,105,173 To the author’s knowledge,none of these studies specified the motor unit re-cruitment pattern in the immediate phase after thelesion occurred. In subacute and chronic stages,however, the pathophysiological characteristics of the disruption of motor command execution havebeen well described. These include impersistent mo-tor unit recruitment with gaps in the interferencepattern28,78 and a reduced integrated electromyo-gram.80,114,210

Failure of Central Voluntary Activation. Abnormalpatterns of motor unit recruitment are explained at least in part by failure of central voluntary activation,as demonstrated by studies using the twitch super-imposition technique.173,196 For example, the meanlevel of maximal voluntary activation of the pareticbiceps brachii in stroke patients was found to be

66%, compared to 89% on the nonparetic side,196 whereas the muscle activation achieved in healthy young subjects is 95%–99%.4,87 Failure of central voluntary activation is associated with a loss of nor-mally functioning motor units in the spinalcord162,163,271 and with a significant reduction in themean and maximal discharge rate of voluntarily driven motor units in the paretic muscles.88,202,227,277

Reductions in firing rate affect high-threshold morethan low-threshold motor units, and a compression




of the range of motor neuron recruitment forces hasbeen found in paretic patients80,88,99 as well as inanimal models of paresis produced by spinal he-misection.22,188 There is in fact a failure to recruit high-threshold motor units and to modulate or in-crease motor unit discharge rate during attempts toincrease voluntary force.56,80,88,277

Changes in Motor Neuronal Properties in the Spinal Cord. In addition to alterations of the descendingdrive, the difficulties in motor neuron recruitment may also be related to direct changes in the proper-ties of spinal motor neurons, as shown in animals with chronic spinal transection using intracellularrecordings. Such changes include increases inthreshold voltages and threshold currents for actionpotential activation by short-duration current pulses.17,110 Regardless of the respective contribu-tions of supraspinal or spinal mechanisms, loss of normally functioning motor units and firing rate

reductions may reduce the efficiency of muscle con-traction, leading to increased effort, to fatigue, andultimately to a perceived sense of weakness for vol-untary force generation.88,115,249

Fatigability. Despite the compression in rangeof motor neuron recruitment, the normal order of recruitment from fatigue-resistant to fatigable unitsis preserved in paretic patients, i.e., no reversal of recruitment order has been found to account fortheir excessive fatigability.91 This is in contrast tosome evidence for recruitment reversal in animalsafter spinal lesion.188 The increased fatigability inpatients with spastic paresis is likely due primarily togreater central fatigue, i.e., greater decreases in vol-untary activation of lower motor neurons with pur-suit of the effort as compared with normal subjects,together with a greater difficulty in isolating contrac-tion to a muscle group.196 In fact, there are indica-tions that less severely paretic subjects are able todrive their paretic muscles to fatigue, i.e., to induceperipheral fatigue, whereas the more severely pareticsubjects—or those with less advanced motor recov-ery—cannot achieve marked peripheral fatigue ascentral fatigue (decreases in voluntary activation)occurs first.196

Compensatory Processes in the Higher Centers. Thehigher centers adapt to the lesional situation in anumber of ways to connect with and activate thelower motor neurons, and achieve movement de-spite disruption of the primary execution pathways.

First, increased task-related activation occurs inregions not normally involved with direct movement execution, such as the supplementary motor andcingulate motor areas, premotor cortex, posteriorand inferior parietal cortex, and cerebellum.179,251

Marked task-related activation in such regions may be a marker of severe disruption of command exe-cution, as this negatively correlates with motor func-tion in functional MRI studies.251,252 Activation of anterior and posterior cingulate and prefrontal cor-tices suggests that selective attentional and inten-tional mechanisms may be important in the recovery

process.255

Second, additional activation of motor areas oc-curs contralateral to the lesion, i.e., ipsilateral to themotor deficit, and the field corresponding to theparetic body parts extends in the perilesional pri-mary (sensori)motor cortex. The motor outputs inthe unaffected hemisphere are significantly changedafter unilateral hemispheric lesion, including a gen-eral increase in excitability of the cortex contralat-eral to the lesion35 and the unmasking of ipsilateralcorticospinal projections.172 The significance of these changes in terms of meaningful functional

recovery has been questioned.172 However, these bi-lateral extensions of the cortical representations of the paretic body parts and their functional impor-tance have been supported by clinical evidence fromsecondary contralateral lesions,77 by studies usingtranscranial magnetic cortical stimulation,244 and by functional MRI or positron emission tomographictechniques measuring the changes in regionalcerebral blood flow elicited during a motortask.41,58,179,209,256

Third, descending inputs other than the fast cor-ticospinal elements are used.245 Numerous animal

studies involving experimental sensorimotor cortexor spinal cord lesions support the hypothesis that motor recovery involves switching of motor activity to the control of brainstem descending pathwayssuch as the cortico-rubrospinal, the cortico-reticu-lospinal, and the cortico-vestibulospinal sys-tems.15,48,72,191,192,250,274 Propriospinal neurons may also be involved in strategies for functional recovery. After incomplete spinal cord injury in rats,transected hindlimb corticospinal tract axons sprout into the cervical gray matter to contact long propri-ospinal neurons that bridge the lesion. In turn, these

propriospinal neurons arborize on lumbar motorneurons, creating a new functional intraspinal cir-cuit that relays cortical input to its original spinaltargets.14 In stroke patients, some evidence existsthat the component of the descending commandpassing through cervical propriospinal relays in-creases during upper-limb recovery.158 These pro-priospinal neurons could be accessed via the reticu-lospinal pathways, as is the case in animalmodels.151,204




Finally, collateral sprouting of intact corticospi-nal fibers may occur.9,254 Lesions of defined compo-nents of the corticospinal motor pathway in adult rodents or monkeys lead to new corticospinal con-nections between undamaged corticospinal fibersand lower motor neurons deprived of their normaldescending input.9,254 Such new synapse formations

associated with sprouting of intact corticospinal fi-bers may contribute to motor recovery.

Significance of Maximal Voluntary Power Measure- ments in Spastic Paresis. Failure of voluntary activa-tion dramatically reduces maximal voluntary poweras the number of recruited motor units is the mainfactor accounting for the power developed by a mus-cle.184 The ability to voluntarily recruit motor unitsin patients with chronic spastic paresis is often asym-metric around joints, with the lower-limb hamstringsand plantarflexors contracting proportionately morethan quadriceps and dorsiflexors.96,173 Similarly,

measurements of maximal voluntary power in spasticparesis commonly show an asymmetric distributionof weakness between agonists and antagonists across joints.42,86,124,173 However, strength measurements inspastic paresis, whether dynamometric or clinicalusing the Medical Research Council scale, do not provide a reliable assessment of voluntary agonist activation, as they may be confounded by resistancefrom soft tissue contracture and antagonistic cocon-traction.96,135 Yet, regardless of their physiologicalmeaning, these measurements consistently correlate with functional outcome in different stud-ies.23,24,29,47,71,170,174

In terms of functional impairment, weaknesscaused primarily by failure of lower motor neuronactivation and potential changes in motor neuronproperties is likely the prominent issue acutely afterlesion onset. However, the relative contribution tofunctional disability of subsequent events such as soft tissue shortening and muscle overactivity may in-crease in the subacute and chronic stages of spasticparesis.173

Flaccidity. Acute disruption of the execution of vo-litional command typically involves descending path-

ways that modulate spinal cord reflex circuitry. Thiscommonly translates into the immediate but usually transient extinction of most spinal reflex responses,including stretch reflexes, which manifests itself clin-ically by an initial flaccidity.139,177,218 In a minority of cases, flaccidity persists chronically after occurrenceof a central lesion, e.g., with some spinal cord in-farcts25,132,193 or cerebral lesions.177 Persistent flac-cidity is often associated with a greater degree of paresis and poorer outcome,36,79,82,133,177,197,221 al-

though this is not always the case.159,201 Occasionally,a secondary reduction of spasticity is also observedmonths after spinal cord injury, which may suggest secondary impairment or degeneration of premotorneuronal circuits or of motor neurons.108

ACUTE AND CHRONIC EFFECTS OF IMMOBILIZATION

AND DISUSE

Most limb-use implies mobilization. Immobilizationis the peripheral situation of lack of passive or activemovement around a joint. Disuse is the central be-havior of lack of voluntary command exerted on alimb. Although these are two different phenomena,they tend to occur in parallel, particularly in patients with disruption of the execution of central com-mand. Thus, evidence in the literature for the re-spective consequences of each is scarce, as a disusedlimb is often relatively immobilized, and an immo-bilized limb (e.g., in a splint) is often relatively dis-

used, both in human patients and animal research.In fact, limb immobilization has often been used asan experimental model of disuse.62,97,125,148,257,273

Most situations of joint immobilization place one of the muscles around the joint in a shortened position,potentially causing decreased neural stimulation onthis muscle secondary to decreased tonic stretch, which may in turn aggravate muscle disuse.224 Thefirst section below addresses the peripheral effects of immobilization and disuse, particularly on muscleand joints; these effects begin acutely and have beenprimarily attributed to immobilization. The second

section addresses the central effects, which seem tohave a slower temporal profile and have been pri-marily attributed to disuse.

PERIPHERAL EFFECTS OF IMMOBILIZATION IN A

SHORTENED POSITION

This series of peripheral events begins acutely afterthe injury while the patient is still in the emergency room or acute care unit.

Muscle Contracture . Paresis immediately leaves theaffected muscles immobilized. In the standard envi-

ronment of acute care, patients are placed in stretch-ers for extended periods, usually with the pareticlower limbs in full extension and the paretic upperlimbs positioned with shoulder internally rotated,elbow flexed and pronated, and often wrist andfingers flexed.2 Thus, among the paretic muscles,some are commonly immobilized in a shortenedposition, often including the lower-limb extensorsand upper-limb internal rotators, pronators, andflexors. This immobilization in a shortened position




causes a reduction in longitudinal tension, or muscleunloading, which is chronologically the first mecha-nism for muscle contracture. Post-unloading mus-cle contracture in spastic paresis includes atrophy (loss of muscle mass), loss of sarcomeres (shorten-ing), and accumulation of connective tissue andfat, as demonstrated both in animals and hu-

mans.12,165–167,222,228,262 In addition, the loss of nor-mal weight-bearing or counter-resistance activity, which occurs during limb immobilization or disuse(bed rest), stimulates a catabolic response within themusculoskeletal system, resulting in a loss of skeletalmuscle mass and cross-sectional area, and a reduc-tion in bone mineralization.5,21,43,75,205,206,273 Each of the mechanisms of contracture in the muscle immo-bilized in a shortened position is reviewed here infurther details.

Atrophy. Immobilization associated with in-duced paresis causes muscle atrophy in animal ex-

periments, with an atrophy rate that negatively cor-relates with the length at which the muscle isimmobilized.66 The muscle atrophy caused by in-duced paresis is incompletely prevented by forcedimmobilization in a lengthened position.66 In non-paretic humans, immobilization causes decreased fi-ber diameter247 and a reduction in the cross-sec-tional area and volume of the whole muscle,247,257,273

and muscle unloading reduces the capacity for pro-tein synthesis.73,85 In chronic hemiplegic patients,hemiparetic skeletal muscles are atrophic comparedto the nonparetic side, more so in the paretic armthan leg.208

Loss of Sarcomeres. Muscles maintained in ashortened position adapt to their resting length andlose sarcomeres until those remaining overlap opti-mally to enable the muscles to develop maximaltension at the immobilized length.222,261 The mainstimulus for adaptation seems to be the imposedlength more than the immobilization itself, as mus-cles immobilized in a neutral position do not develop significant changes in stiffness or sarcomerenumbers and those immobilized in a lengthenedposition undergo an increase in the number of sar-comeres in series.222,261

Accumulation of Intramuscular Connective Tissue.Quantitative and qualitative changes in the intramus-cular connective tissue are also likely to contribute toincreased stiffness (reduced extensibility) of the im-mobilized skeletal muscle and to a deterioration infunction.116,137 Immobilization of rat muscles resultsin a marked increase in the endo- and perimysialconnective tissue, and in a substantial increase in thenumber of perpendicularly oriented collagen fibers with contacts with two adjacent muscle fibers in the

endomysium.116 There is overall an increase in theratio of collagen to muscle-fiber tissue93,222,261,262,268

with concomitant changes in gene expression that are now better understood.95,150,266,270

Increased Fat Content. In chronic hemiplegic pa-tients, hemiparetic skeletal muscles have an in-creased fat content compared to the nonparetic side,

a finding that is more pronounced in the paretic armthan leg.208 Fat accumulation also occurs within thetendons of paretic muscles in both flaccid andspastic paresis, and these abnormal fat deposits com-monly contain disconnected and degeneratedmechanoreceptors, including Ruffini and Pacini cor-puscles, Golgi tendon organs, and free nerve end-ings.119

Degenerative Changes at the Myotendinous Junction .Immobilization causes a decrease in vascular density and degenerative changes at the myotendinous junc-tion, which most likely decrease its tensile

strength.126,138

Increase in Mechanical Spindle Stimulation by

Stretch. Finally, the reduced extensibility after im-mobilization in a shortened position causes any pull-ing force to be transmitted more readily to the spin-dles.89 There is thus an increase in spindle responsesthat augments stretch reflexes and eventually con-tributes to the stretch-sensitive forms of muscle over-activity.89,154,260

Time Course of Muscle Contracture. The process of muscle contracture is acute.12,26,27,165–168 Decreasesin protein synthesis rate in the muscles of immobi-lized limbs occur during the first 6 h of immobiliza-tion, and this decrease probably plays a role in initi-ating muscular atrophy.26,27 In McLachlan’s series of studies on mouse soleus muscles, after only 24-hunloading, there was already a 60% shortening of muscle fiber length and sarcomere disorganiza-tion.165–168 The increase in amount of connectiveperimysium occurs after only 2 days of immobiliza-tion in a shortened position.94

In the subacute and chronic stages of spasticparesis, the emergence of muscle overactivity be-comes an additional mechanism of contracture, su-

perimposed on immobilization, which will lead tochronic aggravation of contractures.

Clinical Manifestations of Muscle Contracture. Clini-cally, adaptive muscle shortening may initially con-tribute to a first clinical stage of decrease in passivemuscle extensibility (also termed increased non-reflex stiffness or reduced muscle compliance) seenin patients with spastic paresis, whereby a noncon-tracting muscle passively opposes stretch with an




abnormally increased torque for a given degree of lengthening, as compared with normal muscle.30,228

There is likely correlation between the degree andduration of immobilization and disuse and the sub-sequent lack of muscle extensibility. Muscle stiffnesscan be quantified in patients with spasticity.104 Inthree studies of chronic hemiparetic patients with

plantarflexor hypertonia, the nonreflex stiffnessmeasured in the paretic limb was greater than thestiffness in the contralaleral nonparetic limb, whichitself was consistently greater than that of age-matched controls.90,141,214 It has been shown that soft tissue contracture makes a significant contributionto clinical ratings of resistance to passive movement,such as with the Ashworth scale.246 For clinical pur-poses, to accurately assess muscle stiffness, the mus-cle should be stretched no more than one time if possible, as a subsequent stretch encounters a stiff-ness reduced by 20%–60% compared to the initial

stiffness, particularly after a prior stretch of largeamplitude.182 It also requires ensuring as much aspossible that the muscle is at rest, as muscle contrac-tion causes greater resistance to stretch, particularly contraction of slow units.182

When insufficiently treated, the ever-decreasingpassive muscle extensibility in spastic paresis leads toa second clinical stage of loss of range of mo-tion.55,112,155,175,213,229 Beyond clinical stiffness andloss of range of motion, muscle contracture may alsocontribute to fatigability, as a shorter muscle is moretaut than normal for a given joint angle, and amuscle contracting in a taut position fatigues morerapidly.10

Joint Retraction. The degree and the clinical signif-icance of joint retraction in spastic paresis shouldnot be underestimated, particularly as a delayed but potentially major phenomenon in chronic stages. A compelling animal study of joint immobilization as-sessed the specific role of articular structures in limbstiffness using myotomies at different times afteronset of the immobilization.238 The authors demon-strated a dramatic increase from 38.5% to 98.5% inthe role played by articular structures in the limita-

tion in range of motion from 2 to 32 weeks of immobilization, whereas the relative myogenic con-tribution reciprocally decreased over time. The gen-eralizability and the time course of such a pattern of changes after immobilization in humans are un-known. However, clinicians experienced in the as-sessments of passive range of motion in patients withchronic spastic paresis may observe that the type of resistance encountered at the end of the range of motion may change from relatively elastic at an early

stage after injury to a more solid, less elastic resis-tance, after some years.

Histological and biochemical animal studies haveshed light on the mechanisms of joint retraction inimmobilized limbs. These include proliferation of fibrofatty connective tissue within the joint space,adhesions between synovial folds, adherence of fi-

brofatty connective tissue to cartilage surfaces, atro-phy of cartilage, ulcerations at points of cartilage–cartilage contact, disorganization of cellular andfibrillar ligament alignment, and regional osteopo-rosis of the involved extremity.3,18,147 In particular, asis the case with muscle and other soft tissue, anincreasing body of evidence suggests that immobi-lized joints adapt to their new position by modifyingthe length of some compartments of the synovialintima.241 The decrease in synovial intima length with immobility suggests that adhesions of synovial villi rather than pannus proliferation are the major

pathophysiological changes leading to contractureafter immobility.239

In nontraumatically immobilized joints of ro-dents, dense connective tissue remodels in such a way that range of motion is still unaffected after 2 weeks, but becomes limited by 6 weeks.195 However,ultrastructural modifications may already be present at 2 weeks. Thinning of intraarticular cartilage andan increase in synovial fluid precede the occurrenceof intraarticular adhesions.76 In a sham-controlledstudy of knees immobilized in flexion in rats, a de-creased number of proliferating synoviocytes andincreased intima adhesion in the posterior capsule was present after 2 weeks of immobilization.241 Car-tilage surface irregularities also appear after 2 weeksof immobilization and progress rapidly to plateauafter 8 weeks.242 These abnormalities are associated with enzymatic changes as prostaglandin endoperox-ide H synthase (PGHS) isozymes (or cyclooxygenase,COX) are decreased in the synovium and increasedin the chondrocytes after immobilization.240

Changes in Contractile Muscle Properties. A switchtoward faster contractile machinery may represent the predominant change in the contractile proper-

ties of immobilized and disused muscles. However,opposite findings (preferential atrophy of fast fibers)are also observed after disuse in animals as well ashumans. The nature of these changes (slow-to-fast orfast-to-slow) may depend on the initial motor unit type and duration of disuse.

Animal Data. In animal experiments of limb im-mobilization, muscles initially composed predomi-nantly of type I fibers (i.e., “red,” low threshold, slow twitch, fatigue-resistant, well equipped for oxidative




metabolism and for semi-isometric contractions,such as soleus muscle fibers), take on propertiescharacteristic of type II muscles, (i.e., “white,” highthreshold, fast twitch, and fatigue-sensitive).26,31,32

However, immobilization-induced changes may vary according to the initial motor unit type, with somefast muscles such as the gastrocnemius, or mixed

type I and type II muscles such as the tibialis anterioror peroneus longus, undergoing a shift toward slow unit behavior183 and preferential atrophy of type IIfibers.188,198

In animal experiments of chronic spinal cordtransection or hindlimb suspension, disused musclesalso assume faster twitch properties as evidenced by shorter time to peak tension, shorter half-relaxationtime, and reduction in fatigue resistance.8,43,156,205,226

Again, these changes may be lacking in the pareticrat tibialis anterior, which is a mixed muscle.98,185,186

Changes in type I fibers also include an initial reduc-

tion of contractile forces and a trend for secondary recovery,226 whereas the oxidative capacity seemsmaintained.176

In biochemical terms, most models of muscledisuse in animals, including microgravity, hindlimbsuspension, spinal cord isolation, spinal cord tran-section, denervation, and immobilization in a short-ened position, result in increased expression of fast myosin heavy chain isoforms at the protein or mRNA levels in normally slow-twitch rat muscles.181,224,225

These muscle changes might be reversible usingelectrical stimulation. Stimulation of fast-twitch mus-cle in animals (beyond 5% of daily time for periodsas short as 4 days) tends to switch back the predom-inant muscle fiber from type II to type I, with in-creased muscle endurance (decreased fatigability),decreased maximal muscle force, and significantly larger forces produced by low motor neuron firingrates.129–131,263 These changes appear to be revers-ible again if the muscle returns to its prior level of activity.131 Short, daily bouts of shortening, length-ening, or isometric contractions are other effectivemeans to limit the loss in mass and force potential of disused muscle in animals, but the isometric stimu-lation regimen is the most effective.207,275

Human Data. In intact humans, a few weeks of muscle immobilization leads to significant loss of force output and integrated electromyogram (EMG)during maximal voluntary contraction, prolongationof twitch contraction and relaxation times, and ahigher proportion of high-threshold motor units re-cruited for a given force development.61,62,247,257,273

The order of recruitment is maintained, with un-changed motor unit firing rate at recruitment but decreased maximal firing rate particularly for low-

threshold motor units.62 Increased muscle fatigabil-ity and a significant shift toward type II fiber typemay take more than 4 weeks of immobilization tooccur.62,102,247,273 Maximal twitch tension may be de-creased,61 unchanged,257 or increased273 dependingon which muscle is immobilized and the duration of immobilization.

Periods without weight bearing in humans withan intact central nervous system (CNS) also havesignificant effects on skeletal muscle.13 Bed rest for a few weeks reduces maximal voluntary strength19,21,64,68,144,145 and maximal rectified EMG,21

decreases the maximum torque per cross-sectionalarea,21 leads to greater fatigability,19 and tends togenerate transformation toward fast phenotypic pro-tein expression including type II myosin heavy chainisoforms,7,276 although this may depend on the du-ration of bed rest and the muscle type.21,74,109

The adaptations of the contractile characteristics

of the affected muscles in spastic hemiplegia andspinal cord injury grossly reproduce those occurringduring immobilization and unloading in subjects with an intact CNS. These include: (1) decreases inmean forces and integrated EMGs generated duringmaximal voluntary efforts235; (2) prolongation of mean twitch contraction times of fast-twitch but not slow-twitch units234,272; (3) larger twitch tensionsgenerated by motor units, especially slow motorunits; (4) appearance of a new type of motor unit characterized by slow-twitch contraction times andincreased fatigability (“slow fatigable” units)272; (5)gradual transformation over months toward fast phe-notypic protein expression including type II myosinheavy chain isoforms (reversible with functional elec-trical stimulation)6,34,39,98,264; and (6) histologicalpredominance of type II fibers.100 Slow-to-fast changes have been found particularly in the tibialisanterior of paretic humans, where an increase inproportion of type II fibers is found compared tonormal muscle, with an accompanying increase inthe torque developed for a given motor unit recruit-ment.69,70,98,114,115 Studies in spastic paresis showinga high-tension development for a moderate increasein EMG activity 54,56,57,113,173,196 are also consistent

with a shift to faster contractile machinery in humanparetic muscles.

However, an increase in torque/EMG ratio alonecannot be taken as an acceptable demonstration of achange toward faster contractile motor unit proper-ties. High torque/EMG ratios may be due to changesin passive muscle properties, in particular to thedecreased resting length of the muscle and concom-itant changes in mechanical advantage: for a given joint position and a given motor unit recruitment, a




shortened muscle, such as is the case in spastic pa-resis is relatively taut before the contraction and thusdevelops greater torque than a slack muscle.1,194 Inaddition, as in animals, there have been suggestionsthat in human subjects the direction of the slow/fast shift may also depend on the initial fiber type. Inspastic hemiplegia, preferential type II fiber atrophy

and predominance of type I fibers are noted in fast muscles such as gastrocnemius,56 and there is pro-longation of twitch contraction times in fast units of the first dorsal interosseous.272 Studies of the EMGresponse to fatigue also show preferential atrophy of type II fibers in paretic gastrocnemius medialis(fast)46 or tibialis anterior (mixed).217,236 Despitethese changes in muscle fibers, the range of axonalconduction velocities in the peripheral nerve is un-changed, suggesting that in humans, there is noselective loss of one class of motor neurons afterparesis.114

Changes at the Endplate. Human muscle immobili-zation, in the absence of any neuromuscular disease,can result in a reversible dysfunction of neuromus-cular transmission, as evidenced by increased neuro-muscular jitter.97 In animals, muscle unloading may induce endplate changes that include decreases inacetylcholine transcripts in nonweight-bearing mus-cles,189 and expansion of acetylcholine vesicles andreceptor areas.50,219 The clinical significance of theseobservations is unknown.

CENTRAL EFFECTS OF DISUSE

In the context of paresis due to injury of the centralmotor pathways, a vicious cycle unfolds whereby self-imposed chronic disuse (which Taub et al. termed“learned non-use”)232 leads to CNS changes that themselves further challenge the execution of volun-tary command. There is compelling evidence in hu-mans that changes in habitual physical activity cancause adaptations in the nervous system.134 Whenthe level of physical activity in a body part declines,for example, due to chronic limb restraint, the re-duced physiological demands evoke adaptations that

decrease the capabilities of the involved organs.63The neural adaptations that accompany alterationsin the chronic patterns of physical activity seem tooccur at all levels of the neuraxis,63 with disuse af-fecting not only the biochemical and physiologicalproperties of the muscle fibers but also motor neu-ron recruitment capabilities.164

Few studies of disuse per se have been carried out in humans. The human studies that have come clos-est to testing disuse from a functional point of view

are experiments of immobilization,62,125,148,211,257,273

muscle unloading, either by limb suspension or by microgravity,5,233 bed rest,127,220,269 and observationsof the nonparetic side in hemiplegic patients in theacute phase after stroke.105 The main consequencesof disuse in the central nervous system are reviewedbelow.

Decrease in Maximal Voluntary Power. Maximal vol-untary power decreases after only a few weeks of muscle immobilization,60,62,111,211,257,273 limb unload-ing without immobilization (e.g., the use of a crutchto prevent one lower limb from weight-bearing),20 orbed rest.21,75,127,220,269 The decline in strength ap-pears to increase with the duration of disuse,101 isparticularly marked in antigravity muscles, and is out of proportion to the decrease in muscle cross-sec-tional area or muscle mass.220 Decreased neural in-put to muscle may be involved, as well as reduced

specific tension of muscle, which has been suggestedby decreased torque/EMG ratios after bed rest orcasting in neurologically intact subjects, i.e., in mod-els of nonparetic unloaded or immobilized mus-cles.21,220,257,269

The nonparetic side of hemiplegic subjects alsoundergoes relative disuse, particularly during theacute period after stroke. It has been shown that weakness dramatically develops in the unaffected legin the first week after acute hemiplegic stroke, and iscorrelated with the percentage change in body weight.105 Weakness on the nonparetic side has beenconfirmed at chronic stages42 together with deficitsin dexterity and coordination.51

Failure of Voluntary Activation. Following immobili-zation, the peak force achieved during a maximum voluntary contraction (MVC) is dramatically lessthan can be evoked from the muscle by electricalstimulation.60 The concomitant reduction of maxi-mal voluntary EMG after periods of bed rest,21,59

limb immobilization,60,62,273 and limb unloading65 isnot solely due to decreases in motor unit size ornumber. The maximal firing rate also decreases inall motor units after immobilization, with greater

decreases in motor units of low threshold than inthose of high threshold.61 The voluntary force devel-oped by the whole muscle at such low firing rates hasbeen found to be relatively enhanced212 despite de-clines in the maximal force developed by individualmotor units.81

Taking these elements together, it has been hy-pothesized that the motor drive, i.e., the ability toactivate muscle by voluntary command, is reducedfollowing disuse.59,60,163 This has been confirmed us-




ing the twitch superimposition technique in bed-rest experiments127 and in the nonparetic side in hemi-plegic subjects.173,196 In the nonparetic side of hemi-plegic patients, however, the ipsilateral commanddysfunction associated with a unilateral brain lesionmay also contribute to the failure of activation, as not all nonparetic muscles remain disused (e.g., grip

strength was found to be normal in chronicstages).51 The question of progressive failure of vol-untary activation in chronically disused nonpareticmuscles may only be answered with a longitudinalstudy.

Altered Cortical Map and Motor Cortex Excitability.

Prolonged disuse of a body part leads to decreasedcortical excitability in the areas involved with thecommand of that body part. Specifically, humanstudies of limb immobilization showed an alteredhigher level of motor command (movement imagi-

nation) and a decreased motor representation of theimmobilized body parts.125,134 For instance, immobi-lization of an ankle joint for 4 to 6 weeks reduces thecortical area from which responses in the tibialisanterior can be evoked with transcranial magneticstimulation, an effect that increases with the dura-tion of immobilization.148 Such decreased corticalexcitability likely contributes to the decline in volun-tary muscle activation after immobilization.

Sensory Disuse: Potential Role in Affecting Voluntary

Motor Neuron Activation. Limb disuse involves im-mobilization, which implies additional disuse of sen-sory afferents. This may eventually alter sensory pro-cessing along spinal and cortical pathways,38 which if prolonged may in turn further impair voluntary ac-tivation of motor neurons. As a part of its critical rolein motor function,161 sensory feedback specifically contributes to the descending drive in simple volun-tary efforts. In humans, there has been no experi-mental situation reproducing global dysfunction incentral sensory pathways from a whole limb. How-ever, compelling acute alterations of motor com-mand have been shown resulting from loss of sen-sory input from a single peripheral nerve (obtained

by transient block). Macefield and colleagues re-corded the discharge rate of motor neurons to thetibialis anterior before and after blocking the com-mon peroneal nerve with anesthesia distal to the siteof intraneural recording.152 The nerve block causedthe average discharge rate during a maximal effort to decrease from 28.2 to 18.6 Hz. It was estimatedthat muscle afferents in the common peroneal nervefacilitated the output of the motor neuron pool by about 30% at all levels of voluntary activation. The

afferent feedback available for calibrating centralmotor command also impacts on the degree of forceresolution during a voluntary effort.106 The magni-tude of alterations of sensory processing along spinaland cortical pathways in chronic disuse and of theirimpact on voluntary activation is unknown.

Increased Reflex Excitability at the Spinal Level. Clas-sic experiments showed that sensory disuse causes anincrease in central synaptic efficacy with increasedhomonymous excitatory postsynaptic potential(EPSP) amplitudes on the deafferented motor neu-ron.84 After hindlimb suspension in animals, alteredsynaptic efficiency has been noted at the spinal cordlevel, with relative enhancement of H reflexes.8,67

Similar findings were observed after immobilizationor unloading in healthy humans.125,211 Decreasedthresholds for spinal reflexes are also observed after3–6 months in microgravity in human astronauts; in

particular, the tendon responses are increased de-spite decreased muscle stiffness.136,140 These changesin spinal cord excitability may depend on the dura-tion of disuse, as they are not found after short periods of human limb immobilization.117,125 They may contribute to the muscle overactivity that grad-ually develops after disruption of the execution of voluntary command.

Reversal of the Effects of Disuse by Forced Use. Re-cent experimental evidence has shown that the CNSeffects of chronic disuse (learned non-use)232 can be

reversed or at least minimized in spastic paresis by forcing patients to use their affected limb again. Inhemiplegic patients, such forced use may beachieved by constraining the nonparetic upper limbfor a few hours a day, using the technique of con-straint-induced movement therapy.231 Application of such a method for a few weeks decreases cerebralactivation during a motor task (as measured by positron emission tomography), and increases mo-tor map size (as measured by transcranial magneticstimulation) in the motor cortex of the affectedhemisphere.267 These changes occur in parallel withfunctional improvement in the affected side and arelikely to reflect improved ability to recruit uppermotor neurons of the paretic limb.267

CONCLUSION

Following a central lesion causing paresis, the stan-dard medical environment and “normal” human be-havior in patients are responsible for two additionalbut potentially avoidable insults to the peripheralsoft tissues and central nervous system: limb immo-




bilization and central disuse. The mechanisms involved in paresis and soft tissue contracture werereviewed, with particular emphasis on the specificconsequences of immobilization and disuse in pa-retic body parts. Failure of voluntary motor neuronactivation and changes in properties of spinal motorneurons are major components in the pathophysiol-

ogy of the paresis due to the initial lesion. However,the motor impairment due to paresis is greatly ag-gravated by the muscle and joint contracture and thechanges in muscle contractile properties caused by immobilization. In addition, chronic disuse causesan alteration of CNS function that further reducesthe ability to voluntarily recruit motor units, i.e., that aggravates paresis. To optimize motor recovery, this vicious cycle of paresis–disuse–further paresis must be disrupted. Intense limb mobilization initiated im-mediately after the CNS lesion and, when possible,intense education and motivation toward daily

forced use or forced mental rehearsing of move-ments with the paretic limbs are logical strategies toprevent these two additional factors.

I am grateful to Mara Lugassy, MD, and Robert Kahoud, MD, fortheir careful and expert review of the manuscript.

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3. fisiopat paresia spastica i paresia y tej blando

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