ABSTRACT: Spastic paresis follows chronic disruption of the central execution of volitional command. Motor function in patients with spastic paresis is subjected over time to three fundamental insults, of which the last two are avoidable: (1) the neural insult itself, which causes paresis, i.e., reduced voluntary motor unit recruitment; (2) the relative immobilization of the paretic body part, commonly imposed by the current care environment, which causes adaptive shortening of the muscles left in a shortened position and joint contracture; and (3) the chronic disuse of the paretic body part, which is typically self-imposed in most patients. Chronic disuse causes plastic rearrangements in the higher centers that further reduce the ability to voluntarily recruit motor units, i.e., that aggravate baseline paresis. Part I of this review focuses on the pathophysiology of the first two factors causing motor impairment in spastic paresis: the vicious cycle of paresis– disuse–paresis and the contracture in soft tissues.
Muscle Nerve 31: 535–551, 2005

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

of the execution of voluntary motor command causes paresis, which in turn commonly leads to relative immobilization and chronic disuse of the paretic body part. The latter two events constitute additional insults to the neural–muscular– skeletal structures involved in movement generation. Lesion- and activity-dependent plastic rearrangements combine to cause adaptative changes within the higher centers, the spinal cord, and the nonneural soft tissues involved in movement (muscles, joints, skin, vessels). As a consequence of these events, an abnormal sensitivity to muscle stretch develops in the paretic body part, manifesting in multiple ways in patients with central paresis. A classic feature is an increased muscle response to phasic stretch,40,149 which invariably follows the rule that the higher the velocity of stretch, the more increased is the reflex.33,230 This observation led to the definition of spasticity as a velocity-dependent increase in stretch reflex.142 Patients with spasticity form a clinically and physiologAbbreviations: CNS, central nervous system; EMG, electromyogram; EPSP, excitatory postsynaptic potential; MRI, magnetic resonance imaging; MVC, maximal voluntary contraction Key words: contracture; disuse; immobilization; paresis; pathophysiology Correspondence to: J.-M. Gracies; e-mail: © 2005 Wiley Periodicals, Inc. Published online 15 February 2005 in Wiley InterScience (www.interscience. DOI 10.1002/mus.20284


ically recognizable population. These patients are disabled by three main features: (1) paresis, i.e., reduced voluntary recruitment of skeletal motor units; (2) soft tissue contracture, in particular muscle shortening and joint retraction; and (3) muscle overactivity, i.e., reduced ability to relax muscle. The first part of this review discusses the pathophysiological mechanisms that lead to the first two of these three disabling factors. In damage from acute events (such as stroke or trauma), it is possible to distinguish events according to their stage of occurrence following the initial lesion: immediate (seconds), acute (hours and days), and subacute/chronic (weeks, months, and years). In damage from chronic and progressive conditions (such as multiple sclerosis or tumors), immediate, acute, and chronic events tend to blend and evolve simultaneously. For the sake of clarity, the mechanisms of motor impairment and their time course after acute damage to the central motor pathways are reviewed.

Paralysis or paresis is defined as decreased voluntary motor unit recruitment, i.e., inability or difficulty to voluntarily recruit skeletal motor units to generate torque or movement. An injury to higher centers may disrupt central voluntary motor command at various

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FIGURE 1. Movement generation. The classically opposed types of movement command, voluntary and reflex, are schematized. The components 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.

levels,190 which can be grouped into higher, middle, and lower levels of command (Fig. 1). The higher level can be subdivided into two functional units. The first unit provides the spatial and temporal representation or guidance of the movement, i.e., it generates the kinematic parameters of the movement required: spatial location of origin and end of movement, as well as a kinematic profile including acceleration, speed, and course. This unit corresponds to activities that have been termed motor imagination, mental representation, movement rehearsal, or spatiotemporal concept.11,103,107,122,123,215,216 The mental representation of movement is assumed to involve the following 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 welllearned skilled actions or internally-based functions, i.e., automatic movements.37,92 Patients with magnetic resonance imaging (MRI)– defined lesions of the lateral prefrontal or posterior parietal cortex may show apraxia and deficits in motor memory.187,203 These syndromes typically generate the clinical impression of excessive motor hesitation with a sense of ineluctable inaccuracy during the performance of voluntary movement, and intense patient frustration. However, these patients are not paretic.37,83


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The second unit of the higher level of motor command generates the voluntary drive, or motivation to move. It may be argued that lack of motivation to move might clinically represent a pure motor form of abulia, which can be a consequence of frontal and bipallidal lesions.248 However, the functional unit involved in the motivation to move likely involves specific limbic pathways, particularly the medial frontal-subcortical (anterior cingulate) circuits, which could interface between deep limbic and neocortical functions.128,160,237,265 The involvement of anterior cingulate cortex activation in volition has been supported in simple reaction tasks by the consistent observation that anterior cingulate cortex activity 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 prefrontal cortex show slow motor performance and have reduced movement-related potentials, but are not paretic.258 The middle level of motor command corresponds to the planning and preparation of the movement. This is the actual programming in time and space of the various muscle contractions and relaxations required to accomplish the movement intended by the higher level’s mental representation, including timing, rapidity of onset, and intensity and duration of each muscle contraction. This level of motor preparation involves the anterior part of the supplementary motor area,45,146,199 which has reciprocal connections with the prefrontal cortex16 and the basal ganglia.121,180 It also involves the cerebellum,118,157,253 which adds this preparatory role to its involvement in monitoring the movement during its execution and in motor learning.103,120,243 Patients with disturbances of movement preparation typically exhibit acceleration deficits. Examples include nigrostriatal dysfunction (e.g., Parkinson’s disease), in which insufficient movement acceleration is associated with decreased movement size (hypometria) and slight asymmetrical weakness44; and cerebellar dysfunction, in which insufficient movement acceleration is associated with increased movement size (hypermetria) by insufficient braking due to delayed antagonist contraction53,259 and with increased reaction times.52,53 However, patients with disturbances of movement preparation are not paretic.44,153 The lower level of central voluntary motor command is the execution of the movement itself, which is disrupted in patients who go on to develop spastic paresis. Once the movement has been conceived, decided, and planned, the plan is executed centrally by the primary motor area (Brodman area 4), centrum semiovale, internal capsule, and corticospinal

tract,103,200 and peripherally by the lower motor neuron, neuromuscular junction, and muscle. A lesion in any of the central execution areas disconnects the concept, will, and program of the movement from its effectors and disrupts the access of the volitional command to the lower motor neuron. Although disturbances at the higher and middle levels may alter motivation to move, ability to conceive movement in space, memory of motor skills, movement planning, or movement monitoring, only lesions involving the lower level cause true paresis and are the direct concern of this article. However, additional alterations of the middle and higher levels remain of fundamental importance in paresis because they may limit considerably the capacity for training and the potential for recovery (discussed later).178 Motor Unit Recruitment Patterns. Paresis may represent the most disabling symptom after disruption of the execution of motor command.143,173 It may occur regardless of the preservation of higher levels of command and, in particular, of the ability to plan the movement.223 Only a few studies have investigated motor weakness early after the paralyzing insult, i.e., before the emergence of the later effects of immobilization and disuse, and their associated neural and muscular plastic rearrangements.49,105,173 To the author’s knowledge, none of these studies specified the motor unit recruitment pattern in the immediate phase after the lesion occurred. In subacute and chronic stages, however, the pathophysiological characteristics of the disruption of motor command execution have been well described. These include impersistent motor unit recruitment with gaps in the interference pattern28,78 and a reduced integrated electromyogram.80,114,210 Failure of Central Voluntary Activation. Abnormal patterns of motor unit recruitment are explained at least in part by failure of central voluntary activation, as demonstrated by studies using the twitch superimposition technique.173,196 For example, the mean level of maximal voluntary activation of the paretic biceps 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 normally functioning motor units in the spinal cord162,163,271 and with a significant reduction in the mean and maximal discharge rate of voluntarily driven motor units in the paretic muscles.88,202,227,277 Reductions in firing rate affect high-threshold more than low-threshold motor units, and a compression
Pathophysiology of Paresis.

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of the range of motor neuron recruitment forces has been found in paretic patients80,88,99 as well as in animal models of paresis produced by spinal hemisection.22,188 There is in fact a failure to recruit high-threshold motor units and to modulate or increase motor unit discharge rate during attempts to increase voluntary force.56,80,88,277 Changes in Motor Neuronal Properties in the Spinal Cord. In addition to alterations of the descending drive, the difficulties in motor neuron recruitment may also be related to direct changes in the properties of spinal motor neurons, as shown in animals with chronic spinal transection using intracellular recordings. Such changes include increases in threshold voltages and threshold currents for action potential activation by short-duration current pulses.17,110 Regardless of the respective contributions of supraspinal or spinal mechanisms, loss of normally functioning motor units and firing rate reductions may reduce the efficiency of muscle contraction, leading to increased effort, to fatigue, and ultimately to a perceived sense of weakness for voluntary force generation.88,115,249 Fatigability. Despite the compression in range of motor neuron recruitment, the normal order of recruitment from fatigue-resistant to fatigable units is preserved in paretic patients, i.e., no reversal of recruitment order has been found to account for their excessive fatigability.91 This is in contrast to some evidence for recruitment reversal in animals after spinal lesion.188 The increased fatigability in patients with spastic paresis is likely due primarily to greater central fatigue, i.e., greater decreases in voluntary activation of lower motor neurons with pursuit of the effort as compared with normal subjects, together with a greater difficulty in isolating contraction to a muscle group.196 In fact, there are indications that less severely paretic subjects are able to drive their paretic muscles to fatigue, i.e., to induce peripheral fatigue, whereas the more severely paretic subjects— or those with less advanced motor recovery— cannot achieve marked peripheral fatigue as central fatigue (decreases in voluntary activation) occurs first.196 Compensatory Processes in the Higher Centers. The higher centers adapt to the lesional situation in a number of ways to connect with and activate the lower motor neurons, and achieve movement despite disruption of the primary execution pathways. First, increased task-related activation occurs in regions not normally involved with direct movement execution, such as the supplementary motor and cingulate motor areas, premotor cortex, posterior and inferior parietal cortex, and cerebellum.179,251

Marked task-related activation in such regions may be a marker of severe disruption of command execution, as this negatively correlates with motor function in functional MRI studies.251,252 Activation of anterior and posterior cingulate and prefrontal cortices suggests that selective attentional and intentional mechanisms may be important in the recovery process.255 Second, additional activation of motor areas occurs contralateral to the lesion, i.e., ipsilateral to the motor deficit, and the field corresponding to the paretic body parts extends in the perilesional primary (sensori)motor cortex. The motor outputs in the unaffected hemisphere are significantly changed after unilateral hemispheric lesion, including a general increase in excitability of the cortex contralateral to the lesion35 and the unmasking of ipsilateral corticospinal projections.172 The significance of these changes in terms of meaningful functional recovery has been questioned.172 However, these bilateral extensions of the cortical representations of the paretic body parts and their functional importance have been supported by clinical evidence from secondary contralateral lesions,77 by studies using transcranial magnetic cortical stimulation,244 and by functional MRI or positron emission tomographic techniques measuring the changes in regional cerebral blood flow elicited during a motor task.41,58,179,209,256 Third, descending inputs other than the fast corticospinal elements are used.245 Numerous animal studies involving experimental sensorimotor cortex or spinal cord lesions support the hypothesis that motor recovery involves switching of motor activity to the control of brainstem descending pathways such as the cortico-rubrospinal, the cortico-reticulospinal, and the cortico-vestibulospinal systems.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 propriospinal neurons that bridge the lesion. In turn, these propriospinal neurons arborize on lumbar motor neurons, creating a new functional intraspinal circuit that relays cortical input to its original spinal targets.14 In stroke patients, some evidence exists that the component of the descending command passing through cervical propriospinal relays increases during upper-limb recovery.158 These propriospinal neurons could be accessed via the reticulospinal pathways, as is the case in animal models.151,204


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Finally, collateral sprouting of intact corticospinal fibers may occur.9,254 Lesions of defined components of the corticospinal motor pathway in adult rodents or monkeys lead to new corticospinal connections between undamaged corticospinal fibers and lower motor neurons deprived of their normal descending input.9,254 Such new synapse formations associated with sprouting of intact corticospinal fibers may contribute to motor recovery. Significance of Maximal Voluntary Power Measurements in Spastic Paresis. Failure of voluntary activation dramatically reduces maximal voluntary power as the number of recruited motor units is the main factor accounting for the power developed by a muscle.184 The ability to voluntarily recruit motor units in patients with chronic spastic paresis is often asymmetric around joints, with the lower-limb hamstrings and plantarflexors contracting proportionately more than quadriceps and dorsiflexors.96,173 Similarly, measurements of maximal voluntary power in spastic paresis commonly show an asymmetric distribution of weakness between agonists and antagonists across joints.42,86,124,173 However, strength measurements in spastic paresis, whether dynamometric or clinical using the Medical Research Council scale, do not provide a reliable assessment of voluntary agonist activation, as they may be confounded by resistance from soft tissue contracture and antagonistic cocontraction.96,135 Yet, regardless of their physiological meaning, these measurements consistently correlate with functional outcome in different studies.23,24,29,47,71,170,174 In terms of functional impairment, weakness caused primarily by failure of lower motor neuron activation and potential changes in motor neuron properties is likely the prominent issue acutely after lesion onset. However, the relative contribution to functional disability of subsequent events such as soft tissue shortening and muscle overactivity may increase in the subacute and chronic stages of spastic paresis.173
Flaccidity. Acute disruption of the execution of volitional command typically involves descending pathways that modulate spinal cord reflex circuitry. This commonly translates into the immediate but usually transient extinction of most spinal reflex responses, including stretch reflexes, which manifests itself clinically by an initial flaccidity.139,177,218 In a minority of cases, flaccidity persists chronically after occurrence of a central lesion, e.g., with some spinal cord infarcts25,132,193 or cerebral lesions.177 Persistent flaccidity 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 observed months after spinal cord injury, which may suggest secondary impairment or degeneration of premotor neuronal circuits or of motor neurons.108

Most limb-use implies mobilization. Immobilization is the peripheral situation of lack of passive or active movement around a joint. Disuse is the central behavior of lack of voluntary command exerted on a limb. Although these are two different phenomena, they tend to occur in parallel, particularly in patients with disruption of the execution of central command. Thus, evidence in the literature for the respective consequences of each is scarce, as a disused limb is often relatively immobilized, and an immobilized limb (e.g., in a splint) is often relatively disused, both in human patients and animal research. In fact, limb immobilization has often been used as an 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 on this muscle secondary to decreased tonic stretch, which may in turn aggravate muscle disuse.224 The first section below addresses the peripheral effects of immobilization and disuse, particularly on muscle and joints; these effects begin acutely and have been primarily attributed to immobilization. The second section addresses the central effects, which seem to have a slower temporal profile and have been primarily attributed to disuse.

This series of peripheral events begins acutely after the injury while the patient is still in the emergency room or acute care unit. Paresis immediately leaves the affected muscles immobilized. In the standard environment of acute care, patients are placed in stretchers for extended periods, usually with the paretic lower limbs in full extension and the paretic upper limbs positioned with shoulder internally rotated, elbow flexed and pronated, and often wrist and fingers flexed.2 Thus, among the paretic muscles, some are commonly immobilized in a shortened position, often including the lower-limb extensors and upper-limb internal rotators, pronators, and flexors. This immobilization in a shortened position
Muscle Contracture.

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causes a reduction in longitudinal tension, or muscle unloading, which is chronologically the first mechanism for muscle contracture. Post-unloading muscle contracture in spastic paresis includes atrophy (loss of muscle mass), loss of sarcomeres (shortening), and accumulation of connective tissue and fat, as demonstrated both in animals and humans.12,165–167,222,228,262 In addition, the loss of normal weight-bearing or counter-resistance activity, which occurs during limb immobilization or disuse (bed rest), stimulates a catabolic response within the musculoskeletal system, resulting in a loss of skeletal muscle mass and cross-sectional area, and a reduction in bone mineralization.5,21,43,75,205,206,273 Each of the mechanisms of contracture in the muscle immobilized in a shortened position is reviewed here in further details. Atrophy. Immobilization associated with induced paresis causes muscle atrophy in animal experiments, with an atrophy rate that negatively correlates with the length at which the muscle is immobilized.66 The muscle atrophy caused by induced paresis is incompletely prevented by forced immobilization in a lengthened position.66 In nonparetic humans, immobilization causes decreased fiber diameter247 and a reduction in the cross-sectional area and volume of the whole muscle,247,257,273 and muscle unloading reduces the capacity for protein synthesis.73,85 In chronic hemiplegic patients, hemiparetic skeletal muscles are atrophic compared to the nonparetic side, more so in the paretic arm than leg.208 Loss of Sarcomeres. Muscles maintained in a shortened position adapt to their resting length and lose sarcomeres until those remaining overlap optimally to enable the muscles to develop maximal tension at the immobilized length.222,261 The main stimulus for adaptation seems to be the imposed length more than the immobilization itself, as muscles immobilized in a neutral position do not develop significant changes in stiffness or sarcomere numbers and those immobilized in a lengthened position undergo an increase in the number of sarcomeres in series.222,261 Accumulation of Intramuscular Connective Tissue. Quantitative and qualitative changes in the intramuscular connective tissue are also likely to contribute to increased stiffness (reduced extensibility) of the immobilized skeletal muscle and to a deterioration in function.116,137 Immobilization of rat muscles results in a marked increase in the endo- and perimysial connective tissue, and in a substantial increase in the number of perpendicularly oriented collagen fibers with contacts with two adjacent muscle fibers in the

endomysium.116 There is overall an increase in the ratio 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 patients, hemiparetic skeletal muscles have an increased fat content compared to the nonparetic side, a finding that is more pronounced in the paretic arm than leg.208 Fat accumulation also occurs within the tendons of paretic muscles in both flaccid and spastic paresis, and these abnormal fat deposits commonly contain disconnected and degenerated mechanoreceptors, including Ruffini and Pacini corpuscles, Golgi tendon organs, and free nerve endings.119 Degenerative Changes at the Myotendinous Junction. Immobilization causes a decrease in vascular density and degenerative changes at the myotendinous junction, which most likely decrease its tensile strength.126,138 Increase in Mechanical Spindle Stimulation by Stretch. Finally, the reduced extensibility after immobilization in a shortened position causes any pulling force to be transmitted more readily to the spindles.89 There is thus an increase in spindle responses that augments stretch reflexes and eventually contributes to the stretch-sensitive forms of muscle overactivity.89,154,260 The process of muscle contracture is acute.12,26,27,165–168 Decreases in protein synthesis rate in the muscles of immobilized limbs occur during the first 6 h of immobilization, and this decrease probably plays a role in initiating muscular atrophy.26,27 In McLachlan’s series of studies on mouse soleus muscles, after only 24-h unloading, there was already a 60% shortening of muscle fiber length and sarcomere disorganization.165–168 The increase in amount of connective perimysium occurs after only 2 days of immobilization in a shortened position.94 In the subacute and chronic stages of spastic paresis, the emergence of muscle overactivity becomes an additional mechanism of contracture, superimposed on immobilization, which will lead to chronic aggravation of contractures.
Time Course of Muscle Contracture. Clinical Manifestations of Muscle Contracture.

Clinically, adaptive muscle shortening may initially contribute to a first clinical stage of decrease in passive muscle extensibility (also termed increased nonreflex stiffness or reduced muscle compliance) seen in patients with spastic paresis, whereby a noncontracting muscle passively opposes stretch with an


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abnormally increased torque for a given degree of lengthening, as compared with normal muscle.30,228 There is likely correlation between the degree and duration of immobilization and disuse and the subsequent lack of muscle extensibility. Muscle stiffness can be quantified in patients with spasticity.104 In three studies of chronic hemiparetic patients with plantarflexor hypertonia, the nonreflex stiffness measured in the paretic limb was greater than the stiffness in the contralaleral nonparetic limb, which itself was consistently greater than that of agematched controls.90,141,214 It has been shown that soft tissue contracture makes a significant contribution to clinical ratings of resistance to passive movement, such as with the Ashworth scale.246 For clinical purposes, to accurately assess muscle stiffness, the muscle should be stretched no more than one time if possible, as a subsequent stretch encounters a stiffness reduced by 20%– 60% compared to the initial stiffness, particularly after a prior stretch of large amplitude.182 It also requires ensuring as much as possible that the muscle is at rest, as muscle contraction causes greater resistance to stretch, particularly contraction of slow units.182 When insufficiently treated, the ever-decreasing passive muscle extensibility in spastic paresis leads to a second clinical stage of loss of range of motion.55,112,155,175,213,229 Beyond clinical stiffness and loss of range of motion, muscle contracture may also contribute to fatigability, as a shorter muscle is more taut than normal for a given joint angle, and a muscle contracting in a taut position fatigues more rapidly.10
Joint Retraction. The degree and the clinical significance of joint retraction in spastic paresis should not be underestimated, particularly as a delayed but potentially major phenomenon in chronic stages. A compelling animal study of joint immobilization assessed the specific role of articular structures in limb stiffness using myotomies at different times after onset of the immobilization.238 The authors demonstrated a dramatic increase from 38.5% to 98.5% in the role played by articular structures in the limitation in range of motion from 2 to 32 weeks of immobilization, whereas the relative myogenic contribution reciprocally decreased over time. The generalizability and the time course of such a pattern of changes after immobilization in humans are unknown. However, clinicians experienced in the assessments of passive range of motion in patients with chronic 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 resistance, after some years. Histological and biochemical animal studies have shed light on the mechanisms of joint retraction in immobilized limbs. These include proliferation of fibrofatty connective tissue within the joint space, adhesions between synovial folds, adherence of fibrofatty connective tissue to cartilage surfaces, atrophy of cartilage, ulcerations at points of cartilage– cartilage contact, disorganization of cellular and fibrillar ligament alignment, and regional osteoporosis of the involved extremity.3,18,147 In particular, as is the case with muscle and other soft tissue, an increasing body of evidence suggests that immobilized joints adapt to their new position by modifying the length of some compartments of the synovial intima.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 contracture after immobility.239 In nontraumatically immobilized joints of rodents, 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 and an increase in synovial fluid precede the occurrence of intraarticular adhesions.76 In a sham-controlled study of knees immobilized in flexion in rats, a decreased number of proliferating synoviocytes and increased intima adhesion in the posterior capsule was present after 2 weeks of immobilization.241 Cartilage surface irregularities also appear after 2 weeks of immobilization and progress rapidly to plateau after 8 weeks.242 These abnormalities are associated with enzymatic changes as prostaglandin endoperoxide H synthase (PGHS) isozymes (or cyclooxygenase, COX) are decreased in the synovium and increased in the chondrocytes after immobilization.240
Changes in Contractile Muscle Properties. A switch toward faster contractile machinery may represent the predominant change in the contractile properties of immobilized and disused muscles. However, opposite findings (preferential atrophy of fast fibers) are also observed after disuse in animals as well as humans. The nature of these changes (slow-to-fast or fast-to-slow) may depend on the initial motor unit type and duration of disuse. Animal Data. In animal experiments of limb immobilization, muscles initially composed predominantly of type I fibers (i.e., “red,” low threshold, slow twitch, fatigue-resistant, well equipped for oxidative

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metabolism and for semi-isometric contractions, such as soleus muscle fibers), take on properties characteristic of type II muscles, (i.e., “white,” high threshold, fast twitch, and fatigue-sensitive).26,31,32 However, immobilization-induced changes may vary according to the initial motor unit type, with some fast muscles such as the gastrocnemius, or mixed type I and type II muscles such as the tibialis anterior or peroneus longus, undergoing a shift toward slow unit behavior183 and preferential atrophy of type II fibers.188,198 In animal experiments of chronic spinal cord transection or hindlimb suspension, disused muscles also assume faster twitch properties as evidenced by shorter time to peak tension, shorter half-relaxation time, and reduction in fatigue resistance.8,43,156,205,226 Again, these changes may be lacking in the paretic rat tibialis anterior, which is a mixed muscle.98,185,186 Changes in type I fibers also include an initial reduction of contractile forces and a trend for secondary recovery,226 whereas the oxidative capacity seems maintained.176 In biochemical terms, most models of muscle disuse in animals, including microgravity, hindlimb suspension, spinal cord isolation, spinal cord transection, denervation, and immobilization in a shortened 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 using electrical stimulation. Stimulation of fast-twitch muscle in animals (beyond 5% of daily time for periods as short as 4 days) tends to switch back the predominant muscle fiber from type II to type I, with increased muscle endurance (decreased fatigability), decreased maximal muscle force, and significantly larger forces produced by low motor neuron firing rates.129 –131,263 These changes appear to be reversible again if the muscle returns to its prior level of activity.131 Short, daily bouts of shortening, lengthening, or isometric contractions are other effective means to limit the loss in mass and force potential of disused muscle in animals, but the isometric stimulation 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, prolongation of twitch contraction and relaxation times, and a higher proportion of high-threshold motor units recruited for a given force development.61,62,247,257,273 The order of recruitment is maintained, with unchanged motor unit firing rate at recruitment but decreased maximal firing rate particularly for low-

threshold motor units.62 Increased muscle fatigability and a significant shift toward type II fiber type may take more than 4 weeks of immobilization to occur.62,102,247,273 Maximal twitch tension may be decreased,61 unchanged,257 or increased273 depending on which muscle is immobilized and the duration of immobilization. Periods without weight bearing in humans with an intact central nervous system (CNS) also have significant 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-sectional area,21 leads to greater fatigability,19 and tends to generate transformation toward fast phenotypic protein expression including type II myosin heavy chain isoforms,7,276 although this may depend on the duration of bed rest and the muscle type.21,74,109 The adaptations of the contractile characteristics of the affected muscles in spastic hemiplegia and spinal cord injury grossly reproduce those occurring during immobilization and unloading in subjects with an intact CNS. These include: (1) decreases in mean forces and integrated EMGs generated during maximal voluntary efforts235; (2) prolongation of mean twitch contraction times of fast-twitch but not slow-twitch units234,272; (3) larger twitch tensions generated by motor units, especially slow motor units; (4) appearance of a new type of motor unit characterized by slow-twitch contraction times and increased fatigability (“slow fatigable” units)272; (5) gradual transformation over months toward fast phenotypic protein expression including type II myosin heavy chain isoforms (reversible with functional electrical stimulation)6,34,39,98,264; and (6) histological predominance of type II fibers.100 Slow-to-fast changes have been found particularly in the tibialis anterior of paretic humans, where an increase in proportion of type II fibers is found compared to normal muscle, with an accompanying increase in the torque developed for a given motor unit recruitment.69,70,98,114,115 Studies in spastic paresis showing a high-tension development for a moderate increase in EMG activity54,56,57,113,173,196 are also consistent with a shift to faster contractile machinery in human paretic muscles. However, an increase in torque/EMG ratio alone cannot be taken as an acceptable demonstration of a change toward faster contractile motor unit properties. High torque/EMG ratios may be due to changes in passive muscle properties, in particular to the decreased resting length of the muscle and concomitant changes in mechanical advantage: for a given joint position and a given motor unit recruitment, a


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shortened muscle, such as is the case in spastic paresis is relatively taut before the contraction and thus develops greater torque than a slack muscle.1,194 In addition, as in animals, there have been suggestions that in human subjects the direction of the slow/fast shift may also depend on the initial fiber type. In spastic hemiplegia, preferential type II fiber atrophy and predominance of type I fibers are noted in fast muscles such as gastrocnemius,56 and there is prolongation of twitch contraction times in fast units of the first dorsal interosseous.272 Studies of the EMG response to fatigue also show preferential atrophy of type II fibers in paretic gastrocnemius medialis (fast)46 or tibialis anterior (mixed).217,236 Despite these changes in muscle fibers, the range of axonal conduction velocities in the peripheral nerve is unchanged, suggesting that in humans, there is no selective loss of one class of motor neurons after paresis.114
Changes at the Endplate. Human muscle immobilization, in the absence of any neuromuscular disease, can result in a reversible dysfunction of neuromuscular transmission, as evidenced by increased neuromuscular jitter.97 In animals, muscle unloading may induce endplate changes that include decreases in acetylcholine transcripts in nonweight-bearing muscles,189 and expansion of acetylcholine vesicles and receptor areas.50,219 The clinical significance of these observations is unknown. CENTRAL EFFECTS OF DISUSE

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 observations of the nonparetic side in hemiplegic patients in the acute phase after stroke.105 The main consequences of disuse in the central nervous system are reviewed below. Maximal voluntary power decreases after only a few weeks of muscle immobilization,60,62,111,211,257,273 limb unloading without immobilization (e.g., the use of a crutch to prevent one lower limb from weight-bearing),20 or bed rest.21,75,127,220,269 The decline in strength appears to increase with the duration of disuse,101 is particularly marked in antigravity muscles, and is out of proportion to the decrease in muscle cross-sectional area or muscle mass.220 Decreased neural input to muscle may be involved, as well as reduced specific tension of muscle, which has been suggested by decreased torque/EMG ratios after bed rest or casting in neurologically intact subjects, i.e., in models of nonparetic unloaded or immobilized muscles.21,220,257,269 The nonparetic side of hemiplegic subjects also undergoes relative disuse, particularly during the acute period after stroke. It has been shown that weakness dramatically develops in the unaffected leg in the first week after acute hemiplegic stroke, and is correlated with the percentage change in body weight.105 Weakness on the nonparetic side has been confirmed at chronic stages42 together with deficits in dexterity and coordination.51
Decrease in Maximal Voluntary Power. Failure of Voluntary Activation. Following immobilization, the peak force achieved during a maximum voluntary contraction (MVC) is dramatically less than can be evoked from the muscle by electrical stimulation.60 The concomitant reduction of maximal voluntary EMG after periods of bed rest,21,59 limb immobilization,60,62,273 and limb unloading65 is not solely due to decreases in motor unit size or number. The maximal firing rate also decreases in all motor units after immobilization, with greater decreases in motor units of low threshold than in those of high threshold.61 The voluntary force developed by the whole muscle at such low firing rates has been found to be relatively enhanced212 despite declines in the maximal force developed by individual motor units.81 Taking these elements together, it has been hypothesized that the motor drive, i.e., the ability to activate muscle by voluntary command, is reduced following disuse.59,60,163 This has been confirmed us-

In the context of paresis due to injury of the central motor pathways, a vicious cycle unfolds whereby selfimposed chronic disuse (which Taub et al. termed “learned non-use”)232 leads to CNS changes that themselves further challenge the execution of voluntary command. There is compelling evidence in humans that changes in habitual physical activity can cause adaptations in the nervous system.134 When the level of physical activity in a body part declines, for example, due to chronic limb restraint, the reduced physiological demands evoke adaptations that decrease the capabilities of the involved organs.63 The neural adaptations that accompany alterations in the chronic patterns of physical activity seem to occur at all levels of the neuraxis,63 with disuse affecting not only the biochemical and physiological properties of the muscle fibers but also motor neuron recruitment capabilities.164 Few studies of disuse per se have been carried out in humans. The human studies that have come closest to testing disuse from a functional point of view

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ing the twitch superimposition technique in bed-rest experiments127 and in the nonparetic side in hemiplegic subjects.173,196 In the nonparetic side of hemiplegic patients, however, the ipsilateral command dysfunction associated with a unilateral brain lesion may also contribute to the failure of activation, as not all nonparetic muscles remain disused (e.g., grip strength was found to be normal in chronic stages).51 The question of progressive failure of voluntary activation in chronically disused nonparetic muscles may only be answered with a longitudinal study.
Altered Cortical Map and Motor Cortex Excitability.

afferent feedback available for calibrating central motor command also impacts on the degree of force resolution during a voluntary effort.106 The magnitude of alterations of sensory processing along spinal and cortical pathways in chronic disuse and of their impact on voluntary activation is unknown.
Increased Reflex Excitability at the Spinal Level. Classic experiments showed that sensory disuse causes an increase in central synaptic efficacy with increased homonymous excitatory postsynaptic potential (EPSP) amplitudes on the deafferented motor neuron.84 After hindlimb suspension in animals, altered synaptic efficiency has been noted at the spinal cord level, with relative enhancement of H reflexes.8,67 Similar findings were observed after immobilization or unloading in healthy humans.125,211 Decreased thresholds for spinal reflexes are also observed after 3– 6 months in microgravity in human astronauts; in particular, the tendon responses are increased despite decreased muscle stiffness.136,140 These changes in spinal cord excitability may depend on the duration of disuse, as they are not found after short periods of human limb immobilization.117,125 They may contribute to the muscle overactivity that gradually develops after disruption of the execution of voluntary command.

Prolonged disuse of a body part leads to decreased cortical excitability in the areas involved with the command of that body part. Specifically, human studies of limb immobilization showed an altered higher level of motor command (movement imagination) and a decreased motor representation of the immobilized body parts.125,134 For instance, immobilization of an ankle joint for 4 to 6 weeks reduces the cortical area from which responses in the tibialis anterior can be evoked with transcranial magnetic stimulation, an effect that increases with the duration of immobilization.148 Such decreased cortical excitability likely contributes to the decline in voluntary muscle activation after immobilization.
Sensory Disuse: Potential Role in Affecting Voluntary Motor Neuron Activation. Limb disuse involves im-

mobilization, which implies additional disuse of sensory afferents. This may eventually alter sensory processing along spinal and cortical pathways,38 which if prolonged may in turn further impair voluntary activation of motor neurons. As a part of its critical role in motor function,161 sensory feedback specifically contributes to the descending drive in simple voluntary efforts. In humans, there has been no experimental situation reproducing global dysfunction in central sensory pathways from a whole limb. However, compelling acute alterations of motor command have been shown resulting from loss of sensory input from a single peripheral nerve (obtained by transient block). Macefield and colleagues recorded the discharge rate of motor neurons to the tibialis anterior before and after blocking the common peroneal nerve with anesthesia distal to the site of intraneural recording.152 The nerve block caused the average discharge rate during a maximal effort to decrease from 28.2 to 18.6 Hz. It was estimated that muscle afferents in the common peroneal nerve facilitated the output of the motor neuron pool by about 30% at all levels of voluntary activation. The

Recent experimental evidence has shown that the CNS effects 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. In hemiplegic patients, such forced use may be achieved by constraining the nonparetic upper limb for a few hours a day, using the technique of constraint-induced movement therapy.231 Application of such a method for a few weeks decreases cerebral activation during a motor task (as measured by positron emission tomography), and increases motor map size (as measured by transcranial magnetic stimulation) in the motor cortex of the affected hemisphere.267 These changes occur in parallel with functional improvement in the affected side and are likely to reflect improved ability to recruit upper motor neurons of the paretic limb.267
Reversal of the Effects of Disuse by Forced Use. CONCLUSION

Following a central lesion causing paresis, the standard medical environment and “normal” human behavior in patients are responsible for two additional but potentially avoidable insults to the peripheral soft tissues and central nervous system: limb immo-


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bilization and central disuse. The mechanisms involved in paresis and soft tissue contracture were reviewed, with particular emphasis on the specific consequences of immobilization and disuse in paretic body parts. Failure of voluntary motor neuron activation and changes in properties of spinal motor neurons are major components in the pathophysiology of the paresis due to the initial lesion. However, the motor impairment due to paresis is greatly aggravated by the muscle and joint contracture and the changes in muscle contractile properties caused by immobilization. In addition, chronic disuse causes an alteration of CNS function that further reduces the 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 immediately after the CNS lesion and, when possible, intense education and motivation toward daily forced use or forced mental rehearsing of movements with the paretic limbs are logical strategies to prevent these two additional factors.
I am grateful to Mara Lugassy, MD, and Robert Kahoud, MD, for their careful and expert review of the manuscript.










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Pathophysiology of Spastic Paresis I


May 2005


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