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Reflex Inhibition of Normal Cramp Following Electrical Stimulation of theMuscle Tendon

Serajul I. Khan and John A. BurneSchool of Medical Sciences, University of Sydney, Lidcombe, New South Wales, AustraliaSubmitted 1 April 2007; accepted in final form 10 July 2007

Khan SI, Burne JA. Reflex inhibition of normal cramp followingelectrical stimulation of the muscle tendon. J Neurophysiol 98: 11021107,2007. First published July 18, 2007; doi:10.1152/jn.00371.2007. Musclecramp was induced in one head of the gastrocnemius muscle (GA) ineight of thirteen subjects using maximum voluntary contraction whenthe muscle was in the shortened position. Cramp in GA was painful,involuntary, and localized. Induction of cramp was indicated by thepresence of electromyographic (EMG) activity in one head of GAwhile the other head remained silent. In all cramping subjects, reflexinhibition of cramp electrical activity was observed following Achil-les tendon electrical stimulation and they all reported subjective reliefof cramp. Thus muscle cramp can be inhibited by stimulation oftendon afferents in the cramped muscle. When the inhibition ofcramp-generated EMG and voluntary EMG was compared at similarmean EMG levels, the area and timing of the two phases of inhibition(I1, I2) did not differ significantly. This strongly suggests that the samereflex pathway was the source of the inhibition in both cases. Thus thecramp-generated EMG is also likely to be driven by spinal synapticinput to the motorneurons. We have found that the muscle conditionsthat appear necessary to facilitate cramp, a near to maximal contrac-tion of the shortened muscle, are also the conditions that render theinhibition generated by tendon afferents ineffective. When thestrength of tendon inhibition in cramping subjects was compared withthat in subjects that failed to cramp, it was found to be significantlyweaker under the same experimental conditions. It is likely thatreduced inhibitory feedback from tendon afferents has an importantrole in generating cramp.

I N T R O D U C T I O N

Common muscle cramp is characterized by sudden, local-ized, involuntary, sustained, and painful contraction attendedby visible and palpable knotting of part or all of the affectedmuscle (Baldissera et al. 1991; Denny-Brown et al. 1948; Rosset al. 1995). Cramp is typically of short duration but maywarrant medical intervention if associated with long-lastingpain (Mills et al. 1982). Its physiology is poorly understood,largely due to its inaccessibility to experimental investigation.It is difficult to induce in many normal subjects, it is typicallyof short duration, and there is no animal model.

Cramp is accompanied by active muscle contraction, asevidenced by high levels of muscle electrical activity. Theorigin of the electrical activity remains unclear. The generatormay lie within the CNS or in peripheral neuromuscular mem-branes. Whatever the location of the generator, it appears to befacilitated by a variety of factors that include strong voluntarycontraction, exercise (Layzer et al. 1986; Miles et al. 1994;Schwellnus et al. 1997), sleep (Gootnick 1943; Nicholson et al.

1945), pregnancy (Oba 1967; Page et al. 1953), and severalpathologies such as myopathy, neuropathy, motoneuron dis-ease (Brown 1951; McGee 1990), metabolic disorders (Layzeret al. 1967; McArdle 1951; Tarui et al. 1965), electrolyteimbalance (Edsall 1908; Oswald 1925; Talbott 1935), andendocrine pathology (Satoh et al. 1983). However, the linkbetween these factors and the involuntary muscle electricalactivity that accompanies cramp remains unclear. In summary,both intramuscular and neural mechanisms appear to contributeto cramp but no integrating theory has been proposed.

Earlier studies suggested a cramp generator within periph-eral nerve segments. It was reported that cramp could beinduced by electrical stimulation of motor fibers distal to ananesthetic block (Lambert 1969). Fasciculations, which arethought to be related to cramp (Denny-Brown 1953; Layzer1971; Roth 1984), may also persist after peripheral nerve block(Conradi 1982; Layzer et al. 1971; Tahmoush et al. 1991) orcomplete section of the nerve (Forster et al. 1946).

A generator within the motorneuron is also suggested bytheories of motorneuron hyperexcitability or bistability (Bald-issera et al. 1991). Bistability indicates an anomalous state inwhich a self-sustained depolarization and repetitive firing ofalpha motor neurons is triggered by a depolarizing pulse orintracellularly injected current (or possibly a short synapticexcitation) and terminated by a hyperpolarizing current pulse(or synaptic inhibition) (Hagbarth et al. 1966). Originallybistability was described as a reflex phenomenon consisting ofa long-latency prolonged contraction of the soleus muscle thatwas evoked by a burst of Ia afferent volleys and terminated bya brief synaptic inhibition (Hultborn et al. 1975).

A limitation of the peripheral generator model is the diffi-culty of incorporating the known systemic and metaboliceffects that can be more easily integrated into a reflex model bymuscle afferents. A few observations suggest that central orreflex factors are able to modulate cramp-related electricalactivity. Voluntary contraction of the antagonist muscle, with-out stretching the cramped muscle, causes an inconsistentreduction of cramp discharge, suggesting spinal reflex inhibi-tion (Norris et al. 1957). The Hoffmann (H) reflex is enhancedafter cramp (Ross et al. 1976) and transcutaneous nerve stim-ulation at sites remote from the cramped muscle are reported torelieve severe, long-lasting, and widespread muscle cramp(Mills et al. 1982).

Muscle stretching is reported to abruptly interrupt crampinduced by voluntary contraction or high-frequency stimula-tion of peripheral nerve (Baldissera et al. 1991; Dennig 1926;

Address for reprint requests and other correspondence: J. A. Burne, Schoolof Biomedical Sciences, University of Sydney, PO Box 170, Lidcombe, NSW1825, Australia (E-mail: [email protected]).

The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked advertisementin accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

J Neurophysiol 98: 11021107, 2007.First published July 18, 2007; doi:10.1152/jn.00371.2007.

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Lanari et al. 1973; Mills et al. 1982; Rowland 1985). Again themechanism is unclear, although it has been suggested (Layzeret al. 1971) that passive stretch of the cramping muscle mayproduce autogenic inhibition by the tendon organ reflex. Thepossibility that cramp is inhibited by reflex afferents is worthfurther exploration because such a mechanism would stronglysupport a central or reflex origin of the cramp-related EMG andmight also guide more effective therapy.

Burne and Lippold (1996) showed that electrical stimulationover muscle tendons produced a strong reflex inhibition of anongoing voluntary contraction. This has been suggested tooriginate from group III tendon afferents (Priori et al. 1998).More recently, Khan and Burne (unpublished observations)found that the strength of reflex inhibition was related tomuscle length, being maximal in the stretched muscle and quiteweak in the fully shortened muscle. This finding is consistentwith the theory that tendon afferents mediate the stretch-induced reduction in cramp.

In the current study, we investigated the effect of tendonelectrical stimulation on the electrical activity associated withmuscle cramp in human subjects. The induced inhibition ofcramp activity was compared with the inhibition of a similarlevel of normal voluntary contraction. If cramp activity showsthe same pattern of inhibition, it implies that it is driven by themotoneurons synaptic connections rather than by an intrinsicor peripheral generator. Conversely, if the cramp activity isunresponsive to reflex input, an origin within the motorneuronor the muscle itself is supported.

M E T H O D S

SubjectsTwo women and eleven men aged 18 to 30 yr with no neurological

disorder but complaining of cramp in the gastrocnemius muscle (GA)were recruited. All subjects gave informed consent and the universityethics committee approved the study.

Tendon stimulationA stimulus intensity of 60 mA was used for all experiments because

it was found to produce maximal inhibition in previous experiments(Khan and Burne, unpublished observations). Small metal platesserved as stimulating electrodes. The cathode was positioned centrallyon the GA tendon, about 1 cm below the musculotendonous junctionand the anode medially on the anterior calf adjacent to the cathode.The technique for obtaining tendon inhibition from GA is described inmore detail in Khan and Burne (unpublished observations).

Electrical recordingThe surface electromyogram (EMG) was recorded with disposable

bipolar silversilver chloride electrodes, attached 3 cm above themuscle tendon junction over the central belly of the lateral and medialheads of GA. Careful attention to skin degreasing allowed lowinterelectrode impedance. An earth electrode was also placed over thetibia. Amlab (Amlab International, Sydney, Australia) hardware wasused to record and filter the EMG (band-pass 5400 Hz), digitize it (1kHz), and display the raw signals and mean root-mean-square (RMS)values in real time on a computer screen. The RMS display wasavailable to subjects to match their isometric contractions to targetlevels. The digitized raw data were saved to computer hard disk andthen further processed and analyzed off-line (Matlab v. 7, The Math-Works, Natick, MA). The raw EMG signals were digitally detrended,

filtered (10- to 80-Hz pass), and full-wave rectified; average curveswere computed from a minimum of 30 successive trials. The area ofinhibitory and excitatory response components was then calculated bysoftware as previously described (Blanch and Burne 2001). The meanvalue and the SD of 100 ms of prestimulus data were calculated andpoints less than the SD were regarded as inhibitory points. The sum ofthese points estimated the area of inhibition.

ProtocolSubjects were positioned on their right side on a stretcher adjustable

for height. The right knee was fully extended and the right foot wasfitted to a footplate and stabilized to a supporting frame. The footplatewas designed to rotate in the horizontal plane, allowing the foot to befixed in its maximally plantarflexed position with GA in its shortenedposition. The ankle joint was fixed to prevent muscle lengthening,which could subsequently break the cramp. In this position, eachsubject maximally contracted GA by pushing against the footplateuntil cramp was induced. Subjects notified the onset, perceivedlocation, and relative intensity of the induced cramp, which wasattended by visible knotting. Subjects were instructed to attemptmaximal relaxation of voluntary drive once cramp was present so thatthe activity present could be attributed to cramp. The typical occur-rence of cramp in one head of GA permitted voluntary relaxation to beassessed by confirming the absence of EMG in the noncramping head.In the testing position, no subjects were able to voluntarily produceEMG in one head of GA only. Induction of cramp was attemptedseveral times in each session, each attempt being followed by 1520min of rest, unless a persisting cramp was obtained.

StatisticsComparison of the inhibitory areas of cramp-related EMG and

voluntary EMG were made by one-way repeated-measures ANOVA.Simple linear regression was used to relate inhibitory area to the meanbackground contraction. Both analyses were performed using Statis-tica (StatSoft, Tulsa, OK). The level set for statistical significance wasP 0.05.

R E S U L T S

Inhibition of voluntary contractionFigure 1, A and B illustrates the simultaneous inhibition of a

normal voluntary contraction [20% of maximum voluntarycontraction (MVC)] in the medial and lateral heads of GAfollowing tendon stimulation (60 mA, 1 ms). The features ofthe reflex response and the timing of inhibitory and excitatoryphases were as described by Khan and Burne (unpublishedobservations). The first and larger inhibitory component (I1)commenced 55 0.57 ms (SD) after the stimulus onset and itsduration was 69.5 11.0 ms. This was followed by a smallerinhibitory phase (I2) of latency 193 10.8 ms and duration39 14.7 ms. I1 was followed by the excitatory peak (E1) oflatency 142.2 8.4 ms and I2 was followed by the excitatorypeak (E2) of latency 240 11.8 ms (mean SD).

Effect of mean background contractionFor all subjects, the strength of reflex inhibition, I1 and I2,

after tendon stimulation was negatively correlated with themean background contraction. The relationship was approxi-mately linear as shown for one subject in Fig. 2, A and B. It canbe seen that the amount of reflex inhibition and the meanbackground contraction were strongly correlated in this subject

1103TENDON REFLEX INHIBITION OF CRAMP

J Neurophysiol VOL 98 SEPTEMBER 2007 www.jn.org

(P 0.014, r2 0.97, linear regression). Figure 2, C and Dshows the pooled data for the reflex inhibition I1 (P 0.0001and r2 0.7809) and I2 (P 0.7538 and r2 0.0001) aftertendon electrical stimulation. These data confirm an approxi-mately linear inverse relation between strength of reflex inhibitionand the mean background contraction in the subject population.

Effect of tendon stimulation on crampOf the thirteen subjects, eight successfully produced cramp

in one head of GA. Relaxation of voluntary contraction wasconfirmed by inspection of the EMG from the noncrampinghead of GA. In all subjects, reflex inhibition of cramp EMG

FIG. 1. Simultaneous inhibition of a nor-mal voluntary contraction at 20% of maxi-mum voluntary contraction (MVC) in themedial (A) and lateral (B) heads of gastroc-nemius muscle (GA) after tendon stimulation(60 mA, 1 ms). Effects of the same stimuluson the cramping medial head (C) and relaxednoncramping lateral head (D) of GA are alsoshown. I1 and I2 denote the first and secondinhibitory periods. E1 and E2 denote the peaksof the first and second excitation that fol-lowed the electromyographic (EMG) inhibi-tion. Stimulus commenced at 300 ms, as in-dicated by the arrow on timescale.

FIG. 2. Effect of mean background con-traction level on the strength of reflex inhibi-tion (A is I1, B is I2) of the contraction (closedcircles) and inhibition of cramp (open circle)in the same subject. Solid line is the linearregression line and the broken lines are 95%confidence intervals for the data shown.Pooled data for the effect of mean back-ground contraction level on the strength ofreflex inhibition (C is I1, D is I2) is alsoshown.

1104 S. I. KHAN AND J. A. BURNE


activity was observed after tendon stimulation and the subjectsreported relief of cramp during or after 30 shocks had beendelivered to the tendon. Figure 1, C and D shows the inhibitionof cramp (I1, I2) after tendon electrical stimulation in the samesubject. The onset latency of I1 was found to be 55 0.58 (SD)ms, similar to that reported earlier for the voluntary contractionand previously in upper limb muscles (Burne et al. 1996a). Theonset latency of I2 was found to be 193 10.8 (SD) ms, whichwas again similar to that reported earlier for the voluntarycontraction. The timing of I2 has not previously been reportedin the literature.

Comparison of inhibition of voluntary contraction andcramp

Because the magnitude of voluntary inhibition varied withthe mean background level, we fitted the cramp inhibitory data(I1, I2) to the regression plot relating voluntary inhibition tomean background contraction level in the same subject (Fig. 2,A and B). It was thus shown that the area of cramp inhibitionlay within the 95% confidence intervals for voluntary inhibi-tion in all subjects. Table 1 summarizes the group data com-paring the magnitude of inhibition of voluntary EMG andcramp-related EMG in the same subjects and at the same levelof background contraction. There was no statistically signifi-cant difference in latency or area of inhibition (P 0.05,repeated-measures ANOVA). In fact, the areas of I1 (P 0.01,r2 0.93) measured during cramp and voluntary contractionwere strongly correlated in the same subjects. This result isillustrated in Fig. 3.

Comparison of tendon inhibition in cramping andnoncramping subjects

The magnitude of reflex inhibition of voluntary contractionfollowing tendon stimulation was compared in subjects thatsubsequently produced cramp during the experiment and sub-jects that could not be induced to cramp during the experiment.It was found that I1 (group mean 2,360 V ms for crampingsubjects, 2, 720 V ms for noncramping subjects, P 0.09)

and I2 (group mean 640 V ms for cramping subjects, 1,120V ms for noncramping subjects, P 0.017, repeated-mea-sures ANOVA) were smaller in the cramping subjects (Fig.4B). This difference was highly significant for I2 but failed tobe significant for I1.

D I S C U S S I O N

Cramp in GA was painful, involuntary, and localized. In halfof the subjects it was absent or incomplete and did not persistlong enough to do the experiment. Induction of cramp wasindicated electrically by the presence of EMG activity in onehead of GA while the other head remained silent. In contrast,no subject was able to voluntarily contract one head of GA andrelax the other in the testing position. These findings confirmthat cramp was localized and involuntary in nature.

Our observations clearly show that muscle cramp can beinhibited by stimulation of tendon afferents in the crampedmuscle. When the inhibition of cramp-generated EMG andvoluntary EMG was compared at similar mean backgroundEMG levels, the area and timing of the inhibition did not differsignificantly. This strongly suggests that the same reflex path-way was the source of the inhibition in both cases. Thus thecramp-generated EMG is also likely to be driven by spinalsynaptic input to the motorneurons.

It is well documented that tendon electrical stimulationproduces strong inhibition of the ongoing voluntary EMGactivity and this inhibition arises from tendon afferents byreflex inhibitory pathway (Burne et al. 1996). Muscle stretch-ing causes a sudden interruption of cramp induced by eithervoluntary contraction or electrical stimulation of the peripheralnerve (Bertolasi et al. 1992; Denny-Brown et al. 1948; Fowler1973; Layzer et al. 1982; Schwellnus et al. 1996). Passivestretch of a contracting muscle effectively activates autogenicinhibitory Ib afferents in the tendon (Granit 1950). However, ithas been proposed that the inhibition following electricalstimulation arises from group III tendon afferents that presyn-aptically inhibit the terminals of 1a stretch reflex afferents(Priori et al. 1998). It is thus possible that these afferents areresponsible for inhibition of cramp, although little is knownabout their response to passive stretch.

Regardless of the species of afferent involved, we haveshown in parallel experiments that tendon electrical inhibitionis approximately linearly related to the length of the contract-ing muscle and maximal when the muscle is fully stretched

FIG. 3. Data from 8 cramped subjects showing the correlation between theareas of inhibition of voluntary and cramp EMG. Solid line is the linearregression line and the broken lines are 95% confidence intervals for the datashown.

TABLE 1. Inhibitory reflex responses during voluntary contractionand cramp

Inhibition (I1) Inhibition (I2)

Voluntary Cramp Voluntary CrampAverage

EMG, V

3,600 3,400 1,175 829 301,600 1,500 641 456 584,900 4,800 2,413 2,131 232,500 2,300 203 127 841,500 1,000 184 100 751,100 800 107 50 1104,500 3,600 1,173 1,084 343,000 3,400 1,150 1,021 25

Mean 2,533.4 2,322.3 794.3 651.7SD 1,609.9 1,572.1 769.1 688.5

Voluntary and cramp inhibitions following tendon electrical stimulationwith the same level of mean background contraction (last column) are com-pared. I1 and I2 represent the first and secondary inhibitory components of thereflex response following tendon stimulation. The reflex response was clearlydistinguished in all experiments. Population mean and SD values are shown.



(Khan and Burne, unpublished observations). This implies thatthese afferents are protective against cramp in the lengthenedmuscle and less effective in preventing cramp when the muscleis fully shortened. This role is further supported by the obser-vation from the current experiments that electrical tendonstimulation less effectively inhibits large than small voluntarycontractions. In summary, the muscle conditions that appearnecessary to facilitate cramp, a near maximal contraction of theshortened muscle, are also the conditions that render theinhibition generated by tendon afferents ineffective. It is thuslikely that reduced inhibitory feedback from the tendon mayhave an important role in generating cramp (see also discussionby Schwellnus et al. 1997). This conclusion is further sup-ported by our observation that noncrampers produced sig-nificantly stronger inhibition than those that were subsequentlyinduced to cramp on the same day.

It was previously shown that stimulation of the nerve sup-plying the cramped muscle was effective in blocking crampactivity (Lanari et al. 1973). Our findings support the proposalof these authors that the inhibition they observed was due tostimulation of tendon afferents.

It is well documented that the muscles most prone tocramping are those that span two joints (Manjra 1991; Nicol1996). Contraction in the shortened position would result indecreased tension in the tendons of the muscle during contrac-tion. Tendon activity would therefore be decreased in plantar-flexion compared with dorsiflexion.

The common observation that the intensity of cramp tends toincrease progressively over time can be interpreted as evidenceof a positive feedback mechanism. There is also much evi-dence that intramuscular mechanisms facilitate cramp (Joekes1982; Layzer et al. 1971; Mills et al. 1982). It is possible thatintramuscular changes, such as those associated with fatigue,stimulate chemically sensitive intramuscular afferents, such asgroup III afferents that are also stretch sensitive. These mayplay a role in facilitating motorneuron activity in the absence ofnegative feedback from tendon afferents. This imbalance inpositive and negative feedback signals can result in abnormal,sustained motorneuron activity. Also Nelson and Hutton(1985) found an increase in resting discharge frequency of typeIa and type II afferents as well as a dramatic decrease in Golgitendon organ (type 1b) firing rates to slow stretches duringfatigue.

Our observation that voluntary inhibition was inverselyrelated to the mean background contraction level is consistentwith the proposal (Priori et al. 1998) that the stimulated groupIII afferents produce presynaptic inhibition of 1a terminals.

The 1a stretch afferents are reported to contribute a decreasingproportion of the total synaptic drive to motorneurons as thecontraction level increases toward maximum (Harrison andTaylor 1981). The effects of tendon inhibition on the totalsynaptic drive should thus also decrease with contraction level.

The central origin of cramp is also supported by studies ofmotor unit properties, which report no marked changes in theirprofiles during voluntary contraction and cramp (Ross et al.1995). This contrasts with studies of fasciculation (Baldisseraet al. 1991; Denny-Brown 1984).

In summary: first, the inhibition of the voluntary EMGactivity recorded after tendon stimulation decreased with in-creased mean background contraction in an approximatelylinear fashion. Second, cramp-related EMG was inhibited aftertendon electrical stimulation and the strength of inhibition wasstrongly correlated with the strength of voluntary EMG inhi-bition at a similar level of mean background contraction in thesame subject. This result suggests that the cramp-generatedEMG is driven by spinal synaptic mechanisms rather than by agenerator within the motorneurons or by intramuscular mech-anisms.

The recordings from both heads of gastrocnemius wereparticularly important to determine the true onset of cramp.Once cramp was induced in one head of gastrocnemius after asustained maximal voluntary contraction, the EMG activity inthe other head remained silent. These data thus provided anobjective measure of the involuntary and localized nature ofcramp (Norris et al. 1957).R E F E R E N C E S

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