transcranial stimulation

Journal of Physiology (1993), 466, pp. 521-534 521With 5 figures

Printed in Great Britain

SILENT PERIOD EVOKED BY TRANSCRANIAL STIMULATION OFTHE HUMAN CORTEX AND CERVICOMEDULLARY JUNCTION

By M. INGHILLERJ, A. BERARDELLI, G. CRUCCU AND M. MANFREDI

From the Department of Neurological Sciences, University of Rome 'La Sapienza',Viale Universita' 30, Rome, Italy

(Received 3 February 1992)

SUMMARY

1. The silent period evoked in the first dorsal interosseous (FDI) muscle afterelectrical and magnetic transcranial stimulation (TCS), electrical stimulation of thecervicomedullary junction and ulnar nerve stimulation was studied in ten healthysubjects.

2. With maximum-intensity shocks, the average duration of the silent periodwas 200 ms after electrical TCS, 300 ms after magnetic TCS, 43 ms afterstimulation at the cervicomedullary junction and 100 ms after peripheral nervestimulation.

3. The duration of the silent period, the amplitude of the motor-evokedpotential, and the twitch force produced in the muscle were compared at increasingintensities of magnetic TCS. When the stimulus strength was increased from 30 to70% of the stimulator output, the duration of the silent period lengthened as theamplitude of the motor potential and force of the muscle twitch increased. At 70 to100 % of the output, the amplitude of the motor potential and force of the muscletwitch saturated, whereas the duration of the silent period continued to increase.

4. Proximal arm muscle twitches induced by direct electrical stimulation of thebiceps and extensor wrist muscles produced no inhibition of voluntary activity inthe contracting FDI muscle.

5. The level of background activation had no effect on the duration of the silentperiod recorded in the FDI muscle after magnetic TCS.

6. Corticomotoneurone excitability after TCS was studied by means of a singlemagnetic conditioning shock and a test stimulus consisting either of one singlemagnetic shock or single and double electrical shocks (interstimulus interval 1P8 ms)in the relaxed muscle. A conditioning magnetic shock completely suppressed theresponse evoked by a second magnetic shock, reduced the size of the responseevoked by a single electrical shock but did not affect the response evoked by doubleelectrical shocks. Inhibition of the test magnetic shock was also present duringmuscle contraction.

7. Our findings indicate that the first 50 ms of the silent period after TCS areproduced mainly by spinal mechanisms such as after-hyperpolarization andrecurrent inhibition of the spinal motoneurones. If descending inhibitory fibres

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M. INGHILLERI AND OTHERS

contribute, their contribution is small. Changes in proprioceptive input probablyhave a minor influence. From 50 ms onwards the silent period is produced mainlyby cortical inhibitory mechanisms.

INTRODUCTION

Marsden, Merton & Morton (1983) first demonstrated that electrical stimulationof the motor cortex in man produces a muscle twitch followed by a silence of EMGactivity. They suggested that this silent period after cortical stimulation wasdifferent from the silent period evoked by stimulation of a peripheral nerve(Merton, 1951). Since then, other authors have recorded a silent period in the handmuscles after transcranial stimulation (TCS) and have investigated the underlyingphysiological mechanisms. Using surface EMG and needle recordings of singlemotor units from the forearm muscle, Calancie, Nordin, Wallin & Hagbarth (1987)studied the silent period after electrical TCS and suggested that the inhibitoryperiod was determined mainly by changes in proprioceptive input induced by themuscle twitch and partly by activation of descending inhibitory influences. In astudy of the silent period and H reflex conditioning in wrist flexors after magneticTCS, Fuhr, Agostino & Hallett (1991) concluded that the silent period dependedinitially on spinal mechanisms and subsequently on the interruption of voluntarycortical drive.

In this study we investigated the physiological mechanisms of the silent periodoccurring after transcranial cortical stimulation. To examine the possible role ofproprioceptive inflow and spinal mechanisms, we measured the duration of thesilent period, the amplitude of the motor-evoked potential (MEP) and the muscletwitch force, at various intensities of the magnetic shock and at different levels ofbackground force. In addition, we compared the silent period evoked by electricaland magnetic TCS with that produced by electrical stimulation of the motor tractsat the cervicomedullary junction (Ugawa, Rothwell, Day, Thompson & Marsden,1991; Berardelli, Inghilleri, Rothwell, Cruccu & Manfredi, 1991 b) and studied theexcitability of muscle responses evoked by transcranial stimulation with pairedtranscranial shocks.

METHODS

Ten normal subjects aged between 25 and 41 years participated in the study. Experimentswere repeated in a smaller group of five subjects including the authors. Informed consent wasobtained and the study was approved by the local ethical committee.

Stimulation techniqueCortical stimuli were delivered by a magnetic stimulator (modified version of Novametrix

Magstim 200) with a flat coil, having an outer diameter of 14 cm. The coil was centred over thevertex, with the current flowing anticlockwise when viewed from above. The cortex was alsostimulated electrically with a prototype electrical stimulator that delivered single or pairedshocks at short time intervals (700 V maximum output, 100 Us time constant). The anode wasplaced on the scalp overlying the motor areas (7 cm from the mid-line on a line joining the vertexto the external auditory meatus) and the cathode on the vertex. Stimulation varied in intensityfrom 50 to 100 % of the output of the stimulator.

Electrical stimulation of the descending motor tracts at the level of the cervicomedullaryjunction was performed using the method of Ugawa et al. (1991). Briefly, surface electrodes wereplaced on the posterior edge of each mastoid process on both sides of the inion, with the anode onthe right and the cathode on the left. Electrical stimuli were delivered with a Digitimer D180

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SILENT PERIOD AFTER TRANSCRANIAL STIMULATION

stimulator. Stimulus intensity varied in different subjects from 40 to 60% of the output. Higherintensities produced spread of current to the cervical roots; this was recognized by a shortening ofresponse latency (latencies to root stimulation were shorter than those evoked by stimulation ofthe descending motor tracts) and the presence of responses at rest (Ugawa et al. 1991).

The ulnar nerve was stimulated at the wrist with supramaximal electrical stimuli (250 V,0-2 ms duration).

The biceps and wrist extensor muscles were activated directly with electrical stimuli (150 V,0'5 ms) delivered through surface electrodes placed over the belly of the muscle.

The rate of TCS, descending motor tracts, peripheral nerve and muscle stimulation was alwayslonger than 0 1 Hz.

Recording techniqueThe subjects were seated comfortably on a chair with their forearm resting on a table. They

were instructed to exert a 30-40 % of maximum voluntary contraction of the first dorsalinterosseous (FDI) muscle and the silent period was recorded after: (1) transcranial magnetic; (2)transcranial electrical; (3) electrical stimulation of the cervicomedullary junction; (4) ulnar nerve;and (5) biceps and wrist extensor muscles stimulation.

The subjects maintained the isometric contraction of the FDI muscle by abducting the indexfinger against a strain gauge. A strap attached to the table immobilized the fingers and wrist so asto prevent finger and hand movement assisting the first dorsal interosseous muscle. A straingauge attached to the proximal interphalangeal joint of the index finger measured the twitchforce produced by cortical and brainstem stimulation in the FDI muscle.The silent period was also studied during three levels of muscle contraction (30, 60 and 100%

of the maximum effort measured using a strain gauge).EMG activity from the FDI muscle was recorded with surface electrodes and sampled with an

OTE Basis device (bandwidth 2-5000 Hz) or a Cambridge Electronic Design 1401 programmableinterface. The EMG was also full-wave rectified and ten trials were averaged. From the rectifiedEMG activity, a screen cursor measured the duration of the silent period, from the end of themuscle potential evoked by cortical stimulation to the return ofEMG activity. The latency of theMEPs was measured at the onset and the amplitude was measured peak to peak. The amplitudeof the twitch force was measured from the onset to the peak.

Conditioning experiments with paired transcranial shocksCortical excitability was tested in five subjects at rest. A single magnetic shock was given as a

conditioning stimulus. This was then followed by a test stimulus consisting of either a singlemagnetic shock or single or double electrical shocks given at short intervals (1P8 ms) (Inghilleri,Berardelli, Cruccu, Priori & Manfredi, 1989, 1990). The intensity of the conditioning magneticstimulus was set to 80 % of the output of the stimulator. When the test stimulus was a magneticshock, two Novametrix Magstim 200 stimulators were used (one for conditioning and the otherfor test shocks) and the two coils were positioned one above the other on the scalp. Theconditioning and test shock were given at a similar intensity (80 %). Because the coil deliveringthe test shock was farther from the scalp, the amplitude of the unconditioned test MEP (control)was slightly smaller than the amplitude of the MEP evoked by the conditioning stimulus. Themagnetic field generated by the conditioning shock had no effect on the current induced by thetest shock and measured by a probe placed near the test coil.When a single electrical shock was used as the test stimulus the intensity of stimulation was

set at 60-70 % of the stimulator output to evoke a response with an amplitude similar to thatevoked by the magnetic test shock.

The use of double instead of single electrical shocks allowed us to evoke MEPs of an amplitudesimilar to that yielded by the magnetic shocks, despite keeping the electrical stimulator at a lowintensity (45 % output).

The intervals between the conditioning and test stimuli (single magnetic and single or doubleelectrical shocks) were 100, 150 and 200 ms. For each interval five trials were averaged and thevarious conditions were randomized and then averaged.

The experiments using double magnetic shocks were also performed during maximumvoluntary contraction. The intervals between the conditioning and test stimulus were 100 and200 ms.

Statistical significance was evaluated using Student's t test. All results are given as means+ S.D. unless otherwise stated.

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RESULTS

Silent period after cortical (magnetic and electrical), cervicomedullary and peripheralnerve stimulationMagnetic stimulation produced an MEP followed by a total inhibition of the on-

going EMG activity. With maximum output of the stimulator, the averageduration of the silent period in ten subjects was 300 + 54 ms (range 190-400 ms).The mean latency of the MEPs was 20X6 + 1 ms and the amplitude was 7X4 + 2 mV.

MEP

AMagneticstimulation

ElectricalBMW1s-? stimulation

Li^ hi.ihiAL.~I~Id~_NerveC stimulation

400 !V100 ms

Fig 1. Silent periods after transcranial magnetic (A), electrical (B), and nerve (C)stimulation. Recordings from the FDI muscle during maximum voluntary contractionin one normal subject. Superimposition of two single trials. Stimulation rate 0 1 Hz.

Electrical cortical stimulation evoked an MEP followed by total inhibition of theon-going EMG activity. At maximum stimulus intensities the average duration ofthe silent period was 205 + 80 ms (range 130-320 ms). The mean latency of theMEP was 20-0 + 1P1 ms and the amplitude was 7-1 + 2-2 mV.

In five subjects electrical stimulation of the cervicomedullary junction evokedMEPs at a latency of 18-3 + 1 ms and an amplitude of 6-6 + 1-6 mV. The MEP wasfollowed by a silent period of 43'1 + 4-6 ms (range 38-50 ms). Supramaximal ulnarnerve stimulation also inhibited on-going EMG activity in the FDI muscle (meanduration of the silent period in ten subjects was 97 7 + 13 1 ms; Fig. 1). The M waveamplitude was 11-7 + 1-9 mV.

Comparison between the silent period evoked by transcranial and cervicomedullaryjunction stimulation

Since the amplitude of MEPs evoked by cervicomedullary junction stimulationwere lower than those produced by transcranial stimulation we compared theduration of the silent period following MEPs of the same size. The intensity ofcervicomedullary junction stimulation, and magnetic and electrical TCS were

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adjusted to produce MEPs of similar amplitude for each of the three stimuli(6-6 + 1P9 mV magnetic MEP; 6-5 + 1P4 mV electric MEP; 66 + 16 mVcervicomedullary MEP). The magnetic and electrical TCS intensities were 65 + 5and 70 + 5 % of the maximum output respectively.

Shock

A

Brainstemstimulation

B

C e^C~ Electrical

I stimulationD

LIa 50 ms

E

Magneticstimulation

F

Fig 2. Silent period after brainstem (A and B), electrical (C and D) and magnetic (E and F)transcranial stimulation. Traces are averages of 10 single trials in one subject. In A, C andEthe EMG is unrectified and in B, D and Fit is rectified. Vertical calibration is 3 mV in A,C and Eand 400,uV in B, D and F

The duration of the silent period was 234 + 68-7 ms after magnetic stimulation,102 + 42 ms after electrical stimulation and 43 1 + 4X6 ms after cervicomedullaryjunction stimulation. Differences between the silent periods were statisticallysignificant (P < 0 001).

Because the twitch force produced by cervicomedullary junction stimulation wasalways smaller than that produced by transcranial stimulation, the silent periodafter transcranial and after cervicomedullary junction stimulation could not becompared at twitch forces of similar amplitude.

Effect of increasing intensities of magnetic cortical stimulation on the silent period,MEP amplitude and twitch force

In six subjects, the behaviour of the silent period was studied with increasingintensities of cortical stimulation. The silent period progressively increased withthe strength of magnetic stimulation. Figures 3 and 4 show the behaviour of thesilent period in relation to the peak size of the MEPs and in relation to the size ofthe twitch force produced by the MEP. When the intensity of magnetic stimulation

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was increased from 30 to 100% of the output of the stimulator the duration of thesilent period progressively increased, unlike the peak-to-peak size of the MEP andthe twitch force, which at first increased and then plateaued at 60-70% of theoutput of the stimulator.

A

1880BGj> _ % ~~~~80%

C

D .

E100 %

F

50 ms

Fig 3. Effect of increasing stimulation intensity (80 and 100 %) on the silent period aftertranscranial magnetic stimulation in one normal subject. Increasing the stimulationintensity from 80 to 100% of maximum caused the duration of the silent period toincrease, whereas the amplitude of the MEPs (A and D) and of the twitch force (C and F)saturated. Traces are averages of 10 single trials. The EMG is unrectified in A and D, and isrectified in B and E. Vertical calibration is 3 mV in A and D; 200 ,uV in B and E; and 5 Nin C and F Horizontal calibration is 50 ms. Stimulation rate 0 1 Hz.

Although the size of the MEP and the twitch force usually reached a plateau atapproximately the same intensity of stimulation, in some subjects the size of theMEP saturated first. This phenomenon has been already described by Day et al.(1987).

Effect of twitches of other muscles on the FDI voluntary activityHigh intensity transcranial stimulation also produces twitches in proximal

muscles. Afferent feedback from these muscles might, therefore, contribute to thesilent period in the FDI muscle. To verify whether afferent activity from proximalarm muscles contributed to the silent period, electrical stimuli were delivereddirectly to the biceps and wrist extensor muscles, thus evoking a strong twitch inthese muscles, while the subjects voluntarily contracted the FDI muscles. In thefive subjects tested twitches in the proximal muscles failed to inhibit EMG activityin the FDI muscle.

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SILENT PERIOD AFTER TRANSCRANIAL STIMULATION 527

Effect of voluntary contraction on the silent period after magnetic stimulationFive subjects were studied at 80% maximum stimulation strength, while

exerting increasing levels of background contraction. With a 30% maximummuscle contraction, the duration of the silent period was 191P4 + 40 ms. With a60 % contraction, the duration of the silent period was 182 + 51 ms and with a100 % contraction, the duration of the silent period was 183 + 60 ms.

12.0 400

E 9-6 J 320X/V E

7*2 -// 240 C-0

E 4-8 - - 160 ,a.u

0~w 24 - -80 lo

0 20 40 60 80 100 120

12 400

9 J 320 EZ

- 240 r-

4)D 6 -10 ~~~~~~~~160 C

U-~ ~ ~- ~~~~~~~80 C

0 30 20 40 60 80 100 120

Intensity (% output)

Fig. 4. Effect of increasing stimulation intensity (20 to 100 %) on the silent period aftertranscranial magnetic stimulation in six normal subjects. The upper panel shows therelationship between the amplitude of muscle evoked responses (MEP, continuous line),the duration of the silent period (SP, dashed line) and the intensity of magneticstimulation. The lower panel shows the relationship between the size of the twitch force(Force, continuous line), duration of the silent period (SP, dashed line) and intensity ofmagnetic stimulation. Increasing the stimulation intensity from 60 to 100% of maximumoutput caused the MEP and the twitch force to increase progressively in size and thensaturate at 60 and 70% respectively, whereas the silent period became longer. Thecontinuous and dashed lines represent the mean values + S.E.M.

Conditioning experiments with paired cortical stimuliIn five subjects, cortical excitability was tested with a magnetic shock as

conditioning stimulus and either a single magnetic shock or electrical shocks (singleand double) as test stimuli. The experiments were performed with the subjects atrest: (1) to minimize the variability due to changes in spinal cord excitability, and(2) to see whether interrupting the voluntary cortical drive played a role inproducing the silent period.At time intervals of 100, 150 and 200 ms the conditioning magnetic shock

completely abolished the test response to the single magnetic shock and markedlyreduced the amplitude of the test response evoked by a single electrical shock (the


test response was 10 + 4 % of the control response at 100 ms; 9 + 4% at 150 ms and57 + 18 % at 200 ms intervals). The conditioning magnetic shock did not suppressthe test response evoked by the double electrical shocks (Fig. 5): the test responsewas 107 + 10% at 100 ms, 100 + 9 % at 150 ms and 115 + 20% at 200 msintervals.

Magneticconditioning Test

shock shock

f. ,.PA Magnetic

SingleelectricalBF

Doubleelectrical

1-5 mV

20 ms

Fig 5. Effect of magnetic conditioning stimulation on magnetic and electrical test stimuligiven at a time interval of 100 ms. The magnetic conditioning shock completelysuppressed the test magnetic response (A), reduced the size of the response evoked by asingle electrical shock (B), but did not inhibit the response evoked by double electricalshocks (C). Traces are averages of 10 single trials in one subject. Dashed traces representthe unconditioned responses.

Figure 5 shows these responses in a normal subject after conditioning and teststimuli given at an interval of 100 ms. The conditioning magnetic shock completelysuppressed the test response to magnetic shocks; the test response to a singleelectrical shock was inhibited but the test response to double electrical shocks wasunaffected.To see whether the inhibition present in relaxed muscle was also evident in

active muscle, the recovery curve of the response to a second magnetic stimulusdelivered at intervals of 100 and 200 ms after a conditioning magnetic shock wasstudied during maximum voluntary contraction. The test response was completelysuppressed at 100 ms and strongly inhibited at 200 ms (29-8 + 25% of the controlresponse).

DISCUSSION

As observed by Marsden et al. (1983), transcranial stimulation of the motorcortex produces a long-lasting silent period. We found silent periods lasting 200 msafter electrical and 300 ms after magnetic stimulation, decidedly longer than thesilent periods evoked by electrical stimulation of the peripheral nerve. With

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magnetic stimulation, silent periods lasting up to 350-400 ms could be obtained bysetting the stimulator to maximum output and placing a large coil over the vertex.The silent period following electrical stimulation of a peripheral nerve in a

contracting muscle is generally agreed to be the result of a sequence of events(Merton, 1951; Shahani & Young, 1973). Initially, a partial collision of orthodromicand antidromic impulses occurs in the motor fibres. Motoneurone inhibition due toafter-hyperpolarization (AHP) and the activation of the recurrent inhibition byantidromic impulses then follows. The last part of the inhibition is multifactorial inorigin. The mechanisms responsible include muscle spindle unloading, Golgi tendonorgan activation, and excitation of cutaneous fibres.

In the silent period after transcranial stimulation, some of the effects ofperipheral nerve stimulation, namely collision and direct activation of sensoryfibres, do not take place. Other spinal mechanisms, including AHP, recurrentinhibition and changes in proprioceptive input produced by the muscle twitch,may follow both transcranial and peripheral stimulation. Activation of descendinginhibitory fibres, interruption of the voluntary cortical drive, and activation ofcortical inhibitory systems may also play a role.

Role of 'spinal' mechanismsIn comparison to the silent period after cortical stimulation, the silent period

that we observed after stimulation of the motor tracts at the cervicomedullary junctionwas remarkably short, 43 ms. Stimulation across the base of the skull activates themotor tracts at a latency that is approximately 1X5-2 ms shorter than the latencyof the responses evoked by cortical stimulation (Ugawa et al. 1991; Berardelli et al.1991 b). On the basis of collision experiments between cortical and medullaryvolleys, Ugawa et al. (1991) suggested activation of the large-diameter axons ofthe corticospinal tract. The authors also commented that the short-onset latencyand stability of the EMG responses suggest that axons with rapid conductionvelocity and monosynaptic connections are activated. Although other ascendingand descending fibres are probably excited by the cervicomedullary junctionstimulation, it is unlikely that activation of other fibres could modify cortical andspinal excitability to shorten the silent period. Single electrical shocks delivered tothe descending tracts produce only short-lasting changes in spinal cord excitability(Lemon & Mantel, 1989; Inghilleri et al. 1990). Excitation of ascending systemsmay alter cortical excitability; for example, cutaneous afferent input can enhancecortical excitability to magnetic stimulation (Day et al. 1988; Deuschl, Michels,Berardelli, Schenck, Inghilleri & Lucking, 1991) but these changes are relativelysmall. Furthermore, the silent period to cervicomedullary stimulation cannot beaffected by post-twitch proprioceptive input until 50 ms after the onset of the MEP(approximately 20 ms for muscle shortening and receptor activation, and 30 ms forafferent and efferent conduction times; Shahani & Young, 1973).

Overall, it seems unlikely that excitation of other systems is responsible for theshort silent period to cervical junction stimulation. In addition, becausecervicomedullary stimulation bypasses the cortex, the silent period to this form ofstimulation is not influenced by the level of cortical excitability.Having excluded these influences as contributing to the short-lasting silent

period after cervicomedullary stimulation, we must now consider the influence of

529


spinal inhibitory mechanisms (AHP and recurrent inhibition) and the activation ofdescending inhibitory fibres on the silent period.

After-hyperpolarization and recurrent inhibition start immediately afterantidromic invasion, quickly reach maximum, decline after 20-25 ms anddisappear within 200 ms (Bussel & Pierrot-Deseilligny, 1977; Kernell, 1983;Morales, Boxer, Fung & Chase, 1987). These mechanisms have also been proposedto explain the refractoriness of motoneurones observed in studies using pairedcortical stimuli (Inghilleri et al. 1990). Activation of descending inhibitory fibresprobably has little bearing upon the production of the silent period. In animalexperiments, stimulation of corticofugal inhibitory fibres (Cheney, Fetz & Palmer,1985; Lemon, Muir & Mantel, 1987) produces a short-lasting suppression of the on-going EMG activity; inhibition starts a few milliseconds after excitation. Usingtranscranial stimulation and the H reflex technique in man, Cowan, Day, Marsden& Rothwell (1986) demonstrated in the upper limbs a short period of facilitationfollowed by an inhibition lasting 1-2 ms.The silent period produced by cervicomedullary stimulation thus appears to

depend mostly on the spinal inhibitory mechanisms that follow motoneuronalexcitation: AHP and recurrent inhibition. The same spinal mechanisms probablyoperate in the first 40-50 ms of the silent period after cortical stimulation.Although the intensity of magnetic cortical stimulation was lowered to produce

MEPs of the same size as those evoked by electrical stimulation at thecervicomedullary junction, magnetic cortical stimulation still produced a silentperiod that lasted far longer (234 versus 43 ms). Assuming that the size of MEPsgives a relative measure of the number of motoneurones excited, the contributionof the spinal mechanisms (AHP and recurrent inhibition) appeared similar in thetwo conditions. Mechanisms other than AHP and recurrent inhibition musttherefore be responsible for the long silence occurring from 50 to 250 ms.

Role of proprioceptive mechanisms in the silent period after cortical stimulationAs though the amplitude of MEPs is smaller than the M wave evoked by

peripheral nerve stimulation, cortical stimulation produces a muscle twitch that iseven larger than that produced by peripheral nerve stimulation (Day et al. 1987).This raises the possibility that there might be greater changes in proprioceptiveinflow after cortical stimulation.In the experiment testing the effect of magnetic TCS at a range of intensities,

increasing the stimulation intensity from 30 to 70% of the output of the stimulatorcaused the duration of the silent period to increase gradually from 80 to 160 ms.This was paralleled by a progressive increase in the MEP amplitude and the twitchforce. However, increasing the stimulation intensity from 70 to 100 % did not leadto a further increase in the MEP amplitude or twitch force, yet the duration of thesilent period continued to increase, reaching 320 ms. If afferent feedback alsoreaches a plateau with muscle contraction, it is unlikely to contribute to thecontinuing prolongation of the silent period as the intensity of stimulation isincreased.However, at high magnetic stimulation intensities, afferent feedback from other

muscles activated by TCS may contribute to the later parts of the silent period in

530


the FDJ. This contribution is unlikely to be a major one since electrically inducedtwitches in other muscles did not inhibit FDI activity.The experiments testing the effect of increasing levels of contraction showed that

when the force of contraction increased, the duration of the silent period aftertranscranial stimulation remained constant. During maximum contraction Golgitendon organs are maximally facilitated and as a consequence the twitch isexpected to generate the maximum proprioceptive input from these receptors.Whether or not the variations in background force alter the duration of the silentperiod evoked by peripheral nerve stimulation is still controversial. According tosome reports the higher the force exerted the shorter the silent period after nervestimulation (Merton, 1951). For the silent period evoked by transcranialstimulation our experiments have ruled out any obvious relationship tobackground force.Taken together all the above experiments suggest that changes in the

proprioceptive input induced by muscle twitch play no major role in the silentperiod after TCS.

Role of cortical mechanisms in the silent period after cortical stimulationSeveral authors suggest that transcranial stimulation may not only excite the

motor cortex but may also interfere with cortical activity. Penfield & Jasper (1954)first observed that direct stimulation of motor cortex produces slowing andinterruption of movements, and more recently Day et al. (1989 b) and Berardelli,Inghilleri, Cruccu & Manfredi (1991 a) have shown that electrical and magnetictranscranial stimulation cause the execution of rapid limb movements to bedelayed or interrupted, an interference they attributed to intracorticalmechanisms.The conditioning experiments with paired cortical stimuli described in this paper

demonstrate that the later part (from 50 ms onward) of the silent period aftermagnetic transcranial stimulation is produced by intracortical mechanisms.Using the technique described by Inghilleri et al. (1989, 1990), we delivered a

short-interval doublet of low-intensity electrical shocks, generating two volleys inthe corticospinal axons in order to excite through temporal summation a largenumber of spinal motoneurones. The motor potential evoked by this doublet ofelectrical shocks was unaffected by a preceding conditioning magnetic shock. Thisproves that the spinal motoneurones were not inhibited at the time of arrival of thedouble descending volleys. As Day, Marsden, Rothwell, Thompson & Ugawa (1990)also point out, inhibition does occur if the response is evoked by a single electricalshock. A single electrical shock that activates the corticospinal axons produces adirect wave, often followed by cortical later waves (Inghilleri et al. 1989; Edgley,Eyre, Lemon & Miller, 1990; Burke, Hicks & Stephen, 1990). With the muscle atrest, the size of the response evoked by transcranial electrical stimulation dependson the arrival of the later cortical waves at the spinal motoneurones (Day et al.1987). The reduction in size of the response to the test electrical shock, produced bythe conditioning magnetic shock, is probably due to inhibition of the later corticalwaves. When we used a second magnetic shock as a test, and the subject was at rest,the test motor potential was abolished by the conditioning magnetic shock. In

531


active muscles the test motor response was strongly inhibited, though notabolished, probably because inhibitory and excitatory inputs summated at thelevel of pyramidal cells. The inhibition of the test magnetic response indicates thatthe second magnetic shock, which is expected to excite predominantly corticalelements, is unable to discharge the pyramidal cells (Hess, Mills & Murray, 1987;Day et al. 1989 a; Berardelli, Inghilleri, Cruccu & Manfredi, 1990).The reasoning above could also explain the shorter duration of the silent period

after electrical transcranial stimulation (200 ms) compared with that aftermagnetic stimulation (300 ms). Inhibition is more powerful after magneticstimulation. This is because it predominantly activates cortical elements whereaselectrical stimulation mainly activates corticospinal axons (Rothwell, Thompson,Day, Boyd & Marsden, 1991).The exact mechanisms underlying cortical inhibition are more difficult to

establish. Using an H reflex technique to test the excitability of the spinalmotorneurone pool during the silent period produced by cortical stimulation, Fuhret al. (1991) propose, as we do, that the beginning of the silent period depends onspinal inhibitory mechanisms, whereas the later part depends on the interruptionof the voluntary cortical drive. The hypothesis of a simple loss of the cortical driveonto the spinal motoneurones is ruled out by our experiments demonstratinginhibition of a test MEP when conditioning and test shocks are delivered in thefully relaxed subject.

Activation of inhibitory collaterals of the pyramidal cells themselves is alsounlikely since stimulation of the motor tracts at the cervicomedullary junction,despite producing antidromic invasion of pyramidal cells, only induced a short-lasting silent period.We believe that the silent period results from activation of inhibitory neurones

projecting onto the pyramidal cells of the motor cortex. These neurones are widelydisseminated in cortical areas. In animals, Krnjevic, Randic & Straughan (1966 a, b)found that direct and indirect cortical electrical stimuli could produce a long-lasting inhibition (100-300 ms) of the cortical neurones. Repetitive, surfacestimulation of the motor cortex itself produced the longest-lasting inhibition of thepyramidal cells. The cells held responsible for the inhibition are the Golgi II cellswith long axons (Krnjevic, Randic & Straughan, 1964).

Finally, the powerful excitation of cortical cells produced by high-intensitymagnetic shocks may give rise to an intense after-hyperpolarization, an effect thatwould also contribute to the block of the motor cortex.In conclusion, the silent period after cortical stimulation is generated by several

mechanisms. In the first 50 ms, spinal factors (recurrent inhibition and AHP)operate, with a possible contribution by descending inhibitory fibres. Although acontribution by post-twitch proprioceptive changes cannot be definitely excluded,we believe that the proprioceptive input cannot be responsible for the later part ofthe silent period after magnetic stimulation. This part of the silent period probablyresults from inhibitory effects at the cortical level.

We would like to thank Dr P.D. Thompson for reading the final version and Mrs DianaBrusoni for typing the manuscript.

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SILENT PERIOD AFTER TRANSCRANIAL STIMULATION 533

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