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  • 1. Journal ofPhysiology (1993), 466, pp. 521-534 521 With 5 figures Printed in Great Britain SILENT PERIOD EVOKED BY TRANSCRANIAL STIMULATION OF THE HUMAN CORTEX AND CERVICOMEDULLARY JUNCTION By M. INGHILLERJ, A. BERARDELLI, G. CRUCCU AND M. MANFREDI From the Department ofNeurological Sciences, University ofRome 'La Sapienza', Viale Universita' 30, Rome, Italy (Received 3 February 1992) SUMMARY 1. The silent period evoked in the first dorsal interosseous (FDI) muscle after electrical and magnetic transcranial stimulation (TCS), electrical stimulation of the cervicomedullary junction and ulnar nerve stimulation was studied in ten healthy subjects. 2. With maximum-intensity shocks, the average duration of the silent period was 200 ms after electrical TCS, 300 ms after magnetic TCS, 43 ms after stimulation at the cervicomedullary junction and 100 ms after peripheral nerve stimulation. 3. The duration of the silent period, the amplitude of the motor-evoked potential, and the twitch force produced in the muscle were compared at increasing intensities of magnetic TCS. When the stimulus strength was increased from 30 to 70 % of the stimulator output, the duration of the silent period lengthened as the amplitude of the motor potential and force of the muscle twitch increased. At 70 to 100 % of the output, the amplitude of the motor potential and force of the muscle twitch saturated, whereas the duration ofthe silent period continued to increase. 4. Proximal arm muscle twitches induced by direct electrical stimulation of the biceps and extensor wrist muscles produced no inhibition of voluntary activity in the contracting FDI muscle. 5. The level of background activation had no effect on the duration of the silent period recorded in the FDI muscle after magnetic TCS. 6. Corticomotoneurone excitability after TCS was studied by means of a single magnetic conditioning shock and a test stimulus consisting either of one single magnetic shock or single and double electrical shocks (interstimulus interval 1P8 ms) in the relaxed muscle. A conditioning magnetic shock completely suppressed the response evoked by a second magnetic shock, reduced the size of the response evoked by a single electrical shock but did not affect the response evoked by double electrical shocks. Inhibition of the test magnetic shock was also present during muscle contraction. 7. Our findings indicate that the first 50 ms of the silent period after TCS are produced mainly by spinal mechanisms such as after-hyperpolarization and recurrent inhibition of the spinal motoneurones. If descending inhibitory fibres MS 1085
  • 2. M. INGHILLERI AND OTHERS contribute, their contribution is small. Changes in proprioceptive input probably have a minor influence. From 50 ms onwards the silent period is produced mainly by cortical inhibitory mechanisms. INTRODUCTION Marsden, Merton & Morton (1983) first demonstrated that electrical stimulation of the motor cortex in man produces a muscle twitch followed by a silence of EMG activity. They suggested that this silent period after cortical stimulation was different from the silent period evoked by stimulation of a peripheral nerve (Merton, 1951). Since then, other authors have recorded a silent period in the hand muscles after transcranial stimulation (TCS) and have investigated the underlying physiological mechanisms. Using surface EMG and needle recordings of single motor units from the forearm muscle, Calancie, Nordin, Wallin & Hagbarth (1987) studied the silent period after electrical TCS and suggested that the inhibitory period was determined mainly by changes in proprioceptive input induced by the muscle twitch and partly by activation of descending inhibitory influences. In a study of the silent period and H reflex conditioning in wrist flexors after magnetic TCS, Fuhr, Agostino & Hallett (1991) concluded that the silent period depended initially on spinal mechanisms and subsequently on the interruption of voluntary cortical drive. In this study we investigated the physiological mechanisms of the silent period occurring after transcranial cortical stimulation. To examine the possible role of proprioceptive inflow and spinal mechanisms, we measured the duration of the silent period, the amplitude of the motor-evoked potential (MEP) and the muscle twitch force, at various intensities of the magnetic shock and at different levels of background force. In addition, we compared the silent period evoked by electrical and magnetic TCS with that produced by electrical stimulation of the motor tracts at the cervicomedullary junction (Ugawa, Rothwell, Day, Thompson & Marsden, 1991; Berardelli, Inghilleri, Rothwell, Cruccu & Manfredi, 1991 b) and studied the excitability of muscle responses evoked by transcranial stimulation with paired transcranial shocks. METHODS Ten normal subjects aged between 25 and 41 years participated in the study. Experiments were repeated in a smaller group of five subjects including the authors. Informed consent was obtained and the study was approved by the local ethical committee. Stimulation technique Cortical 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 the vertex, with the current flowing anticlockwise when viewed from above. The cortex was also stimulated electrically with a prototype electrical stimulator that delivered single or paired shocks at short time intervals (700 V maximum output, 100 Us time constant). The anode was placed on the scalp overlying the motor areas (7 cm from the mid-line on a line joining the vertex to the external auditory meatus) and the cathode on the vertex. Stimulation varied in intensity from 50 to 100 % ofthe output ofthe stimulator. Electrical stimulation of the descending motor tracts at the level of the cervicomedullary junction was performed using the method of Ugawa et al. (1991). Briefly, surface electrodes were placed on the posterior edge of each mastoid process on both sides of the inion, with the anode on the right and the cathode on the left. Electrical stimuli were delivered with a Digitimer D180 522
  • 3. SILENT PERIOD AFTER TRANSCRANIAL STIMULATION stimulator. Stimulus intensity varied in different subjects from 40 to 60 % of the output. Higher intensities produced spread of current to the cervical roots; this was recognized by a shortening of response latency (latencies to root stimulation were shorter than those evoked by stimulation of the descending motor tracts) and the presence ofresponses 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 ofthe muscle. The rate of TCS, descending motor tracts, peripheral nerve and muscle stimulation was always longer than 0 1 Hz. Recording technique The 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 dorsal interosseous (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 index finger against a strain gauge. A strap attached to the table immobilized the fingers and wrist so as to prevent finger and hand movement assisting the first dorsal interosseous muscle. A strain gauge attached to the proximal interphalangeal joint of the index finger measured the twitch force 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 programmable interface. The EMG was also full-wave rectified and ten trials were averaged. From the rectified EMG activity, a screen cursor measured the duration of the silent period, from the end of the muscle potential evoked by cortical stimulation to the return of EMG activity. The latency ofthe MEPs was measured at the onset and the amplitude was measured peak to peak. The amplitude of the twitch force was measured from the onset to the peak. Conditioning experiments with paired transcranial shocks Cortical 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 single magnetic 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 magnetic stimulus was set to 80 % of the output of the stimulator. When the test stimulus was a magnetic shock, two Novametrix Magstim 200 stimulators were used (one for conditioning and the other for test shocks) and the two coils were positioned one above the other on the scalp. The conditioning and test shock were given at a similar intensity (80 %). Because the coil delivering the 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. The magnetic field generated by the conditioning shock had no effect on the current induced by the test 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 that evoked by the magnetic test shock. The use of double instead of single electrical shocks allowed us to evoke MEPs of an amplitude similar to that yielded by the magnetic shocks, despite keeping the electrical stimulator at a low intensity (45 % output). The intervals between the conditioning and test stimuli (single magnetic and single or double electrical shocks) were 100, 150 and 200 ms. For each interval five trials were averaged and the various conditions were randomized and then averaged. The experiments using double magnetic shocks were also performed during maximum voluntary contraction. The intervals between the conditioning and test stimulus were 100 and 200 ms. Statistical significance was evaluated using Student's t test. All results are given as means + S.D. unless otherwise stated. 523
  • 4. M. INGHILLERI AND OTHERS RESULTS Silent period after cortical (magnetic and electrical), cervicomedullary and peripheral nerve stimulation Magnetic stimulation produced an MEP followed by a total inhibition of the on- going EMG activity. With maximum output of the stimulator, the average duration 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 A Magnetic stimulation Electrical BMW1s-? stimulation Li^ hi.ihiAL.~I~Id~_Nerve C stimulation 400 !V 100 ms Fig 1. Silent periods after transcranial magnetic (A), electrical (B), and nerve (C) stimulation. Recordings from the FDI muscle during maximum voluntary contraction in one normal subject. Superimposition oftwo single trials. Stimulation rate 0 1 Hz. Electrical cortical stimulation evoked an MEP followed by total inhibition of the on-going EMG activity. At maximum stimulus intensities the average duration of the silent period was 205 + 80 ms (range 130-320 ms). The mean latency of the MEP was 20-0 + 1P1 ms and the amplitude was 7-1 + 2-2 mV. In five subjects electrical stimulation of the cervicomedullary junction evoked MEPs at a latency of 18-3 + 1 ms and an amplitude of 6-6 + 1-6 mV. The MEP was followed by a silent period of 43'1 + 4-6 ms (range 38-50 ms). Supramaximal ulnar nerve stimulation also inhibited on-going EMG activity in the FDI muscle (mean duration of the silent period in ten subjects was 97 7 + 13 1 ms; Fig. 1). The M wave amplitude was 11-7 + 1-9 mV. Comparison between the silent period evoked by transcranial and cervicomedullary junction stimulation Since the amplitude of MEPs evoked by cervicomedullary junction stimulation were lower than those produced by transcranial stimulation we compared the duration of the silent period following MEPs of the same size. The intensity of cervicomedullary junction stimulation, and magnetic and electrical TCS were 524
  • 5. SILENT PERIOD AFTER TRANSCRANIAL STIMULATION 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 mV cervicomedullary MEP). The magnetic and electrical TCS intensities were 65 + 5 and 70 + 5 % of the maximum output respectively. Shock A Brainstem stimulation B C e^ C~ Electrical I stimulation D LIa 50 ms E Magnetic stimulation 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 and Ethe EMG is unrectified and in B, D and Fit is rectified. Vertical calibration is 3 mV in A, Cand 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 cervicomedullary junction stimulation. Differences between the silent periods were statistically significant (P < 0 001). Because the twitch force produced by cervicomedullary junction stimulation was always smaller than that produced by transcranial stimulation, the silent period after transcranial and after cervicomedullary junction stimulation could not be compared at twitch forces ofsimilar 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 increasing intensities of cortical stimulation. The silent period progressively increased with the strength of magnetic stimulation. Figures 3 and 4 show the behaviour of the silent period in relation to the peak size of the MEPs and in relation to the size of the twitch force produced by the MEP. When the intensity ofmagnetic stimulation 525
  • 6. M. INGHILLERI AND OTHERS was increased from 30 to 100 % of the output of the stimulator the duration of the silent period progressively increased, unlike the peak-to-peak size of the MEP and the twitch force, which at first increased and then plateaued at 60-70 % of the output ofthe stimulator. A 1880BGj> _ % ~~~~80% C D . E 100 % F 50 ms Fig 3. Effect of increasing stimulation intensity (80 and 100 %) on the silent period after transcranial magnetic stimulation in one normal subject. Increasing the stimulation intensity from 80 to 100% of maximum caused the duration of the silent period to increase, 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 is rectified in B and E. Vertical calibration is 3 mV in A and D; 200 ,uV in B and E; and 5 N in Cand 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 at approximately the same intensity of stimulation, in some subjects the size of the MEP saturated first. This phenomenon has been already described by Day et al. (1987). Effect of twitches of other muscles on the FDI voluntary activity High intensity transcranial stimulation also produces twitches in proximal muscles. Afferent feedback from these muscles might, therefore, contribute to the silent period in the FDI muscle. To verify whether afferent activity from proximal arm muscles contributed to the silent period, electrical stimuli were delivered directly to the biceps and wrist extensor muscles, thus evoking a strong twitch in these muscles, while the subjects voluntarily contracted the FDI muscles. In the five subjects tested twitches in the proximal muscles failed to inhibit EMG activity in the FDI muscle. 526
  • 7. SILENT PERIOD AFTER TRANSCRANIAL STIMULATION 527 Effect of voluntary contraction on the silent period after magnetic stimulation Five subjects were studied at 80 % maximum stimulation strength, while exerting increasing levels of background contraction. With a 30 % maximum muscle contraction, the duration of the silent period was 191P4 + 40 ms. With a 60 % contraction, the duration of the silent period was 182 + 51 ms and with a 100 % contraction, the duration ofthe 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 E Z - 240 r- 4)D 6 -1 0 ~~~~~~~~160 C U-~ ~ ~ - ~~~~~~~80 C 0 3 0 20 40 60 80 100 120 Intensity (% output) Fig. 4. Effect of increasing stimulation intensity (20 to 100 %) on the silent period after transcranial magnetic stimulation in six normal subjects. The upper panel shows the relationship between the amplitude of muscle evoked responses (MEP, continuous line), the duration of the silent period (SP, dashed line) and the intensity of magnetic stimulation. 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 of magnetic stimulation. Increasing the stimulation intensity from 60 to 100 % of maximum output caused the MEP and the twitch force to increase progressively in size and then saturate at 60 and 70 % respectively, whereas the silent period became longer. The continuous and dashed lines represent the mean values + S.E.M. Conditioning experiments with paired cortical stimuli In five subjects, cortical excitability was tested with a magnetic shock as conditioning stimulus and either a single magnetic shock or electrical shocks (single and double) as test stimuli. The experiments were performed with the subjects at rest: (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 in producing 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 markedly reduced the amplitude of the test response evoked by a single electrical shock (the
  • 8. M. INGHILLERI AND OTHERS test response was 10 + 4 % of the control response at 100 ms; 9 + 4 % at 150 ms and 57 + 18 % at 200 ms intervals). The conditioning magnetic shock did not suppress the test response evoked by the double electrical shocks (Fig. 5): the test response was 107 + 10 % at 100 ms, 100 + 9 % at 150 ms and 115 + 20 % at 200 ms intervals. Magnetic conditioning Test shock shock f. ,.PA Magnetic Single electrical BF Double electrical 1-5 mV 20 ms Fig 5. Effect ofmagnetic conditioning stimulation on magnetic and electrical test stimuli given at a time interval of 100 ms. The magnetic conditioning shock completely suppressed the test magnetic response (A), reduced the size of the response evoked by a single electrical shock (B), but did not inhibit the response evoked by double electrical shocks (C). Traces are averages of 10 single trials in one subject. Dashed traces represent the unconditioned responses. Figure 5 shows these responses in a normal subject after conditioning and test stimuli given at an interval of 100 ms. The conditioning magnetic shock completely suppressed the test response to magnetic shocks; the test response to a single electrical shock was inhibited but the test response to double electrical shocks was unaffected. 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 stimulus delivered at intervals of 100 and 200 ms after a conditioning magnetic shock was studied during maximum voluntary contraction. The test response was completely suppressed at 100 ms and strongly inhibited at 200 ms (29-8 + 25 % of the control response). DISCUSSION As observed by Marsden et al. (1983), transcranial stimulation of the motor cortex produces a long-lasting silent period. We found silent periods lasting 200 ms after electrical and 300 ms after magnetic stimulation, decidedly longer than the silent periods evoked by electrical stimulation of the peripheral nerve. With 528
  • 9. SILENT PERIOD AFTER TRANSCRANIAL STIMULATION magnetic stimulation, silent periods lasting up to 350-400 ms could be obtained by setting 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 orthodromic and antidromic impulses occurs in the motor fibres. Motoneurone inhibition due to after-hyperpolarization (AHP) and the activation of the recurrent inhibition by antidromic impulses then follows. The last part ofthe inhibition is multifactorial in origin. The mechanisms responsible include muscle spindle unloading, Golgi tendon organ activation, and excitation ofcutaneous fibres. In the silent period after transcranial stimulation, some of the effects of peripheral nerve stimulation, namely collision and direct activation of sensory fibres, do not take place. Other spinal mechanisms, including AHP, recurrent inhibition and changes in proprioceptive input produced by the muscle twitch, may follow both transcranial and peripheral stimulation. Activation of descending inhibitory fibres, interruption of the voluntary cortical drive, and activation of cortical inhibitory systems may also play a role. Role of 'spinal' mechanisms In comparison to the silent period after cortical stimulation, the silent period that we observed after stimulation of the motor tracts at the cervicomedullary junction was remarkably short, 43 ms. Stimulation across the base of the skull activates the motor tracts at a latency that is approximately 1X5-2 ms shorter than the latency of the responses evoked by cortical stimulation (Ugawa et al. 1991; Berardelli et al. 1991 b). On the basis of collision experiments between cortical and medullary volleys, Ugawa et al. (1991) suggested activation of the large-diameter axons of the corticospinal tract. The authors also commented that the short-onset latency and stability of the EMG responses suggest that axons with rapid conduction velocity and monosynaptic connections are activated. Although other ascending and descending fibres are probably excited by the cervicomedullary junction stimulation, it is unlikely that activation of other fibres could modify cortical and spinal excitability to shorten the silent period. Single electrical shocks delivered to the descending tracts produce only short-lasting changes in spinal cord excitability (Lemon & Mantel, 1989; Inghilleri et al. 1990). Excitation of ascending systems may alter cortical excitability; for example, cutaneous afferent input can enhance cortical excitability to magnetic stimulation (Day et al. 1988; Deuschl, Michels, Berardelli, Schenck, Inghilleri & Lucking, 1991) but these changes are relatively small. Furthermore, the silent period to cervicomedullary stimulation cannot be affected 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 for afferent and efferent conduction times; Shahani & Young, 1973). Overall, it seems unlikely that excitation of other systems is responsible for the short silent period to cervical junction stimulation. In addition, because cervicomedullary stimulation bypasses the cortex, the silent period to this form of stimulation 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
  • 10. M. INGHILLERI AND OTHERS spinal inhibitory mechanisms (AHP and recurrent inhibition) and the activation of descending inhibitory fibres on the silent period. After-hyperpolarization and recurrent inhibition start immediately after antidromic invasion, quickly reach maximum, decline after 20-25 ms and disappear within 200 ms (Bussel & Pierrot-Deseilligny, 1977; Kernell, 1983; Morales, Boxer, Fung & Chase, 1987). These mechanisms have also been proposed to explain the refractoriness of motoneurones observed in studies using paired cortical stimuli (Inghilleri et al. 1990). Activation of descending inhibitory fibres probably has little bearing upon the production of the silent period. In animal experiments, 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. Using transcranial stimulation and the H reflex technique in man, Cowan, Day, Marsden & Rothwell (1986) demonstrated in the upper limbs a short period of facilitation followed 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 motoneuronal excitation: AHP and recurrent inhibition. The same spinal mechanisms probably operate in the first 40-50 ms ofthe 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 the cervicomedullary junction, magnetic cortical stimulation still produced a silent period that lasted far longer (234 versus 43 ms). Assuming that the size of MEPs gives a relative measure of the number of motoneurones excited, the contribution of the spinal mechanisms (AHP and recurrent inhibition) appeared similar in the two conditions. Mechanisms other than AHP and recurrent inhibition must therefore be responsible for the long silence occurring from 50 to 250 ms. Role ofproprioceptive mechanisms in the silent period after cortical stimulation As though the amplitude of MEPs is smaller than the M wave evoked by peripheral nerve stimulation, cortical stimulation produces a muscle twitch that is even larger than that produced by peripheral nerve stimulation (Day et al. 1987). This raises the possibility that there might be greater changes in proprioceptive inflow 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 stimulator caused 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 twitch force. However, increasing the stimulation intensity from 70 to 100 % did not lead to a further increase in the MEP amplitude or twitch force, yet the duration of the silent period continued to increase, reaching 320 ms. If afferent feedback also reaches a plateau with muscle contraction, it is unlikely to contribute to the continuing prolongation of the silent period as the intensity of stimulation is increased. 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
  • 11. SILENT PERIOD AFTER TRANSCRANIAL STIMULATION the FDJ. This contribution is unlikely to be a major one since electrically induced twitches 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 after transcranial stimulation remained constant. During maximum contraction Golgi tendon organs are maximally facilitated and as a consequence the twitch is expected to generate the maximum proprioceptive input from these receptors. Whether or not the variations in background force alter the duration of the silent period evoked by peripheral nerve stimulation is still controversial. According to some reports the higher the force exerted the shorter the silent period after nerve stimulation (Merton, 1951). For the silent period evoked by transcranial stimulation our experiments have ruled out any obvious relationship to background force. Taken together all the above experiments suggest that changes in the proprioceptive input induced by muscle twitch play no major role in the silent period after TCS. Role of cortical mechanisms in the silent period after cortical stimulation Several 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 and interruption of movements, and more recently Day et al. (1989 b) and Berardelli, Inghilleri, Cruccu & Manfredi (1991 a) have shown that electrical and magnetic transcranial stimulation cause the execution of rapid limb movements to be delayed or interrupted, an interference they attributed to intracortical mechanisms. The conditioning experiments with paired cortical stimuli described in this paper demonstrate that the later part (from 50 ms onward) of the silent period after magnetic 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 in the corticospinal axons in order to excite through temporal summation a large number of spinal motoneurones. The motor potential evoked by this doublet of electrical shocks was unaffected by a preceding conditioning magnetic shock. This proves that the spinal motoneurones were not inhibited at the time of arrival ofthe double descending volleys. As Day, Marsden, Rothwell, Thompson & Ugawa (1990) also point out, inhibition does occur if the response is evoked by a single electrical shock. A single electrical shock that activates the corticospinal axons produces a direct wave, often followed by cortical later waves (Inghilleri et al. 1989; Edgley, Eyre, Lemon & Miller, 1990; Burke, Hicks & Stephen, 1990). With the muscle at rest, the size of the response evoked by transcranial electrical stimulation depends on 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 by the conditioning magnetic shock, is probably due to inhibition of the later cortical waves. 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
  • 12. M. INGHILLERI AND OTHERS active muscles the test motor response was strongly inhibited, though not abolished, probably because inhibitory and excitatory inputs summated at the level of pyramidal cells. The inhibition of the test magnetic response indicates that the second magnetic shock, which is expected to excite predominantly cortical elements, 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 after magnetic stimulation (300 ms). Inhibition is more powerful after magnetic stimulation. This is because it predominantly activates cortical elements whereas electrical 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 spinal motorneurone pool during the silent period produced by cortical stimulation, Fuhr et al. (1991) propose, as we do, that the beginning of the silent period depends on spinal inhibitory mechanisms, whereas the later part depends on the interruption of the voluntary cortical drive. The hypothesis of a simple loss of the cortical drive onto the spinal motoneurones is ruled out by our experiments demonstrating inhibition of a test MEP when conditioning and test shocks are delivered in the fully relaxed subject. Activation of inhibitory collaterals of the pyramidal cells themselves is also unlikely 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 widely disseminated in cortical areas. In animals, Krnjevic, Randic & Straughan (1966a, b) found that direct and indirect cortical electrical stimuli could produce a long- lasting inhibition (100-300 ms) of the cortical neurones. Repetitive, surface stimulation of the motor cortex itself produced the longest-lasting inhibition of the pyramidal cells. The cells held responsible for the inhibition are the Golgi II cells with long axons (Krnjevic, Randic & Straughan, 1964). Finally, the powerful excitation of cortical cells produced by high-intensity magnetic shocks may give rise to an intense after-hyperpolarization, an effect that would also contribute to the block ofthe 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 a contribution by post-twitch proprioceptive changes cannot be definitely excluded, we believe that the proprioceptive input cannot be responsible for the later part of the silent period after magnetic stimulation. This part ofthe silent period probably results from inhibitory effects at the cortical level. We would like to thank Dr P.D. Thompson for reading the final version and Mrs Diana Brusoni for typing the manuscript. 532
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