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1Institute of Neurology, Università Cattolica, Rome, Italy; 2Unidad de Neurologia Funcional, Hospital Nacional de Paraplejicos, Finca la Peraleda, Toledo, Spain; 3Neurochirurgia CTO, and 4Neurofisiologia CTO, and 5Fondazione Don C Gnocchi, Rome, Italy; and 6Sobell Department of Neurophysiology, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom
Submitted 6 April 2006; accepted in final form 22 May 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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studied the interaction between pairs of transcranial magnetic stimuli delivered through a single coil to the motor cortex. They found that a small, subthreshold conditioning stimulus could suppress the response to a later suprathreshold test stimulus if the interval between the stimuli [interstimulus interval (ISI)] was 5 ms or less. In contrast, there was facilitation when the ISI was from 10 to 25 ms. Because the intensity of the conditioning stimulus was below threshold both for producing a direct motor response and any effects on spinal H-reflexes, they suggested that the interaction occurred between circuits activated within the cerebral cortex. Direct evidence of intracortical origin of the short latency inhibitory component was obtained by recording from electrodes inserted into the cervical epidural space of conscious patients (Di Lazzaro et al. 1998; Nakamura et al. 1997). These showed that a conditioning shock could reduce the amplitude of corticospinal volleys evoked by the test stimulus, confirming that the interaction between stimuli did occur within the motor cortex. The periods of inhibition and facilitation are now termed short interval intracortical inhibition (SICI) and intracortical facilitation (ICF).
Although there is good evidence for the intracortical origin of SICI, there is rather less direct information, despite its name, about the origin of ICF. As far as we are aware, the only experiments are those of Kujrai et al. (1993) and Ziemann et al. (1996), who showed that H-reflexes were not facilitated at facilitatory ISIs. The aim of this study was to provide more evidence about the origin of ICF from direct recordings of descending volleys evoked by transcranial magnetic stimulation (TMS) pulses in the cervical cord of conscious human subjects. As reported in previous papers, these individuals had epidural electrodes implanted into the cervical epidural space for the treatment of pain. During the initial screening period, we were able to record from the electrode contacts and correlate the effect of ICF on descending volleys with that on MEPs in distal hand muscles. The results were obtained in six conscious patients who had a stimulator implanted in the cervical cord for the treatment of intractable pain.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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As described in previous publications (Di Lazzaro et al. 1998), we recorded descending corticospinal activity evoked by single and paired transcranial magnetic stimulation of the motor cortex directly from the high cervical epidural space of six conscious patients [mean age, 52 ± 9.4 (SD) yr] with no abnormality of CNS who had electrodes inserted for control of intractable dorsolumbar pain. Recordings were made simultaneously from the epidural electrode and from the relaxed first dorsal interosseous muscle (FDI) of the left hand. Motor-evoked potentials (MEPs) and the corticospinal volleys were amplified and filtered (bandwidth, 3 Hz to 3 kHz) by D360 amplifiers (Digitimer, Welwyn Garden City, Herts, UK). Data were collected on a computer and stored for later analysis using a CED 1401 A-D converter (Cambridge Electronic Design, Cambridge, UK).
Magnetic stimulation was performed with a high-power Magstim 200 (Magstim, Whitland, Dyfed, UK). A figure-of-eight coil with external loop diameters of 9 cm was held over the right motor cortex at the optimum scalp position to elicit motor responses in the contralateral FDI. Intensities were expressed as a percentage of the maximum output of the stimulator. Resting motor threshold (RMT) was defined according to the recommendations of the IFCN Committee (Rossini et al. 1994) as the minimum stimulus intensity that produced a liminal MEP (>50 µV in 50% of 10 trials) with the tested muscle at rest. Active motor threshold (AMT) was defined as the minimum stimulus intensity that produced a liminal motor-evoked response (
200 µV in 50% of 10 trials) during isometric contraction of the tested muscle at about 20% maximum. A constant level of voluntary contraction was maintained with reference to an oscilloscope display of EMG in front of the subject. Auditory feedback of the EMG activity was also provided.
Single pulse magnetic stimulation
Single pulse magnetic stimulation was used to identify the descending volleys. Two different orientations of the stimulating coil over the motor strip were used, with the induced current flowing either in a latero-medial (LM) or in a posterior-anterior (PA) direction. In subject 6, we also recorded the responses evoked by stimulating with the induced current flowing in the antero-posterior (AP) direction. The responses to 10 stimuli were averaged at rest in all subjects using a stimulus intensity that evoked a MEP in relaxed FDI with an amplitude of 1 mV peak-to-peak.
LM magnetic stimulation was used to identify the latency of the earliest (D-wave) descending volley (Di Lazzaro et al. 2004). PA magnetic stimulation of the motor cortex was used to identify the latency of the later (I waves) descending volleys (Di Lazzaro et al. 2004).
The latency of each component of the descending volley was measured to its peak, because the precise onset was often difficult to define for all but the first component.
Paired pulse magnetic stimulation
Magnetic stimulation was performed with a high power Magstim 200 (Magstim, Whitland, Dyfed, UK). A figure-of-eight coil with external loop diameters of 9 cm was held over the right motor cortex (at the optimum scalp position to elicit motor responses in the contralateral FDI) with the induced current flowing in a PA direction.
Intracortical facilitation was studied using the technique of Kujrai et al. (1993). Two magnetic stimuli were given through the same stimulating coil, using a Bistim module, over the motor cortex, and the effect of the first (conditioning) stimulus on the second (test) stimulus was studied. The conditioning stimulus was set at an intensity of 5% (of stimulator output) below active threshold. The second test, shock intensity, was adjusted to evoke a MEP in relaxed FDI with an amplitude of 1 mV peak-to-peak in five of the subjects; in the remaining subject (patient 6), we used a test stimulus intensity that evoked a lower amplitude MEPs. This was done because previous studies showed that I wave facilitation (with a different paradigm of intracortical facilitation, at short ISIs of 1–2 ms) occurs if the test stimulus intensity is close to motor threshold (Di Lazzaro et al. 1999) and also that MEP facilitation becomes more pronounced with smaller test MEPs (Daskalakis et al. 2002). The timing of the conditioning shock was altered in relation to the test shock. Facilitatory ISIs of 10, 15, and 25 ms were studied.
To evaluate the effects of changing the intensity of the conditioning stimulus in subject 1, paired stimulation was also performed using a conditioning stimulus intensity of 10% (of stimulator output) below AMT and a conditioning stimulus intensity of AMT. In this subject, we also evaluated the inhibitory intervals 2 and 3 ms to evaluate whether intracortical inhibition and intracortical facilitation represent independent phenomena with different thresholds as suggested by Ziemann et al. (1996) on the basis of MEPs recording.
Previous studies have shown differences in the facilitation produced by paired cortical stimulation using different direction of stimulating current induced in the brain (Hanajima et al. 2002; Ziemann et al. 1996). This was evaluated in subject 6 by also stimulating with the induced current flowing in an AP direction. Because the study by Hanajima et al. (2002) had shown that AP-induced current in the brain gives clear facilitation at short ISIs, we also evaluated the effects of paired stimulation at 2-ms ISI.
Ten stimuli were delivered at each ISI. For these recordings, muscle relaxation is very important and the subject was given audio-visual feedback of the EMG signal at high gain to assist in maintaining complete relaxation.
Amplitudes of the descending volleys were measured from the peak to the next trough to minimize distortions caused by stimulus artifact. Only consistent deflections with a mean amplitude over 10 responses of >2 mV were analyzed.
We also evaluated the total area of the descending waves measured from the onset of the first descending wave to the trough of the last descending wave in the volley.
Amplitude of the conditioned MEPs and amplitude of conditioned volleys were expressed as percentage of the amplitude of the test MEPs and volleys.
Cervico-medullary junction stimulation
In six different subjects [mean age, 29 ± 4 (SD) yr], the effects produced by a subthreshold cortical conditioning stimulus on MEPs evoked by cervico-medullary junction stimulation were compared with those produced by the same conditioning stimulus on the MEPs evoked by a suprathreshold cortical stimulus at an ISI of 10 ms. The ISI between the cortical conditioning stimulus and the cervico-medullary junction stimulus was adjusted to maintain an interval between any descending activity produced by the conditioning stimulus and the descending activity produced by the test cervicomedullary junction stimulation of 10 ms. This was done by measuring the latency of the MEPs evoked by the suprathreshold conditioning stimulus and the latency of the MEPs evoked by cervicomedullary junction stimulation and adding the obtained difference to 10. The result obtained in each subject was used as ISI between cortical conditioning stimulus and cervicomedullary junction stimulation. Single pulse cortical stimulation, paired cortical stimulation at an ISI of 10 ms, cervico-medullary junction stimulation, and cervicomedullary junction stimulation preceded by cortical subthreshold conditioning stimulus at an ISI of 10 ms, plus the difference in latency between cortical and cervicomedullary MEP (CMEP) was randomly intermixed. The responses to 10 stimuli for each condition were averaged at rest in all subjects using a stimulus intensity that evoked an MEP or CMEP in relaxed FDI with an amplitude of 0.2 mV peak-to-peak. This rather small baseline was chosen because most subjects were uncomfortable if we used cervicomedullary stimulation at higher intensities. The amplitude of the conditioned MEPs was expressed as percentage of the amplitude of the test MEP and the conditioning stimulus was set at an intensity of 10% (of maximum stimulator output) below AMT. Cervicomedullary junction stimulation was performed by passing an electrical pulse (100 µs; D180A stimulator, Digitimer, Welwyn Garden City, UK) between Ag-AgCl surface electrodes fixed over the mastoids (Ugawa et al. 1991). Stimulus intensity varied from 30 to 60% of maximum stimulator output in different subjects. MEPs were recorded from left FDI.
Statistics
One-way ANOVA was used to compare the results obtained using single and double cortical stimulation at individual ISIs. Post hoc analysis was performed using Fisher's protected least significant difference (PLSD) test.
To record clear I waves, we used a relatively large test stimulus intensity that evoked large test MEPs in most of our patients. This might have interfered with the possibility of showing I wave facilitation in epidural recordings because of a ceiling effect. For this reason, the data obtained in the subject in whom we recorded the smallest MEP were analyzed separately. To perform a statistical analysis on this single subject, we compared the amplitude of descending volleys and of MEPs in individual trials after single and paired stimulation using paired t-test.
The responses evoked by cervico-medullary junction stimulation alone were compared with the responses evoked by cervico-medullary junction stimulation conditioned by subthreshold conditioning stimulus with Student's paired t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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When both the conditioning and test magnetic stimulus were given, separated by 10, 15, and 25 ms, the size of the MEP to the test stimulus was significantly increased [F(3,20) = 3.1, P < 0.05]. Post hoc analysis showed that the increase in MEP size was significant at ISIs 10 and 15 ms (P < 0.05). The time-course of this effect is shown for the six subjects in Fig. 1.
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SINGLE PULSE MAGNETIC STIMULATION.
LM magnetic stimulation evoked the earliest negative potential in all subjects with a mean latency of 2.3 ± 0.2 ms. The short latency of this wave is consistent with direct activation of corticospinal axons. We therefore termed this volley D-wave (Di Lazzaro et al. 2004).
In all subjects, single pulse PA magnetic stimulation evoked a series of waves: four waves in subjects 1 and 3, three waves in subjects 2, 4, and 5, and five waves in subject 6. The largest wave had a mean latency of 3.7 ± 0.2 ms. Because this was 1.1–1.6 ms longer than the earliest wave evoked by LM magnetic stimulation, we considered it to be an I1 wave (Di Lazzaro et al. 2004). Later I waves were numbered in order of their appearance. At the stimulation intensity used, a small D wave was also recorded in patient 6 after PA magnetic stimulation (Fig. 3).
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) the time-course of the amplitude of the I1 and of the later I waves (the sum of the amplitude of all the individual waves after the I1 wave) were analyzed separately. When both the conditioning and test magnetic stimulus were given, separated by 10, 15, and 25 ms, no change either in the I1 or in the later I wave amplitude was observed [I1: F(3,16) = 0.034, P > 0.05; later I waves: F(3,16) = 0.01, P > 0.05]. However, visual inspection of the epidural volleys showed that a small further late I wave was observed at 25-ms ISI in subjects 1 and 3. The time-course of the amplitude of the volleys for the five subjects is shown in Fig. 1. We also calculated the total area of the descending waves, but like the amplitude data, this was not modified by paired stimulation. The total area of the volley was as follows: 15.7 ± 9.2 µV · s after test stimulus, 17.8 ± 9.4 µV · s at 10-ms ISI, 16.6 ± 8.9 µV · s at 15-ms ISI, and 16.7 ± 9.4 µV · s at 25-ms ISI, [F(3,20) = 0.06, P > 0.05].
In subject 1, who was studied at a range of conditioning intensities, the usual suppression of later I waves at ISI of 2 and 3 ms was more pronounced with a conditioning stimulus intensity of AMT (Fig. 2). However, there was no change in the descending volleys at 10- and 15-ms ISIs. A small I5 wave was recruited at 25-ms ISI but only with a conditioning stimulus intensity of AMT or 5% of maximum stimulator output below this value (Fig. 2). With a conditioning stimulus of AMT, a small descending wave was recognizable after the conditioning stimulus (Fig. 2).
Control experiments
It has been reported (Daskalakis et al. 2002) that ICF is more pronounced with low intensities of test shock. In several of our subjects, the intensity that we used gave MEPs larger than the standard 1-mV peak-to-peak (e.g., subject 1, Fig. 1), and it is possible that this led to a ceiling effect in the amplitude of I wave that obscured any facilitation of the volleys. However, this seems unlikely. In subject 6, the MEP amplitude was only 0.3 mV and was facilitated by 200% at ISI = 10 ms (Fig. 3A), yet despite this, there was no evidence of facilitation of I waves in the descending volleys (P > 0.05).
Given that we obtained some evidence for facilitation of later I waves in some subjects at 25 ms, we tested whether this might be clearer at ISI = 10 ms if we rotated the stimulating coil to induce AP current in the brain. This experiment was performed in subject 6. As reported previously (Di Lazzaro et al. 2001; Sakai et al. 1997), a single AP test pulse recruited a small D wave and an I3 wave. In addition, there was a small I4 wave that had a slightly longer latency (0.3 ms) than that seen after PA stimulation and a very small wave in the latency range of the I5 wave (Fig. 3). When this test pulse was preceded by a conditioning pulse at 10 ms, the facilitation of the MEP disappeared (see also Ziemann et al. 1996) and was in this case replaced by slight suppression of the MEP as previously reported by Hanajima et al. (1998). There was no change in the amplitude of D, I3, and I4 waves, but the small I5 wave was completely suppressed. Interestingly, as reported by Hanajima et al. (2002), conditioning at ISI = 2 ms caused MEP facilitation to 160% baseline. This facilitation was accompanied by an increase of 190% in the amplitude of I waves (P < 0.001). Visual inspection of the epidural volleys shows the appearance of an I2 wave, facilitation of the I3 wave, and a slight increase in the amplitude of the (late) I4 wave (Fig. 3).
Cervico-medullary junction stimulation
The recordings obtained in one subject are shown in Fig. 4.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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, who reported a slight facilitation of corticospinal volleys at 25-ms ISI using a conditioning stimulus subthreshold for MEPs but suprathreshold for corticospinal volleys. The lack of correspondence between descending volley and MEP size is puzzling. Previous paired pulse studies on intracortical inhibition (SICI) showed that conditioning test intervals that led to suppression of MEPs also suppressed descending volleys. Why are the increased MEPs during ICF not accompanied by larger (or more numerous) descending volleys? There are two possible categories of explanation for this. 1) The conditioning stimulus could raise the excitability of spinal mechanisms so that motoneurons are more readily discharged by a given descending volley. Thus the MEP would be larger even though the volley remained the same. 2) The second possibility is that the descending volleys are not a good reflection of the total corticospinal output produced by the test TMS pulse. Effectively the test pulse could activate excitatory output to FDI over and above that which can be observed in the epidural volleys: the MEP could be larger even though the measurable volley remained the same.
With regard to the first possibility, there is little evidence in the literature that conditioning stimuli of the intensity used in these experiments can on their own change the excitability of spinal cord. Di Lazzaro et al. (1998) could not record detectable volleys in epidural recordings, and H-reflex studies by Kujrai et al. (1993) and Ziemann et al. (1996) failed to show any changes in monosynaptic excitability. It should be considered that neither method is perfect. For example, it is possible that the activity evoked by the conditioning stimulus is too small/dispersed to be visible in epidural recordings. However, the lack of any effect of the conditioning stimulus on CMEPs evoked by cervicomedullary junction stimulation strongly suggests that there is no descending activity evoked by the conditioning stimulus. One possible alternative explanation is that the conditioning stimulus could change the level of any tonic output from cortex and remove ongoing inhibition (or increase ongoing facilitation) either directly onto spinal motoneurons or onto any interneurons (such as the C3–C4 propriospinal system; Pierrot-Deseilligny and Burke 2005) that are involved in conducting corticospinal facilitation to the motoneurons. It could be argued that both effects should produce changes in H-reflex excitability and on CMEPs. This was not observed for H-reflexes (Kujrai et al. 1993; Ziemann et al. 1996). However, H-reflexes may lack sensitivity because they can sample excitability in a population of spinal motoneurons that is different from that involved in the MEP (Petersen et al. 2003). There has been no work on the recruitment order of motor units in the CMEPs produced by cervico-medullary stimulation, but lack of effect on this response as well as the H-reflex makes it unlikely that the conditioning stimulus led to any direct or indirect change in spinal excitability.
With regard to the second possibility, it is known that the conditioning stimulus evokes a mixture of long-lasting inhibition and later facilitation (Hanajima et al. 1998). Thus it is possible that it could increase the proportion of the descending volley destined for the target muscle (FDI) while at the same time producing a matched suppression of volleys intended for other muscles. This would predict that, at the same time as MEPs were facilitated in FDI, they were suppressed in other muscles. Because the latter has never been documented, this seems an unlikely explanation. An alternative is that the epidural volleys do not represent all the activity destined for the FDI muscle after the test pulse. There may be additional activity that is more dispersed that is not evident in the records. If this increased, the MEP would also be larger.
There is some evidence to support the idea that dispersed descending activity could contribute to ICF. For example, Di Lazzaro et al. (2001) showed that reversing the direction of the induced current (AP stimulation) could evoke descending activity with slightly different peak latencies than those seen after PA stimulation. This can be seen in the present data from subject 6. Indeed, using AP stimulation in this subject, we found that facilitation of MEPs at an ISI = 2 ms was accompanied by an increase in size of I waves, including the late I4 that occurred 0.3 ms after the usual I4 evoked by PA stimulation. Thus it may well be that such components are also facilitated when paired PA stimulation is applied at ISI = 10 ms, but they are obscured in the mean volleys because the amplitude of the volleys evoked by PA magnetic stimulation are much more pronounced. The facilitation of descending waves at 2 ms using AP stimulation confirms the cortical origin of this phenomenon as previously suggested by Hanajima et al. (1998) and also that the mechanisms of intracortical facilitation are different for different directions of the induced current in the brain (Hanajima et al. 2002). As previously reported by Hanajima et al. (1998) using AP stimulation, we observed a MEP suppression at 10-ms ISI; this was accompanied by a suppression of the latest wave, thus confirming the cortical origin of this inhibitory phenomenon.
A final possibility is that our recording method was not sensitive enough to detect small changes in the epidural volley that might be required to lead to ICF of the MEP. Daskalakis et al. (2002) found that ICF (and SICI) was larger when they used smaller test MEPs than we used in this experiment. It may be that we would have had more chance of detecting a larger facilitation in the presence of a smaller control epidural volley. Nevertheless, ICF is usually measured with test MEPs of 1 mV, and in previous experiments, we could clearly show that SICI with 1-mV test MEPs was accompanied by a reduction in size of the epidural volleys (Di Lazzaro et al. 1998). Moreover, analysis of the data in one of our subjects in whom we recorded a low-amplitude MEP shows that even at lower intensities there is no consistent change in the epidural volley amplitude despite a pronounced increase in MEP amplitude.
Whatever the mechanism of MEP facilitation, these findings are compatible with the idea that the inhibition and the facilitation produced by a subthreshold conditioning stimulus at different interstimulus intervals are different in nature and are independent phenomena. This confirms the original suggestions of Ziemann et al. (1996) on the basis of MEP recording and of Matsunaga et al. (2002), who evaluated the effects of paired stimulation through subdural electrodes. The recordings in subject 1, who was studied using a range of conditioning stimulus intensities and was also studied at inhibitory intervals, also confirm that inhibition at short ISIs and facilitation at longer ISIs may have a different threshold. This subject paradoxically had a lower threshold for ICF than for SICI, which is opposite to the situation in most individuals (Ziemann et al. 1996). Nevertheless, the fact that the thresholds differed is still consistent with the idea that ICF and SICI have independent mechanisms.
In conclusion, these results pose something of a problem since they provide no clear evidence that, as presumed by many previous authors, ICF has a cortical origin. This was despite the fact that epidural volleys in the same subjects were reduced in size when the interval between the conditioning and the test pulses was decreased to evoke SICI instead of ICF. As we have noted above, there are a number of possible reasons why we may have failed to detect an influence on epidural volleys when ICF was manifest in the MEP. However, the present data suggest that the interpretation of ICF may be more complex than that of SICI.
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FOOTNOTES |
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Address for reprint requests and other correspondence: V. Di Lazzaro, Inst. of Neurology, Univ. Cattolica, L.go A. Gemelli 8, 00168 Rome, Italy (E-mail: vdilazzaro{at}rm.unicatt.it)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone P, Insola A, Tonali PA, and Rothwell JC. The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115: 255–266, 2004.[CrossRef][ISI][Medline]
Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Insola A, Mazzone P, Profice P, Tonali P, and Rothwell JC. The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation. Exp Brain Res 138: 268–273, 2001.[CrossRef][ISI][Medline]
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