Edited by: Mikhail Lebedev, Duke University, USA
Reviewed by: Matt J. N. Brown, University Health Network, Canada; Tsuyoshi Nakajima, Kyorin University, Japan
*Correspondence: Koichi Hiraoka
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The present study investigated whether the long-interval interhemispheric inhibition (LIHI) is induced by the transcranial magnetic stimulation over the primary sensory area (S1-TMS) without activation of the conditioning side of the primary motor area (M1) contributing to the contralateral motor evoked potential (MEP), whether the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input, and whether the pathways mediating the LIHI are different from those mediating the M1-TMS-induced LIHI. In order to give the TMS over the S1 without eliciting the MEP, the intensity of the S1-TMS was adjusted to be the sub-motor-threshold level and the trials with the MEP response elicited by the S1-TMS were discarded online. The LIHI was induced by the S1-TMS given 40 ms before the test TMS in the participants with the attenuation of the tactile perception of the digit stimulation (TPDS) induced by the S1-TMS, indicating that the LIHI is induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP in the participants in which the pathways mediating the TPDS is sensitive to the S1-TMS. The S1-TMS-induced LIHI was positively correlated with the attenuation of the TPDS induced by the S1-TMS, indicating that the S1-TMS-induced LIHI is dependent on the effect of the S1-TMS on the pathways mediating the TPDS at the S1. In another experiment, the effect of the digit stimulation given before the conditioning TMS on the S1- or M1-TMS-induced LIHI was examined. The digit stimulation produces tactile input to the S1 causing change in the status of the S1. The S1-TMS-induced LIHI was enhanced when the S1-TMS was given in the period in which the tactile afferent volley produced by the digit stimulation just arrived at the S1, while the LIHI induced by above-motor-threshold TMS over the contralateral M1 was not enhanced by the tactile input. Thus, the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input, and the pathways mediating the sub-motor-threshold S1-TMS-induced LIHI are not the same as the pathways mediating the above-motor-threshold M1-TMS-induced LIHI.
Interhemispheric inhibition (IHI) is the neural mechanism that causes the inhibition of one hemisphere in response to the activation of another. The IHI between the primary motor cortices (M1s) has been observed through giving the transcranial magnetic stimulation (TMS) over the primary motor area (M1); the conditioning TMS over the M1 inhibits the test motor evoked potential (MEP) in the hand muscle ipsilateral to the conditioning TMS side (Ferbert et al.,
A previous study reported a negative finding on this issue; the sub-motor-threshold transcranial magnetic stimulation over the primary sensory area (S1-TMS) given 50 ms before test TMS over the contralateral M1 did not modulate the test MEP in the first dorsal interosseous (FDI) muscle (Mochizuki et al.,
The reason for the conflicting findings between the study by Mochizuki et al. (
In the present study, an investigation was made to elucidate whether the LIHI is induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP. We expect that the LIHI induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP is not apparent when it is estimated across healthy adult humans, based on the negative findings on the S1-TMS-induced LIHI in the study by Mochizuki et al. (
In the present study, S1-TMS-elicited MEP was strictly excluded, in order to investigate whether the LIHI is induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP. That is, the S1-TMS was given at the intensity at which the contralateral MEP response larger than 50 μV was not elicited in 10 consecutive preliminary trials, and the trials with the MEP response larger than 50 μV were discarded online.
Another question is whether the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input. The change in the activity of the left S1 induced by the TMS over the right parietal cortex (2–4 cm posterior to the hotspot of the muscle representation) was modulated by the electrical stimulus over the right median nerve (MN) projecting to the left S1 (Blankenburg et al.,
In order to investigate the effect of the tactile input to the conditioning side of the S1 on the S1-TMS-induced LIHI, the status of the conditioning side of the S1 was modulated by the tactile stimulation to the digit (DS). Generally, the MN is stimulated at the wrist in order to induce the sensory evoked potential (SEP) in the contralateral hemisphere (Nuwer et al.,
In addition, the effect of the DS on the LIHI induced by the above-motor-threshold M1-TMS was also examined as the control experiment for the effect of the DS on the S1-TMS-induced LIHI. If the S1-TMS-induced LIHI is modulated by the DS, but the above-motor-threshold M1-TMS-induced LIHI is not, the S1-TMS-induced LIHI and M1-TMS-induced LIHI must be mediated by different mechanisms. Given this is true, the finding indirectly supports our view that the LIHI is induced by the S1-TMS without activating the conditioning side of the M1 contributing to the MEP.
The other question is whether the pathways mediating the TPDS at the S1 interact with the pathways mediating the LIHI. The S1-TMS induces attenuation of the TPDS (Cohen et al.,
Seventeen healthy humans aged 28.8 ± 1.4 years (10 males and 7 females) participated in Experiment 1 (Table
Test MEP size (0.5–1.5 mV) | TP ratio (<1.0) | ||
---|---|---|---|
Experiment 1 | 17 | ||
TP ratio | 17 | ||
S1-TMS-induced IHI | ✓ | 14 | |
Correlation between IHI and TP ratio | ✓ | 14 | |
S1-TMS-induced IHI (sub-group analysis) | ✓ | ✓ | 10 |
DS effect on test MEP | ✓ | ✓ | 10 |
DS effect on S1-TMS-induced IHI | ✓ | ✓ | 10 |
Experiment 2 | 13 | ||
TP ratio | 13 | ||
DS effect on S1-TMS-induced LIHI | ✓ | 13 | |
DS effect on S1-TMS-induced | |||
LIHI (sub-group analysis) | ✓ | ✓ | 10 |
DS effect on M1-TMS-induced | |||
LIHI (sub-group analysis) | ✓ | ✓ | 9 |
Electrical stimulation was given over the left index finger for inducing the tactile input to the S1 producing the tactile perception. A pair of ring electrodes that electrically elicits a tactile sensation was braced over the left index finger as shown in Figure
The Ag/AgCl surface electrodes recording electromyographic (EMG) activity were placed over the left and right FDI muscles configured in belly-tendon montages. The EMG signals were amplified by an EMG amplifier (MEG-2100; Nihon Kohden, Tokyo, Japan) with a band-pass filter from 15 Hz to 3 kHz. The amplified EMG signals were converted to digital signals at a sampling rate of 10 kHz using an A/D converter (PowerLab 800 s; ADInstruments, Colorado Springs, CO, USA), and the digital signals were stored on a personal computer.
The test TMS was given over the hotspot of the right FDI muscle representation using a figure-of-eight-shaped coil (YM-131B; Nihon Kohden) connected to a magnetic stimulator (SMN-1200; Nihon Kohden). The coil had an outer diameter of 99 mm for one half of the coil. The maximum intensity of the coil was 1.03 T. The coil oriented to the direction in which the TMS induced an anterior-medial current in the brain (posterior-anterior position [PA]) as shown in Figure
The conditioning TMS over the right S1 (S1-TMS) was given using a figure-of-eight-shaped coil (YM-132B; Nihon Kohden) connected to another magnetic stimulator (SMN-1200; Nihon Kohden). The coil had an outer diameter of 110 mm for one half of the coil. The maximum intensity of the coil was 0.71 T. The coil oriented to the direction in which the TMS induced a posterior-lateral current in the brain (anterior-posterior position [AP]) as shown in Figure
Previous studies have used different procedures to determine the site of the S1-TMS. In some studies, the C3 or C4 was targeted for the S1-TMS administration (Cohen et al.,
The time course of the IHI induced by the S1-TMS, DS, or S1-TMS with the DS was examined. The intensity of the DS was 1.5 times the intensity at the perceptual threshold. The S1-TMS was given 5, 10, 20, 40, or 60 ms before the test TMS under the S1-TMS condition (Figure
Attenuation of the TPDS induced by the S1-TMS was tested in previous studies (Cohen et al.,
The MEP amplitude was estimated on a peak-to-peak basis. The TMS intensity was preliminarily determined so that the test MEP amplitude in the control condition was around 1 mV. This procedure was conducted to rule out the across-participant variability in the sensitivity of the test MEP to the conditioning stimulus. Nevertheless, the test MEP amplitude under the control condition in the experimental session may deviate from the target amplitude. Thus, participants in whom the mean amplitude of the test MEP under the control condition of the experimental session was outside the range of 0.5–1.5 mV were excluded from the analysis of the IHI. The TP ratio indirectly implies the effect of the TMS on the pathways mediating the TPDS at the S1. Thus, in the subgroup analysis, participants with the TP ratio equal to or more than 1.0 were excluded from the analysis of the IHI, in order to estimate the S1-TMS-induced IHI particularly in the participants in which the S1-TMS is effective on the pathways mediating the TPDS at the S1. The magnitude of the IHI was the test MEP amplitude under the S1-TMS condition expressed as a percentage of the test MEP amplitude under the control condition.
One-way ANOVA was conducted to test the difference in the test MEP amplitude among the control condition and five C-T intervals under the DS or S1-TMS condition, and to test the difference in the probability of the TPDS among the three experimental conditions. When one-way ANOVA revealed a significant difference among the means, it was followed by a multiple comparison test (Bonferroni test). Two-way ANOVA was conducted to test the difference in the change in the test MEP amplitude among the five C-T intervals and between the two experimental conditions. Pearson’s correlation coefficient between the magnitude of the S1-TMS-induced IHI and the TP ratio was estimated. A
The probability of the TPDS under each condition across 17 participants is shown in Figure
The hotspot of the right FDI muscle representation was 5.8 ± 0.2 cm left to and 1.0 ± 0.3 cm anterior to the vertex in 17 participants. The test TMS intensity was 80.2 ± 4.1% of the maximum stimulator output. The S1-TMS site was 5.6 ± 0.3 cm right to and 1.6 ± 0.2 cm posterior to the vertex. The intensity of the S1-TMS was 89.1 ± 2.3% of the maximum stimulator output. The intensity of the S1-TMS was not significantly correlated with the TP ratio (
Three out of 17 the participants were excluded from the analysis of the IHI, because the average amplitude of the test MEP in the control trials in the experimental session was not within the range of 0.5–1.5 mV. Thus 14 participants (7 males and 7 females) were included in the analysis of the IHI (Table
The IHI induced by the S1-TMS as a function of the TP ratio in these 14 participants is shown in Figure
Four out of 14 participants in whom the TP ratio was 1.0 or more were excluded from the sub-group analysis of the IHI of the participants with attenuation of the TPDS induced by the S1-TMS. That is, 10 participants were included in the sub-group analysis of the IHI (Table
The effect of the DS on the test MEP was analyzed in 10 participants with attenuation of the TPDS induced by S1-TMS (Table
The effect of the DS on the S1-TMS-induced IHI was analyzed in 10 participants with attenuation of the TPDS induced by S1-TMS (Table
In Experiment 1, the test MEP was inhibited by sub-motor-threshold S1-TMS given 40 ms before the test TMS in the participants with attenuation of the TPDS by the S1-TMS. Nevertheless, the effect of the DS on the S1-TMS-induced IHI was not apparent. In Experiment 2, further investigation was conducted to confirm that the IHI induced by the S1-TMS observed in Experiment 1 is modulated by the tactile input to the S1. In Experiment 1, the interval between the DS and the S1-TMS (conditioning-conditioning [C-C] interval), in which the attenuation of the TPDS was prominent in our preliminary trial, was 30 ms. The N20 of the SEP has been thought to be the activity of the S1, indicating that the afferent volley arrives at the S1 in the period 20 ms after the DS (Allison and Hume,
In order to examine this hypothesis, the S1-TMS-induced IHI was conditioned by the DS with various C-C intervals. In addition, the effect of the DS on the M1-TMS-induced IHI was tested to confirm a hypothesis that the IHI between the M1s is not dependent on the status of the S1 modulated by the tactile input. If this hypothesis is true, the tactile input to the S1 particularly modulates the S1-TMS-induced IHI.
Thirteen healthy humans aged 30.3 ± 1.5 years (11 males and 2 females) participated (Table
The effect of the DS on the S1-TMS-induced IHI was investigated. The intensities of the DS and S1-TMS were the same as those in the investigation of the IHI in Experiment 1. The S1-TMS was given 40 ms before the test TMS under the S1-TMS condition, because a statistically significant IHI induced by the S1-TMS was present only in this C-T interval in Experiment 1 (Figure
The effect of the DS on the M1-TMS-induced IHI was investigated. The experimental protocol for this investigation was the same as that used to investigate the effect of the DS on the S1-TMS-induced IHI in Experiment 1, except for the intensity and site of the conditioning TMS. The conditioning TMS was given over the hotspot of the left FDI representation. The coil was in the LM position (Harris-Love et al.,
The TP ratio was estimated in all of the participants. The participants in which the test MEP amplitude was within the range of 0.5–1.5 mV were included in the data analysis of the IHI. In the subgroup analysis, only the participants in which the TP ratio was less than 1.0 were included in the data analysis of the IHI. These processes were done, because the significant IHI induced by the S1-TMS was present only when the analysis was conducted for this type of participant in Experiment 1, and we intended to conduct Experiment 2 in the participants whose characteristics were similar to the participants analyzed for the time course of the S1-TMS-induced IHI in Experiment 1. The test MEP amplitude was expressed as a percentage of the average test MEP amplitude under the control condition in each participant.
A
The test TMS site was 6.1 ± 0.3 cm left to and 1.0 ± 0.3 cm anterior to the vertex in 13 participants. The test TMS intensity was 76.5 ± 4.4% of the maximum stimulator output. The site of the M1-TMS was 6.2 ± 0.2 cm right to and 0.9 ± 0.3 cm anterior to the vertex. The intensity of the M1-TMS at the resting motor threshold was 65.3 ± 3.1% of the maximum stimulator output. The intensity of the M1-TMS was 78.4 ± 3.7% of the maximum stimulator output. The site of the S1-TMS was 6.2 ± 0.2 cm right to and 2.1 ± 0.3 cm posterior to the vertex. The intensity of the S1-TMS was 94.7 ± 3.3% of the maximum stimulator output. The average TP ratio was 0.81 ± 0.19. The number of participants in whom the TP ratio was equal to 1.0 or more was 3.
The effect of the DS on the S1-TMS-induced LIHI across all participants is shown in Figure
Four participants were excluded from the data analysis of the effect of the DS on the M1-TMS-induced LIHI in accordance with the exclusion criteria. Thus, 9 participants (9 males) were included in this analysis (Table
In the present study, the IHI was not induced by sub-motor-threshold S1-TMS given 5–20 ms before the test TMS. The IHI induced by the conditioning TMS around 10 ms before the test TMS is considered to be the short-interval IHI (Chen et al.,
The S1-TMS given 40 ms after the test TMS did not induce the IHI when estimating the IHI across the participants, but induced that when estimating that in the participants with the TP ratio less than 1.0. The decrease in the test MEP induced by the conditioning TMS over the scalp contralateral to the test TMS site given from 40 to 50 ms before the test TMS is considered to be mediated by the LIHI (Chen et al.,
The present finding was consistent with a previous finding that the LIHI was induced by the S1-TMS (Ni et al.,
Nevertheless, the interpretation of the present finding must be cautiously treated. That is, even the trials with the MEP response elicited by the S1-TMS were discarded from data analysis, this procedure does not guarantee that the whole population of the interneurons in the M1 is not activated by the S1-TMS, because some interneurons in the M1 do not contribute to the MEP, as stated in a previous study that the inhibitory fibers, that had a lower threshold than the S1-TMS, may be activated without producing the contralateral MEP response (Ni et al.,
The long-lasting IHI of the S1 induced by DS over the hind limb in rats is mediated by the GABAB-ergic neurons (Palmer et al.,
Our present finding on the LIHI induced by the sub-motor-threshold S1-TMS was contrary to the previous finding by Ni et al. (
An important experimental procedure that is different from the previous studies is exclusion of the particular characteristics of the participants. In the present study, the participants without the attenuation of the TPDS induced by the S1-TMS were excluded in the sub-group analysis. This procedure allowed us to obtain apparent LIHI induced by the S1-TMS in the present study. Thus, most likely interpretation for the apparent LIHI induced by the sub-motor-threshold S1-TMS particularly for the sub-group analysis in the present study is that the S1-TMS-induced LIHI occurs only when the S1-TMS affects the pathways mediating the TPDS at the S1.
Moreover, the attenuation of the TPDS by the S1-TMS well correlated with the S1-TMS-induced LIHI. These findings must reflect a fact that both the effects of the DS on the S1-TMS-induced LIHI and the S1-TMS-induced LIHI are dependent on the effect of the S1-TMS on the pathways mediating the TPDS at the S1.
The attenuation of the TPDS induced by the S1-TMS indicates that the S1-TMS interferes the activity of the pathways mediating the TPDS at the S1. Thus, one possible interpretation of the findings on the subgroup analysis is that the pathways mediating the TPDS at the S1 have the inhibitory input to the pathways mediating the S1-TMS-induced LIHI and the pathways mediating the tactile input. Given this is true, in the participants with the attenuation of the TPDS induced by the S1-TMS, inhibitory inputs to the pathways mediating the S1-TMS-induced LIHI and to those mediating the tactile input are decreased, and these decreases cause apparent S1-TMS-induced LIHI and the apparent effect of the DS on the S1-TMS-induced LIHI. Further investigations are needed to elucidate this hypothetical mechanism.
The M1-TMS-induced LIHI was not enhanced, while the S1-TMS-induced IHI was enhanced by the DS, indicating that the pathways mediating the LIHI induced by the S1-TMS and those mediating the LIHI induced by the M1-TMS have different sensitivity to the DS. A previous study reported that the regression line of the S1-TMS-induced LIHI as a function of the amplitude of the MEP elicited by the S1-TMS was different from that of the M1-TMS-induced LIHI as a function of the amplitude of the MEP response elicited by the M1-TMS, indicating different neural mechanism underlying the S1- and M1-TMS-induced IHIs (Ni et al.,
In a previous study, the activity of the M1 was decreased by the DS over the ipsilateral fingers (Hlushchuk and Hari,
The N20 of the SEP reflects the activity of the S1 (Allison and Hume,
Several present findings imply the interaction between the pathways and events related to the IHI. The LIHI was induced by the TMS over the S1, indicating the S1-TMS activates the pathways mediating the LIHI. The DS given 20 ms before the S1-TMS increased the IHI, indicating that the tactile input to the S1 enhances the pathways mediating the S1-TMS-induced IHI. In contrast, the S1-TMS attenuates the TPDS, indicating that the pathways mediating the TPDS are inhibited by the TMS given over the S1. The LIHI was positively correlated with the attenuation of the TPDS induced by the S1-TMS, and was apparent only in the participants with the attenuation of the TPDS induced by the S1-TMS. Accordingly, it is likely that the pathways mediating the TPDS have the inhibitory inputs to the pathways mediating the S1-TMS-induced IHI. Tactile input to the S1 enhanced the S1-TMS-induced IHI, and the enhancement was apparent in the participants with attenuation of the TPDS by the S1-TMS. Thus, the pathways mediating the TPDS may have the inhibitory inputs to the pathways mediating the tactile input to the S1. Further investigations are needed for elucidating these hypothetical mechanisms.
In the present study, the LIHI of the left M1 was induced by the TMS over the contralateral S1. The testing and conditioning TMS sides were same as the previous study by Ni et al. (
The S1-TMS-induced LIHI was not found when the data analysis was conducted across all participants. In some previous studies, the locus of the S1 was identified using anatomical MRI (Meehan et al.,
The LIHI was not induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP when the IHI was estimated across the participants, but was induced by that when the LIHI was estimated in the participants with the attenuation of the TPDS induced by the S1-TMS. The S1-TMS-induced LIHI was positively correlated with the attenuation of the TPDS induced by S1-TMS, indicating that the S1-TMS-induced LIHI is dependent on the effectiveness of the S1-TMS on the pathways mediating the TPDS at the S1. The S1-TMS-induced LIHI was enhanced when S1-TMS was given in the period in which the tactile afferent volley produced by the digit stimulation just arrived at the S1, while the LIHI induced by above-motor-threshold TMS over the contralateral M1 was not enhanced by the tactile input. These findings indicate that the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input, and the pathways mediating the sub-motor-threshold S1-TMS-induced LIHI are not the same as the pathways mediating the above-motor-threshold M1-TMS-induced LIHI.
YI and KH, study design, conducted the experiment, analyzed the data, writing article. YJ, HM and AK, conducted the experiment.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.